Chapter 40Coagulation Disorders in Pregnancy Charles J. Lockwood, MD, and Robert M. Silver, MDDisorders of the hemostatic system can lead to both hemorrhage and vation of phospholipase C, which causes the generation of inositolthrombosis. The former can result from inherited and acquired defects triphosphate and 1,2,-diacylglycerol. The former triggers a calciumin hemostasis and platelets, and the latter is greatly increased in the ﬂux, and the latter activates protein kinase C, which, in turn, triggerspresence of inherited and acquired defects in the endogenous antico- platelet secretory activity and activates various signaling pathways.agulant system.1,2 In addition to their association with thrombosis, the Such signaling promotes activation of the GpIIb-IIIa (αIIBβ3 integrin)leading cause of maternal death in the United States, inherited and receptor, a crucial step in subsequent platelet aggregation (see lateracquired thrombophilias as well as certain bleeding dyscrasias, have discussion). Thus, collagen serves to promote both platelet adhesionalso been associated with adverse pregnancy outcomes. This chapter and platelet activation. However, maximal platelet activation requiresreviews the hemostatic system and its modulators and then discusses binding of thrombin to platelet type 1 and 4 protease-activated recep-the various common inherited and acquired disorders of platelet tors (PAR-1, PAR-4).5 Platelet activation is also mediated by receptorfunction, coagulation, and anticoagulation and their impact on both binding to thromboxane A2 (TXA2) and adenosine diphosphate (ADP),mother and fetus. which are released by adjacent activated platelets. Collagen and these circulating agonists induce calcium-mediated formation of platelet pseudopodia, promoting further adhesion.The Hemostatic System Platelet secretory activity includes the release of α-granules con- taining vWF, vitronectin, ﬁbronectin, thrombospondin, partially acti-The hemostatic system is designed to ensure that hemorrhage is vated factor V, ﬁbrinogen, β-thromboglobulin, and platelet-derivedavoided in the setting of vascular injury while the ﬂuidity of blood is growth factor. These factors either enhance adhesion or promotemaintained in the intact circulation. After vascular injury, activation clotting. Secretory activity also includes the release of dense granulesof the clotting cascade and simultaneous platelet adherence, activation, containing ADP and serotonin, which enhance, respectively, plateletand aggregation are required to form the optimal ﬁbrin-platelet plug activation and vasoconstriction in damaged vessels. Calcium ﬂux pro-and thus avoid bleeding. The system is held in check by a potent series motes the synthesis of TXA2 by the sequential action of phospholipaseof anticoagulant proteins as well as a highly regulated ﬁbrinolytic A2, cyclooxygenase-1 (COX-1) and TXA2 synthase and its passive dif-system. Pregnancy presents an additional challenge to this system, fusion across platelet membranes to promote both vasoconstrictionbecause the risk of hemorrhage during placentation and in the third and, as noted, activation of adjacent platelets.4 Inherited disorders ofstage of labor is high, and the risk of thrombosis in the highly vulner- α-granule homeostatic and release proteins result in gray platelet syn-able uteroplacental and intervillous circulations is also great. Through drome, whereas deﬁciencies in dense granule–related genes are associ-a series of local and systemic adaptations, the vast majority of pregnant ated with Wiskott-Aldrich, Chediak-Higashi, Hermansky-Pudlak, andwomen are able to balance these paradoxical requirements and achieve thrombocytopenia–absent radius syndrome. Inhibition of COX-1–uncomplicated pregnancies. mediated TXA2 synthesis by nonsteroidal anti-inﬂammatory drugs (NSAIDs) also can also impair platelet function. Platelet aggregation follows activation-induced conformationalPlatelet Plug Formation changes in the platelet membrane GpIIb-IIIa receptor, so-called inside-After vascular injury, platelets rolling and ﬂowing in the bloodstream out signaling. The receptor forms a high-afﬁnity bond to divalentare arrested at sites of endothelial disruption by the interaction of col- ﬁbrinogen molecules. The same ﬁbrinogen molecule is also able tolagen with von Willebrand factor (vWF). Attachment to collagen bind to adjacent platelet GpIIb-IIIa receptors.6 Because these receptorsexposes sites on the vWF molecule that permit it to bind to the platelet are abundant (40,000 to 80,000 copies), large platelet rosettes quicklyglycoprotein Ib/IX/V complex (GpIb-IX-V) receptor.3 Abnormal form, reducing blood ﬂow and sealing vascular leaks.4 Mutations in theplatelet adhesion and bleeding can result from mutations in GpIb-X-V GpIIb-IIIa gene cause the bleeding dyscrasia known as Glanzmann(e.g., Bernard-Soulier disease) or from defects in the vWF gene (von thrombasthenia. Figure 40-1 presents a schematic review of plateletWillebrand disease [vWD]). Platelets can also adhere to subendothelial function.collagen via their GpIa-IIa (α2β1 integrin) and GpVI receptors. Deﬁ- Platelet activation and aggregation are prevented in intact endothe-ciencies in either receptor cause mild bleeding diatheses. lium via the latter’s elaboration of prostacyclin, nitric oxide, and Adherent platelets are activated by collagen after binding to the ADPase as well as by active blood ﬂow. Cyclic adenosine monophos-GpVI receptor.4 This triggers receptor phosphorylation, leading to acti- phate (cAMP) inhibits platelet activation, and this is the basis for the
826 CHAPTER 40 Coagulation Disorders in Pregnancy is unique in that it has low intrinsic clotting activity. In addition, it Platelet Plug Formation may autoactivate after binding to TF or be activated by thrombin or Platelet Adhesion factors IXa or Xa.12 Activation of factor VII to VIIa increases its cata- • GpIb/IX/V binding to vWF lytic activity more than 100-fold, and its promiscuous activation • GpIa/IIa binding to collagen potential ensures that factor VIIa will be readily available to initiate clotting. The complex of TF and factor VII(a) can activate both factor X and Platelet Activation factor IX. Factor Xa remains active as long as it is bound to TF-VIIa • GpVI binding to collagen in the cell membrane–bound prothrombinase complex. However, • PAR-1 and PAR-4 binding to thrombin when factor Xa diffuses away from the site of vascular injury, it is • Receptor binding to ADP and TXA2 rapidly inhibited by tissue factor pathway inhibitor (TFPI) or anti- thrombin (AT). This serves to prevent inappropriate propagation of the clot throughout the vascular tree.9 Factor Xa ultimately binds to its cofactor, Va, which is generated from its inactive form by the action of Platelet Aggregation Platelet Secretion factor Xa itself or by thrombin. Partially activated factor Va can also • GpIIb/IIIa binding to • α-Granules contain fibrinogen, be delivered to the site of clot initiation after its release from platelet fibrinogen and other fibronectin, vitronectin, platelet factor α-granules (Fig. 40-2A).8 The Xa/Va complex catalyzes the conversion large glycoproteins 4, fibrinogen, vWF, thrombospondin, and platelet-derived growth factor, of prothrombin (factor II) to thrombin (factor IIa). Thrombin, in turn, which enhance adhesion or clotting converts ﬁbrinogen to ﬁbrin, and, as noted, activates platelets (see Fig. • Dense granules contain ADP and 40-2A). serotonin, which amplify platelet Following this initial TF-mediated reaction, the clotting cascade activation is ampliﬁed by clotting reactions that occur on adjacent activated • Thromboxane A2, which promotes platelets.9 Locally generated factor IXa diffuses to adjacent activated platelet activation and vasoconstriction platelet membranes, or to perturbed endothelial cell membranes, where it binds to factor VIIIa. This cofactor is not only directly acti-FIGURE 40-1 Schematic review of platelet function. ADP, vated by thrombin but is released from its vWF carrier moleculeadenosine diphosphate; Gp, glycoprotein; PAR, protease-activated through the action of thrombin.9 The factor IXa/VIIIa complexreceptor; TXA2, thromboxane A2; vWF, von Willebrand factor. can then generate factor Xa at these sites to further drive thrombin generation (see Fig. 40-2B). The signiﬁcant hemorrhagic sequelae of hemophilia underscore the vital role played by platelet surface factortherapeutic effects of dipyridamole. Normal pregnancy is associated IXa-VIIIa–mediated factor Xa generation in ensuring hemostasis.9with a modest decline in platelet number7 and with evidence of pro- The clotting cascade can also be ampliﬁed via the activation ofgressive platelet activation.8 factor XI to XIa by thrombin on activated platelet surfaces; factor XIa also activates factor IX (see Fig. 40-2C). The lack of signiﬁcant hem- orrhagic sequelae in patients with factor XI deﬁciency emphasizesFibrin Plug Formation that this mechanism is of lesser importance in the maintenance ofEffective hemostasis requires the synergistic interaction of the clotting hemostasis. Factor XIa has been describing as serving a “boostercascade with platelet activation and aggregation. This synergism is in function” in coagulation.9part mechanical, because ﬁbrin and platelets together form an effective A third, theoretical coagulation ampliﬁcation pathway may behemostatic plug after signiﬁcant vascular disruption. However, bio- mediated by circulating TF-bearing microparticles that bind to acti-chemical synergism also occurs, because activated platelets contribute vated platelets at sites of vascular injury through the interactionclotting factors and form an ideal surface for clot propagation. Con- between P-selectin glycoprotein ligand-1 on the microparticles and P-versely, optimal platelet activation and subsequent aggregation require selectin on activated platelets (see Fig. 40-2C).13 Taken together factorexogenous thrombin generation (see Fig. 40-1). Therefore, the avoid- IXa, factor XIa, and TF-platelet surface events lead to additional factorance of hemorrhage ultimately depends on the interplay between Xa generation and thence to enhanced production of thrombin andplatelets and the coagulation cascade. ﬁbrin. They also reﬂect the synergism that exists between platelet acti- Understanding of the coagulation component of hemostasis has vation and the coagulation cascade.evolved rapidly in the past two decades. Clotting is no longer thought The stable hemostatic plug is ﬁnally formed only when ﬁbrinof as a seemingly inﬁnite cascade of enzymatic reactions occurring in monomers self-polymerize and are cross-linked by thrombin-activatedthe blood but rather as a highly localized cell surface phenomenon.9 factor XIIIa (see Fig. 40-2D). This last reaction highlights the dominantClotting is initiated when subendothelial (extravascular) cells express- role that thrombin plays in the coagulation cascade: Thrombin acti-ing tissue factor (TF), a cell membrane–bound glycoprotein, come into vates platelets, generates ﬁbrin, and activates the crucial clotting cofac-contact with circulating factor VII. Intrauterine survival is not possible tors V and VIII, as well as the key clotting factors VII, XI, and XIII.in the absence TF.10 TF is primarily expressed on the cell membranes This accounts for the primacy of antithrombin factors in preventingof perivascular smooth muscle cells, ﬁbroblasts, and tissue parenchy- inappropriate intravascular clotting (i.e., thrombosis).mal cells, but not on healthy endothelial cells. However, TF also circu-lates in the blood in very low concentrations, as part of cell-derivedmicroparticles or in a truncated soluble form.8,11 Prevention of Thrombosis: The After vascular disruption and in the presence of ionized calcium, Anticoagulant Systemperivascular cell TF comes into contact with plasma factor VII on As noted, the hemostatic system not only must prevent hemorrhagenegatively charged (anionic) cell membrane phospholipids. Factor VII after vascular injury but also must maintain the ﬂuidity of the circula-
CHAPTER 40 Coagulation Disorders in Pregnancy 827 Vascular Injury Vascular Injury X IX X IX TF/ TF/ VII(a) VII(a) Platelet Xa IXa Xa IXa Platelet activation activation Va VIIIa IXa Va II IIa II IIa VIII Fibrinogen Fibrin Fibrinogen Fibrin A B Vascular Injury Vascular Injury X IX X IX Stable fibrin TF/ polymers VII(a) TF/ VII(a) TF XIIIa XIa Xa IXa Platelet Xa IXa activation Fibrin Va XI polymers II IIa Va II IIa XIII Fibrinogen Fibrin Self- Fibrinogen Fibrin polymerization C monomers D FIGURE 40-2 Fibrin plug formation. A, After vascular disruption, plasma factor VII binds to tissue factor (TF) to form the TF/VII(a) complex, which activates both factor X and factor IX. Factor Xa binds to factor Va, which has been activated by thrombin (factor IIa) or released from platelet α-granules. The Xa/Va complex catalyzes the conversion of prothrombin (factor II) to thrombin, which, in turn, converts ﬁbrinogen to ﬁbrin and activates platelets. B, The clotting cascade is ampliﬁed by clotting reactions that occur on adjacent activated platelets. Locally generated factor IXa binds to factor VIIIa, which is activated by thrombin. The factor IXa/VIIIa complex then generates factor Xa. C, Coagulation is further boosted by the thrombin-mediated activation of factor XI to factor XIa, which also activates factor IX. Circulating TF-bearing microparticles may also bind to activated platelets at sites of vascular injury. D, The stable hemostatic plug is ﬁnally formed when ﬁbrin monomers self-polymerize and are cross-linked by thrombin-activated factor XIIIa.tion in an intact vasculature. Indeed, thrombotic disease is a conse- lets. This local coagulation reaction is relatively protected from thequence of inappropriate and/or excess thrombin generation. As was dampening effects of circulating endogenous anticoagulants, boththe case with avoiding hemorrhage, avoidance of thrombosis is again because of its intensity and because it is shielded by the initial layer ofdependent on the synergistic interaction of platelets and the coagulant adherent and activated platelets. However, maximal platelet activationsystem. As noted earlier, clotting is initiated locally at sites of vascular occurs only after stimulation by both subendothelial collagen andinjury and ampliﬁed by the arrival, adherence, and activation of plate- thrombin, so, as additional platelets aggregate on top of the initial layer
828 CHAPTER 40 Coagulation Disorders in Pregnancy ( ) X TFPI IX FXIII IIa TF/VIIa Fibrin monomer Fibrinogen Fibrin polymer IXa VIIIa ( ) FXIIIa AT Xa X X-linked Fibrin tPA/uPA Va ( ) Plasmin Plasminogen PZ/ZPI PAI-1 2 plasmin TAFI PAI-2 inhibitor aPC PS PC FDPs Thrombomodulin ( ) II IIa EPCR AT Thrombomodulin FIGURE 40-4 Fibrinolysis. The cross-linked ﬁbrin polymer (X-linked Fibrin), which was stabilized by thrombin (factor IIa)-activated factor Fibrin monomer Fibrinogen XIIIa, is degraded to ﬁbrin degradation products (FDPs) by the action of plasmin, which is generated by the proteolysis of plasminogen viaFIGURE 40-3 The anticoagulant system. Tissue factor pathway tissue-type plasminogen activator (tPA) and urokinase-typeinhibitor (TFPI) binds with tissue factor (TF), factor VIIa, and factor Xa plasminogen activator (uPA). To prevent excessive ﬁbrinolysis,to form the prothrombinase complex. Thrombin, after binding to plasmin is inhibited by α2-plasmin inhibitor, and tPA and uPA arethrombomodulin, can activate protein C (PC) when bound to the inhibited by plasminogen activator inhibitor type 1 (PAI-1) and type 2endothelial protein C receptor (EPCR). Activated protein C (aPC) then (PAI-2). In addition, thrombin-activated ﬁbrinolytic inhibitor (TAFI),binds to its cofactor, protein S (PS), to inactivate factors VIIIa and Va. which is activated by the thrombin-thrombomodulin complex, cleavesFactor Xa is inhibited by the protein Z-dependent protease inhibitor terminal lysine residues from ﬁbrin to render it resistant to plasmin.(ZPI) when complexed to its cofactor, protein Z (PZ). Antithrombin(AT) potently inhibits both factor Xa and thrombin. Xa. The resultant conformational change facilitates AT binding to endothelial surface heparanoids or exogenous heparin, which aug-of platelets, they become progressively less activated, and their clotting ments thrombin inactivation more than 1000-fold.17 Although throm-reaction becomes more susceptible to the action of circulating inhibi- bin generated at the initial site of vascular injury is relatively “protected”tors, thus attenuating the clotting cascade.9 from AT, thrombin produced more distally on the surface of activated Prevention of disseminated intravascular coagulation (DIC) ulti- platelets is readily susceptible.9 Similar inhibitory mechanisms utilizemately requires the presence of inhibitor molecules (Fig. 40-3). The heparin cofactor II and α2-macroglobulin.ﬁrst inhibitory molecule is TFPI which forms a complex with TF, VIIa,and Xa (the prothrombinase complex).14 As noted earlier, TFPI is mosteffective distal to the initial site of clotting, and it can be bypassed by Restoration of Blood Flow: Fibrinolysisthe generation of factors IXa and XIa. Fibrinolysis permits the restoration of circulatory ﬂuidity and serves Paralleling its pivotal role in initiating the hemostatic reaction, as another barrier to thrombosis (Fig. 40-4). The cross-linked ﬁbrinthrombin also plays a central role in initiating the anticoagulant system. polymer is degraded to ﬁbrin degradation products (FDPs) by theThrombin binds to thrombomodulin, and the resultant conforma- action of plasmin embedded in the ﬁbrin clot.18 Plasmin is, in turn,tional change permits thrombin to activate protein C (PC) when generated by the proteolysis of plasminogen via tissue-type plasmino-bound to damaged endothelium or the endothelial protein C receptor gen activator (tPA), which is also embedded in ﬁbrin. Endothelial cells(EPCR). Activated protein C (aPC) then binds to its cofactor, protein also synthesize a second plasminogen activator, urokinase-type plas-S (PS), to inactivate factors VIIIa and Va. However, this process is far minogen activator (uPA), whose primary function is cell migrationless efﬁcient at blocking thrombin generation on activated platelets, and extracellular matrix remodeling.possibly because platelet-derived, partially activated factor Va is resis- Fibrinolysis is, in turn, modulated by a series of inhibitors. Plasmintant to aPC/PS inactivation.15 Therefore, additional anticoagulant reac- is inhibited by α2-plasmin inhibitor, which, like plasmin and plasmino-tions are required. Factor Xa can be efﬁciently inhibited by the protein gen, is bound to the ﬁbrin clot, where it is positioned to prevent pre-Z–dependent protease inhibitor (ZPI) when complexed to its cofactor, mature ﬁbrinolysis. Platelets and endothelial cells release type-1protein Z (PZ).16 ZPI also inhibits factor XIa in a process that does not plasminogen activator inhibitor (PAI-1) in response to thrombinrequire PZ. Deﬁciencies of PZ can promote both intracerebral bleeding binding to PARs. The PAI-1 molecule inhibits both tPA and uPA. Inand systemic thrombosis, the latter predominating in the setting of pregnancy, the decidua is also a very rich source of PAI-1,19 and thecoexistent inherited thrombophilias. placenta can synthesize another antiﬁbrinolytic molecule, PAI-2. Fibri- The most potent inhibitor of both factor Xa and thrombin is anti- nolysis can also be inhibited by thrombin-activated ﬁbrinolytic inhibi-thrombin (AT, previously known as antithrombin III or ATIII) (see Fig. tor (TAFI). This carboxypeptidase cleaves terminal lysine residues40-3). Antithrombin bound to vitronectin can bind thrombin or factor from ﬁbrin to render it resistant to plasmin. TAFI is activated by the
CHAPTER 40 Coagulation Disorders in Pregnancy 829thrombin-thrombomodulin complex.20 In the initial stages of clotting, estrogen and local production of prostacyclin and nitric oxide. Preg-platelets and endothelial cells release PAI-1, but, after a delay, endothe- nancy is also frequently associated with obesity, insulin resistance, andlial cells release tPA and uPA to promote ﬁbrinolysis. This biologic hyperlipidemia, all of which further increase levels of PAI-1.31process permits sequential clotting followed by ﬁbrinolysis to restorevascular patency. The ﬁbrinolytic system can also interact with the coagulationcascade. FDPs inhibit the action of thrombin, and this is a major source Disorders Promotingof hemorrhage in DIC. Moreover, PAI-1 bound to vitronectin andheparin also inhibits thrombin and factor Xa activity.21 Thrombosis in Pregnancy Acquired Thrombophilias:The Effect of Pregnancy Antiphospholipid Antibodieson Hemostasis The combination of VTE, obstetric complications, and antiphospho-As noted, pregnancy and delivery present unique and paradoxical chal- lipid antibodies (APA) deﬁnes the antiphospholipid antibody syn-lenges to a woman’s hemostatic system. They also present one of the drome (APS).32 These antibodies are directed against proteins boundgreatest risks for venous thromboembolism (VTE) that most young to negatively charged surfaces, usually anionic phospholipids. There-women will face. Profound alterations in both local uterine and sys- fore, APAs can be detected (1) by screening for antibodies that directlytemic clotting, anticoagulant, and ﬁbrinolytic systems are required to bind protein epitopes such as β2-glycoprotein-1, prothrombin, annexinmeet this enormously complex challenge. The uterine decidua is ideally V, aPC, PS, protein Z, ZPI, tPA, factor VII(a), and XII, the complementpositioned to regulate hemostasis during placentation and the third cascade constituents C4 and CH50, and oxidized low-density lipopro-stage of labor. Progesterone augments expression of TF22 and PAI-119 teins, or (2) by indirectly assessing antibodies that react to proteinson perivascular decidualized endometrial stromal cells. The crucial present in an anionic phospholipid matrix (e.g., cardiolipin, phospha-importance of the decidua in the maintenance of puerperal hemostasis tidylserine), or (3) by assessing the downstream effects of these anti-is highlighted by the massive hemorrhage that accompanies obstetric bodies on prothrombin activation in a phospholipid milieu (i.e., lupusconditions associated with impaired decidualization (e.g., ectopic and anticoagulants).33cesarean scar pregnancy, placenta previa, and accreta). That decidual The diagnosis of APS has been a controversial topic. A recent con-TF plays the primary role in mediating puerperal hemostasis is sensus conference proposed the criteria outlined in Table 40-1.34 Indemonstrated by the observation that transgenic TF knockout mice brief, APS requires the presence of at least one clinical criterionrescued by the expression of low levels of human TF have a 14% (conﬁrmed thrombosis or pregnancy morbidity) and one laboratoryincidence of fatal postpartum hemorrhage despite far less invasive criterion (lupus anticoagulant [LA], anticardiolipin (ACA), or anti-placentation.23 β2-glycoprotein-1 antibody). However, the presence of thrombosis The extraordinarily high level of TF expression in human decidua must take into account confounding variables that lessen the certaintycan also serve a pathologic function if local hemostasis proves inade- of the diagnosis (see Table 40-1). Uteroplacental insufﬁciency may bequate to contain spiral artery damage and hemorrhage into the decidua recognized by the sequelae of nonreassuring fetal surveillance testsoccurs (i.e., abruption). This bleeding results in intense generation of suggestive of fetal hypoxemia, abnormal Doppler ﬂow velocimetrythrombin and occasionally in frank hypoﬁbrinogenemia and DIC. waveform analysis suggestive of fetal hypoxemia, oligohydramniosHowever, thrombin can also bind to decidual PAR-1 receptors to (amniotic ﬂuid index ≤5 cm), or birth weight less than the 10th per-promote production of matrix metalloproteinases and cytokines, centile. Classiﬁcation of APS should not be made if less than 12 wk orcontributing to the tissue breakdown and inﬂammation associated more than 5 years separates the positive APA test and the clinicalwith abruptio placenta and preterm premature rupture of the manifestation.membranes.24-27 Venous thrombotic events associated with APA include deep venous Pregnancy also induces systemic changes in the hemostatic system. thrombosis (DVT) with or without acute pulmonary emboli; cerebralIt is associated with a doubling in concentration of ﬁbrinogen and vascular accidents and transient ischemic attacks are the most commonincreases of 20% to 1000% in factors VII, VIII, IX, and X as well as arterial events. At least half of patients with APA have systemic lupusvWF.28 Levels of prothrombin and factor V remain relatively unchanged, erythematosus (SLE). A meta-analysis of 18 studies examining theand levels of factor XI decline modestly. The net effect is an increase thrombotic risk among SLE patients with LA, found odds ratios (OR)in thrombin-generating potential. Pregnancy is also associated with of 6.32 (95% conﬁdence interval [CI], 3.71 to 10.78) for a VTE episode60% to 70% declines in free PS levels, which nadir at delivery due to and 11.6 (CI, 3.65 to 36.91) for recurrent VTE.35 By contrast, ACAshormonally induced increases in levels of its carrier protein, the com- were associated with lower ORs of 2.50 (CI, 1.51 to 4.14) for an acuteplement 4B–binding protein.29 As a consequence, pregnancy is associ- VTE and 3.91 (CI, 1.14 to 13.38) for recurrent VTE. A meta-analysisated with an increased resistance to aPC. These effects are exacerbated of studies involving more than 7000 patients in the general populationby cesarean delivery and infection, which drive further reduction in identiﬁed a range of ORs for arterial and venous thromboses in patientsthe concentration of free PS. Levels of PAI-1 increase threefold to with LA: 8.6 to 10.8 and 4.1 to 16.2, respectively.33 The comparablefourfold during pregnancy, and plasma PAI-2 values, which are negli- numbers for ACA were 1 to 18 and 1 to 2.5. Therefore, there appearsgible before pregnancy, reach high concentrations at term.30 Thus, to be a consistently greater risk of VTE associated with LA comparedpregnancy is associated with increased clotting potential, decreased with isolated ACA. Recurrence risks of up to 30% have been reportedanticoagulant activity, and decreased ﬁbrinolysis.30 in affected patients, so long-term prophylaxis is required.36 The risk of Pregnancy is also associated with venous stasis in the lower extremi- VTE in pregnancy and the puerperium accruing to affected patients isties resulting from compression of the inferior vena cava and pelvic poorly studied but may be as high as 5% despite treatment.37veins by the enlarging uterus as well as a hormone-mediated increase As noted, APA are associated with obstetric complications includ-in deep vein capacitance secondary to increased circulating levels of ing fetal loss, abruption, severe preeclampsia, and intrauterine growth
