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  1. 1. 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
  2. 2. 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-
  3. 3. 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
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. 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.
  8. 8. 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;
  9. 9. 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
  10. 10. 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)
  11. 11. 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-
  12. 12. 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-

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