830 CHAPTER 40 Coagulation Disorders in Pregnancy TABLE 40-1 REVISED CLASSIFICATION CRITERIA FOR DIAGNOSIS OF THE ANTIPHOSPHOLIPID ANTIBODY SYNDROME (APS)* Clinical Criteria 1. Vascular thrombosis†: One or more clinical episodes of arterial, venous, or small-vessel thrombosis, in any tissue or organ conﬁrmed by objective, validated criteria (i.e., unequivocal ﬁndings of appropriate imaging studies or histopathology). 2. Pregnancy morbidity: a. One or more unexplained deaths of a morphologically normal fetus at or beyond 10 weeks of gestation, with normal fetal morphology documented by ultrasound or by direct examination of the fetus, or b. One or more premature births of a morphologically normal neonate before the 34th week of gestation because of (i) eclampsia or severe preeclampsia or (ii) recognized uteroplacental insufﬁciency, or c. Three or more unexplained consecutive euploid spontaneous abortions before 10 weeks of gestation, with maternal anatomic or hormonal abnormalities and paternal and parental chromosomal causes excluded. Laboratory Criteria‡ 1. Lupus anticoagulant (LA) present in plasma, on two or more occasions at least 12 wk apart, detected according to the guidelines of the ISTH Scientiﬁc Subcommittee on Lupus Anticoagulants/Phospholipid-Dependent Antibodies. 2. Anticardiolipin antibody (aCL) of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i.e., >40 GPL or MPL, or >99th percentile), on two or more occasions, at least 12 wk apart, measured by a standardized ELISA. 3. Anti-β2-glycoprotein-1 antibody of IgG and/or IgM isotype in serum or plasma (in titer >99th percentile), present on two or more occasions, at least 12 wk apart, measured by a standardized ELISA, according to recommended procedures. *APS is present if at least one clinical criterion and one laboratory criterion are met. † Coexisting inherited or acquired factors for thrombosis are not reasons for excluding patients from APS trials. However, two subgroups of APS patients should be recognized, according to (1) the presence or (2) the absence of additional risk factors for thrombosis. Indicative (but not exhaustive) of such factors are age (>55 yr in men, >65 yr in women); presence of any of the established risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated LDL or low HDL cholesterol, cigarette smoking, family history of premature cardiovascular disease, BMI ≥30 kg/m2, microalbuminuria, estimated GFR <60 mL/min), inherited thrombophilias, oral contraceptive use, nephrotic syndrome, malignancy, immobilization, and surgery. Patients who fulﬁll criteria should be stratiﬁed according to contributing causes of thrombosis. ‡ Investigators are strongly advised to classify APS patients in studies into one of the following categories: I, more than one laboratory criteria present (any combination); IIa, LA present alone; IIb, aCL antibody present alone; IIc, Anti-b2 glycoprotein-1 antibody present alone. APA, antiphospholipid antibody; BMI, body mass index; ELISA, enzyme-linked immunosorbent assay; GFR, glomerular ﬁltration rate; GPL, IgG phospholipid units; HDL, high-density lipoprotein; IgG, immunoglobulin G; IgM, immunoglobulin M; ISTH, International Society on Thrombosis and Hemostasis; LDL, low-density lipoprotein; MPL, IgM phospholipid units. Modiﬁed from Miyakis S, Lockshin MD, Atsumi D, et al: International consensus statement on an update of the classiﬁcation criteria for deﬁnite antiphospholipid syndrome (APS). J Thromb Haemost 4:295-306, 2006.restriction (IUGR). LA are associated with fetal loss after the ﬁrst tri- spective and prospective studies have not found an association betweenmester, with ORs ranging from 3.0 to 4.8, and ACA display a wider these conditions and APA.45 This is not surprising, given the commonrange of ORs, 0.86 to 20.0.33 It is controversial whether APA are occurrence of preeclampsia and IUGR and the relative infrequency ofassociated with recurrent (more than three) early (<10 weeks) sponta- APS.neous abortions in the absence of stillbirth. At least 50% of pregnancy A myriad of mechanisms have been proposed for APA-mediatedlosses in patients with APA occur after the 10th week of gestation.38 arterial and venous thrombosis. Direct inhibition of the anticoagulantMoreover, compared with patients who have unexplained ﬁrst-trimes- effects of anionic phospholipid-binding proteins such as β2-glycopro-ter spontaneous abortions without APA, those with antibodies more tein-1 and annexin V has been shown.46,47 In addition, APA appear tooften have demonstrable embryonic cardiac activity (86% versus 43%; inhibit thrombomodulin, aPC, and AT activity; to induce TF, PAI-1,P < .01).39 and vWF expression in endothelial cells; and to augment platelet acti- The association between APA and infertility also is uncertain. vation. Recently, APA induction of complement activation has beenIncreased levels of APA have been reported in women with infertil- suggested to play a role in fetal loss, with heparin preventing suchity.40,41 However, a meta-analysis of seven studies of affected patients aberrant activation.48undergoing in vitro fertilization found no signiﬁcant association Contemporary management of affected patients during pregnancybetween APA and either clinical pregnancy (OR, 0.99; CI, 0.64 to 1.53) requires treatment with either unfractionated heparin or low-molecu-or live birth rate (OR, 1.07; CI, 0.66 to 1.75).42 Finally, there is also no lar-weight heparin (LMWH) plus low-dose aspirin (LDA) at 50 toevidence that treating patients who have APA with anticoagulant medi- 80 mg/day. Rai and colleagues conducted a randomized, controlledcations improves outcomes of in vitro fertilization.43 trial among 90 APA-positive women with a history of recurrent fetal Women with APS who have pregnancies reaching viability are at loss who received either LDA alone or LDA plus 5000 U of unfraction-increased risk for obstetric outcomes associated with abnormal placen- ated heparin SQ every 12 hours until either recurrent loss or 34 weekstation such as preeclampsia and IUGR. Up to 50% of pregnancies in of gestation.39 The live birth rate was signiﬁcantly higher with com-women with APS develop preeclampsia, and one third have IUGR.37 bined heparin and LDA than with LDA alone: 71% (32/45) versus 42%Abnormal fetal heart rate tracings prompting cesarean delivery are also (19/45) (OR, 3.37; CI, 1.40 to 8.10). Interestingly, 90% of the lossescommon. Conversely, most cases of preeclampsia and IUGR occur in occurred in the ﬁrst trimester, and there was no difference in out-women without APA. Although increased positive tests for APA have come between the two groups for women whose pregnanciesbeen reported in women with preeclampsia, especially in severe disease advanced beyond 13 weeks’ gestation. Similar results were found in awith onset before 34 weeks’ gestation44 and IUGR, most large retro- nonrandomized trial by Kutteh.49 On the other hand, Farquharson and
CHAPTER 40 Coagulation Disorders in Pregnancy 831coworkers found no advantage to adding LMWH to LDA.50 However, patient requires any therapy, but the latter patient needs therapeuticthis latter study has been criticized because of the very low levels of unfractionated heparin or LMWH with LDA.57 Tincani and associatesAPA present in affected patients as well as imperfect randomization. reported on a survey of members of the International Advisory BoardMeta-analysis found that unfractionated heparin plus LDA (two trials; of the 10th International Congress on Antiphospholipid Antibodies.N = 140) signiﬁcantly reduced pregnancy loss compared with LDA The consensus of the group was that treatment for APA-positive preg-alone (relative risk [RR], 0.46; CI, 0.29 to 0.71) and that there was no nant patients should be LMWH and LDA.57 The dosage and frequencyadvantage of high-dose over low-dose unfractionated heparin (one of LMWH depends on the situation, including the patient’s bodytrial; N = 50).51 Another meta-analysis found that enoxaparin treat- weight and past history. Patients with previous thromboses shouldment resulted in an increased live birth rate, compared with LDA (RR, receive two injections per day. The use of IVIG should be restricted to10.0; CI, 1.56 to 64.20).52 Three studies of LDA alone versus placebo patients with pregnancy losses despite conventional treatment (seeincluded in the meta-analysis showed no signiﬁcant reduction in preg- later discussion for details of heparin dosing).nancy loss (RR, 1.05; CI, 0.66 to 1.68).51 Adverse pregnancy outcomes can still occur despite treatment.Backos and associates conducted a prospective observational study of Inherited Thrombophilias150 women treated with LDA and either unfractionated heparin Inherited thrombophilias have been linked to VTE. However, the(5000 U given SQ every 12 hours) or enoxaparin (20 mg daily) from occurrence of VTE in patients with an inherited thrombophilia isthe time of positive embryonic cardiac activity to either pregnancy loss highly dependent on the presence of other predisposing factors, espe-or 34 weeks of gestation.53 The live birth rate was 71%. However, 27% cially a personal or family history of VTE. Even more controversial isof the patients miscarried (mostly in the ﬁrst trimester), and gesta- the association between inherited thrombophilias and adverse preg-tional hypertension occurred in 17%, abruption in 7%, and IUGR in nancy outcomes.15%. Intravenous immune globulin (IVIG) has been reported to improve Factor V Leiden Mutationoutcome in women with APS for whom treatment with heparin and Present in about 5% of the European population and 3% of African-LDA has failed.54 The efﬁcacy of the combination of LDA and LMWH Americans, factor V Leiden (FVL) is the most common of the seriousin affected patients was compared with that of IVIG for the prevention heritable thrombophilias.58 The mutation is virtually absent in Africanof recurrent fetal loss in a study including 40 women,55 who were ran- blacks, Chinese, Japanese, and other Asians. The mutation causes adomized to receive either LMWH (5700 IU/day SQ) and LDA or IVIG substitution of glutamine for arginine at position 506, the site of pro-(400 mg/kg IV for 2 days, followed by 400 mg/kg every month). teolysis and inactivation by aPC/PS, and FVL is the leading cause ofAlthough the clinical characteristics of the two groups were similar at aPC resistance. The heterozygous state is symptomatic, with a ﬁvefoldthe time of randomization, women receiving LMWH and LDA had a increased risk of VTE, but homozygous patients have a 25-foldhigher live birth rate (84%) than those receiving IVIG alone (57%). increased risk (Table 40-2). FVL is associated with about 40% of VTEMoreover, IVIG plus heparin and LDA was also not superior to heparin events in pregnant patients.59 However, given the low prevalence ofand LDA alone in another small, randomized trial.56 Therefore, IVIG VTE in pregnancy (1/1400) and the high incidence of the mutation inis not recommended as ﬁrst-line therapy for APS. the European-derived population, the risk of VTE among FVL hetero- Given these small study sizes and heterogeneous therapies employed, zygotes without a personal history of VTE or an affected ﬁrst-degreerecommendations for treatment are difﬁcult to make. It is unlikely that relative is less than 0.3%.59 Nevertheless, the risk is at least 10% amonga patient with no history of VTE who has repetitive early losses and pregnant women who have either a personal history of VTE or anborderline positive APA levels reﬂects the same degree of risk or need affected ﬁrst-degree relative.60 Pregnant homozygous patients withoutfor intense therapy as a patient with high levels of APA, prior VTE, and a personal history of VTE or an affected ﬁrst-degree relative have arecurrent growth-retarded stillbirths. It is unclear whether the former 1.5% risk for VTE in pregnancy; if there is a personal or family history TABLE 40-2 INHERITED THROMBOPHILIAS AND THEIR ASSOCIATION WITH VENOUS THROMBOEMBOLISM (VTE) IN PREGNANCY Probability of VTE (%) without or with a Personal History of VTE or a First-Degree Relative with VTE Thrombophilia Relative Risk of VTE (95% CI) Without With Ref. No. FVL (homozygous) 25.4 (8.8-66) 1.5 17 46 FVL (heterozygous) 5.3 (3.7-7.6) 0.20-0.26 10 45, 46 PGM (homozygous) NA 2.8 >17 46 PGM (heterozygous) 6.1 (3.4-11.2) 0.37 >10 45, 46 FVL/PGM (compound heterozygous) 84 (19-369) 4.7 NA 46 Antithrombin deﬁciency (<60% activity) 119 3.0-7.2 >40% 46, 47 Protein S deﬁciency (<55% activity) NA <1 6.6 46, 47 Protein C deﬁciency (<50% activity) 13.0 (1.4-123) 0.8-1.7 2-8 46, 47 CI, conﬁdence interval; FVL, factor V Leiden mutation; NA, not available; PGM, prothrombin gene mutation.
832 CHAPTER 40 Coagulation Disorders in Pregnancyof VTE, the risk is 17% (see Table 40-2). Screening can be done by Early pregnancy is associated with a low-oxygen environment, withassessing aPC resistance using a second-generation coagulation assay intervillous oxygen pressures of 17.9 ± 6.9 mm Hg at 8 to 10 weeks,followed by genotyping for the FVL mutation if aPC resistance is found rising to 60.7 ± 8.5 mm Hg at 12 to 13 weeks.71 Trophoblast plugging ofin a pregnant or nonpregnant woman. Alternatively, patients can the spiral arteries has been demonstrated in placental histologic studiessimply be genotyped for FVL. before 10 weeks of gestation, and low Doppler ﬂow is noted in the The College of American Pathologists Consensus Conference on uteroplacental circulation before 10 weeks.72 Indeed, the undetectableThrombophilia compared 16 case-control studies reporting a link levels of superoxide dismutase in trophoblast before 10 weeks of gesta-between FVL and unexplained recurrent fetal loss and 6 studies failing tion are consistent with a hypoxic state.73 Therefore, if FVL or otherto establish such an association and concluded that the latter studies thrombophilias are associated with early pregnancy loss, it is mostwere smaller and tended to include patients with early ﬁrst-trimester likely through mechanisms other than placental thrombosis. Also,losses.61,62 In a meta-analysis of 31 studies, FVL was associated with because a majority of early pregnancy losses are associated with aneu-early (<13 weeks) pregnancy loss, with an OR of 2.01 (CI, 1.13 to 3.58), ploidy, thrombophilias are likely to play a far lesser role in such cases.but it was more strongly associated with late (>19 weeks), nonrecur- In contrast, uteroplacental thrombosis after 9 weeks would be expectedrent fetal loss, with an OR of 3.26 (CI, 1.82 to 5.83).63 A case-control to reduce oxygen and nutrient delivery to a progressively larger embryo,study noted an even stronger link between FVL and recurrent fetal accounting for the apparent link between FVL and the other maternallosses after 22 weeks’ gestation (OR, 7.83; CI, 2.83 to 21.67).64 Dudding thrombophilias and later adverse pregnancy outcomes.and Attia conducted a meta-analysis and found no signiﬁcant associa- The correlation between FVL and other later adverse pregnancytion between FVL and ﬁrst-trimester loss but an OR of 2.4 (CI, 1.1 to events is more controversial. Kupferminc and associates studied 1105.2) for isolated (nonrecurrent) third-trimester fetal loss, which women and reported a link between FVL and severe preeclampsia (OR,increased to 10.7 (CI, 4.0 to 28.5) for two or more second- or third- 5.3; CI, 1.8 to 15.6).74 However, multiple case-control studies havetrimester fetal losses.65 Similarly, Lissalde-Lavigne and associates failed to demonstrate a link between FVL and moderate or severe pre-reported the results of a case-control study nested in the 32,700 Nimes eclampsia.75-77 Dudding and Attia’s meta-analysis estimated a 2.9-foldObstetricians and Haematologists (NOHA) First study cohort.66 Mul- (CI, 2.0 to 4.3) increased risk of severe preeclampsia among FVL car-tivariate analysis revealed an association between FVL and pregnancy riers.65 Similarly, Lin and August conducted a meta-analysis of 31loss after 10 weeks (OR, 3.46; CI, 2.53 to 4.72) but not for losses occur- studies involving 7522 patients and reported pooled ORs of 1.81 (CI,ring between 3 and 9 weeks. These studies strongly suggest that FVL 1.14 to 2.87) for FVL and all preeclampsia and 2.24 (CI, 1.28 to 3.94)is associated with fetal (>9 weeks) and not embryonic (<9 weeks) for FVL and severe preeclampsia.78 However, Kosmas and coauthorslosses. evaluated 19 studies involving 2742 hypertensive women and 2403 The association between FVL and late, compared with early, preg- controls and reported that, whereas the studies published before 2000nancy losses was also demonstrated by a large European retrospective found a modest association between FVL and preeclampsia (OR, 3.16;cohort study involving 571 women with thrombophilia having 1524 CI, 2.04 to 4.92), those published after 2000 did not (OR, 0.97; CI, 0.61pregnancies, compared with 395 controls having 1019 pregnancies.67 to 1.54).79 This suggests a reporting bias. Therefore, there is not sufﬁ-There was a statistically signiﬁcant association between any inherited cient evidence to conclude that FVL is associated with an increasedthrombophilia and stillbirth (OR, 3.6; CI, 1.4 to 9.4) but not spontane- occurrence of preeclampsia, although there is inadequate power to ruleous abortion (OR, 1.27; CI, 0.94 to 1.71). The same trend was noted out an association between this thrombophilia and severe, early-onsetfor FVL, with an OR for stillbirth of 2.0 (CI, 0.5 to 7.7) compared with preeclampsia.0.9 for spontaneous abortion (CI, 0.5 to 1.5). These same investigators Kupferminc and colleagues also reported a modest associationthen monitored a subset of 39 thrombophilic and 51 control patients between FVL and abruption (OR, 4.9; CI, 1.4 to 17.4).74 A second case-who had no previous history of fetal loss and did not receive antico- control study found that 17 of 27 patients with abruption had aPCagulation during the prospective follow-up aspect of the study.68 They resistance, compared with 5 of 29 control subjects (OR, 8.16; CI, 3.6reported a modestly increased overall risk of fetal loss in a subsequent to 12.75), and 8 cases were found to have the FVL mutation, comparedpregnancy among women with thrombophilia (7/39 versus 7/51; RR, with one control.80 Prochazka and associates conducted a retrospective1.4; CI, 0.4 to 4.7) and also among those with FVL (RR, 1.4; CI, 0.3 to case-control study among 180 women with placental abruption and5.5). However, this study lacked power to exclude the usually reported 196 controls and found a signiﬁcantly increased incidence of FVL car-twofold to threefold higher rates of loss associated with FVL, because riage among cases compared with controls (14.1% versus 5.1%; OR,there were only 21 patients. Nevertheless, given the trends, the authors 3.0; CI, 1.4 to 6.7).81 Alﬁrevic and coworkers conducted a meta-analysisconcluded that “Women with thrombophilia appear to have an that revealed a strong association between placental abruption andincreased risk of fetal loss, although the likelihood of a positive outcome both homozygosity and heterozygosity for the FVL mutation (OR,is high in both women with thrombophilia and in controls.”68 16.9; CI, 2.0 to 141.9, and OR, 6.7; CI, 2.0 to 21.6, respectively).82 In a retrospective cohort study, Roque and colleagues evaluated 491 Therefore, there appears to be evidence of an association between FVLpatients with a history of various adverse pregnancy outcomes for a carriage and placental abruption, although large case-control and ret-variety of thrombophilias and reported that the presence of FVL was rospective cohort studies are needed to conﬁrm this link.paradoxically protective against losses before 10 weeks of gestation There is less consistent evidence for an association between FVL(OR, 0.23; CI, 0.07 to 0.77) but was signiﬁcantly associated with losses and IUGR. Martinelli and coauthors reported a strong associationafter 14 weeks (OR, 3.71; CI, 1.68 to 8.23).69 Moreover, women who between FVL and IUGR (OR, 6.9; CI, 1.4 to 33.5).83 However, multiple,experienced only euploid losses were not more likely to have an identi- large case-control and cohort studies have reported no statisticallyﬁed thrombophilia than women who experienced only aneuploid early signiﬁcant association between FVL and IUGR of less than the 10th orlosses (OR, 1.03; CI, 0.38 to 2.75). Consistent with this protective effect less than the 5th percentile.74,77,84 Howley and colleagues conducted aof FVL on early pregnancy is the observation that implantation rates systematic review of studies describing the association between FVLafter in vitro fertilization were substantially higher among FVL carriers and IUGR; among 10 case-control studies meeting selection criteria,than among noncarriers (90% versus 49%; P = .02).70 there was a signiﬁcant association between FVL and IUGR (OR, 2.7;
CHAPTER 40 Coagulation Disorders in Pregnancy 833CI, 1.3 to 5.5).85 However, no association was found among ﬁve cohort greater thrombotic risk than either FVL or PGM homozygotes. Pregnantstudies, of which three were prospective and two retrospective (RR, patients who are compound heterozygotes without a personal or strong0.99; CI, 0.5 to 1.9). The authors suggested that the putative association family history have a 4.7% risk of VTE.59,60between IUGR and FVL was most likely driven by small, poor-quality The PGM has been associated with an increased risk of pregnancystudies that demonstrated extreme associations. loss in multiple case-control studies. One such study reported the pres- In summary, there appears to be a modest association between FVL ence of the PGM in 7 of 80 patients with recurrent miscarriage, com-and fetal loss after 10 weeks, and particularly with isolated losses after pared with 2 of 100 control patients (9% versus 2%; P = .04; OR, 4.7;22 weeks. There is a possible association between FVL and abruption. CI, 0.9 to 23).92 Finan and associates also found an association betweenHowever, no clear association exists between FVL and either pre- PGM and recurrent abortion, with an OR of 5.05 (CI, 1.14 to 23.2).93eclampsia or IUGR, although studies have been underpowered to However, other studies have failed to identify a link.94,95 A 2004 meta-deﬁnitely exclude a link with severe early-onset preeclampsia or analysis of seven studies evaluating the correlation between PGM andsevere IUGR. It also is noteworthy that two prospective cohort studies recurrent pregnancy loss, deﬁned as two or more losses in the ﬁrst orfound no association between FVL and any adverse obstetric outcome, second trimester, found a combined OR of 2.0 (CI, 1.0 to 4.0).96 Analo-including pregnancy loss, preeclampsia, and IUGR,86.87 but these gous to FVL, the association between PGM and pregnancy loss increasesstudies were underpowered to draw ﬁrm conclusions. It is important with increasing gestational age. In the meta-analysis by Rey and col-to note that, although thrombophilia may be sufﬁcient to cause preg- leagues, an association was reported between PGM and recurrent lossnancy loss and perhaps abruption, most affected individuals without before 13 weeks’ gestation (OR, 2.3; CI, 1.2 to 4.79), but, as with FVL,such prior obstetric complications are at low risk for subsequent a stronger association was observed between PGM and recurrent fetaladverse pregnancy outcomes. loss before 25 weeks (OR, 2.56; CI, 1.04 to 6.29).63 Therefore, PGM appears to ﬁt the pattern displayed by FVL carriers of progressivelyOther Factor V Mutations greater risk of fetal loss with advancing gestation; however, these risksOther mutations in the factor V gene have been variably linked to remain quite modest.maternal VTE and adverse pregnancy outcomes. The factor V HR2 There are more limited data on the association between PGM andhaplotype causes decreased factor V cofactor activity in the aPC- abruption. The case-control study of Kupferminc and associates foundmediated degradation of factor VIIIa; however, a meta-analysis an association between the PGM and abruptio placenta (OR, 8.9; CI,demonstrated no statistically signiﬁcant association between the HR2 1.8 to 43.6),74 whereas Prochazka and colleagues found no such link.81haplotype and risk of VTE (OR, 1.15; CI, 0.98 to 1.36).88 There are Meta-analyses suggested a strong link between PGM heterozygosity andconﬂicting reports about the linkage of the factor V HR2 haplotype placental abruption (OR, 28.9; CI, 3.5 to 236.7).82 It can be concludedand recurrent pregnancy loss. Zammiti and associates reported no that there is probably a link between the PGM and abruptio placentae.association with losses before 8 weeks, but homozygosity for the factor The link between the PGM and other adverse pregnancy events isV HR2 haplotype was associated with signiﬁcant and independent far less certain. Kupferminc and colleagues found an associationrisks of pregnancy loss during weeks 8 and 9, which increased during between the PGM and IUGR of less than the 5th percentile (OR, 4.6;weeks 10 to 12 and culminated after 12 weeks.89 In contrast, Dilley and CI, 1 to 20) but no link between the PGM and severe preeclampsia.74colleagues found no association between carriage of the factor V HR2 Martinelli and coworkers noted a strong association between PGM andhaplotype and pregnancy loss.90 The sample sizes of these studies were IUGR in their case-control study (OR, 5.9; CI, 1.2 to 29.4).83 In con-too small to draw ﬁrm conclusions from, nor can conclusions be trast, the large case-control study of Infante-Rivard and colleaguesreached about the link between factor V HR2 haplotype and other reported no link in heterozygotes between PGM and IUGR, with anadverse pregnancy outcomes. OR of 0.92 (CI, 0.36 to 2.35).84 Similar results have been observed by Two other mutations in the factor V gene that occur at the second other workers.74,80 A number of other case-control studies and meta-aPC cleavage site, factor V R306G Hong Kong and factor V R306T analyses have failed to establish a link between PGM and either pre-Cambridge, have also been described but do not appear to be strongly eclampsia or severe preeclampsia.77,78,97,98associated with VTE.91 There are inadequate data to assess any linkage Therefore, although most individual studies are limited by smallbetween these mutations and adverse pregnancy outcomes.89 sample size, case-control design, and the potential for selection biases (as was the case with FVL), there may be a weak association betweenProthrombin Gene Mutation the PGM and fetal loss as well as abruptio placenta. However, thereThe prothrombin G20210A polymorphism is a point mutation causing does not appear to be a signiﬁcant link between PGM and IUGR ora guanine→adenine switch at nucleotide position 20210 in the 3′- preeclampsia.untranslated region of the gene.58 This nucleotide switch results inincreased translation, possibly due to enhanced stability of messenger HyperhomocysteinemiaRNA (mRNA). As a consequence, there are increased circulating levels Hyperhomocysteinemia can result from a number of mutations in theof prothrombin. Although the mutation is present in only 2% to 3% of methionine metabolic pathway. Homozygosity for mutations in thethe European population, it is associated with 17% of VTEs in preg- methylene tetrahydrofolate reductase (MTHFR) gene is by far the mostnancy.59 However, as was the case with FVL, the risk of VTE in pregnant common cause. Homozygosity for the MTHFR C677T polymorphismpatients who are heterozygous for the prothrombin G20210A gene is present in 10% to 16% of all Europeans, and that for the A1298Cmutation (PGM) but who are without a personal or strong family mutation occurs in 4% to 6%.99 Importantly, about 40% of whites arehistory of VTE is less than 0.5%.59 Pregnant PGM-heterozygous patients heterozygous for this polymorphism, and most heterozygotes havewith such a history have at least a 10% risk of VTE.60 PGM-homozygous normal levels of homocysteine. Moreover, because homocysteine levelspatients without a personal or strong family history have a 2.8% risk for decrease in pregnancy and U.S. diets are replete with folic acid supple-VTE in pregnancy, whereas such a history probably confers a risk of at mentation, hyperhomocysteinemia is extremely rare even amongleast 20% (see Table 40-2). Because the combination of FVL and PGM homozygotes. In addition, although hyperhomocysteinemia is a riskhas synergistic hypercoagulable effects, compound heterozygotes are at factor for VTE (OR, 2.5; CI, 1.8 to 3.5),100 MTHFR mutations per se
834 CHAPTER 40 Coagulation Disorders in Pregnancydo not appear to convey an increased risk for VTE in either nonpreg- tion (OR, 5.2; CI, 1.5 to 18.1) but had a more modest association withnant101 or pregnant women.102 miscarriage before 28 weeks (OR, 1.7; CI, 1.0 to 2.8).67 Given its rarity, As with thrombotic risk, meta-analyses suggest that elevated fasting there is a paucity of evidence concerning the link between AT deﬁ-homocysteine levels are more strongly associated with recurrent preg- ciency and other adverse pregnancy outcomes. Roque and associatesnancy loss (<16 weeks) than are MTHFR mutations, with an OR of 2.7 found it to be associated with increased risks of IUGR (OR, 12.93; CI,(CI, 1.4 to 5.2) versus 1.4 (CI, 1.0 to 2.0), respectively.103 The Hordaland 2.72 to 61.45), abruption (OR, 60.01; CI, 12.02 to 300.46), and pretermHomocysteine Study assessed the relationship between plasma homo- delivery (OR, 4.72; CI, 1.22 to 18.26).69cysteine values in 5883 women and their prior 14,492 pregnancy out-comes.104 When the authors compared the upper with the lower Protein C Deﬁciencyquartile of plasma homocysteine levels, elevated levels trended toward Deﬁciency of PC results from more than 160 distinct mutations, pro-an association with preeclampsia (OR, 1.32; CI, 0.98 to 1.77), very low ducing a highly variable phenotype. As was the case with AT deﬁciency,birth weight (OR, 2.01; CI, 1.23 to 3.27), and stillbirth (OR, 2.03; CI, PC deﬁciency can be associated with either reductions in both antigen0.98 to 4.21), although none of these associations reached statistical and activity (type 1) or normal levels of antigen but decreased activitysigniﬁcance.105 In contrast, a clear association was demonstrated (type 2).58 The very rare homozygous PC deﬁciency results in neonatalbetween placental abruption and homocysteine levels greater than purpura fulminans and a requirement for lifelong anticoagulation.11115 μmol/L (OR, 3.13; CI, 1.63 to 6.03), and a weaker but signiﬁcant Activity levels can be ascertained by either a functional (clotting) orassociation was observed between homozygosity for the C677T chromogenic assay.MTHFR mutation and abruption (OR, 1.6; CI, 1.4 to 4.8). Indeed, a Estimates of prevalence and thrombotic risk reﬂect the cutoffmeta-analysis of these two risk factors found that hyperhomocystein- values employed. Most laboratories use activity cutoff values of 50%emia had a larger pooled OR for abruption (5.3; CI, 1.8 to 15.9) than to 60%, which are associated with prevalence estimates of 0.2% to 0.3%did homozygosity for the MTHFR mutation (2.3; CI, 1.1 to 4.9).106 and RRs for VTE of 6.5 to 12.5.58,68,108. The risk of VTE in pregnancy These studies strongly suggest that hyperhomocysteinemia, but not among PC-deﬁcient patients has been reported to range from 2% tosimply the presence of the MTHFR mutations, is linked to VTE and 8%.30,112,113 Because of its rarity, there are few reports linking PC deﬁ-adverse pregnancy outcomes. Moreover, whereas homozygosity for ciency to adverse pregnancy outcomes, and those that exist involve tooMTHFR mutations is very common (10% to 20% in European popula- few patients to draw any ﬁrm conclusions. In their case-control study,tions), hyperhomocysteinemia is quite rare. Therefore, screening for Roque and colleagues reported a strong link between PC deﬁciencythis disorder should be limited, requiring a fasting homocysteine level and abruption (OR, 13.9; CI, 2.21 to 86.9) and between PC deﬁciencygreater than 12 μmol/L to be considered positive in pregnant patients.146 and preeclampsia (OR, 6.85; CI, 1.09 to 43.2).69 A meta-analysis also reported a strong association of this deﬁciency and preeclampsia/Antithrombin Deﬁciency eclampsia (OR, 21.5; CI, 1.1 to 414.4) but not stillbirth.82 It is biologi-Deﬁciency of AT is both the rarest and the most thrombogenic of the cally plausible that PC deﬁciency should pose risks of fetal loss andheritable thrombophilias. More than 250 mutations have been identi- abruption analogous to those associated with FVL. However, given theﬁed in the AT gene, producing a highly variable phenotype. In general, very small sample sizes, no ﬁrm conclusions can be drawn regardingdisorders can be classiﬁed into three types: type 1, those associated the link between PC deﬁciency and either preeclampsia or IUGR.with reductions in both antigen and activity; type 2, those associatedwith normal levels of antigen but decreased activity; and type 3, the Protein S Deﬁciencyvery rare homozygous deﬁciency associated with little or no activ- More than 130 mutations have been linked to deﬁciency of PS.58 Theity.58,108 Complicating matters further, patients can develop acquired great majority of affected patients can be characterized as having lowAT deﬁciency due to liver impairment, increased consumption of AT levels of both total and free PS antigen (type 1) or as having only a lowassociated with sepsis or DIC, or increased renal excretion in severe free PS level due to enhanced binding to the complement 4B–bindingnephrotic syndrome. However, both inherited and acquired AT deﬁ- protein (type 2a). The latter condition is frequently caused by a serineciencies are associated with VTE. 460 to proline mutation (protein S Heerlen), which has been associated Because screening for AT deﬁciency is done by assessing activity, its with either FVL or PC mutation in about half of affected patients.114prevalence varies with the activity cutoff level employed, ranging from As with PC deﬁciency, homozygous PS deﬁciency results in neonatal0.02% to 1.1%. The recommended cutoff for “abnormality” is 50% purpura fulminans.111activity, which is associated with a prevalence of 0.04% (1/2500 Screening for PS deﬁciency can be done with an activity assay, butpeople).108 Although it increases the risk of VTE up to 25-fold in the this approach is associated with substantial interassay and intra-assaynonpregnant state,108 because of its rarity AT deﬁciency is associated variability, in part because of frequently changing physiologic levels ofwith only 1% to 8% of VTE episodes.58 Pregnancy may increase its complement 4B–binding protein.115 Detection of free PS antigen levelsthrombogenic potential substantially (see Table 40-2). Moreover, use lower than 55% in a nonpregnant woman is consistent with the diag-of a less stringent threshold yields a higher prevalence of AT deﬁciency nosis.115 However, Paidas and colleagues found far lower levels inin patients with VTE. For example, in one study, 19.3% of pregnant normal pregnancy, with suggested cutoff levels for free PS of 29% forwomen with VTE had less than 80% AT activity,59 but many of these the ﬁrst and second trimesters and 23% for the third trimester.29 Withcases may have been acquired due to clot-associated AT consumption. such criteria, the prevalence of true PS deﬁciency is low (0.03% toConversely, the overall risk of VTE in pregnancy associated with AT 0.13%) in the nonpregnant state and rises up to 3% in the pregnantdeﬁciency has been variably reported as 3% to 48%.30,60,109,110 The risk state, but its degree of thrombogenicity is modest (OR, 2.4; CI, 0.8 toof VTE in pregnancy among AT-deﬁcient patients most likely varies 7.9).29,58,115 Among those patients with PS deﬁciency and a strongalso with a personal or family history (from 3% to 7% without such a family history of VTE, the risk of VTE in pregnancy is 6.6% (see Tablehistory to as much as 40% with such a history).60 40-2).112 In the largest retrospective cohort study, AT deﬁciency was associ- The meta-analysis by Rey and colleagues reported an associationated with a signiﬁcantly increased risk of stillbirth after 28 weeks’ gesta- between PS deﬁciency and recurrent late (>22 weeks or <25 weeks)
CHAPTER 40 Coagulation Disorders in Pregnancy 835fetal loss (OR, 14.7; CI, 1.0 to 2181) as well as nonrecurrent fetal losses described a modest association between 4G/4G homozygosity and theat greater than 22 weeks (OR, 7.4; CI, 1.3 to 43).63 A second meta- occurrence of severe preeclampsia (OR, 1.62; CI, 1.02 to 2.57).130analysis suggested an even stronger link between PS deﬁciency and Glueck and colleagues conducted a case-control study and observedstillbirth (OR, 16.2; CI, 5.0 to 52.3), IUGR (OR, 10.2; CI, 1.1 to 91.0), that compared to patients with either the 5G/5G or the 4G/5G allele,and preeclampsia/eclampsia (OR, 12.7; CI, 4 to 39.7), but not abrup- those who were homozygous for the 4G/4G allele had greater rates oftion.82 Again, the small sample sizes limit the ability to draw ﬁrm prematurity (14% versus 3%; P = .001), second- and third-trimesterconclusions. deaths (9% versus 2%; P = .004), and IUGR (4% versus 0.4%; P = .012).131 However, caution must be exercised in the interpretationProtein Z-Dependent Protease Inhibitor and of these data, because the occurrence of adverse outcomes was lowerProtein Z Deﬁciency in the control group than would be expected in the general population,Two nonsense mutations in the coding region of the ZPI gene have and 30% of patients who were homozygous for the 4G/4G mutationbeen identiﬁed to occur more often in patients with VTE (4.4%) than had coexisting thrombophilias.131 As was the case for the associationin controls (0.8%) (OR, 5.7; CI, 1.25 to 26.0).116 Deﬁciency of PZ between 4G/4G homozygosity and VTE, this mutation may be more(activity <5th percentile) has been associated with strokes but not with likely to be linked with adverse pregnancy outcomes when it occursVTE.117 PZ deﬁciency was linked to late fetal loss (10 to 16 weeks’ gesta- simultaneously with other thrombophilic disorders or with triggers oftion) in one study (OR, 6.7; CI, 3.1 to 14.8)118 but not in another.119 increased PAI-1 expression such as the ACE D/D genotype and disor-Paidas and associates prospectively compared PZ levels in 103 patients ders linked to insulin resistance (e.g., obesity, type 2 diabetes, hyper-with subsequent normal pregnancy outcome and 106 women with lipidemia, polycystic ovary syndrome).various adverse pregnancy outcomes including fetal loss, IUGR, pre- Polymorphisms have been described in the TAFI and tPA genes, buteclampsia, and abruption; they noted lower ﬁrst-trimester PZ levels no clear link has been established for either with increased VTE riskamong the patients with subsequent adverse outcomes (1.81 ± 0.7 or adverse pregnancy outcomes.versus 2.21 ± 0.8 μg/mL; P < .001).29 There were also lower PZ levelsin affected patients in the second trimester (1.5 ± 0.4 versus 2.0 ± Other Thrombophilic Mutations0.5 μg/mL; P < .0001) and in the third trimester (1.6 ± 0.5 versus 1.9 The -455GtoA polymorphism in the ﬁbrinogen β gene leads to± 0.5 μg/mL; P < .0002). However, it is unclear whether low PZ levels increased plasma ﬁbrinogen levels but an unclear thrombotic risk.132were causative or whether PZ was reduced as a result of other throm- Both the apolipoprotein B R3500Q and E2/E3/E4 polymorphisms andbophilias or the ongoing uteroplacental pathologic processes. Although the platelet receptor gene polymorphisms GpIIIa L33P and GpIaPZ deﬁciency may have its own pathogenic potential, its presence with 807CtoT also offer an uncertain VTE risk, although they may contrib-other thrombophilic mutations in patients with prior fetal loss may ute to coronary and cerebral artery thrombosis, particularly in thealso confer resistance to heparin therapy.119 presence of other risk factors such as smoking, hypertension, obesity, and diabetes. The common hereditary hemochromatosis gene (HFEMutations in Fibrinolytic Pathway Genes gene C282Y mutation) does not appear to be a risk factor for VTE,Two polymorphisms, 675 4G/5G and A844G, in the promoter region even when it is present in patients with FVL.133 An analysis of linksof the PAI-1 gene have been described.120 Homozygosity for the 4G/4G between fetal loss and β-ﬁbrinogen -455GtoA, between apolipoproteinallele in the PAI-1 gene results in the presence of four instead of ﬁve B R3500Q and E2/E3/E4, and between GpIIIa L33P and HFE C282Yconsecutive guanine nucleotides in the promoter region, producing a found no signiﬁcant associations.134site that is too small to permit repressor binding. Conversely, the Polymorphisms have also been described in the thrombomodulin,A844G polymorphism affects a consensus sequence binding site for the TFPI, and endothelial PC receptor genes, but they are of no or unknownregulatory protein Ets, enhancing PAI-1 gene transcription. The preva- thrombogenic potential.58 The Val34Leu polymorphism in the factorlence of the 4G/4G genotype in the general population is high, ranging XIII gene is associated with increased activation by thrombin and afrom 23.5% to 32.3%.121,122 Moreover, most studies have not found any potentially thrombotic phenotype135 but confers uncertain risks forindependent relationship between the 4G/4G polymorphism and the VTE and adverse pregnancy outcome.development of VTE in unselected patients.123-125 However, the 4G/4Ggenotype has been linked to a further increased risk for VTE when it Summaryis present in patients with PS deﬁciency or FVL, suggesting that it plays A great number of potentially thrombophilic polymorphisms are beingan additive but not independent role in the genesis of VTE.126,127 No uncovered, at an ever-increasing pace. Although most of these muta-relationship has been demonstrated between the A844G polymor- tions do not appear to be highly thrombogenic when present in isola-phism and VTE.123 tion, they may exert an additive or even a synergistic effect on the There are limited data on the association between the 4G/4G allele thrombogenicity of other disorders. This might account for the ﬁndingand adverse pregnancy outcomes. No statistically signiﬁcant associa- of a very modest association between a given thrombophilic state (e.g.,tion was found between isolated homozygosity for the 4G/4G muta- FVL, PS deﬁciency) and the isolated occurrence of VTE or adversetion and recurrent spontaneous abortion in several small studies.128,129 pregnancy outcomes in low-risk populations together with a far higherHowever, endothelial expression of PAI-1 is induced by angiotensin II, concordance rate within certain families.and generation of the latter molecule is increased by a deletion (D)/insertion (I) polymorphism in the angiotensin I–converting enzyme(ACE) gene. Buchholz and associates observed a signiﬁcant increase in Screening for Thrombophiliasthe combination of the PAI-1 4G/4G and ACE D/D genotypes amongpatients with recurrent spontaneous abortion compared with controls Screening and Prevention of(13.6% versus 4.7%; OR, 3.2; P = .01).121 Venous Thromboembolism Moreover, a possible association exists between the 4G/4G allele The presence of a known thrombophilia increases the recurrence riskand later adverse pregnancy outcomes. Yamada and coworkers of VTE among pregnant women. Brill-Edwards and associates pro-
836 CHAPTER 40 Coagulation Disorders in Pregnancyspectively evaluated 125 pregnant women with a prior VTE, 95 of Alternatively, prophylaxis can employ LMWH. Regimens canwhom were tested for acquired and inherited thrombophilias (includ- include dalteparin 5000 U SQ, given every 12 hours or once a day, oring APAs, FVL, and PGM) and for PC, PS and AT deﬁciencies.136 enoxaparin 30 mg SQ, every 12 hours or 40 mg SQ once a day. WhereasAntenatal heparin was withheld in all patients, but postpartum anti- monitoring of anti-factor Xa levels is not necessary in nonpregnantcoagulation was provided. The overall antepartum recurrence rate for patients, given the absence of data in pregnancy, the greater variabilityVTE was 2.4% (CI, 0.2% to 6.9%), but no recurrences were observed in heparin binding, and the increased volume of distribution and/orin the 44 women who had no evidence of thrombophilia and whose metabolism and excretion in pregnancy, we recommend serial mea-previous episode of thrombosis was associated with temporary risk surements of anti-factor Xa levels, with a goal of 0.1 to 0.2 U/mL at 4factors that included pregnancy itself. Among the 51 women who had hours after each injection.a thrombophilia or whose previous VTE was considered idiopathic, the For patients with highly thrombogenic thrombophilias (e.g., homo-antepartum recurrence rate was 5.9% (CI, 1.2% to 16.2%), and among zygotes or compound heterozygotes for FVL and PGM, patients withthe 25 thrombophilic patients the recurrence risk was 16% (4 patients) AT deﬁciency or APS with prior VTE) who have a personal or strong(OR, 6.5; CI, 0.8 to 56.3). Therefore, there appears to be evidence-based family history of VTE, and for patients with recurrent VTE, therapeuticjustiﬁcation to test pregnant patients with a prior history of VTE (high-dose) unfractionated heparin or LMWH should be used. Theassociated with temporary and reversible risk factors (e.g., fractures, goal of unfractionated heparin therapy is to obtain and maintain anprolonged immobilization, cancer), because the presence of a throm- activated partial thromboplastin time (aPTT) of 1.5 to 2.5 timesbophilic state would be an indication for antepartum as well as post- control values or a plasma heparin concentration of 0.2 to 0.4 U/mL,partum thromboprophylaxis. Conversely, women with a prior VTE or an anti-factor Xa concentration of 0.4 to 0.7 U/mL. The aPTTassociated with a nonrecurring risk factor who are without thrombo- should not be used to guide unfractionated heparin therapy in patientsphilia or other current major risk or susceptibility factors (e.g., need with prolonged aPTT due to LAs. Therapeutic LMWH therapy consistsfor prolonged bed rest, obesity, current superﬁcial thrombophlebitis) of enoxaparin 1 mg/kg SQ twice daily or a comparable dose of dalte-may not need antepartum prophylactic heparin therapy during preg- parin (e.g., 10,000 U SQ every 12 hours). Barbour and colleaguesnancy.136 However, because thrombotic events during pregnancy in evaluated whether the standard therapeutic doses of dalteparin main-such women have been reported on rare occasions,110 the risks and tained peak therapeutic levels of anticoagulation during pregnancybeneﬁts of antepartum thromboprophylaxis should be discussed with and reported that 85% (11/13) of patients required an upward dosagethe patient. Also, such patients should receive postpartum prophylaxis, adjustment.139 Therefore, we recommend titrating either agent tobecause most pregnancy-associated fatal pulmonary embolisms occur maintain factor Xa levels at 0.6 to 1.0 U/mL 4 hours after injection.in the postpartum period. In this setting, knowledge of the thrombo- For patients with highly thrombogenic thrombophilias in the absencephilic state affects management. of a personal or strong family history of VTE, we recommend using The 7th American College of Chest Physicians Guidelines for the an intermediate or “high prophylactic” dose of LMWH, titrating theAntenatal and Peripartum Management of Thrombophilia suggest that dose to maintain factor Xa levels at 0.4 to 0.6 U/mL.the occurrence of VTE in nonpregnant patients who are receiving Regardless of whether the patient is receiving prophylactic, thera-estrogen-containing contraceptives is comparable with such events peutic, or high prophylactic doses of LMWH, we recommend switch-occurring in pregnancy. In either case they would recommend ante- ing to the comparable dose of unfractionated heparin at 36 weeks, topartum and postpartum prophylaxis in a subsequent pregnancy, permit application of neuraxial anesthesia if desired or indicatedregardless of thrombophilia status in women who had a VTE during a during labor or delivery. Both heparin and LMWH are associated withprior pregnancy or while taking estrogen-containing contraceptives.137 an increased risk for osteopenia. Although of unproven beneﬁt, itSimilarly, consideration should also be given to screening of pregnant seems prudent to advise axial skeleton weight-bearing exercise andwomen who have a strong family history (i.e., affected ﬁrst-degree calcium supplementation. These medications also increase the risk forrelative) of VTE. Given the greater than 10% risk of VTE in pregnancy heparin-induced thrombocytopenia, which paradoxically is associatedamong patients with such a history and a thrombophilia (see Table with thrombosis. With therapeutic doses of LMWH and with any dose40-2), thromboprophylaxis, although of unproven efﬁcacy, is a reason- of unfractionated heparin, platelet counts should be obtained after 3able option. Cost-effective screens should be initially limited to the to 4 days of therapy and intermittently for the ﬁrst 3 weeks ofmost common and most thrombogenic disorders, including FVL and treatment.140PGM. Negative results should lead to evaluation of fasting homocys- Postpartum thromboprophylaxis is also required. Warfarin is con-teine levels and PC, PS, and AT deﬁciencies. sidered safe to take while breast feeding. Warfarin is started within 24 The dosing regimen to be employed varies with the severity of the hours of commencing heparin therapy. Doses are determined by moni-thrombophilia, the patient’s family history, and the nature of the prior toring the international normalized ratio (INR). To avoid paradoxicalVTE episodes. In general, for patients with a personal or strong family thrombosis and skin necrosis from warfarin’s early, predominantlyhistory of VTE and a lesser thrombogenic thrombophilia (e.g., FVL, anti-PC effect, it is critical to maintain these women on therapeuticPGM, hyperhomocysteinemia refractory to folate therapy, PC or PS doses of unfractionated heparin or LMWH for a minimum of 5 daysdeﬁciency), antepartum prophylaxis with either mini-dose unfraction- and until the INR is in the therapeutic range (2.0 to 3.0) for 2 consecu-ated heparin or low-dose LMWH is effective in preventing DVT in tive days.pregnant patients at risk. The standard regimen of unfractionatedheparin used in pregnancy consists of 5000 units administered SQ Screening and Prevention of Adverseevery 12 hours, increased by 2500 units in the second and third tri- Pregnancy Outcomesmesters. However, Barbour and associates observed that this standard As can be discerned from the preceding review, there appears to be aunfractionated heparin regimen was inadequate to achieve the desired modest and consistent association between the major inherited throm-anti-factor Xa therapeutic range in 5 of 9 second-trimester pregnancies bophilias (including FVL, PGM, elevated fasting homocysteine levelsand in 6 of 13 third-trimester pregnancies.138 Therefore, assessment of and PC, PS, and AT deﬁciency) and fetal loss after 10 weeks, and par-anti-factor Xa levels may be important. ticularly isolated losses after 22 weeks. There is also a possible associa-
CHAPTER 40 Coagulation Disorders in Pregnancy 837tion between these thrombophilic states and abruption. However, no informed consent is obtained regarding the unproven efﬁcacyclear association exists between FVL or the other major thrombophil- of this treatment. They should receive postpartum thrombopro-ias and either preeclampsia or IUGR, although studies have been phylaxis if they require a cesarean delivery, because most fatalunderpowered to deﬁnitely exclude a link with severe early-onset pre- acute pulmonary emboli occur during this period.eclampsia and/or severe (<5th percentile) IUGR. 4. It is unclear whether patients with recurrent abruption in the There are few studies examining the effectiveness of anticoagula- absence of other known risk factors (e.g., smoking, renal disease,tion therapy in patients harboring inherited thrombophilias who have hypertension, uterine anomalies) should be offered antepartumexperienced recurrent fetal loss or other adverse pregnancy outcomes. prophylaxis.Kupferminc and associates treated pregnant thrombophilic women 5. At this time, there appears to be no justiﬁcation for offeringwho had a prior history of severe preeclampsia, abruption, IUGR, or antepartum thromboprophylaxis to asymptomatic, otherwisestillbirth with enoxaparin 40 mg/day and LDA, plus folate supplemen- low-risk women with lesser thrombophilias who have recurrenttation for those patients found to be homozygous for the MTHFR preeclampsia or IUGR. However, given the possible associationmutation.141 They reported that, compared to their prior pregnancies, between inherited thrombophilias and later adverse pregnancypatients receiving LMWH plus LDA had an increased mean gestational outcomes, it is reasonable to consider close maternal/fetal sur-age at delivery (32.1 [±5.0] versus 37.6 [±2.3] weeks) and also increased veillance appropriate in this population. Fetal growth may bebirth weight of their infants (1175 [±590] versus 2719 [±526] g) monitored with serial ultrasound examinations (every 4 to 6(P < .0001 for both comparisons). weeks) beginning at 20 weeks’ gestation. Doppler ﬂow studies In a prospective cohort study, Folkeringa and colleagues assessed of the umbilical artery may be used as a fetal assessment tool inthe effects of anticoagulant drugs on fetal loss in women with AT, PC, the setting of IUGR. Nonstress testing and biophysical proﬁlesor PS deﬁciency.142 Of 37 women with a deﬁciency, 26 (70%) received may be appropriate at 36 weeks or earlier, as clinically indicated.thromboprophylaxis during pregnancy, with no fetal losses, compared Early delivery may be indicated for deteriorating maternal orto 45% fetal loss in deﬁcient women not receiving thromboprophylaxis fetal condition. Surveillance can be decreased if there is no evi-(P = .001). The adjusted RR of fetal loss with versus without throm- dence of placental insufﬁciency.boprophylaxis was 0.07 (CI, 0.001 to 0.7). Gris and colleagues conducted a randomized trial of anticoagula-tion in 160 women who had had one unexplained fetal loss after 10 Acquired Platelet Disordersweeks of gestation and who were heterozygous for FVL, PGM, or PSdeﬁciency.119 All patients were given 5 mg folic acid daily before con- Idiopathic Thrombocytopenic Purpuraception; once pregnant, they were randomized to receive either LDA Also known as primary immune or autoimmune thrombocytopenic(100 mg daily) or enoxaparin (40 mg daily) beginning in the 8th week. purpura, idiopathic thrombocytopenic purpura (ITP) is a syndromeUncomplicated live births were noted in 28.8% of the LDA group and of immunologically mediated thrombocytopenia that is characterizedin 86.2% of the enoxaparin group (P < .0001; OR, 15.5; CI, 7 to 34). by increased platelet destruction. Immunoglobulin G (IgG) antibodyEnoxaparin proved superior to LDA among FVL patients. PZ deﬁ- binds to platelets, rendering them more susceptible to sequestrationciency and/or positive anti-PZ antibodies was associated with poorer and premature destruction in the reticuloendothelial system, espe-outcomes. Although these results are impressive, this study has been cially the spleen. The rate of destruction exceeds the compensatorycriticized because of its lack of blinding and the high loss rate in the ability of the bone marrow to produce new platelets, leading toLDA-only group. thrombocytopenia. In summary, observational, prospective cohort, and randomized, In adults, ITP is usually chronic. It may coexist with pregnancy,controlled trials all suggest that LMWH with or without LDA reduces because the disease usually manifests in the second to third decade ofthe recurrence risk of fetal loss in thrombophilic patients. Based on life and has a female preponderance of 2 : 1.143 In fact, ITP is the mostthese ﬁndings, the following recommendations can be made: common autoimmune bleeding disorder encountered during preg- nancy. The overall course of ITP is not consistently inﬂuenced by 1. Women with hyperhomocysteinemia should receive folic acid pregnancy (although, rarely, women experience repeated ﬂares with supplementation regardless of their antecedent VTE or obstetric each pregnancy); however, pregnancy may be adversely affected by ITP, history, given its low toxicity. For those with a history of VTE or and the primary risk is hemorrhage in the peripartum period. Because recurrent fetal loss in whom folate does not correct the meta- the placenta selectively transports maternal IgG antiplatelet anti- bolic disorder, prophylactic unfractionated heparin or LMWH bodies into the fetal circulation, fetal thrombocytopenia also may should be considered. occur. 2. As noted earlier, patients in the highly thrombogenic thrombo- philia group (AT deﬁciency, homozygous or compound hetero- DIAGNOSIS zygous FVL or PGM), regardless of their obstetric history, Most women with ITP have a history of petechiae, ecchymoses, easy should be offered “high prophylactic” doses of LMWH, with the bruising, menorrhagia, or other bleeding manifestations. The diagno- dose titrated to maintain factor Xa levels at 0.4 to 0.6 U/mL (if sis is primarily one of exclusion and is based on the history, physical there is no personal or strong family history of VTE) or to examination, complete blood count (CBC), and examination of the maintain therapeutic doses of LMWH (if there is such a peripheral blood smear.144 The CBC is normal except for thrombocy- history). topenia (platelet count <100,000/μL), and the smear may show an 3. Pregnant women with less thrombogenic thrombophilias (e.g., increased proportion of slightly enlarged platelets. The history and heterozygous FVL or PGM, PC or PD deﬁciency, hyperhomo- physical examination usually exclude other causes of thrombocytope- cysteinemia unresponsive to folate therapy) who have no per- nia. Rarely, a bone marrow biopsy is required to clarify the diagnosis. sonal or strong family history of VTE but unexplained fetal loss Typical bone marrow ﬁndings include increased numbers of immature after 9 weeks can be offered antepartum prophylaxis after full megakaryocytes. Although the issue is controversial, many authorities
838 CHAPTER 40 Coagulation Disorders in Pregnancydo not routinely perform this procedure in typical cases of ITP, espe- Improvement usually occurs within 3 to 7 days and reaches a maximumcially in women younger than 40 years of age.143 within 2 to 3 weeks. Some increase in the platelet count occurs in 50% It can be difﬁcult to distinguish ITP from other causes of maternal to more than 70% of patients, depending on the duration and intensitythrombocytopenia. The condition most commonly confused with ITP of therapy.144 Complete remission has been reported in 5% to 30% ofis incidental thrombocytopenia of pregnancy, also known as “essential” cases.144 If platelet counts become normal, the steroid dose can beor “gestational” thrombocytopenia. Incidental thrombocytopenia of tapered by 10% to 20% per week until the lowest dosage required topregnancy is mild (platelets >70,000 cells/μL), asymptomatic, and maintain the platelet count higher than 50,000/μL is reached.often ﬁrst noted by the clinician after a CBC obtained as part of a It is uncertain how steroids improve platelet counts and decreaseroutine automated prenatal screening test.145,146 In contrast to ITP, bleeding in patients with ITP. Proposed mechanisms of action153incidental thrombocytopenia of pregnancy is common. It occurs in up include increased platelet production, decreased production of anti-to 5% of pregnant women and accounts for more than 70% of mater- platelet antibodies and platelet-associated IgG, decreased clearance ofnal thrombocytopenia.146,147 Individuals with incidental thrombocyto- antibody-coated platelets by the reticuloendothelial system, andpenia have no prior history of thrombocytopenia and are not at risk decreased capillary fragility. Adverse effects of steroid use in pregnancyfor bleeding complications or fetal thrombocytopenia. No special care are well known and include glucose intolerance, osteoporosis, hyper-is required for these women. Other causes of maternal thrombocyto- tension, psychosis, and moon facies. Accordingly, the dose and dura-penia that should be considered are preeclampsia, pseudothrombocy- tion of therapy should be minimized.topenia due to laboratory artifact, SLE, APS, human immunodeﬁciency Intravenous Immune Globulin. IVIG is used in cases of ITPvirus (HIV) or hepatitis C virus infection, drug-induced thrombocy- refractory to corticosteroids as well as in urgent circumstances, such astopenia, thrombotic thrombocytopenia, immunodeﬁciency states, preoperatively, in the peripartum period, or when the platelet count ishereditary thrombocytopenias, and DIC. less than 10,000/μL (or <30,000/μL in a bleeding patient). IVIG is a Numerous direct and indirect assays of antiplatelet antibodies have pooled concentrate of immunoglobulins collected from many donors.been developed to conﬁrm the diagnosis of ITP. Most patients with High doses of IVIG (1000 mg/kg/day for 2 to 5 days) usually induce aITP have platelet-associated immunoglobulin, and many also have peak platelet count within 7 to 9 days. More than 80% of patientscirculating unbound antiplatelet antibodies. Levels of direct (platelet- treated with this regimen will have a peak platelet count greater thanassociated) IgG have a strong inverse correlation with the maternal 50,000/μL, and in 30% of patients the duration of the response lastsplatelet count and intravascular platelet life span.148 Nonetheless, a for more than 30 days.154,155 Although the mechanism of action isnegative result does not exclude a diagnosis of ITP.149 Concentrations unclear, it seems to involve depression of antiplatelet antibody produc-of indirect (circulating) antiplatelet antibodies less reliably predict tion, interference with antibody attachment to platelets, inhibition ofmaternal platelet counts. Although assays for direct and indirect anti- macrophage receptor-mediated immune complex clearance, andplatelet antibodies are widely available, they are not recommended for blockage of Fc receptors in the reticuloendothelial system.155-157 Inthe routine evaluation of maternal thrombocytopenia or ITP.144 Assays responders, only 2 or 3 days of IVIG therapy may be needed, andfor antiplatelet antibodies are hampered by a variety of problems, higher doses of 800 or 1000 mg/kg may sufﬁce as a single or doubleincluding the use of several different assays, a large degree of interlabo- infusion.158ratory variation, and a high background rate of platelet-associated IgG. Although IVIG had previously been associated with occasionalFurthermore, women with ITP cannot be distinguished from those hepatitis C transmission, the current puriﬁcation process eliminateswith incidental thrombocytopenia of pregnancy on the basis of anti- the risk of blood-borne infections. HIV transmission has never beenplatelet antibody testing.150 associated with IVIG use. Untoward effects of IVIG include headache, chills, nausea, liver dysfunction, alopecia, transient neutropenia, ﬂush- MATERNAL CONSIDERATIONS ing, autoimmune hemolytic anemia, and anaphylactic reactions in The goal of maternal therapy during pregnancy is to minimize the patients with IgA deﬁciencies.159 There are no known adverse fetalrisk of hemorrhage and to restore a normal platelet count. Asympto- effects. IVIG is extremely expensive, and for that reason its use is bestmatic pregnant women with ITP and platelet counts greater than reserved for urgent cases and for ITP refractory to corticosteroids.50,000/μL do not require treatment. In nonpregnant patients, most Examples include a platelet count less than 5000/μL despite treatmentauthorities recommend treatment if the platelet count is lower than with steroids for several days, active bleeding, and extensive and pro-10,000/μL or in the presence of bleeding, but it is controversial whether gressive purpura.143a particular platelet count (e.g., <50,000/μL or <30,000/μL) is sufﬁ- Platelet Transfusions. Platelet transfusions should be consideredcient indication for therapy during pregnancy in asymptomatic women. only as a temporary measure to control life-threatening hemorrhageA reasonable approach is to aim for a platelet count greater than or to prepare a patient for cesarean delivery or other surgery. Survival30,000/μL throughout pregnancy and greater than 50,000/μL near of transfused platelets is decreased in patients with ITP, because anti-term. platelet antibodies also bind to platelets. Therefore, the usual elevation The American Society of Hematology ITP Practice Guideline in platelets of approximately 10,000/μL per unit of platelet concentratePanel151 recommends treating pregnant women with platelet counts is not achieved in patients with ITP. A transfusion of 8 to 10 packs isbetween 10,000 and 30,000/μL during the second or third trimester. sufﬁcient in most cases.More aggressive treatment is often pursued close to the estimated due Splenectomy. Complete remission is obtained in 80% of patientsdate, in anticipation of potential bleeding, surgery, or need for regional with ITP who undergo splenectomy. This operation, which removesanesthesia. Some anesthesiologists may require a platelet count greater the major sites of platelet destruction and antiplatelet antibody pro-than 80,000/μL before deeming the woman’s condition safe for place- duction, is usually avoided during pregnancy because of risks to thement of an epidural catheter.152 fetus and technical difﬁculties with the procedure. Nonetheless, sple- Glucocorticoid Drugs. Glucocorticoid drugs have been the cor- nectomy can be safely accomplished during pregnancy if necessary,nerstone of ITP therapy in pregnancy. Prednisone, 1 to 1.5 mg/kg/day, ideally in the second trimester. It also has been combined with cesareanor the therapeutic equivalent, is the initial treatment of choice. delivery at term without reported morbidity. Splenectomy (during
CHAPTER 40 Coagulation Disorders in Pregnancy 839pregnancy) is appropriate for women with platelet counts lower than because it involves negligible risk to mother and fetus and uses an assay10,000/μL who are bleeding and have not responded to IVIG and (platelet count) that is widely available and inexpensive. Indeed, fetalsteroids.144 scalp sampling has allowed 80% of fetuses with platelet counts greater Rhesus Immune Globulin. Anti-Rh(D) immune globulin has than 50,000/μL to safely deliver vaginally.169 The major drawback is thebeen successfully used to treat ITP in RhD-positive individuals. Indeed, occasional occurrence of falsely low platelet counts, resulting in unnec-immune globulin against Rh(D) (75 μg per kilogram of maternal essary cesarean deliveries.174-176 Further, fetal scalp sampling cannotweight) works as well as corticosteroids at initial presentation.160 It is always easily be accomplished if there is limited cervical dilation or amore costly than steroids but has fewer side effects. Anti-Rh(D) is not high presenting part.typically used during pregnancy because of a theoretic risk of fetal These problems can be circumvented with the use of cordocentesiserythrocyte destruction, although it would most likely bind maternal to determine the fetal platelet count. This method results in accuratered blood cells before reaching the fetal circulation. Cases of successful platelet counts and can be performed before labor.162,177.178 The proce-and safe use of anti-Rh(D) during pregnancy (in RhD-positive women) dure is usually deferred until fetal maturity is present. As with scalphave been reported.161 sampling, the delivery route is based on the fetal platelet count. Other drugs used to treat ITP, such as vinca alkaloids, colchicine, However, cordocentesis cannot always be accomplished in the late thirdcyclophosphamide, and danazol, are best avoided in pregnancy because trimester,177,178 the skills required are not available in all centers, andof the potential for adverse effects on the fetus. Azathioprine may be the procedure is expensive. Cordocentesis also may result in seriousconsidered in refractory cases. complications.176 Hemorrhage at the puncture site, cord hematoma, and cord spasm with fetal bradycardia contribute to an overall associ- FETAL CONSIDERATIONS ated mortality rate of 2.7%.179 Procedure-related complications have Because the placenta is permeable to circulating maternal antiplate- been reported in about 4% to 5% of cordocenteses in patients withlet IgG, fetal thrombocytopenia may occur with maternal ITP. Occa- presumed ITP.180 In several instances, fetuses with normal plateletsionally, this results in minor clinical bleeding, such as purpura, counts were delivered by cesarean section or incurred serious morbid-ecchymoses, hematuria, or melena. In rare cases, fetal thrombocytope- ity. Bleeding is more likely in the presence of severe thrombocytope-nia can lead to intracranial hemorrhage (ICH), resulting in severe nia.181,182 The true incidence of complications may be even higher:neurologic impairment or death. Indeed, concern for ICH and its procedure-related complications often go unreported, and reportingavoidance has become the central issue in the obstetric management centers tend to have the most expertise with the procedure and areof ITP. likely to have lower complication rates than other facilities.179 Clinicians have tried a variety of strategies intended to minimize Problems with fetal scalp sampling and cordocentesis havefetal bleeding problems in women with ITP. It is now clear that mater- prompted reevaluation of the efﬁcacy of these procedures in the man-nal medical therapies such as IVIG162 and steroids162-164 do not reliably agement of pregnancies complicated by ITP.163,183,184 In addition, severalprevent fetal thrombocytopenia. On the basis of reports of ICH associ- reports have suggested that hemorrhagic complications in thrombo-ated with vaginal birth,165 some clinicians recommended cesarean cytopenic neonates are unrelated to the route of delivery.163,168,176,185 Indelivery for women with ITP.166 Others have proposed that cesarean a review of 474 neonates born to mothers with ITP, 29% of thrombo-delivery be reserved for fetuses with platelet counts lower than 50,000/ cytopenic infants delivered vaginally suffered clinically apparent bleed-μL.167 This tactic was prompted by observations that hemorrhagic ing, compared with 30% of those delivered by cesarean section.163 Acomplications are extremely rare in infants with platelet counts greater careful analysis of the literature also suggests that no case of ICH hasthan 50,000/μL, and the risk of fetal bleeding is inversely proportional been directly attributable to intrapartum events.176,184to the platelet count.163.168 With this plan, however, a method is needed Another important consideration is the relative infrequency of ICHto determine which fetuses are thrombocytopenic—ideally, one that is in infants born to mothers with ITP. For example, in a comprehensivenoninvasive, reproducible, and sensitive in identifying at-risk fetuses. population-based study of almost 16,000 pregnancies complicated byNo such test is available. ITP, there were no cases of ICH.147 The only three infants with ICH Maternal characteristics and serologic ﬁndings, including throm- had alloimmune, not autoimmune, thrombocytopenia. These observa-bocytopenia, previous splenectomy, and platelet-associated antibodies, tions were conﬁrmed in retrospective analyses of ITP in pregnancy.do not correlate strongly with neonatal thrombocytopenia.146,169 Fetal The proportion of infants with platelet counts lower than 50,000/μLthrombocytopenia is uncommon in the absence of circulating is about 15%, and this may be an overestimate of the risk because ofantiplatelet antibodies,170 but exceptional cases have been reported.171 publication bias. Serious bleeding complications occurred in 22 of 688In addition, positive results have a low positive predictive value,170 neonates,180 and only 6 (0.87%) had ICH. None of the cases of ICHand assays for indirect antiplatelet antibodies can be difﬁcult to were clearly demonstrated to be caused by intrapartum events. In oneperform. review of 288 ITP pregnancies wherein fetal platelet counts were deter- Good correlation has been reported between neonatal platelet mined at the time of delivery, there were no cases of ICH or perinatalcounts and the platelet count of infants born previously to a woman death.168with ITP.164 However, older siblings are not always available for com- In summary, obstetric management of ITP remains controversial,parison, and concordance among sibling platelet counts is imperfect.164 but most investigators now believe that fetal scalp sampling, cordocen-Furthermore, discordant platelet counts have been detected in twin tesis, and cesarean delivery contribute to cost and morbidity withoutgestations complicated by ITP.169,172 Therefore, no historical factor or preventing neonatal bleeding complications. Therefore, it is recom-maternal blood test can accurately predict the fetal platelet count in all mended that ITP be managed without determination of the fetal plate-cases. let count and that cesarean delivery be reserved for the usual obstetric Some investigators have advocated the use of fetal scalp sampling indications.163,168,176,184 In contrast, others have found that the potentialduring labor to directly measure the fetal platelet count.167,173 Vaginal 1% risk of ICH warrants cesarean delivery in selected cases.144,186 Thosedelivery is permitted if the platelet count is greater than 50,000/μL; clinicians who favor interventional management use fetal scalp sam-otherwise, the birth is by cesarean delivery. This method is attractive pling to determine the fetal platelet count in pregnancies most at risk
840 CHAPTER 40 Coagulation Disorders in Pregnancyfor thrombocytopenia (e.g., when there is a sibling with severe throm- TABLE 40-3 PLATELET-SPECIFICbocytopenia). The use of cordocentesis in the obstetric management ALLOANTIGENS THAT AREof ITP is difﬁcult to justify. ASSOCIATED WITH ALLOIMMUNE Delivery should be accomplished in a setting in which platelets, THROMBOCYTOPENIAfresh-frozen plasma, and IVIG are available. A neonatologist or pedia-trician familiar with the disorder should be present to promptly treat HPA System Name Antigen Familiar Nameany hemorrhagic complications in the neonate. The platelet count ofthe affected newborn usually falls after delivery, and the lowest platelet Polymorphisms of GpIIIa HPA-1 HPA-1a P1A1, Zwªcount is not reached for several days.187 Most infants are asymptomatic, HPA-1b P1A1, Zwband the thrombocytopenia is self-limited. Nonetheless, daily platelet HPA-4 HPA-4a Pena, Yukbcounts should be obtained for several days. Although breastfeeding HPA-4b Penb, Yukaearly in the puerperium may theoretically cause neonatal thrombocy- HPA-6 HPA-6bw Ca, Tutopenia, many women with ITP have done so without clinical HPA-7 HPA-7bw Mosequelae. HPA-8 HPA-8w Sr-a HPA-10 HPA-10bw La(a)Neonatal Alloimmune Thrombocytopenia HPA-11 HPA-11bw Gro(a)In contrast to the minimal fetal risks in maternal ITP, fetal/neonatal HPA-14 HPA-14bw Oe(a)alloimmune thrombocytopenia (NAIT) is a serious and potentially HPA-16 HPA-16bw Duv(a)life-threatening condition that affects 0.2 to 1.0 of every 1000 live Polymorphisms of GpIIbbirths in white people.188-190 Rates vary by ethnicity, and African HPA-3 HPA-3a Baka, LekAmericans appear to be affected less frequently.191 The disorder occurs HPA-3b Bakbas the result of maternal alloimmunization against fetal platelet HPA-9 HPA-9bw Maxaantigens that are lacking on the mother’s own platelets; it is analogousto the hemolytic anemia caused by maternal alloimmunization against Polymorphisms of GpIafetal erythrocyte antigens. HPA-5 HPA-5a Brb, Zavb Several polymorphic, diallelic platelet antigen systems are respon- HPA-5b Bra, Zavasible for NAIT. Many of these antigen systems were simultaneously HPA-13 HPA-13bw Sit(a)identiﬁed in different parts of the world and given several names. Tominimize confusion, uniform nomenclature has been adopted to Polymorphisms of GpIb HPA-2 HPA-2b Koa, Sib-adescribe these antigen systems as human platelet antigens (e.g., HPA- HPA-12 HPA-12bw Ly(a)1), with alleles designated as “a” or “b.”192 The most frequent cause ofNAIT in whites is sensitization against HPA-1a, also known as PLAT Other probable platelet alloantigen speciﬁcitiesor Zwa. The antigens HPA-1a (PLAl) and HPA-lb (PLA2) are the HPA-15 HPA-15a Gov aproduct of polymorphic alleles that differ by a single base-pair change HPA-15b Gov bin the gene encoding the platelet glycoprotein GpIIIa (integrin β3).193In turn, this causes a substitution of proline for leucine in the protein, Gp, glycoprotein; HPA, human platelet antigen. Modiﬁed from Mark E. Brecher (ed): Platelet and granulocyte antigensresulting in antigenically distinct conformations. Of all white people, and antibodies. In Technical Manual, 15th ed. Bethesda, MD: American97% are HPA-1a positive; 69% are homozygous HPA-1a, and 28% are Association of Blood Banks. Reprinted with permission fromheterozygous.194 Several other antigens, including HPA-lb, HPA-5b Berkowitz RL, Bussel JB, McFarland JG: Alloimmune(Br), HPA-3b (Bak), and HPA-4b (Yuk), also may cause NAIT (Table thrombocytopenia: State of the art 2006. Am J Obstet Gynecol40-3). In Asians, sensitization against HPA-4 is the most common 195:907-13.a, 2006.cause of NAIT. Although approximately 1 in 42 pregnancies is incompatible forHPA-1a, NAIT develops in only 1 of every 20 to 40 of these cases. In hemorrhage and porencephalic cysts. Obstructive hydrocephalus alsosome instances,195 the disorder remains subclinical because the anti- may be present. As with red cell alloimmunization, the condition tendsplatelet antibodies are not potent enough to induce thrombocytopenia to worsen throughout pregnancy, as well as in subsequent pregnan-in the infant.196 In addition to antigen exposure, there appears to be a cies.200,202,203 NAIT should be suspected in cases of otherwise unex-need for an immunologic susceptibility to HPA-la sensitization. The plained fetal or neonatal thrombocytopenia, in utero or ex utero ICH,human leukocyte antigen (HLA) class II determinant, Dw52a, appears or porencephaly. Serologic evaluation should be performed in an expe-to be a requirement for the development of antibodies against HPA- rienced laboratory with special interest and expertise in NAIT.1a.197 Associations between sensitization to other platelet antigens and In most cases, the diagnosis of NAIT can be determined by testingHLA phenotypes are less well characterized, although DR6 has been the parents; testing of fetal or neonatal blood is conﬁrmatory andlinked to anti-HPA-5.198 In contrast to rhesus isoimmunization, NAIT occasionally helpful. Appropriate assays include serologic conﬁrmationcan occur during a ﬁrst pregnancy without prior exposure to the of maternal antiplatelet antibodies that are speciﬁc for paternal oroffending antigen. The diagnosis is usually made after birth in an fetal/neonatal platelets. In addition, individuals should undergo plate-infant with unexplained severe thrombocytopenia, often associated let typing with zygosity testing. This can be determined serologicallywith ecchymoses or petechiae.188,199 The most serious bleeding compli- or with DNA-based tests, because the genes and polymorphisms forcation is ICH, which occurs in 10% to 20% of infants with NAIT.199,200 HPAs recognized to cause NAIT are well characterized. This is particu-Fetal ICH due to NAIT can occur in utero,201 and 25% to 50% of cases larly useful for obstetric management, because fetal HPA typing canof ICH are detected by sonography before delivery.201 Characteristic be accomplished with amniocytes.204 Chorionic villus sampling shouldsonographic ﬁndings include evidence of intracranial hematoma or be avoided, because it may exacerbate the alloimmune reaction.
CHAPTER 40 Coagulation Disorders in Pregnancy 841 Occasionally, results are ambiguous, and in some cases, an antigen centesis.182 Although the efﬁcacy of this approach is unproved, it mayincompatibility cannot be identiﬁed. The management of such difﬁcult decrease the risk of bleeding complications at the time of the proce-cases is best individualized and underscores the need for consultation dure. It is important to distinguish this use of platelets from plateletwith physicians and laboratories familiar with the disorder. transfusions intended as primary therapy (see later discussion). The natural history of NAIT is difﬁcult to ascertain, because it is The optimal timing of the initial cordocentesis is controversial. ICHusually unrecognized during ﬁrst affected pregnancies, and subsequent can occur early in gestation,206 prompting some authorities to recom-pregnancies are inﬂuenced by therapeutic interventions. Nonetheless, mend fetal blood sampling as soon as the procedure is technically fea-several observations can be made from a large cohort of 107 fetuses sible (18 to 20 weeks). Such cases are rare, however, and the consequenceswith NAIT (97 with HPA-la incompatibility) who were followed with of bleeding complications from cordocentesis are potentially moreserial cordocenteses to determine the fetal platelet count:205 grave at previable gestational ages. Fetal blood sampling can probably be safely delayed until 24 to 26 weeks in most cases. Further studies 1. The recurrence risk of NAIT is extremely high and is 100% if should resolve some of these issues. Meanwhile, it seems prudent to the fetus has the HPA-la antigen in sensitized HPA-la-negative individualize the management of each case, depending on the perti- mothers. nent antigen and the severity of NAIT during previously affected 2. Fetal thrombocytopenia caused by HPA-la sensitization is often pregnancies. severe and can occur early in gestation. Of the patients studied, Proposed therapies to increase the fetal platelet count and prevent 50% had initial platelet counts of less than 20,000/μL. This ICH include maternal treatment with steroids and IVIG,189,207-210 fetal included 21 (46%) of 46 fetuses tested before 24 weeks’ treatment with IVIG,211-213 and fetal platelet transfusions.203 However, gestation. no therapy is effective in all cases. 3. A history of a sibling with antepartum ICH is a risk factor for The administration of IVIG directly to the fetus has not consistently the development of severe thrombocytopenia. However, neither raised fetal platelet counts216; however, because only a small number of a sibling platelet count nor a sibling with ICH recognized after patients have been treated, lack of efﬁcacy has not been proved. Platelet delivery reliably predicts the initial fetal platelet count. transfusions are effective,217 but the short half-life of transfused plate- 4. Thrombocytopenia uniformly worsens in untreated fetuses. lets necessitates weekly procedures. The potential risks involved with Seven fetuses in this cohort had initial platelet counts higher multiple transfusions and the potential for increased sensitiza- than 80,000/μL and were not treated. All demonstrated rapid tion191,217,218 limit the attractiveness of this treatment. Platelet transfu- and substantial decreases in their platelet counts. sions are perhaps best reserved for severe cases refractory to other therapies.NAIT associated with antigens other than HPA-la is less well Administration of IVIG to the mother appears to be the moststudied. In the large series reported by Bussel and colleagues, throm- consistently effective antenatal therapy for NAIT. Bussel and colleaguesbocytopenia associated with anti-HPA-la was more severe than NAIT demonstrated that weekly infusions of 1 g/kg maternal weight of IVIGcaused by other antigen incompatibilities.205 Therefore, data regarding often stabilize or increase the fetal platelet count.189,207,209 In a study ofHPA-la incompatibility cannot be generalized to other causes of 55 women with NAIT and thrombocytopenic fetuses, between 62%NAIT. and 85% of fetuses responded to IVIG therapy, depending on how The explicit goal of the obstetric management of pregnancies at risk “response” was deﬁned.207 No fetus suffered ICH. In fact, ICH isfor NAIT is to prevent ICH and its associated complications. As with extremely rare in pregnancies treated with IVIG, occurring in only 1ITP, antepartum management is controversial and few randomized of more than 100 cases managed by Bussel and his collaborators.202 Thedata are available to guide therapy. In contrast to ITP, however, the mechanism of action is uncertain but may be related to placental Fcdramatically higher frequency of ICH associated with NAIT justiﬁes receptor blockade preventing active transport of antiplatelet antibod-more aggressive interventions. Also, therapy must be initiated antena- ies across the placenta.219tally because of the risk of in utero ICH. If the diagnosis is uncertain, Bussel and coworkers207 also showed that low-dose dexamethasonethe risk of NAIT should be conﬁrmed by documentation of platelet therapy does not improve fetal platelet counts beyond the effectincompatibility or maternal antiplatelet antibodies speciﬁc for paternal achieved with IVIG. Fetal platelet counts increased to a similar degreeor fetal platelets. It is unnecessary to repeat testing in a family with a in NAIT patients randomized to treatment with either IVIG alone orcase of previously conﬁrmed NAIT. Antibody titers are poorly predic- IVIG plus 1.5 mg/day of dexamethasone.207 In contrast, 5 of 10 patientstive of risk to the current pregnancy and need not be obtained once with no response to IVIG had increased fetal platelet counts after thethe diagnosis is secure. If the father is heterozygous for the offending addition of 60 mg/day of prednisone.207 They also noted that fewerantigen, fetal genotyping should be accomplished with amniocytes. than half of fetuses with platelet counts lower than 20,000/μL respondedThis strategy can prevent additional expensive and risky interventions to the initial dose of IVIG.in approximately 50% of cases. This led to a subsequent parallel set of randomized trials, in which If the fetus is considered to be at risk, most investigators recom- patients were stratiﬁed by level of risk for severe thrombocytopeniamend cordocentesis to determine the fetal platelet count. This strategy and ICH. The ﬁrst trial, conducted in 40 women with either a prioravoids treatment of fetuses with normal platelet counts and provides infant with ex utero ICH or a current fetus with a platelet count of lessfeedback about treatment response in cases of thrombocytopenia. The than 20,000/μL, randomized treatment IVIG 1 g/kg/wk plus predni-drawback is the modest but clinically important risk of fetal hemor- sone 1 mg/kg/day versus IVIG 1 mg/kg/wk alone, after a cordocentesisrhage after cordocentesis in the setting of severe NAIT.182,191 Because of at 20 weeks.220 IVIG and steroids increased the mean platelet countthis risk, a case could be made to initiate therapy without knowledge over 3 to 8 weeks by 67,100/μL, compared with 17,300/μL for IVIGof the fetal platelet count. It is controversial whether the beneﬁts of alone (P < .001). Moreover, the difference in treatment was more pro-fetal blood sampling outweigh the risks in most cases. Many clinicians found in the subgroup of cases with initial fetal platelet counts lowernow transfuse between 5 and 15 mL of packed, washed, and irradiated than 10,000/μL. In these cases, IVIG and prednisone increased thematernal platelets (obtained by plateletpheresis) at the time of cordo- platelet count in 82% of cases, compared with 18% for IVIG alone.200
842 CHAPTER 40 Coagulation Disorders in Pregnancy Thirty-nine women at lower risk for fetal ICH (i.e., no prior infantwith ICH and current fetal platelet count >20,000/μL) were random- Thrombotic Thrombocytopenic Purpura andized to treatment with IVIG (1 g/kg/wk) or lower-dose prednisone Hemolytic Uremic Syndrome(0.5 mg/kg/day). There was no signiﬁcant difference in fetal response Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremicto these two regimens.200 The same group also treated 15 women who syndrome (HUS) are thrombotic microangiopathies that are charac-had prior infants with in utero ICH with IVIG, 1 or 2 g/kg/wk, begin- terized by thrombocytopenia, hemolytic anemia, and multisystemning at 12 weeks’ gestation. Therapy was intensiﬁed (increased IVIG organ failure. They are rare entities, but they may occur during preg-and/or adding steroids) if there was severe thrombocytopenia at 20 nancy, are life-threatening, and can be difﬁcult to distinguish from theweeks. All fetuses responded adequately to intensiﬁed therapy, except HELLP syndrome (hemolysis, elevated liver enzymes, and low plate-one that had in utero ICH at 19 weeks’ gestation.189 lets). The incidence is estimated to be 1 : 25,000 births.222 Early diag- Berkowitz, Bussel, and colleagues reported further results of a nosis and treatment are critical, because mortality may be reduced byrecent randomized clinical trial comparing outcome in “standard risk 90%.223(no prior infant with ICH)” pregnancies for NAIT treated with IVIG TTP is characterized by central nervous system (CNS) abnormali-2 g/kg/wk versus IVIG 1 g/kg/wk plus 0.5 mg/kg/day of prednisone.200 ties, severe thrombocytopenia, and intravascular hemolytic anemia.Outcomes were similar and excellent in both groups, with no cases of The most common CNS abnormalities are headache, altered con-ICH. Empiric therapy was started at 20 weeks’ gestation, and cordo- sciousness, seizures, and sensory-motor deﬁcits. Renal dysfunction andcentesis was done once at 32 weeks. Salvage therapy (either adding fever also may occur. Individuals with HUS have renal involvement assteroids or increasing the dose of IVIG) was done if the platelet count the major ﬁnding, as well as thrombocytopenia and hemolytic anemia.was lower than 50,000/μL.200 The conditions are difﬁcult to distinguish from each other, because up Most authorities recommend cesarean delivery for fetuses with to 50% of patients with HUS have CNS abnormalities, and renal dys-platelet counts of less than 50,000/μL.191 As discussed in the section on function may occur in up to 80% of those with TTP. For this reason,ITP, vaginal delivery has never been shown to cause ICH, and cesarean the two disorders are often considered as a single entity.224,225delivery has never prevented it. Furthermore, the use of 50,000/μL as The pathophysiology of both conditions is abnormal and profounda cutoff is entirely arbitrary. Nonetheless, the substantial rate of ICH intravascular platelet aggregation leading to multiorgan ischemia. Inprobably justiﬁes cesarean delivery in pregnancies with severe NAIT. HUS, this occurs predominantly in the kidney. The inciting event in In summary, according to the available current data, it seems appro- TTP is uncertain. One possibility is an abnormal immune response,priate to stratify treatment based on the level of risk for NAIT. In because the condition is associated with several autoimmune disorders.families with prior in utero ICH, empiric treatment early in pregnancy It is more common in women, consistent with many other autoim-is advised. In women who previously delivered infants with ex utero mune conditions. Other possibilities are medications such as chemo-ICH, or who currently have a fetus with a platelet count lower than therapy agents, viral infection, and perhaps pregnancy itself, although20,000/μL, appropriate treatment is IVIG and glucocorticoids. many individuals have no risk factors. Larger than average vWF mul-However, lower doses of IVIG (or glucocorticoids) may be used in timers appear to contribute to the pathophysiology, promoting abnor-lower-risk cases. It is controversial whether the information obtained mal platelet aggregation.226 A plasma enzyme termed ADAMTS13from assessment of fetal platelet count by cordocentesis justiﬁes the cleaves these vWF multimers, thereby preventing the formation ofrisk of that procedure.191,220,221 There appears to be value in adjusting platelet clumps. ADAMTS13 activity may be absent in patients withthe initial treatment based on fetal platelet count—increasing the dose TTP, making it a risk factor for the condition.227 Deﬁciency inof IVIG or adding glucocorticoids, or both—in cases of treatment ADAMTS13 may be congenital,228 or it may be acquired through thefailure.191,207,220 Therefore, we consider assessment of the fetal platelet development of autoantibodies.229 HUS is most often seen in childrencount between 24 and 32 weeks’ gestation in fetuses at risk based on after a diarrheal illness caused by Escherichia coli. Hemolysin fromgenotyping or paternal testing. The procedure can usually be safely Shiga toxin–negative E. coli O26 attaches to receptors in renal epithe-delayed until the fetus reaches viability. Cordocentesis may be espe- lium, leading to endothelial injury, platelet activation/aggregation, andcially helpful in cases that are not caused by HPA-1a, because the ischemia.230 In adults, HUS is often precipitated by pregnancy, chemo-recurrence risk is less and the clinical course less predictable. The fetal therapy, or bone marrow transplantation. The recurrence risk is higherplatelet count may be again determined at term to guide the route of in adults and in patients who do not have infectious diarrhea as andelivery, as outlined, if vaginal birth is desired. Alternatively, a platelet inciting event.count of greater than 100,000/μL at 32 weeks can be used as a threshold The diagnosis of these conditions is clinical, because there is noto allow vaginal delivery at term.200 This strategy usually limits the laboratory “gold standard.” CBC and peripheral blood smear conﬁrmsnumber of cordocenteses to no more than two or three per pregnancy. thrombocytopenia and microangiopathic hemolytic anemia (schisto-Empiric treatment without cordocentesis also is a reasonable option, cytes, helmet cells, and burr cells). Lactate dehydrogenase and bilirubinand care should be individualized after appropriate counseling regard- are elevated, indicating hemolysis. Serum creatinine and blood ureaing pros and cons of cordocentesis. nitrogen may be elevated, especially in HUS. Clotting studies are typi- There are no data to support population-wide screening for poten- cally normal early in the disease process. However, secondary DIC maytial HPA incompatibility.191 Studies are ongoing to address the efﬁcacy occur after tissue necrosis. Large multimers of vWF may be present inand cost-effectiveness of such programs. Another clinical dilemma is cases of TTP, and renal biopsy may show microvascular occlusions andthe patient whose sister has had a pregnancy with NAIT. It may be intraglomerular platelet aggregates in HUS. ADAMTS13 activity mayworthwhile to assess platelet antigen incompatibility, HLA phenotype, be decreased in both TTP and HUS.227 However, in many centers,and (in cases at risk based on these tests) fetal platelet count in such results may not be available in a timely fashion.231 Both disorders arepatients. However, we have not found such testing to be useful. Instead, hard to distinguish from preeclampsia.231,232 Potential clinical signs andwe reassure such women that their prospective risk of NAIT is low and laboratory tests to differentiate these conditions are shown in Tablethat we are unsure about the clinical relevance of such testing. 40-4.233 The distinction between preeclampsia and TTP or HUS is
CHAPTER 40 Coagulation Disorders in Pregnancy 843 TABLE 40-4 CLINICAL CHARACTERISTICS or postpartum period. If TTP or HUS manifests during pregnancy, AND LABORATORY FINDINGS there is a risk of up to 33% for fetal mortality.238,239 Fetal death is caused by previable delivery, severe maternal illness, and placental insufﬁ- IN TTP, HUS, AND SEVERE ciency. If TTP or HUS occurs early in gestation, aggressive treatment PREECLAMPSIA/HELLP with plasma infusions, plasmapheresis, and steroids should be initi- SYNDROME ated. Delivery of the fetus should be considered in refractory cases, TTP HUS Preeclampsia/HELLP because improvement has been reported in sporadic cases.233 At later gestational ages, delivery becomes a more attractive option. It is impor- Neurologic symptoms +++ +/− +/− tant to consider TTP and HUS in cases of apparent preeclampsia or Fever ++ +/− − HELLP syndrome that do not improve without 48 to 72 hours after Hypertension +/− +/− +/− delivery. Renal dysfunction +/− +++ +/− It also is important to counsel women about the recurrence risk for Skin lesions (purpura) + − − Platelets ↓↓↓ ↓↓ ↓ these conditions. In a small series of women with TTP or HUS in PT/PTT ↔ ↔ ↓ or ↔ pregnancy, half had a least one recurrence.222 Long-term morbidity and Fibrinogen ↔ ↔ ↓ or ↔ mortality were substantial. However, good outcomes have been BUN/Cr ↑ ↑↑↑ ↑ reported in subsequent pregnancies in women with prior TTP or HUS AST/ALT ↔ ↔ ↑ associated with pregnancy.240,241 Serial and prophylactic plasma LDH ↑↑↑ ↑↑↑ ↑ exchange may be useful in women with prior TTP or HUS and persis- Multimeric forms of vWF + + − tent severely reduced ADAMTS13 activity.241 ADAMTS13 activity ↓↓↓ ↓↓↓ ??? − Drug-Induced Thrombocytopenia and + = mild symptoms present; + + = moderate symptoms present; + + + = severe symptoms present; +/− = mild or no symptoms present; Functional Platelet Defects - = no symptoms present; Ø = mildly decreased; ØØ = moderately Some drugs, such as heparin and quinidine, can cause thrombocyto- decreased; ØØØ = severely decreased; ≠ = mild elevation; ≠≠≠ = severe penia. Functional platelet defects occur when there are normal numbers elevation; ´ = no change. of platelets that do not function properly. Drugs are a common cause ADAMTS13, von Willebrand factor–cleaving protease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea of this condition. Examples include aspirin, NSAIDs, antimicrobial nitrogen; Cr, creatinine; HELLP, hemolysis, elevated liver enzymes, and agents such as carbenicillin, and glyceryl guaiacolate, which is present low platelets; HUS, hemolytic uremic syndrome; LDH, lactate in some cold remedies. dehydrogenase; PT, prothrombin time; PTT, partial thromboplastin time; TTP, thrombotic thrombocytopenic purpura; vWF, von Willebrand factor. Modiﬁed from Esplin MS, Branch DW: Diagnosis and management of Congential Platelet Disorders thrombotic microangiopathies during pregnancy. Clin Obstet Gynecol 42:360, 1999. Von Willebrand Disease vWD occurs in 1.3% of individuals, making it the most common inherited bleeding disorder.242,243 The condition is caused by abnormalcritical, because the former will improve with delivery, but TTP and platelet adhesion resulting from deﬁciencies or abnormalities in vWF.HUS require additional therapy. There are three types. Type I, the most common variety, accounts for Plasmapheresis has been reported to substantially increase the sur- 80% of cases; it is usually inherited in an autosomal dominant fashionvival rate with TTP to about 80%.234,235 Efﬁcacy is less certain for HUS, and is characterized by deﬁciencies in structurally normal factor VIIIbut good outcomes have been reported.233,235 The mechanism of action and vWF. In type I vWD, platelets fail to aggregate in the presence ofis unclear but may involve removal of platelet-aggregating agents, such ristocetin. Type II vWD is less common and may be transmitted in anas large vWF multimers, or autoantibodies against ADAMTS13. Addi- autosomal recessive fashion. There are several subtypes of type II vWD,tional treatment includes infusion of platelet-poor or cryoprecipitate- which is notable for vWF that does not function normally. Type IIApoor fresh-frozen plasma (30 mL/kg/day), which may replace involves a deﬁciency of normal high-molecular-weight multimers ofADAMTS13, thus reducing vWF multimer size and reducing platelet vWF, with consequent decreased afﬁnity for platelets. Type IIB is char-aggregation. Platelet transfusions should be avoided, because it may acterized by vWF with an increased afﬁnity for platelets due to anprecipitate the disease.223 However, red blood cell transfusion is often increased afﬁnity for GpIb. The clinical disorder is similar to thatnecessary. Glucocorticoids or other immunosuppressive therapy may caused by pseudo-vWD, which results from defective GpIb and alsobe useful (potentially to reduce antibodies to ADAMTS13) and is rec- leads to hyperactive platelet binding to vWF. Type IIM is notable forommended for patients who do not respond immediately to plasma morphologically and qualitatively abnormal vWF with reduced inter-exchange.227 Efﬁcacy is uncertain. Treatment should continue for action with GpIb. Type IIN is caused by vWF with impaired bindingseveral days after recovery. Refractory cases may beneﬁt from cytotoxic to factor VIII. Type III also is an autosomal recessive trait and is theimmunosuppressive agents. These therapies are generally accepted for least common of the three types. Individuals with type III vWD haveTTP. Therapy is similar for HUS, although efﬁcacy is less certain. severe deﬁciencies of vWF/factor VIII. vWD and its subtypes may beIndividuals with HUS often require dialysis as well. diagnosed with a variety of laboratory studies, as summarized in Table About 10% to 25% of TTP cases occur during pregnancy or the 40-5.244,245postpartum period. Indeed, pregnancy is considered to be a risk factor A primary treatment for many women with vWD is desmopressinfor TTP and HUS, perhaps because of physiologic reduction in (DDAVP), which increases plasma factor VIII and vWF levels (TableADAMTS13 levels, general hypercoagulability, and synergistic features 40-6).246,247 Response to DDAVP is highly variable among women withwith preeclampsia.236,237 HUS is more likely to occur in the peripartum vWD, although most of those with type I disease have a favorable
844 CHAPTER 40 Coagulation Disorders in Pregnancy TABLE 40-5 CONGENITAL BLEEDING AND PLATELET DISORDERS Disorders Deﬁnition Diagnostic Assays Hemophilia A Severe Factor VIII <2% Prolonged aPTT, low factor VIII Mild Factor VIII 2-25% Prolonged aPTT, low factor VIII Carrier Factor VIII ≈50% aPTT usually normal, low factor VIII Hemophilia B Severe Factor IX <2% Prolonged aPTT, low factor IX Mild Factor IX 2-25% Prolonged aPTT, low factor IX Carrier Factor IX ≈50% aPTT usually normal, low factor IX Factor VII deﬁciency Low factor VII Prolonged INR, low factor VII Factor X deﬁciency Low factor X Prolonged aPTT, prolonged INR, low factor X Factor XI deﬁciency Low factor XI Prolonged aPTT, low factor XII Factor XII deﬁciency Low factor XII Prolonged aPTT, low factor XII Factor XIII deﬁciency Low factor XIII Normal aPTT and INR, low factor XIII Hypoﬁbrinogenemia Low ﬁbrinogen Low ﬁbrinogen vWD Types I and III Deﬁcient (type I) or absent (type III) vWF Absent vWF:RCoF and RIPA; platelets aggregate with bovine plasma Type IIA Qualitatively abnormal vWF: lack of HMW multimers Multimeric analysis Type IIB Qualitatively abnormal vWF; spontaneously binds Platelets aggregate to 0.5 mg/mL of ristocetin; platelets; lack of HMW multimers multimeric analysis ↓ platelets Pseudo-vWD Platelets spontaneously bind GpIb-IX-V complex Absent vWF:RCoF activity; differentiated from vWD by no clumping to bovine plasma Bernard-Soulier syndrome Platelet GpIb is defective Absent vWF:RCoF activity; differentiated from vWD by no clumping to bovine plasma Secretion defects Arachidonic acid and prostaglandin pathway Aspirin/NSAIDs are common causes; abnormal abnormalities response to collagen, arachidonic acid; normal primary wave only Storage pool deﬁciencies Abnormal function or component deﬁciency of Primary wave only; decreased collagen assay; platelet granules (α, δ, or both) variable arachidonic acid assay; mepacrine labeling Glanzmann thrombasthenia GpIIb-IIIa is absent, present in minimal amounts, or Platelets not activated by ADP, collagen, or qualitatively abnormal arachidonic acid ADP, adenosine diphosphate; aPTT, activated partial thromboplastin time; Gp glycoprotein; HMW, high molecular weight; INR, international normalized ratio; NSAIDs, nonsteroidal anti-inﬂammatory drugs; RCoF, ristocetin cofactor; RIPA, ristocetin-induced platelet agglutination; vWD, von Willebrand disease; vWF, von Willebrand factor.response. Some women with type IIA vWD also respond well to when using DDAVP near the time of childbirth.243 Women who do notDDAVP. However, the drug should be avoided in women with type IIB respond to DDAVP may be treated with factor VIII/vWF plasma con-disease, because it may cause thrombocytopenia.248 Patients with type centrate in the form of plasma, cryoprecipitate, Humate-P, and Koate.III disease rarely respond. Ideally, an individual’s response to DDAVP These products are typically labeled with vWF:Ac concentrations indi-should be tested under nonurgent circumstances. A typical dose is cating functional activity: 1 IU/kg of vWF:Ac increases the plasma level0.3 μg/kg to a maximum of 20 μg SQ or diluted in 50 to 100 mL of by 2.0 U/dL. Ideally, vWF:Ac levels should be 50% of normal (50 IU/normal saline and given intravenously over 30 minutes. If the patient dL) in prophylactic settings; 100% of normal is the goal in cases ofis not pregnant, the drug may be administered on day 1 of menses. A bleeding or surgery. This level should be maintained for at least 3 dayssubjective decrease in ﬂow is considered a positive response. If the after vaginal delivery or 5 days after cesarean delivery.247 Tranexamicpatient is pregnant or not bleeding, the response is gauged by assessing acid also may be useful in controlling or preventing postpartuma change in platelet count and vWF:ristocetin cofactor (RCoF) peak hemorrhage.247activity at 90 minutes after the administration of DDAVP. Adverse Pregnancy is not contraindicated in women with vWD, but theyeffects of DDAVP include headache, ﬂushing, changes in blood pres- should be informed of the potential for bleeding.243,244 A recent largesure, ﬂuid retention, and hyponatremia. The drug is pregnancy cate- epidemiologic study estimated the OR of postpartum hemorrhage forgory B. women with vWD to be 1.5 (CI, 1.1 to 2.0).249 The OR for needing a Replacement of clotting factors is the other standard treatment for blood transfusion was 4.7 (CI, 3.2 to 7.0), and 5 of 4067 women diedVWD. In cases with factor VIII:c or vWF levels less than 50 IU/dL, (a rate 10-fold higher than in the general population).249 The antepar-prophylactic treatment should be given to cover invasive procedures tum period is an ideal time to characterize the type of vWD and theand delivery.247 Patients with low vWF levels and either known positive response to DDAVP. If possible, a multidisciplinary team including aresponses to DDAVP or type I disease should be given prophylactic hematologist, obstetrician, and anesthesiologist should coordinate caretreatment with a single dose of DDAVP, either 60 minutes before and a management plan.247 Prenatal diagnosis is possible in many cases,anticipated delivery or at the time of cord clamping.247 Additional and genetic counseling should be offered to affected families (Tabledoses are of uncertain beneﬁt and may be harmful. Special attention 40-7). This is especially pertinent for patients who are at risk of havingmust be given to the possibility of ﬂuid retention and hyponatremia a fetus with severe type III disease. At times, genetic testing of amnio-
CHAPTER 40 Coagulation Disorders in Pregnancy 845 TABLE 40-6 TREATMENT OF CONGENITAL BLEEDING AND PLATELET DISORDERS Disorder Threshold for Treatment Treatment Hemophilia A Bleeding; before delivery/procedures if factor Factor VIII concentrate, cryoprecipitate, DDAVP VIII level <50 IU/dL Hemophilia B Bleeding; before delivery/procedures if factor Factor IX concentrate, cryoprecipitate IX level <50 IU/dL Factor VII deﬁciency Bleeding; before delivery/procedures if factor rFVIIa, factor VII concentrate VII level <50 IU/dL Factor X deﬁciency Bleeding; possibly before delivery/procedures Factor IX concentrate, FFP Factor XI deﬁciency Bleeding; before delivery/procedures if factor Factor XI concentrate, FFP (do not exceed peak factor XI XI level <15 IU/dL levels of 70 IU/dL) Factor XII deﬁciency ? ? Factor XIII deﬁciency Bleeding; pregnancy Factor XIII concentrate, FFP, cryoprecipitate (keep XIIIa antigen or activity >10% of normal) Hypoﬁbrinogenemia Bleeding; ﬁbrinogen <150 mg/dL; pregnancy FFP, cryoprecipitate (keep ﬁbrinogen >100 mg/dL) vWD Type I Bleeding DDAVP (if favorable response), tranexamic acid, FFP, cryoprecipitate, Humate-P, Koate (goals are >50 IU/dL of vWF:Ac) Type IIA Bleeding; operative delivery; procedures DDAVP (if favorable response), transexamic acid, FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of vWF:Ac) Type IIB Bleeding; operative delivery; procedures FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of vWF:Ac); DDAVP is contraindicated Type IIN Bleeding; operative delivery; procedures FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of vWF:Ac) Type IIM Bleeding; operative delivery; procedures FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of vWF:Ac) Type III Bleeding; all deliveries; procedures FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of vWF:Ac); DDAVP is not effective Bernard-Soulier syndrome Bleeding (prophylaxis for delivery is Platelet transfusion (possibly DDAVP, transexaminic acid, controversial) immune suppression, rFVIIa) Storage pool deﬁciencies Bleeding (prophylaxis for delivery is Platelet transfusion; ? DDAVP controversial) Glanzmann thrombasthenia Bleeding; delivery; procedures Platelet transfusion, rFVIIa DDAVP, desmopressin; FFP, fresh-frozen plasma; rFVIIa, recombinant activated factor VII; vWD, von Willebrand disease; vWF, von Willebrand factor.cytes or chorionic villi is possible in cases of known mutations or vFW levels, and prolonged prophylaxis may reduce this risk, but thisrestriction fragment length polymorphisms.250,251 Also, cordocentesis also is unproven.243to perform functional assays on fetal blood may be diagnostic, althoughresults can be unreliable due to variable penetrance, and the risk of Bernard-Soulier Syndomebleeding at cordocentesis is increased in affected cases.252,253 It may be Bernard-Soulier syndrome is usually transmitted in an autosomalhelpful to assess levels of vWF antigen (vWF:Ag), vWF:Ac, and factor recessive fashion; therefore, a family history is rare, although a variantVIII:c on a serial basis (e.g., on the initial visit, at 28 and 34 weeks’ appears to be autosomal dominant. Affected individuals have muco-gestation, and before invasive procedures and delivery).247 VIII/vWF cutaneous bleeding due to a defect or deﬁciency in the platelet glyco-concentrates, DDAVP, skilled anesthesia personnel, and hematology proteins (GpIb-IX-V) that form a transmembrane complex that bindsconsultation should be available at delivery. vWF.257 The result is platelets that cannot bind to subendothelial Neuraxial anesthesia is considered to be contraindicated in most surface. Laboratory diagnosis includes a decreased number of relativelywomen with vWD, but safe use of regional anesthesia has been reported large platelets, absent ristocetin response, a failure of platelets to aggre-in a few women with mild type I disease.254,255 Regional anesthesia is gate in response to bovine plasma, and decreased platelet GpIb-IX-Vthought to be safe if factor VIII and vWF:RCoF levels are greater than complex density as measured by ﬂow cytometry.258 Successful treat-50 IU/dL, although this is unproven.243,247 Cesarean delivery has been ment requires platelet transfusion.advised by some authorities in an attempt to avoid fetal bleeding.256 Prenatal diagnosis is possible in many cases and should be offeredHowever, the procedure is of unproven efﬁcacy and bleeding has been to families with a prior affected child. Because of previous plateletreported in affected infants born by cesarean.256 Given the unproven transfusions, affected mothers often are at risk for NAIT. Cesareanefﬁcacy and the risk of maternal hemorrhage, elective cesarean delivery delivery is controversial and should be reserved for obstetric indica-is not routinely advised in cases of vWD.244,247 However, traumatic tions.244,259 Regional anesthesia is considered to be contraindicated.delivery, such as vacuum or rotational forceps, should be avoided. Prophylactic platelet transfusion before delivery in this setting is alsoNeonates born to mothers with vWD should be tested to determine controversial because of the risk of alloimmune thrombocytopenia.their vWF status. There is an increased risk of hemorrhage after deliv- This risk must be weighed against frequent hemorrhagic complicationsery, even several weeks later. Frequent patient contact, monitoring of related to delivery, especially postpartum complications.259 The use of
846 CHAPTER 40 Coagulation Disorders in Pregnancy TABLE 40-7 PRENATAL DIAGNOSIS OF CONGENITAL BLEEDING AND PLATELET DISORDERS* Disorder Tissue Required Tests Comment Hemophilia A Amniocytes, Fetal gender; factor VIII mutation Because of the risk of bleeding, cordocentesis is fetal blood analysis, linkage analysis (if family reserved for cases in which genetic testing is mutation is known); cord blood nondiagnostic. factor VIII levels Hemophilia B Amniocytes, Fetal gender; factor IX mutation Because of the risk of bleeding, cordocentesis is fetal blood analysis, linkage analysis (if family reserved for cases in which genetic testing is mutation is known); cord blood nondiagnostic. factor IX levels Factor VII deﬁciency Amniocytes, Factor VII mutation analysis, linkage Because of the risk of bleeding, cordocentesis is fetal blood analysis (if family mutation is reserved for cases in which genetic testing is known); cord blood factor VII levels nondiagnostic. Factor X deﬁciency Amniocytes, Factor X mutation analysis, linkage Because of the risk of bleeding, cordocentesis is fetal blood analysis (if family mutation is reserved for cases in which genetic testing is known); cord blood factor X levels nondiagnostic. vWD (types I and III) Amniocytes or Mutation analysis, linkage analysis if Because of the risk of bleeding, cordocentesis is fetal blood family mutation known; vWF:RCoF reserved for cases in which genetic testing is nondiagnostic. vWD (type II) Amniocytes or Mutation analysis, linkage analysis if Because of the risk of bleeding, cordocentesis is fetal blood family mutation known; vWF:RCoF reserved for cases in which genetic testing is nondiagnostic. Bernard-Soulier Amniocytes or Mutation analysis, linkage analysis if Because of the risk of bleeding, cordocentesis is syndrome fetal blood family mutation known; vWF: reserved for cases in which genetic testing is RCoF; bovine plasma nondiagnostic. Cordocentesis is extremely hazardous if fetus is positive for the mutation. Glanzmann Amniocytes or Mutation analysis, linkage analysis if Because of the risk of bleeding, cordocentesis is thrombasthenia fetal blood family mutation known; functional reserved for cases in which genetic testing is assays; anti-GpIIb-IIIa antibody nondiagnostic. Cordocentesis is extremely hazardous binding if fetus is positive for the mutation. Gray platelet syndrome Fetal blood Microscopic analysis Normal fetal platelets have α-granules. Wiscott-Aldrich Amniocytes or Mutation analysis, linkage analysis if Because of the risk of bleeding, cordocentesis is syndrome fetal blood family mutation known; platelet reserved for cases in which genetic testing is size/volume nondiagnostic. Chediak-Higashi Fetal blood Peroxidase stain of neutrophils Proven successful in feline model. syndrome Hermansky-Pudlak Amniocytes Mutation analysis, linkage analysis if — syndrome family mutation known *Genes and some mutations have been identiﬁed for deﬁciencies of factors X, XI, XII, XIII, and ﬁbrinogen. Therefore, prenatal diagnosis using amniocytes may be possible. Cordocentesis also may be informative through the direct measurement of factor levels. Gp, glycoprotein; RCoF, ristocetin cofactor; vWD, von Willebrand disease; vWF, von Willebrand factor.HLA and platelet antigen–matched platelets may reduce this risk. staining with Romanowsky solution. Treatment includes platelet trans-Several other strategies may reduce the risk of bleeding, or may be used fusion. Good pregnancy outcome was reported in a patient with grayto treat bleeding after delivery, in women with Bernard-Soulier syn- platelet syndrome after platelet transfusion.263drome. These include DDAVP, antiﬁbrinolytic therapy with tranexamicacid, immune suppression to prolong platelet survival, and recombi- DELTA STORAGE POOL DISEASEnant activated factor VII (rFVIIa).259-262 The optimal dose of rFVIIa is Delta (δ) storage pool disease involves a deﬁciency in dense gran-uncertain, but a dose of 90 to 120 μg/kg body weight, repeated every ules (δ granules) in platelets containing ADP. Diagnosis is made by2 hours (if there is a good response), has been recommended.259 electron microscopy or by an adenosine triphosphate (ATP)-to-ADP ratio greater than 3 : 1 in inactive platelets. Other syndromes associatedDisorders of Platelet Secretion with δ storage pool disease include the Chediak-Higashi, Wiskott-Disorders of platelet secretion include several rare conditions charac- Aldrich, thrombocytopenia with absent radii (TAR), and Hemansky-terized by platelet storage pool deﬁciencies. These disorders involve Pudlak syndromes. Most patients with δ-storage pool diseases responddeﬁcient or abnormal platelet granules or their contents. to platelet transfusion, although some may respond to DDAVP. Rarely, individuals have congenital or acquired abnormalities of d and a gran- GRAY PLATELET SYNDROME ules, termed αδ storage pool disease. A case of an uncomplicated Gray platelet syndrome is caused by a deﬁciency of α-granules in pregnancy without treatment was reported in a patient with Chediak-platelets and megakaryocytes. Platelet α-granules contain vWF, platelet Higashi syndrome.264 Wiscott-Aldrich syndrome is an X-linked immu-factor 4, and platelet-derived growth factor. Characteristic gray-appear- nodeﬁciency syndrome that is associated with early mortality. Prenataling platelets are noted on peripheral smear or marrow aspirate after diagnosis is possible and should be offered to affected families.265
CHAPTER 40 Coagulation Disorders in Pregnancy 847Thrombocytopenia associated with TAR typically resolves at 1 year of remits spontaneously, with or without the use of immunosuppressivelife. Prenatal diagnosis of the syndrome has been reported.266 Several therapy.277pregnancies have been reported in women with Hermansky-Pudlaksyndrome.267,268 This autosomal recessive condition is characterized byoculocutaneous albinism, platelet storage pool deﬁciency, and the Congenital Bleeding Disordersaccumulation of ceroid (a yellow, granular substance) in reticuloendo-thelial cells. It is common in some areas of Puerto Rico.267,268 Hemophilia A (Factor VIII Deﬁciency) and Hemophilia B (Factor IX Deﬁciency) GLANZMANN THROMBASTHENIA Hemophilia A and B are caused by congenital deﬁciencies of factor VIII Glanzmann thrombasthenia is an abnormality in the quantity or and IX, respectively. They are inherited in an X-linked recessive fashion.quality (or both) of the platelet membrane glycoprotein, GpIIb-IIIa.269 Therefore, affected females are uncommon. Heterozygous carriers areThe disease is transmitted in an autosomal dominant fashion and has usually asymptomatic. Rarely, a heterozygous female has clinical symp-been reported to occur most often in Iraqi-Jewish and Arab popula- toms of bleeding, perhaps because of skewed X inactivation of the Xtions in Israel, in Southern India, and among European Gypsies.270,271 chromosome containing the normal gene. Symptoms tend to be mild,Patients with type 1 Glanzmann thrombasthenia lack detectable GpIIb- and serious hemorrhage during labor and delivery is rare. TreatmentIIIa, whereas those with type 2 disease have only 10% to 20% of normal may be accomplished with factor VIII concentrate or cryoprecipitateplatelet surface GpIIb-IIIa. for hemophilia A and factor IX concentrate or fresh-frozen plasma for These patients are at lifelong risk for bleeding, often requiring fre- hemophilia B.247quent platelet transfusions. Accordingly, many develop alloimmune Pregnancy issues often focus on the fetus/neonate, because 50% ofantibodies against platelet antigens, causing their pregnancies to be at male offspring born to female carriers will be affected. Carrier detec-risk for NAIT (see earlier discussion).272 Women with a history of tion of hemophilia A may be accomplished using assays for factor VIIImultiple platelet transfusions should undergo evaluation for parental and is reliable during pregnancy. Prenatal diagnosis is feasible throughplatelet antigen incompatibility and the presence of speciﬁc anti-plate- factor VIII and IX gene mutation analysis or linkage analysis (orlet antibodies for fetal antigens. Cordocentesis has been particularly both).251 Rarely, cordocentesis may be used to detect an affected fetusrisky in affected pregnancies and is best avoided if possible. This makes by testing levels of factors VIII and IX (which are normally lower in aprenatal diagnosis more difﬁcult. In cases of known mutations, fetal fetus than in an adult). However, this approach is reserved for cases ingenotype may be obtained from amniocytes or chorionic villi (avoid which genetic testing is not diagnostic, because the procedure ischorionic villus sampling if the patient has antibodies). risky.247 The primary intrapartum treatment for Glanzmann thrombasthe- Levels of factor VIII or IX, or both, should be assessed at the initialnia is platelet transfusion.273,274 If possible, type-speciﬁc platelets should pregnancy visit, at 28 and 34 weeks of gestation, and again at deliv-be used to avoid platelet alloimmunization. If pooled platelets must be ery.247 Recombinant factor VIII and IX should be used as the treatmentused in sensitized women, immunosuppressive therapy may prolong of choice in pregnant carriers of hemophilia A and B, respectively.the lifespan and effectiveness of the platelets. Cesarean delivery should Treatment should be initiated in the setting of bleeding or factor VIIIbe reserved for the usual obstetric indications, including alloimmune or IX levels lower than 50 IU/dL.247 DDAVP may be helpful in womenthrombocytopenia. Postpartum hemorrhage is common. Hormonal with hemophilia A, but not in those with hemophilia B. Regionaltreatment and prolonged use of uterotonic agents may reduce the risk anesthesia should be safe in women with normal coagulation studiesof this complication, although this approach is of unproven efﬁcacy. and factor levels greater than 50 IU/dL. Vaginal delivery has not beenThe use of rFVIIa appears to be safe and relatively effective in patients shown to increase bleeding in affected male infants. However, fetalwith Glanzmann thrombasthenia,274-276 and it may prove to be an scalp electrodes, operative vaginal delivery, and circumcision shouldimportant tool for the treatment of this disease during pregnancy. be avoided in male infants born to carriers of hemophilia A. Postnatal diagnosis may be established in newborns through assays of maternal and cord blood. Carriers of hemophilia B are detected by factor IX assay. Levels of factor IX in carriers are usually decreased, althoughBleeding Disorders they may be normal. Delivery issues with hemophilia B are similar to those for hemophilia A.Acquired Bleeding Disorders Other Factor DeﬁcienciesFactor VIII Inhibitors Deﬁciencies of factors VII, X, XI, and XIII are uncommon hereditaryThe development of antibodies against factor VIII is a rare but serious bleeding disorders. Factor VII, X, and XIII deﬁciencies are probablyacquired bleeding disorder. The inciting event is unknown, but the autosomal recessive traits, whereas factor XI deﬁciency appears to becondition often manifests in the postpartum period.277 Clinical fea- an incompletely autosomal-recessive trait. Replacement with rFVIIa istures are similar to those seen in hemophilia. Diagnosis is made by the treatment of choice for women with factor VII deﬁciency.278 Factorprolonged clotting times that do not normalize in response to mixing X–deﬁcient women may be treated with fresh-frozen plasma or factorstudies with normal plasma. Demonstration of a speciﬁc factor VIII IX concentrates to treat active bleeding.279,280 Prophylactic transfusioninhibitor and documentation of low levels of factor VIII in the plasma may be useful before vaginal or cesarean delivery.279,281 Individuals whoconﬁrm the diagnosis. Hemorrhage may be severe and may respond are homozygous for factor XI deﬁciency have levels less than 20% ofto activated prothrombin complex concentrate or rFVIIa.276,277 Mild normal, whereas heterozygotes have levels that are 30% to 65% ofcases often respond to DDAVP and factor VIII concentrates.277 Plasma- normal.282 Bleeding does not always correlate with factor XI concentra-pheresis may be helpful in refractory cases. The disease typically tions, and heterozygotes may have minor bleeding problems. Mostregresses spontaneously over time. Although IgG antibodies to factor women do not experience hemorrhage during delivery,283,284 and it mayVIII may develop, infants are rarely affected. The condition usually be possible to stratify patients with the condition into bleeding and
848 CHAPTER 40 Coagulation Disorders in Pregnancynonbleeding phenotypes.284 Prophylactic treatment is not required forall deliveries, and treatment may be reserved for excessive bleeding.283,284 ReferencesThis may be accomplished with fresh-frozen plasma given as a 10 mL/ 1. Martinelli I, Mannucci PM, De Stefano V, et al: Different risks of throm-kg load followed by 5 mL/kg per day, or through direct replacement bosis in four coagulation defects associated with inherited thrombophilia:with factor XI concentrate. A study of 150 families. Blood 92:2353-2358, 1998. 2. Nurden AT, Nurden P: Inherited disorders of platelets: an update. Curr Factor XIII deﬁciency is rare but can lead to severe bleeding such Opin Hematol 13:157-162, 2006.as ICH after minor trauma and abnormal wound healing. Life-threat- 3. Ruggeri ZM, Dent JA, Saldivar E: Contribution of distinct adhesiveening umbilical cord stump hemorrhage has occurred in affected new- interactions to platelet aggregation in ﬂowing blood. Blood 94:172-178,borns. An increased risk of recurrent pregnancy loss also has been 1999.reported in women with factor XIII deﬁciency.285 This is thought to be 4. Abrams CS: Intracellular signaling in platelets. Curr Opin Hematolthe result of decidual bleeding, and successful pregnancy rarely occurs 12:401-405, 2005.without treatment. Diagnosis is made by assessment of factor XIII (A 5. Bevers EM, Comfurius P, Hemker HC, et al: On the procoagulant activityand S subunits) or by dissolution of clot in 5-molar urea. Treatment of platelets stimulated by collagen and thrombin. Thromb Res 33:553-554,includes transfusion with factor XIII concentrate, fresh-frozen plasma, 1984.cryoprecipitate, and/or whole blood. Small amounts of plasma may 6. Pytela R, et al: Platelet membrane glycoprotein IIb/IIIa: Member of a family of Arg-Gly-Asp—Speciﬁc adhesion receptors. Science 231:1559-provide adequate factor XIII for hemostasis. Although of uncertain 1562, 1986.efﬁcacy, maintenance of XIIIA-antigen (Ag) or XIII-activity (act) at 7. Sill PR, Lind T, Walker W: Platelet values during normal pregnancy. Br J10% is advised.285 This may require the administration of 1 vial of Obstet Gynaecol 92:480-483, 1985.XIIIA concentrate (250 IU) every 7 days in early pregnancy, followed 8. Wallenburg HC, van Kessel PH: Platelet lifespan in normal pregnancy asby 2 vials every 7 days after 23 weeks gestation.285,286 Extra replacement determined by a nonradioisotopic technique. Br J Obstet Gynaecol 85:33-(e.g., 4 vials) may be helpful at the time of delivery.285 36, 1978. 9. Monroe DM, Hoffman M: What does it take to make the perfect clot? Arterioscler Thromb Vasc Biol 26:41-48, 2006.Hypoﬁbrinogenemia/Aﬁbrinogenemia 10. Mackman N: Role of tissue factor in hemostasis, thrombosis, and vascularCongenital hypoﬁbrinogenemia is a rare, autosomal-dominant condi- development. Arterioscler Thromb Vasc Biol 24:1015-1022, 2004. 11. Giesen PL, Nemerson Y: Tissue factor on the loose. Semin Thromb Hemosttion characterized by bleeding as well as obstetric problems such as 26:379-384, 2000.abruption, postpartum hemorrhage, and recurrent pregnancy loss.287,288 12. Neuenschwander PF, Fiore MM, Morrissey JH: Factor VII autoactivationThe condition is deﬁned as the presence of structurally normal ﬁbrino- proceeds via interaction of distinct protease-cofactor and zymogen-cofac-gen in concentrations of less than 150 mg/dL.287 Miscarriage at mid- tor complexes: Implications of a two-dimensional enzyme kinetic mecha-gestation appears to be caused by perigestational hemorrhage.288 This nism. J Biol Chem 268:21489-21492, 1993.is supported by data from transgenic mice lacking ﬁbrinogen, who 13. Falati S, Liu Q, Gross P, et al: Accumulation of tissue factor into developingsuffer uniform pregnancy loss at day 10.289 Pregnancy loss in these mice thrombi in vivo is dependent upon microparticle P-selectin glycoproteinis corrected by the addition of ﬁbrinogen. Dysﬁbrinogenemia has been ligand 1 and platelet P-selectin. J Exp Med 197:1585-1598, 2003.weakly associated with hypercoagulability, rather than hypocoagulabil- 14. Broze GJ Jr: The rediscovery and isolation of TFPI. J Thromb Haemostity. Successful pregnancies in women with hypoﬁbrinogenemia have 1:1671-1675, 2003. 15. Oliver JA, Monroe DM, Churen FC, et al: Activated protein C cleavesbeen reported with the use of fresh-frozen plasma or cryoprecipitate factor Va more efﬁciently on endothelium than on platelet surfaces. Bloodto maintain ﬁbrinogen levels greater than 100 to 150 mg/dL.287,288 Each 100:539-546, 2002.unit of cryoprecipitate contains about 300 mg of ﬁbrinogen, which 16. Broze GJ Jr: Protein Z-dependent regulation of coagulation. Thrombraises the plasma concentration by approximately 6 mg/dL. Haemost 86:8-13, 2001. 17. Preissner KT, Zwicker L, Muller-Berghaus G: Formation, characterization and detection of a ternary complex between S protein, thrombin andFactor XII deﬁciency antithrombin III in serum. Biochem J 243:105-111, 1987.Factor XII is involved in both coagulation and ﬁbrinolysis, and deﬁ- 18. Ranby M, Brandstrom A: Biological control of tissue plasminogen activa-cient individuals have been reported to be at increased risk for both tor-mediated ﬁbrinolysis. Enzyme 40:130-143, 1988.bleeding and thrombosis. However, it is not clear that this condition 19. Schatz F, Lockwood CJ: Progestin regulation of plasminogen activator inhibitor type 1 in primary cultures of endometrial stromal and decidualincreases the risk for either bleeding or thrombosis.290 The condition cells. J Clin Endocrinol Metab 77:621-625, 1993.is of interest because it is associated with recurrent pregnancy 20. Bouma BN, Meijers JC: New insights into factors affecting clot stability:loss.291,292 A role for thrombin activatable ﬁbrinolysis inhibitor (TAFI; plasma pro- carboxypeptidase B, plasma procarboxypeptidase U, procarboxypeptidase R). Semin Hematol 41(1 Suppl 1):13-19, 2004.Plasminogen Activator Inhibitor 1 Deﬁciency 21. Urano T, Ihara H, Takada Y, et al: The inhibition of human factor Xa byIndividuals with elevated levels of PAI-1 are at increased risk for plasminogen activator inhibitor type 1 in the presence of calcium ion, andthrombosis and possibly for pregnancy loss. In contrast, deﬁciency of its enhancement by heparin and vitronectin. Biochim Biophys ActaPAI-1 has been reported to be associated with an increased risk 1298:199-208, 1996.of bleeding.293 The condition often manifests as menorrhagia and may 22. Lockwood CJ, Krikun G, Rahman M, et al: The role of decidualization in regulating endometrial hemostasis during the menstrual cycle, gestation,be responsive to aminocaproic acid.293 Indeed, low PAI-1 activity has and in pathological states. Semin Thromb Hemost 33:111-117, 2007.been reported in 23% of patients referred for evaluation of bleeding 23. Erlich J, Parry GC, Fearns C, et al: Tissue factor is required for uterinediathesis, compared with 10% of controls (OR, 2.75; CI, 1.39 to hemostasis and maintenance of the placental labyrinth during gestation.5.42).294 It may prove to be an important cause of abnormal bleeding. Proc Natl Acad Sci USA 96:8138-8143, 1999.There are few data regarding pregnancy in women with PAI-1 24. Mackenzie AP, Schatz F, Krikun G, et al: Mechanisms of abruption-deﬁciency. induced premature rupture of the fetal membranes: Thrombin enhanced
CHAPTER 40 Coagulation Disorders in Pregnancy 849 decidual matrix metalloproteinase-3 (stromelysin-1) expression. Am J 46. Field SL, Brighton TA, McNeil HP, et al: Recent insights into antiphospho- Obstet Gynecol 191:1996-2001, 2004. lipid antibody-mediated thrombosis. Baillieres Best Pract Res Clin Hae-25. Lockwood CJ, Toti P, Arcuri F, et al: Mechanisms of abruption-induced matol 12:407-422, 1999. premature rupture of the fetal membranes: Thrombin-enhanced 47. Rand JH, Wu XX, Andree HA, et al: Pregnancy loss in the interleukin-8 expression in term decidua. Am J Pathol 167:1443-1449, antiphospholipid-antibody syndrome: A possible thrombogenic 2005. mechanism. N Engl J Med 337:154-160, 1997.26. Cakmak H, Schatz F, Huang ST, et al: Progestin suppresses thrombin- and 48. Girardi G, Redecha P, Salmon JE: Heparin prevents antiphospholipid anti- interleukin-1beta-induced interleukin-11 production in term decidual body-induced fetal loss by inhibiting complement activation. Nat Med cells: Implications for preterm delivery. J Clin Endocrinol Metab 90:5279- 10:1222-1226, 2004. 5286, 2005. 49. Kutteh WH: Antiphospholipid antibody-associated recurrent pregnancy27. Matta P, Lockwood CJ, Schatz F, et al: Thrombin regulates monocyte che- loss: Treatment with heparin and low-dose aspirin is superior to low-dose moattractant protein-1 expression in human ﬁrst trimester and term aspirin alone. Am J Obstet Gynecol 174:1584-1589, 1996. decidual cells. Am J Obstet Gynecol 196:268e1-268e8, 2007. 50. Farquharson RG, Quenby S, Greaves M: Antiphospholipid syndrome in28. Bremme KA: Haemostatic changes in pregnancy. Best Pract Res Clin Hae- pregnancy: A randomized, controlled trial of treatment. Obstet Gynecol matol 16:153-168, 2003. 100:408-413, 2002.29. Paidas MJ, Ku DH, Lee MJ, et al: Protein Z, protein S levels are lower in 51. Empson M, Lassere M, Craig J, et al: Prevention of recurrent miscarriage patients with thrombophilia and subsequent pregnancy complications. J for women with antiphospholipid antibody or lupus anticoagulant. Thromb Haemost 3:497-501, 2005. Cochrane Database Syst Rev (2):CD002859, 2005.30. Hellgren M: Hemostasis during normal pregnancy and puerperium. 52. Di Nisio M, Peters L, Middeldorp S: Anticoagulants for the treatment of Semin Thromb Hemost 29:125-130, 2003. recurrent pregnancy loss in women without antiphospholipid syndrome.31. Juhan-Vague I, Alessi MC, Vague P: Increased plasma plasminogen activa- Cochrane Database Syst Rev (2):CD004734, 2005. tor inhibitor 1 levels: A possible link between insulin resistance and ath- 53. Backos M, Rai R, Baxter N, et al: Pregnancy complications in women with erothrombosis. Diabetologia 34:457-462, 1991. recurrent miscarriage associated with antiphospholipid antibodies treated32. Wilson WA, Gharari AE, Koike T, et al: International consensus statement with low dose aspirin and heparin. Br J Obstet Gynaecol 106:102-107, on preliminary classiﬁcation criteria for deﬁnite antiphospholipid syn- 1999. drome: Report of an international workshop. Arthritis Rheum 42:1309- 54. Clark AL, Branch DW, Silver RM, et al: Pregnancy complicated by the 1311, 1999. antiphospholipid syndrome: Outcomes with intravenous immunoglobu-33. Galli M, Luciani D, Bertolini G, et al: Anti-beta 2-glycoprotein I, antipro- lin therapy. Obstet Gynecol 93:437-441, 1999. thrombin antibodies, and the risk of thrombosis in the antiphospholipid 55. Triolo G, Ferrante A, Ciccia F, et al: Randomized study of subcutaneous syndrome. Blood 102:2717-2723, 2003. low molecular weight heparin plus aspirin versus intravenous immuno-34. Miyakis S, Lockshin MD, Atsumi D, et al: International consensus state- globulin in the treatment of recurrent fetal loss associated with antiphos- ment on an update of the classiﬁcation criteria for deﬁnite antiphospho- pholipid antibodies. Arthritis Rheum 48:728-731, 2003. lipid syndrome (APS). J Thromb Haemost 4:295-306, 2006. 56. Branch DW, Peaceman AM, Druzin M, et al: A multicenter, placebo-35. Wahl DG, Guillemin F, de Maistre E, et al: Risk for venous thrombosis controlled pilot study of intravenous immune globulin treatment of related to antiphospholipid antibodies in systemic lupus erythematosus: antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study A meta-analysis. Lupus 6:467-473, 1997. Group. Am J Obstet Gynecol 182(1 Pt 1):122-127, 2000.36. Crowther MA, Ginsberg JS, Julian J, et al: A comparison of two intensities 57. Tincani A, Branch W, Levy RA, et al: Treatment of pregnant patients with of warfarin for the prevention of recurrent thrombosis in patients with antiphospholipid syndrome. Lupus 12:524-529, 2003. the antiphospholipid antibody syndrome. N Engl J Med 349:1133-1138, 58. Franco RF, Reitsma PH: Genetic risk factors of venous thrombosis. Hum 2003. Genet 109:369-384, 2001.37. Branch DW, Silver RM, Blackwell JL, et al: Outcome of treated pregnancies 59. Gerhardt A, Scharf RE, Beckmann MW, et al: Prothrombin and factor V in women with antiphospholipid syndrome: An update of the Utah expe- mutations in women with a history of thrombosis during pregnancy and rience. Obstet Gynecol 80:614-620, 1992. the puerperium. N Engl J Med 342:374-380, 2000.38. Branch DW, Silver RM: Criteria for antiphospholipid syndrome: Early 60. Zotz RB, Gerhardt A, Scharf RE: Inherited thrombophilia and gestational pregnancy loss, fetal loss, or recurrent pregnancy loss? Lupus 5:409-413, venous thromboembolism. Best Pract Res Clin Haematol 16:243-259, 1996. 2003.39. Rai RS, Clifford K, Cohen H, et al: High prospective fetal loss rate in 61. Press RD, Bauer KA, Kujorich JL, et al: Clinical utility of factor V Leiden untreated pregnancies of women with recurrent miscarriage and antiphos- (R506Q) testing for the diagnosis and management of thromboembolic pholipid antibodies. Hum Reprod 10:3301-3304, 1995. disorders. Arch Pathol Lab Med 126:1304-1318, 2002.40. Birkenfeld A, Mukaida T, Minichiello L, et al: Incidence of autoimmune 62. Brenner BR, Nowak-Gottl U, Kosch A, et al: Diagnostic studies for throm- antibodies in failed embryo transfer cycles. Am J Reprod Immunol 31:65- bophilia in women on hormonal therapy and during pregnancy, and in 68, 1994. children. Arch Pathol Lab Med 126:1296-1303, 2002.41. Birdsall MA, Lockwood GM, Ledger WL, et al: Antiphospholipid antibod- 63. Rey E, Kahn SR, David M, et al: Thrombophilic disorders and fetal loss: ies in women having in-vitro fertilization. Hum Reprod 11:1185-1189, A meta-analysis. Lancet 361:901-908, 2003. 1996. 64. Gris JC, Quere I, Monpeyroux F, et al: Case-control study of the frequency42. Hornstein MD, Davis OK, Massey JB, et al: Antiphospholipid antibodies of thrombophilic disorders in couples with late foetal loss and no throm- and in vitro fertilization success: A meta-analysis. Fertil Steril 73:330-333, botic antecedent: The Nimes Obstetricians and Haematologists Study 5 2000. (NOHA5). Thromb Haemost 81:891-899, 1999.43. Stern C, Chamley L, Norris H, et al: A randomized, double-blind, placebo- 65. Dudding TE, Attia J: The association between adverse pregnancy out- controlled trial of heparin and aspirin for women with in vitro fertiliza- comes and maternal factor V Leiden genotype: A meta-analysis. Thromb tion implantation failure and antiphospholipid or antinuclear antibodies. Haemost 91:700-711, 2004. Fertil Steril 80:376-383, 2003. 66. Lissalde-Lavigne G, Fabbro-Peray P, Quere I, et al: Factor V Leiden and44. Branch DW, Andres R, Digrek B, et al: The association of antiphospholipid prothrombin G20210A polymorphisms as risk factors for miscarriage antibodies with severe preeclampsia. Obstet Gynecol 73:541-545, 1989. during a ﬁrst intended pregnancy: The matched case-control “NOHA45. Lee RM, Brown MA, Branch DW, et al: Anticardiolipin and anti-beta2- First” study. J Thromb Haemost 3:2178-2184, 2005. glycoprotein-I antibodies in preeclampsia. Obstet Gynecol 102:294-300, 67. Preston FE, Rosendaal FR, Walker ID, et al: Increased fetal loss in women 2003. with heritable thrombophilia. Lancet 48:913-916, 1996.
850 CHAPTER 40 Coagulation Disorders in Pregnancy68. Vossen CY, Preston FE, Conard J, et al: Hereditary thrombophilia and 91. Franco RF, Maffei FH, Lourenco D, et al: Factor V Arg306→Thr (factor V fetal loss: A prospective follow-up study. J Thromb Haemost 2:592-596, Cambridge) and factor V Arg306→Gly mutations in venous thrombotic 2004. disease. Br J Haematol 103:888-890, 1998.69. Roque H, Paidas MJ, Funai EF, et al: Maternal thrombophilias are not 92. Foka ZJ, Lambropoulos AF, Saravelos H, et al: Factor V Leiden and pro- associated with early pregnancy loss. Thromb Haemost 91:290-295, thrombin G20210A mutations, but not methylenetetrahydrofolate reduc- 2004. tase C677T, are associated with recurrent miscarriages. Hum Reprod70. Gopel W, Ludwig M, Junge AK, et al: Selection pressure for the factor-V- 15:458-462, 2000. Leiden mutation and embryo implantation. Lancet 358:1238-1239, 2001. 93. Finan RR, Tamim H, Ameen G, et al: Prevalence of factor V G1691A71. Rodesch F, Simon P, Donner C, et al: Oxygen measurements in endome- (factor V-Leiden) and prothrombin G20210A gene mutations in trial and trophoblastic tissues during early pregnancy. Obstet Gynecol a recurrent miscarriage population. Am J Hematol 71:300-305, 80:283-285, 1992. 2002.72. Jaffe R: Investigation of abnormal ﬁrst-trimester gestations by color 94. Carp H, Salomon O, Seidman D, et al: Prevalence of genetic markers for Doppler imaging. J Clin Ultrasound 21:521-526, 1993. thrombophilia in recurrent pregnancy loss. Hum Reprod 17:1633-1637,73. Watson AL, Skepper JN, Jauniaux E, et al: Susceptibility of human placen- 2002. tal syncytiotrophoblastic mitochondria to oxygen-mediated damage in 95. Jivraj S, Rai R, Underwood J, et al: Genetic thrombophilic mutations relation to gestational age. J Clin Endocrinol Metab 83:1697-1705, 1998. among couples with recurrent miscarriage. Hum Reprod 21:1161-1165,74. Kupferminc MJ, Eldor A, Steinman N, et al: Increased frequency of genetic 2006. thrombophilia in women with complications of pregnancy. N Engl J Med 96. Kovalevsky G, Gracia CR, Berlin JA, et al: Evaluation of the association 340:9-13, 1999. between hereditary thrombophilias and recurrent pregnancy loss: A meta-75. Currie L, Peek M, McNiven M, et al: Is there an increased maternal-infant analysis. Arch Intern Med 164:558-563, 2004. prevalence of factor V Leiden in association with severe pre-eclampsia? 97. Morrison ER, Miedzybrodzka ZH, Campbell DM, et al: Prothrombotic BJOG 109:191-196, 2002. genotypes are not associated with pre-eclampsia and gestational hyperten-76. van Pampus MG, Wolf H, Koopman MM, et al: Prothrombin 20210 G: A sion: Results from a large population-based study and systematic review. mutation and factor V Leiden mutation in women with a history of severe Thromb Haemost 87:779-785, 2002. preeclampsia and (H)ELLP syndrome. Hypertens Pregnancy 20:291-298, 98. Livingston JC, Barton JR, Park V, et al: Maternal and fetal inherited throm- 2001. bophilias are not related to the development of severe preeclampsia. Am77. D’Elia AV, Driul L, Giacomello R, et al: Frequency of factor V, prothrombin J Obstet Gynecol 185:153-157, 2001. and methylenetetrahydrofolate reductase gene variants in preeclampsia. 99. Peng F, Labelle LA, Rainey BJ, et al: Single nucleotide polymorphisms Gynecol Obstet Invest 53:84-87, 2002. in the methylenetetrahydrofolate reductase gene are common in US78. Lin J, August P: Genetic thrombophilias and preeclampsia: A meta-analy- Caucasian and Hispanic American populations. Int J Mol Med 8:509-511, sis. Obstet Gynecol 105:182-192, 2005. 2001.79. Kosmas IP, Tatsioni A, Ioannidis JP: Association of Leiden mutation in 100. den Heijer M, Rosendaal FR, Blom HJ, et al: Hyperhomocysteinemia and factor V gene with hypertension in pregnancy and pre-eclampsia: A meta- venous thrombosis: A meta-analysis. Thromb Haemost 80:874-877, analysis. J Hypertens 21:1221-1228, 2003. 1998.80. Wiener-Megnagi Z, Ben-Shlomo I, Goldberg Y, Shalev E: Resistance to 101. Domagala TB, Adamek L, Nizankowska E, et al: Mutations C677T and activated protein C and the Leiden mutation: High prevalence in patients A1298C of the 5,10-methylenetetrahydrofolate reductase gene and fasting with abruptio placentae. Am J Obstet Gynecol 179:1565-1567,1998. plasma homocysteine levels are not associated with the increased risk of81. Procházka M, Lubuský M, Slavík L, et al: Frequency of selected thrombo- venous thromboembolic disease. Blood Coagul Fibrinolysis 13:423-431, philias in women with placental abruption. Aust N Z J Obstet Gynaecol 2002. 47(4):297-301, 2007. 102. McColl MD, Ellison J, Reid F, et al: Prothrombin 20210 G→A, MTHFR82. Alﬁrevic Z, Roberts D, Martlew V: How strong is the association between C677T mutations in women with venous thromboembolism associated maternal thrombophilia and adverse pregnancy outcome? A systematic with pregnancy. BJOG 107:565-569, 2000. review. Eur J Obstet Gynecol Reprod Biol 101:6-14, 2002. 103. Nelen WL, Blom HJ, Steegers EA, et al: Hyperhomocysteinemia and recur-83. Martinelli P, Grandone E, Colaizzo D, et al: Familial thrombophilia and rent early pregnancy loss: A meta-analysis. Fertil Steril 74:1196-1199, the occurrence of fetal growth restriction. Haematologica 86:428-431, 2000. 2001. 104. Vollset SE, Refsum H, Irgens LM, et al: Plasma total homocysteine, preg-84. Infante-Rivard C, Rivard GE, Yotov WV, et al: Absence of association of nancy complications, and adverse pregnancy outcomes: The Hordaland thrombophilia polymorphisms with intrauterine growth restriction. N Homocysteine study. Am J Clin Nutr 71:962-968, 2000. Engl J Med 347:19-25, 2002. 105. Nurk E, Tell GS, Refsum H, et al: Associations between maternal methy-85. Howley HE, Walker M, Rodger MA: A systematic review of the association lenetetrahydrofolate reductase polymorphisms and adverse outcomes of between factor V Leiden or prothrombin gene variant and intrauterine pregnancy: The Hordaland Homocysteine Study. Am J Med 117:26-31, growth restriction. Am J Obstet Gynecol 192:694-708, 2005. 2004.86. Lindqvist PG, Svensson PJ, Marsaal K, et al: Activated protein C resistance 106. Ray JG, Laskin CA: Folic acid and homocyst(e)ine metabolic defects and (FV:Q506) and pregnancy. Thromb Haemost 81:532-537, 1999. the risk of placental abruption, pre-eclampsia and spontaneous pregnancy87. Dizon-Townson D, Miller C, Sibai B, et al: The relationship of the factor loss: A systematic review. Placenta 20:519-529, 1999. V Leiden mutation and pregnancy outcomes for mother and fetus. Obstet 107. Castanon MM, Lauricella AM, Kordich L, et al: Plasma homocysteine Gynecol 106:517-524, 2005. cutoff values for venous thrombosis. Clin Chem Lab Med 45:232-236,88. Castaman G, Faioni EM, Tosetto A, et al: The factor V HR2 haplotype and 2007. the risk of venous thrombosis: A meta-analysis. Haematologia 88:1182- 108. Carraro P: Guidelines for the laboratory investigation of inherited throm- 1189, 2003. bophilias: Recommendations for the ﬁrst level clinical laboratories. Clin89. Zammiti W, Mtiraoui N, Mercier E, et al: Association of factor V gene Chem Lab Med 41:382-391, 2003. polymorphisms (Leiden; Cambridge; Hong Kong and HR2 haplotype) 109. Conard J, Horellon MH, Van Dreden P, et al: Thrombosis and pregnancy with recurrent idiopathic pregnancy loss in Tunisia: A case-control study. in congenital deﬁciencies in AT III, protein C or protein S: Study of 78 Thromb Haemost 95:612-617, 2006. women. Thromb Haemost 63:319-320, 1990.90. Dilley A, Benito C, Hooper WC, et al: Mutations in the factor V, prothrom- 110. De Stefano V, Martinelli I, Rossi E, et al: The risk of recurrent venous bin and MTHFR genes are not risk factors for recurrent fetal loss. J Matern thromboembolism in pregnancy and puerperium without antithrombotic Fetal Neonatal Med 11:176-182, 2002. prophylaxis. Br J Haematol 135:386-391, 2006.
CHAPTER 40 Coagulation Disorders in Pregnancy 851111. Marlar RA, Neumann A: Neonatal purpura fulminans due to homozygous 130. Yamada N, Arinami T, Yamakawa-Kobayashi K, et al: The 4G/5G polymor- protein C or protein S deﬁciencies. Semin Thromb Hemost 16:299-309, phism of the plasminogen activator inhibitor-1 gene is associated with 1990. severe preeclampsia. J Hum Genet 45:138-141, 2000.112. Friederich PW, Sanson BJ, Simioni P, et al: Frequency of pregnancy-related 131. Glueck CJ, Phillips H, Cameron D, et al: The 4G/4G polymorphism of the venous thromboembolism in anticoagulant factor-deﬁcient women: hypoﬁbrinolytic plasminogen activator inhibitor type 1 gene: An indepen- Implications for prophylaxis. Ann Intern Med 125:955-960, 1996. dent risk factor for serious pregnancy complications. Metabolism 49:845-113. Hellgren M, Tengborn L, Abildgaard U: Pregnancy in women with con- 852, 2000. genital antithrombin III deﬁciency: Experience of treatment with heparin 132. van der Bom JG, de Maat MP, Bots ML, et al: Elevated plasma ﬁbrinogen: and antithrombin. Gynecol Obstet Invest 14:127-141, 1982. Cause or consequence of cardiovascular disease? Arterioscler Thromb114. Borgel D, Duchemin J, Alhenc-Gelas M, et al: Molecular basis for protein Vasc Biol 18:621-625, 1998. S hereditary deﬁciency: Genetic defects observed in 118 patients with type 133. Brown K, Luddington R, Taylor SA, et al: Risk of venous thromboembo- I and type IIa deﬁciencies. The French Network on Molecular Abnormali- lism associated with the common hereditary haemochromatosis Hfe gene ties Responsible for Protein C and Protein S Deﬁciencies. J Lab Clin Med (C282Y) mutation. Br J Haematol 105:95-97, 1999. 128:218-227, 1996. 134. Heﬂer L, Jirecek S, Heim K, et al: Genetic polymorphisms associated with115. Goodwin AJ, Rosendaal FR, Kottke-Marchant K, et al: A review of the thrombophilia and vascular disease in women with unexplained late intra- technical, diagnostic, and epidemiologic considerations for protein S uterine fetal death: A multicenter study. J Soc Gynecol Investig 11:42-44, assays. Arch Pathol Lab Med 126:1349-1366, 2002. 2004.116. Water N, Tan T, Ashton F, et al: Mutations within the protein Z-dependent 135. Kobbervig C, Williams E: FXIII polymorphisms, ﬁbrin clot structure and protease inhibitor gene are associated with venous thromboembolic thrombotic risk. Biophys Chem 112:223-228, 2004. disease: A new form of thrombophilia. Br J Haematol 127:190-194, 136. Brill-Edwards P, Ginsberg JS, Gent M, et al: Recurrence of clot in this 2004. pregnancy study group: Safety of withholding heparin in pregnant women117. Vasse M, Guegan-Massardier E, Borg JY, et al: Frequency of protein with a history of venous thromboembolism. N Engl J Med 343:1439-1444, Z deﬁciency in patients with ischaemic stroke. Lancet 357:933-934, 2000. 2001. 137. Blickstein D: The 7th American College of Chest Physicians Guidelines118. Gris JC, Quere I, Dechaud H, et al: High frequency of protein Z deﬁ- for the Antenatal and Peripartum Management of Thrombophilia: A ciency in patients with unexplained early fetal loss. Blood 99:2606-2608, Tutorial. Obstet Gynecol Clin North Am 33:499-505, 2006. 2002. 138. Barbour LA, Smith JM, Marlar RA: Heparin levels to guide thromboem-119. Gris JC, Mercier E, Quere I, et al: Low-molecular-weight heparin versus bolism prophylaxis during pregnancy. Am J Obstet Gynecol 173:1869- low-dose aspirin in women with one fetal loss and a constitutional throm- 1873, 1995. bophilic disorder. Blood 103:3695-3699, 2004. 139. Barbour LA, Oja JL, Schultz LK: A prospective trial that demonstrates120. Morange PE, Henry M, Tregouet D, et al: The A844G polymorphism in that dalteparin requirements increase in pregnancy to maintain the PAI-1 gene is associated with a higher risk of venous thrombosis in therapeutic levels of anticoagulation. Am J Obstet Gynecol 191:1024-1029, factor V Leiden carriers. Arterioscler Thromb Vasc Biol 20:1387-1391, 2004. 2000. 140. Warkentin TE, Greinacher A: Heparin-induced thrombocytopenia: Rec-121. Buchholz T, Lohse P, Rogenhofer N, et al: Polymorphisms in the ACE and ognition, treatment, and prevention. The seventh ACCP conference on PAI-1 genes are associated with recurrent spontaneous miscarriages. Hum Antithrombotic and Thrombolytic Therapy. Chest 126(3 Suppl):311S- Reprod 18:2473-2477, 2003. 317S, 2004.122. Varela ML, Adamczuk YP, Forastiero RR, et al: Major and potential pro- 141. Kupferminc MJ, Fait G, Many A, et al: Low-molecular-weight heparin for thrombotic genotypes in a cohort of patients with venous thromboembo- the prevention of obstetric complications in women with thrombophilias. lism. Thromb Res 104:317-324, 2001. Hypertens Pregnancy 20:35-44, 2001.123. Gubric N, Stegnar M, Peternel P, et al: A novel G/A and the 4G/5G poly- 142. Folkeringa N, Brouwer JL, Korteweg FJ, et al: Reduction of high fetal loss morphism within the promoter of the plasminogen activator inhibitor-1 rate by anticoagulant treatment during pregnancy in antithrombin, gene in patients with deep vein thrombosis. Thromb Res 84:431-443, protein C or protein S deﬁcient women. Br J Haematol 136:656-661, 1996. 2007.124. Ridker PM, Hennekens CH, Lindpaintner K, et al: Arterial and venous 143. Cines DB, Blanchette VS: Immune thrombocytopenic purtpura. N Engl J thrombosis is not associated with the 4G/5G polymorphism in the pro- Med 346:995-1008, 2002. moter of the plasminogen activator inhibitor gene in a large cohort of US 144. George JN, Woolf SH, Raskob GE, et al: Idiopathic thrombocytopenic men. Circulation 95:59-62, 1997. purpura: A practice guideline developed by explicit methods for the125. Stegnar M, Uhrin P, Peternel P, et al: The 4G/5G sequence polymorphism American Society of Hematology. Blood 88:3, 1996. in the promoter of plasminogen activator inhibitor-1 (PAI-1) gene: Rela- 145. Burrows RF, Kelton JG: Incidentally detected thrombocytopenia in healthy tionship to plasma PAI-1 level in venous thromboembolism. Thromb mothers and their infants. N Engl J Med 319:142, 1988. Haemost 79:975-979, 1998. 146. Burrows RF, Kelton JG: Thrombocytopenia at delivery: A pros-126. Zöller B, Garcia de Frutos P, Dahlbäck B: A common 4G allele in the pro- pective survey of 6715 deliveries. Am J Obstet Gynecol 162:731.a, moter of the plasminogen activator inhibitor-1 (PAI-1) gene as a risk 1990. factor for pulmonary embolism and arterial thrombosis in hereditary 147. Burrows BF, Kelton JG: Fetal thrombocytopenia and its relation to mater- protein S deﬁciency. Thromb Haemost 79:802-807, 1998. nal thrombocytopenia. N Engl J Med 329:1463.a, 1993.127. Junker R, Nabavi DG, Wolff E, et al: Plasminogen activator inhibitor-1 148. George JN, El-Harake MA, Raskob GE: Chronic idiopathic thromboeyto- 4G/4G genotype is associated with cerebral sinus thrombosis in factor V penic purpura. N Engl J Med 331:1207, 1994. Leiden carriers. Thromb Haemost 80:706-707, 1998. 149. Raife TJ, Olsen JD, Lentz SR: Platelet antibody testing in idiopathic throm-128. Wolf CE, Haubelt H, Pauer HU, et al: Recurrent pregnancy loss and its bocytopenic purpura. Blood 89:1112-1114, 1996. relation to FV Leiden, FII G20210A and polymorphisms of plasminogen 150. Lescale KB, Eddleman KA, Cines DB, et al: Antiplatelet antibody testing activator and plasminogen activator inhibitor. Pathophysiol Haemost in thrombocytopenic pregnant women. Am J Obstet Gynecol 114:1014, Thromb 33:134-137, 2003. 1996.129. Dossenbach-Glaninger A, van Trotsenburg M, Dossenbach M, et al: Plas- 151. American Society of Hematology ITP Practice Guideline Panel: Diagnosis minogen activator inhibitor 1 4G/5G polymorphism and coagulation and treatment of idiopathic thrombocytopenic purpura: Recommenda- factor XIII Val34Leu polymorphism: impaired ﬁbrinolysis and early preg- tions of the American Society of Hematology. Ann Intern Med 126:319, nancy loss. Clin Chem 49:1081-1086, 2003. 1997.
852 CHAPTER 40 Coagulation Disorders in Pregnancy152. Webert KE, Mittai R, Sigouin C, et al: A retrospective 11-year analysis of 176. Payne SD, Resnik R, Moore TR, et al: Maternal characteristics and risk of obstetric patients with idiopathic thrombocytopenic purpura. Blood severe neonatal thrombocytopenia and intra-cranial hemorrhage in preg- 102:4306-4311, 2003. nancies complicated by autoirnmune thrombocytopenia. Am J Obstet153. Martin JN, Morrison JC, Files JC: Autoimmune thrombocytopenic Gynecol 177:149, 1997. purpura: Current concepts and recommended practices. Am J Obstet 177. Moise KJ Jr, Carpenter RJ Jr, Cotton DB, et al: Percutaneous umbilical Gynecol 150:86, 1984. cord blood sampling in the evaluation of fetal platelet counts in pregnant154. Imbach P, Jungi TW: Possible mechanisms of intravenous immunoglobu- patients with autoimmune thrombocytopenic purpura. Obstet Gynecol lin: Treatment in childhood idiopathic thrombocytopenic purpura. Blood 72:346, 1988. 46:117, 1983. 178. Scioscia AL, Grannum PAT, Copel JA, Hobbins JC: The use of percutane-155. Bussel JB, Pham LC: Intravenous treatment with gamma globulin in adults ous umbilical blood sampling in immune thrombocytopenic purpura. Am with immune thrombocytopenia purpura: Review of the literature. Vox J Obstet Gynecol 159:1066, 1988. Sang 52:206, 1987. 179. Ghidini A, Sepulveda W, Lockwood CJ, Romero R: Complications of fetal156. Barton JC, Saleh MN: Case report: Immune thrombocytopenia: Effects of blood sampling. Am J Obstet Gvnecol 168:1339, 1993. maternal gammaglobulin infusion in maternal and fetal serum, platelet, 180. Silver RM: Management of idiopathic thrombocytopenic purpura in preg- and monocyte IgG. Am J Med Sci 293:112, 1987. nancy. Clin Obstet Gynecol 41:436, 1998.157. Fehr J, Hofmann V, Kappeler U: Transient reversal of thrombocytopenia 181. Segal NI, Manning FA, Harman CR, Menticoglou S: Bleeding after intra- in idiopathic thrombocytopenic purpura by high-dose intravenous vascular transfusion: Experimental and clinical observations. Am J Obstet gamma globulin. N Engl J Med 306:1254, 1982. Gynecol 165:1.414, 1991.158. Newland AC: The use and mechanisms of action of intravenous immune 182. Paidas MJ, Berkowitz RL, Lynch L, et al: Alloimmune thrombocytopenia: globulin: An update. Br J Haematol 72:301, 1989. Fetal and neonatal losses related to cordocentesis. Am J Obstet Gynecol159. Ben-Chetrit E, Putterman C: Transient neutropenia induced by intrave- 172:475, 1995. nous immune globulin. N Engl J Med 326:270, 1992. 183. Burrows RF, Kelton JG: Low fetal risks in pregnancies associated with160. Newman GC, Novoa MV, Fodero EM, et al: A dose of 75 μg/kg/d of i.v. idiopathic thrombocytopenic purpura. Am J Obstet Gynecol 163:1147.b, anti-D increases the platelet count more rapidly and for a longer period 1990. of time than 50 μg/kg/d in adults with immune thrombocytopenic 184. Silver RM, Branch DW, Scott JR: Maternal thrombocytopenia in preg- purpura. Br J Haematol 112:1076-1078, 2001. nancy: Time for a reassessment. Am J Obstet Gynecol 173:479, 1995.161. Michel M, Novoa MV, Bussel JB: Intravenous anti-D as a treatment for 185. Laros RK, Kagan R: Route of delivery for patients with immune throm- immune thrombocytopenic purpura (ITP) during pregnancy. Br J Hae- bocytopenia. Am J Obstet Gynecol 148:901, 1984. matol 123:142-146, 2003. 186. Skupski DW, Bussel JB: Further insights into autoimmune thrombocyto-162. Kaplan C, Daffos F, Forestier F, et al: Fetal platelet counts in thrombocy- penia and pregnancy. Am J Obstet Gynecol 174:1944, 1996. topenic pregnancy. Lancet 336:979, 1990. 187. Kelton JG, Inwood MJ, Barr RM, et al: The prenatal prediction of throm-163. Cook RL, Miller RC, Katz VL, Cefalo RC: Immune thrombocytopenic bocytopenia in infants of mothers with clinically diagnosed immune purpura in pregnancy: A reappraisal of management. Obstet Gynecol thrombocytopenia. Am J Obstet Gynecol 144:449, 1992. 78:578, 1991. 188. Blanchette VS, Chen L, Defreidberg A, et al: Alloimmunization to the164. Christiaens CCML, Nieuwenhuis HK, Von Dens Borne AEGKr, et al: Idio- PLAT platelet antigen: Results of a prospective study. Br J Haematol pathic thrombocytopenic purpura in pregnancy: A randomized trial on 14:209, 1990. the effect of antenatal low dose corticosteroids on neonatal platelet count. 189. Bussel JB, Berkowitz RL, McFarland JG, et al: Antenatal treatment of Br J Obstet Gynaecol 97:893, 1990. neonatal alloimmune thrombocytopenia. N Engl J Med 319:1374, 1988.165. Jones RW, Asher MI, Rutherford CJ, Munro HM: Autoimmune (idio- 190. Williamson LM, Hacket G, Rennie J, et al: The natural history of fetoma- pathic) thrombocytopenic purpura in pregnancy and the newborn. Br J ternal alloimmunization to the platelet speciﬁc antigen HPA-1a (PlA1, Obstet Gynaecol 84:679, 1977. Zwa) as determined by antenatal screening. Blood 92:2280-2287, 1998.166. Carloss H, McMillan R, Crosby WH: Management of pregnancy in women 191. Berkowitz RL, Bussel JB, McFarland JG: Alloimmune thrombocytopenia: with immune thrombocytopenic purpura. JAMA 224:2756, 1980. State of the art 2006. Am J Obstet Gynecol 195:907-13.a, 2006.167. Ayromlooi J: A new approach to the management of immunologic throm- 192. Von dens Borne AEG, Decary F: Nomenclature of platelet-speciﬁc anti- bocytopenic purpura in pregnancy. Am J Obstet Gynecol 130:235, 1978. gens. Transfusion 30:477, 1990.168. Burrows RF, Kelton JC: Pregnancy in patients with idiopathic thrombo- 193. Newman PJ, Derbes RS, Aster RH: The human platelet alloantigens, PLA’ cytopenic purpura: Assessing the risks for the infant at delivery. Obstet and PLA2, are associated with a leucine33/proline33 amino acid polymor- Gymecol Surv 48:781.b, 1993. phism in membrane glycoprotein IIIA and are distinguishable by DNA169. Scott JR, Rote NS, Cruikshank DP: Antiplatelet antibodies and platelet typing. J Clin Invest 83:1778, 1989. counts in pregnancies complicated by autoimmune thrombocytopenic 194. Shulman NR, Jordan JV: Platelet immunology. In Colman RW Hirsh J, purpura. Am J Obstet Gynecol 145:932, 1983. Marder VJ, Salzman EW (eds): Hemostasis and Thrombosis: Basic Prin-170. Samuels P, Russel JB, Braitman LE, et al: Estimation of the risk of throm- ciples and Clinical Practice. Philadelphia: JB Lippincott, 1982, pp bocytopenia in the offspring of pregnant women with presumed immune 274-342. thrombocytopenia purpura. N Engl J Med 323:229, 1990. 195. Shulman NR, Marder VJ, Heller MC, Collier EM: Platelet and leukocyte171. Rauch AE, Mycek JA, Mills CR, et al: Risk of hrombocytopenia in offspring isoantigens and their antibodies: Serologic, physiologic and clinical of mothers with presumed immune thrombocytopenic purpura. N Engl studies. Prog Hematol 4:222, 1964. J Med 326:1841, 1990. 196. Tanning E, Sldbsted L: The frequency of platelet alloantibodies in172. Moise KJ, Cotton DB: Discordant fetal platelet counts in a twin gestation pregnant women and the occurrence and management of neonatal complicated by idiopathic thrombocytopenic purpura. Am J Obstet alloimmune thrombocytopenic purpura. Obstet Gynecol Surv 45:521, Gynecol 156:1141, 1987. 1990.173. Scott JR, Cruikshank DP, Kochenour NK, et al: Fetal platelet counts in the 197. Valentin N, Vergracht A, Bignon JD, et al: HLA-DRw52a is involved in obstetric management of immunologic thrombocytopenic purpura. Am alloimmunization against PLA1 antigen. Hum Immunol 27:73, 1990. J Obstet Gynecol 136:495, 1980. 198. Mueller-Eckhardt C, Mueller-Eckhardt G, Willen-Ohff H, et al: A new174. Wahbeh CJ, Eden RD, Killam AP, Gall SA: Pregnancy and immune throm- immune response marker for immunization against the platelet alloanti- bocytopenic purpura. Am J Obstet Gynecol 149:238, 1984. gen Br. Vox Sang 57:90.a, 1989.175. Christiaens GCML, Helmerhorst FM: Validity of intrapartum diagnosis 199. Mueller-Eckhardt C, Kiefel V, Grubert A, et al: 347 cases of suspected of fetal thrombocytopenia. Am J Obstet Gynecol 157:864, 1987. neonatal alloimmune thrombocytopenia. Lancet i:363.b, 1989.
CHAPTER 40 Coagulation Disorders in Pregnancy 853200. Berkowitz R, Bussel JB, Hung C, Wissert M: A randomized prospective 223. Bell WR, Braine HG, Ness PM, et al: Improved survival in thrombocyto- treatment trial for patients with “standard risk” alloimmune thrombocy- penic purpura-hemolytic uremic syndrome. N Engl J Med 325:398, topenia (AIT). Am J Obstet Gynecol 195:S23, 2006. 1991.201. Herman JH, Jumbelic MI, Ancona RJ, Kiclder TS: In utero cerebral hemor- 224. Remuzzi G: HUS and TTP: Variable expression of a single entity [Clinical rhage in alloimmune thrombocytopenia. Am J Pediatr Hematol Oncol conference]. Kidney Int 32:292, 1987. 8:312, 1986. 225. Vesey SK, George JN, Lammle B, et al: ADAMTS13 activity in thrombotic202. Bussel JB, Skupski DW, MacFarland JG: Fetal alloimmune thrombocyto- thombocytoepnic purpura-hemolytic uremic syndrome: Relation to pre- penic: Consensus and controversy. J Matern Fetal Med 5:281.b, 1996. senting features and clinical outcomes in a prospective cohort of 142203. Kaplan C, Forestier F, Cox WL, et al: Management of alloimmune throm- patients. Blood 101:60, 2003. bocytopenia: Antenatal diagnosis and in utero transfusion of maternal 226. Furlan M, Robles R, Galbusera M, et al: Von Willebrand factor-cleaving platelets. Blood 72:340, 1988. protease in thrombotic thrombocytopenic purpura and the hemolytic204. McFarland JG, Aster RH, Bussel JB, et al: Prenatal diagnosis of neonatal uremic syndrome. N Engl J Med 339:1578-1584, 1998. alloimmune thrombocytopenia using allele-speciﬁc oligonucleotide 227. George JN: ADAMTS13, thrombotic thrombocytopenic purpura, and probes. Blood 78:2276, 1991. hemolytic syndrome. Curent Hematol Rep 4:167, 2005.205. Bussel JB, Zabusky MR, Berkowitz RL, McFarland JG: Fetal alloimmune 228. Levy GG, Nichols WC, Lian EC, et al: Mutations in a member of the thrombocytopenia. N Engl J Med 337:22-26, 1997. ADAMTS gene family cause thrombotic thrombocytopenicpurpura.206. Giovangrandi Y, Daffos E, Kaplan C, et al: Very early intracranial hemor- Nature 413:488, 2001. rhage in alloimmune thrombocytopenia. Lancet 11:310, 1990. 229. Starke R, Machin S, Scully M, et al: The clinical utility of ADAMTS13207. Bussel JB, Berkowitz RL, Lynch L, et al: Antenatal management of alloim- activity, antigen and autoantibody assays in thrombotic thrombocytope- mune thrombocytopenia with intravenous-γ-globulin: A randomized trial nic purpura. Br J Haematol 136:649, 2006. of the addition of low dose steroid to intravenous-γ-globulin. Am J Obstet 230. Gordjani N, Sutor AH, Zimmerhackl LB, Brandis M: Hemolytic uremic Gynecol 174:1414.a, 1996. syndromes in childhood. Semin Thromb Hemost 23:281, 1997.208. Mir N, Samson D, House MJ, et al: Failure of antenatal high-dose immu- 231. Rehberg JF, Briery C, Hudson WT, et al: Thrombotic thrombocytopenic noglobulin to improve fetal platelet count in neonatal alloimmune throm- purpura masquerading as hemolysis, elevated liver enzymes, low platelets bocytopenia. Vox Sang 55:188, 1988. (HELLP) syndrome in late pregnancy. Obstet Gyncol 108:817, 2006.209. Lynch L, Bussel JB, McFarland JC, et al: Antenatal treatment of alloim- 232. Brostrom S, Bergman OJ: Thrombotic thrombocytopenic purpura: A dif- mune thrombocytopenia. Obstet Gynecol 80:67, 1992. ﬁcult differential diagnosis in pregnancy. Acta Obstet Gynecol Scand210. Marzusch K, Shcnaidt M, Dietl J, et al: High-dose immunoglobulin in the 79:84, 2000. antenatal treatment of neonatal alloimmune thrombocytopenia: Case 233. Esplin MS, Branch DW: Diagnosis and management of thrombotic micro- report and review. Br J Obstet Gynaecol 99:260, 1992. angiopathies during pregnancy. Clin Obstet Gynecol 42:360, 1999.211. Nicolini U, Tannirandorn Y, Gonzalez P, et al: Continuing controversy 234. Rock GA, Shumak KH, Buskard NA, et al: Comparison of plasma exchange in alloimmune thrombocytopenia: Fetal hyperimmunoglobulinemia with plasma infusion in the treatment of thrombotic thrombocytopenic fails to prevent thrombocytopenia. Am J Obstet Gynecol 163:1144, purpura. Canadian Apheresis Study Group [see comments]. N Engl J Med 1990. 325:393, 1991.212. Bowman J, Harman C, Menrigolou S, Pollack J: Intravenous fetal transfu- 235. Rock G, Shumak KH, Kelton J, et al: Thrombotic thrombocytopenic sion of immunoglobulin for alloimmune thrombocytopenia. Lancet purpura: Outcome in 24 patients with renal impairment treated with 340:1034, 1992. plasma exchange. Transfusion (Paris) 32:710, 1992.213. Zimmerman R, Huch A: In utero fetal therapy with immunoglobulin for 236. George JN: The association of pregnancy with thrombotic thrombocyto- alloimmune thrombocytopenia. Lancet 340:606, 1992. penic purpura-hemolytic syndrome. Curr Opin Hematol 10:339, 2003.214. Nicoliru U, Bedeck CH, Kochenour NK, et al: In-utero platelet transfusion 237. Sanchez-Luceros, A, Farias CE, Amaral MM, et al: von Willebrand for alloimmune thrombocytopenia [Letter]. Lancet 2:506, 1988. factor-cleaving protease (ADAMTS13) activity in normal non-pregnant215. Murphy MF, Pullon HW II, Metcalfe P, et al: Management of fetal alloim- women, pregnant and post-delivery women. Thromb Haemost 92:1320, mune thrombocytopenia by weekly in utero platelet transfusions. Vox 2004. Sang 58:45, 1990. 238. Egerman RS, Witlin AG, Friedman SA, et al: Thrombotic thrombocytope-216. Silver RM, Porter TF, Branch DW, et al: Neonatal alloimmune thrombo- nic purpura and hemolytic uremic syndrome in pregnancy: Review of 11 ctytopenia: Antenatal management. Am J Obstet Gynecol 182:1233, cases. Am J Obstet Gynecol 175:950, 1996. 2000. 239. Castella M, Pujol M, Julia A, et al: Thombotic thrombocytopenic purpura217. Overton TG, Duncan KR, Jolley M, et al: Serial platelet transfusion for and pregnancy: A review of 10 cases. Vox Sanguinis 87:287, 2004. fetal alloimmune thrombocytopenia: Platelet dynamics and perinatal 240. Vesely SK, Li X, McMinn JR, et al: Pregnancy outcomes after recovery from outcome. Am J Obstet Gynecol 186:826-831, 2002. thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.218. Birchall JE, Murphy MF, Kaplan C, Kroll H: European collaborative study Transfusion 44:1149, 2004. of the antenatal management of feto-maternal alloimune thrombocyto- 241. Scully M, Starke R, Lee R, et al: Successful management of pregnancy in penia. Br J Haematol 122:175-288, 2003. women with a history of thrombotic thrombocytopaenic purpura. Blood219. Morgan CL, Cannell GR, Addison RS, Minchinton RM: The effect of Coagul Fibrinolysis 17:459, 2006. intravenous immunoglobulin on placental transfer of a platelet-speciﬁc 242. Bloom AL: von Willebrand factor: Clinical features of inherited and antibody: Anti-PL. Transfus Med 1:209, 1991. acquired disorders. Mayo Clin Proc 66:743, 1991.220. Berkowitz RL, Kolb A, McFarland JG, et al: Parallel randomized trials of 243. James AH: Von Willebrand disease. Obstet Gynecol Surv 61:136, 2006. risk-based therapy for fetal alloimmune thrombocytopenia. Obstet 244. Fausett B, Silver RM: Congenital disorders of platelet function. Clin Gynecol 107:91-6.b/?, 2006. Obstet Gynecol 42:390, 1999.221. Thung SF, Grobman WA: The cost effectiveness of empiric intravenous 245. Roque H, Funai E, Lockwood CJ: Von Willebrand disease and pregnancy. immunoglobulin for the antepartum treatment of fetal and neonatal J Matern Fetal Med 9:257, 2000. alloimune thrombocytopenia. Am J Obstet Gynecol 193:1094-1099, 246. Phillips MD, Santhouse A: von Willebrand disease: Recent advances in 2005. pathophysiology and treatment. Am J Med Sci 316:77, 1998.222. Dashe JS, Ramin SM, Cunningham FG: The long term consequences of 247. Lee CA, Chi C, Pavord SR, et al: The obstetric and gynaecological manage- thrombotic microangiopathy (thrombotic thrombocytopenic purpura ment of women with inherited bleeding disorders: Review with guidelines and hemolytic uremic syndrome) in pregnancy. Obstet Gynecol 91:662, produced by a taskforce of UK Haemophilia Centre Doctor’s Organiza- 1998. tion. Haemophilia 12:301, 2006.
854 CHAPTER 40 Coagulation Disorders in Pregnancy248. Holmberg L, Nillson IM, Borge L, et al: Plaetlet aggregation induced by 272. Leticee N, Kaplan C, Lemery D: Pregnancy in mother with Glanzmann’s 1-desamino-8-D-arginine vasoporessin (DDAVP) in type IIB von Wille- thrombasthenia and isoantibody against GPIIb-IIIa: Is there a foetal risk? brand disease. N Engl J Med 309:816, 1983. Eur J Obstet Gynecol Reprod Biol 121:139, 2005.249. James AH, Jamison MG: Bleeding events and other complications during 273. Sherer DM, Lerner R: Glanzmann’s thrombasthenia in pregnancy: A case pregnancy and childbirth in women with von Willebrand disease. J and review of the literature. Am J Perinatol 16:297, 1999. Thromb Haemost 5:1165-1169, 2007. 274. Kale A, Bayhan G, Yalinkaya A, et al: The use of recombinant factor VIIa250. Peake IR, Bowen D, Bignell P, et al: Family studies and prenatal diagnosis in a primagravida with Glanzmann’s thrombasthenia during delivery. J in severe von Willebrand disease by polymerase chain reaction ampliﬁca- Perinat Med 32:456, 2004. tion of a variable number tandem repeat region of the von Willebrand 275. Poon MC, d’Orion R, Hann I, et al: Use of recombinant factor VIIa factor gene. Blood 76:555, 1990. (NovoSeven) in patients with Glanzmann thrombasthenia. Semin Hematol251. Peyvandi F, Jayandharan G, Chandy M, et al: Genetic diagnosis of 38:21, 2001. haemophilia and other inherited bleeding disordes. Haemophilia 12:82, 276. Franchini M, Lippi G, Franchi M: The use of recombinant activated factor 2006. VII in obstetric and gynaecological hemorrhage. BJOG 114:8, 2006.252. Rothschild C, Forestier F, Daffos F, et al: Prenatal diagnosis in type IIA von 277. Franchini M: Postpartum acquired factor VII inhibitors. Am J Hematol Willebrand disease. Nouv Rev Fr Hematol 32:125, 1990. 81:768, 2006.253. Shetty S, Ghosh K: Robustness of factor assays following cordocentesis in 278. Kulkarni AA, Lee CA, Kadir RA: Pregnancy in women with congenital the prenatal diagnosis of hemophilia and other bleeding disorders. Hae- factor VII deﬁciency. Haemophilia 12:413, 2006. mophilia 13:172, 2007. 279. Romagnolo C, Burati S, Ciaffoni S, et al: Severe factor X deﬁciency in254. Sage DJ: Epidurals, spinals, and bleeding disorders in pregnancy: A review. pregnancy: Case report and review of the literature. Haemophilia 10:665, Anesth Intensive Care 18:319, 1990. 2004.255. Marrache D, Mercier FJ, Boyer-Newman C, et al: Epidural analgesia for 280. Uprichard J, Perry DJ: Factor X deﬁciency. Blod Rev 16:97-110, 2002. parturients with type 1 von Willebrand disease. Int J Obstet Anesth 281. Boﬁll JA, Young RA, Perry KG: Successful pregnancy in a woman with 16:231-235, 2007. severe factor X deﬁciency. Obstet Gynecol 88:723, 1996.256. Chediak JR, Alban GM, Maxey B: von Willebrand’s disease and pregnancy: 282. Leiba H, Ramot B, Many A: Heredity and coagulation studies in ten fami- Management during delivery and outcome of offspring. Am J Obstet lies with factor XI deﬁciency. Br J Haematol 11:654, 1965. Gynecol 155:618, 1986. 283. Salomon O, Steinberg DM, Tamarin I, et al: Plasma replacement therapy257. Berndt MC, Gregory C, Chong BH, et al: Additional glycoprotein defects during labor is not mandatory for women with severe factor XI deﬁciency. in Bernard-Soulier’s syndrome: Conﬁrmation of genetic basis by parental Blood Coagul Fibrinolysis 16:37, 2005. analysis. Blood 62:800, 1983. 284. Myers B, Pavrod S, Kean L, et al: Pregnancy outcome in factor XI deﬁ-258. Lopez JA, Andrews RK, Afshar-Kharghan V, Berndt MC: Bernard-Soulier ciency: Incidence of miscarriage, antenatal and postnatal hemorrhage in syndrome. Blood 91:4397, 1998. 33 women with factor XI deﬁciency. BJOG 114:643, 2007.259. Prabu P, Parapia LA: Bernard-Soulier syndrome in pregnancy. Clin Lab 285. Asahina T, Kobayashi T, Takeuchi K, et al: Congenital blood coagulation Haematol 28:198, 2006. factor XIII deﬁciency and successful deliveries: A review of the literature.260. Peaceman AM, Katz AR, Laville M: Bernar-Soulier syndrome complicat- Obstet Gynecol Surv 62:255, 2007. ing pregnancy: A case report. Obstet Gynecol 73:457, 1989. 286. Kobayashi T, Terao T, Kojima T, et al: Congenital factor XIII deﬁciency261. Saade G, Homsi R, Seoud M: Bernard-Soulier syndrome in pregnancy: A with treatment of factor XIII concentrate and normal vaginal delivery. report of four pregnancies in one patient, and review of the literature. Eur Gynecol Obstet Invest 29:235, 1990. J Obstet Gynecol Reprod Biol 40:149, 1991. 287. Frenkel E, Duskin C, Herman A, et al: Congenital hypoﬁbrinogenemia in262. Kaleelrahman M, Minford A, Parapia LA: Use of recombinant factor VIIa pregnancy: Report of two cases and review of the literature. Obstet in inherited platelet disorders. Br J Haematol 125:95, 2004. Gynecol Surv 59:775, 2004.263. Edozien LC, Jip J, Mayers FN: Platelet storage pool deﬁciency in preg- 288. Funai EF, Klein SA, Lockwood CJ: Successful pregnancy outcome in a nancy. Br J Clin Pract 49:220, 1995. patient with both congenital hypoﬁbrinogenemia and protein S deﬁ-264. Price FV, Legro RS, Watt-Morse M, Kaplan SS: Chediak-Higashi syndrome ciency. Obstet Gynecol 20:858, 1997. in pregnancy. Obstet Gynecol 79:804-806, 1992. 289. Iwaki T, Sandoval-Cooper MJ, Pavia M, et al: Fibrinogen stabilizes placen-265. Siminovitch KA: Prenatal diagnosis and genetic analysis of Wiskott- tal-maternal attatchment during embryonic development in the mouse. Aldrich syndrome. Prenat Diagn 23:1014, 2003. Am J Pathol 160:1021, 2002.266. Shelton SD, Paulyson K, Kay HH: Prenatal diagnosis of thrombocytopenia 290. Girolami A, Randi ML, Gavasso S, et al: The occasional venous thrombo- absent radius (TAR) syndrome and vaginal delivery. Prenat Diagn 19:54, ses seen in patients with severe (homozygous) FXII deﬁciency are 1999. probably due to associated risk factors: A study of prevalence in 21267. Reiss RE, Copel JA, Roberts NS, Hobbins JC: Hermansky-Pudlak syn- patients and review of the literature. J Thromb Thrombolysis 17:139, drome in pregnancy: Two case studies. Am J Obstet Gynecol 153:564, 2004. 1985. 291. Girolami A, Zocca N, Girolami B, et al: Pregnancies and oral contraceptive268. Wax JR, Rosengren S, Spector E, et al: DNA diagnosis and management therapy in severe (homozygous) FXII deﬁciency: A study in 12 patients of Hermansky-Pudlak syndrome in pregnancy. Am J Perinat 18:159, and review of the literature. J Thromb Thrombolysis 18:209, 2004. 2001. 292. Sotiriadis A, Makrigiannakis A, Stefos T, et al: Fibrinolytic defects and269. Seligsohn U, Mibashan RS, Rodeck CH, et al: Prenatal diagnosis of recurrent miscarriage. Obstet Gynecol 109:1146, 2007. Glanzmann’s thrombasthenia [Letter]. Lancet 2:1419, 1985. 293. Repine T, Osswald M: Menorrhagia due to a qualitative deﬁciency of270. Reichert N, Seligsohn U, Ramot B: Clinical and genetic aspects of plasminogen activator inhibitor-1: Case report and literature review. Clin Glanzmann’s thrombasthenia in Israel: A report of 22 cases. Thromb Appl Thrombosis/Hemostasis 10:293-296, 2004. Diath Hemorrh 3:806, 1975. 294. Agren A, Wiman B, Stiller V, et al: Evaluation of low PAI-1 activity as a271. Walters JP, Hall JS: Glanzmann’s thrombasthenia and pregnancy. West risk factor for hemorrhagic diathesis. J Thromb Haemost 4:201-208, Indian Med J 39:256, 1990. 2006.