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Obstet gynecol surv 67 (426 35) 2012
1. 20 CME REVIEW ARTICLE Volume 67, Number 7 OBSTETRICAL AND GYNECOLOGICAL SURVEY Copyright * 2012 by Lippincott Williams & Wilkins CHIEF EDITOR’S NOTE: This article is part of a series of continuing education activities in this Journal through which a total of 36 AMA/PRA Category 1 Creditsi can be earned in 2012. Instructions for how CME credits can be earned appear on the last page of the Table of Contents. Obstetric Hemorrhage and Coagulation: An Update. Thromboelastography, Thromboelastometry, and Conventional Coagulation Tests in the Diagnosis and Prediction of Postpartum Hemorrhage Natascha M. de Lange, MD,* Marcus D. Lance, MD,† Renee de Groot, MD,‡ ´ ´ Erik A.M. Beckers, MD, PhD,§ Yvonne M. Henskens, PhD,¶ and Hubertina C.J. Scheepers, MD, PhD|| *Resident in Gynecology, Department of Obstetrics and Gynecology, Orbis Medical Centre, Sittard; †Anesthesiologist, Departments of Anesthesiology and Pain Treatment, ‡Resident in Prenatal Diagnosis, Department of Obstetrics and Gynecology, §Hematologist, Department of Internal Medicine-Hematology, ¶Clinical Chemist, Hematological Laboratory, ||Gynecologist, GROW School for Oncology and Developmental Biology and Department of Obstetrics and Gynecology, Maastricht University Medical Center, Maastricht, the Netherlands Globally, postpartum hemorrhage (PPH) is the leading cause of maternal morbidity and mortality. In the current treatment of severe PPH, ﬁrst-line therapy includes transfusion of packed cells and fresh- frozen plasma in addition to uterotonic medical management and surgical interventions. In persistent PPH, tranexamic acid, ﬁbrinogen, and coagulation factors are often administered. Secondary coa- gulopathy due to PPH or its treatment is often underestimated and therefore remains untreated, potentially causing progression to even more severe PPH. In most cases, medical and transfusion therapy is not based on the actual coagulation state because conventional laboratory test results are usually not available for 45 to 60 minutes. Thromboelastography and rotational thromboelastometry are point-of-care coagulation tests. A good correlation has been shown between thromboelastometric and conventional coagulation tests, and the use of these in massive bleeding in nonobstetric patients is widely practiced and it has been proven to be cost-effective. As with conventional laboratory tests, there is an inﬂuence of ﬂuid dilution on coagulation test results, which is more pronounced with colloid ﬂuids. Fibrinogen seems to play a major role in the course of PPH and can be an early predictor of the severity of PPH. The FIBTEM values (in thromboelastometry, reagent speciﬁc for the ﬁbrin polymerization process) decline even more rapidly than ﬁbrinogen levels and can be useful for early guidance of interventions. Data on thromboelastography and thromboelastometry in pregnant women are limited, particularly during the peripartum period and in women with PPH, so more research in this ﬁeld is needed. Target Audience: Obstetricians & Gynecologists, Family Physicians Learning Objectives: After participating in this CME activity, physicians should be better able to manage postpartum hemorrhage and to evaluate the possible uses of thromboelastography and thromboelastometry to treat obstetric hemorrhage. All authors and staff in a position to control the content of this CME VII and procoagulative agents for the treatment of obstetric hem- activity and their spouses/life partners (if any) have disclosed that orrhage as discussed in this article. Please consult the product’s they have no ﬁnancial relationships with, or ﬁnancial interests in, any labeling for approved information. commerical organizations pertaining to this educational activity. Correspondence requests to: Natascha M. de Lange, MD, Poli The authors have disclosed that the US Food and Drug Admin- gynaecologie/Oost 11, Postbus 5500, 6130 MB Sittard, the istration has not approved the use of recombinant activated factor Netherlands. E-mail: firstname.lastname@example.org. www.obgynsurvey.com | 426 Copyright © 2012 by Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstetric Hemorrhage and Coagulation: Update & CME Review Article 427 PRACTICE PEARLS because speciﬁc pregnancy- and peripartum-related hemodynamic and hemostatic changes are likely to in- & The usefulness of conventional laboratory clot- ﬂuence TEG/TEM results. For a correct interpretation ting tests is very limited in immediate situations of TEG/TEM in women with PPH, reference values such as PPH. for pregnancy have yet to be determined. The aim of & Do not underestimate coagulopathy (by dilution) this narrative review was to discuss: in the course and treatment of PPH. & Thromboelastography or thromboelastometry might 1) hemostasis and hemostatic changes during pregnancy, be helpful in the treatment of PPH once normal 2) deﬁnitions and management of PPH, values and evaluated cutoff values for intervention 3) coagulation and PPH, have been deﬁned. 4) the principles of TEG and ROTEM, and 5) the use of TEG and ROTEM in obstetric hemorrhage. Globally, obstetric hemorrhage is the leading causeof maternal morbidity and mortality, with approxi- Hemostasis and Hemostatic Changesmately 25% of all maternal deaths caused by excessive During Pregnancyblood loss and inadequate treatment or resources.1Berg et al2 reported that 40% of pregnancy-related Hemostasis is vital for preventing major blood lossdeaths are potentially preventable, particularly deaths because it seals sites of injury in the vascular system;that occur as a consequence of hemorrhage. Obstetric however, it must be controlled to prevent blood fromhemorrhage currently causes 7% of maternal deaths coagulating within the vasculature and restrictingin the Netherlands.3 In addition to mortality, severe normal blood ﬂow. In the last decades, our knowledgemorbidity may occur after postpartum hemorrhage of coagulation has grown with development of the(PPH), that is, loss of fertility, Sheehan syndrome, cell-based model of coagulation.14,15 There has been aand multiple-organ failure due to hypovolemic shock.4 transition in knowledge, whereby the intrinsic andTaking these numbers and consequences into consid- extrinsic coagulation pathways are recognized to beeration, there is a need to improve the care around PPH. not redundant but as parallel generators of factor Xa The most common cause of massive PPH is uterine that occurs on different cell surfaces.atony; other causes include surgical incisions, lacera- The cell-based model of coagulation consists oftions, and coagulation disorders. Abnormal placen- initiation, ampliﬁcation, and propagation phases. Newtation, such as placenta previa or placenta accreta, is a in vivo models have identiﬁed tissue factor (TF) as theknown risk factor for PPH, with an increasing inci- sole initiator of coagulation. Tissue factor is expres-dence mainly because of the rising rate of cesarean sed on cells outside the vascular system; once an in-deliveries. jury occurs, the TF-bearing cells are exposed to blood Coagulation disorders may present as a primary or and circulating factor VIIa immediately binds to TF.secondary cause of massive PPH; the latter is often This results in the generation of a small amount ofunderestimated and undertreated. Secondary coagu- factor IXa and thrombin, which then diffuse to thelation disorders may result from dilution (dilutional platelets. In the ampliﬁcation phase, thrombin relea-coagulopathy) or depletion of clotting factors or sub- ses von Willebrand factor (vWF) and leads to gen-strates such as erythrocytes or platelets (consumptive eration of activated forms of factors V, VIII, and XI.coagulopathy). The development of secondary coag- In the propagation phase, the various factors andulation disorders with delay in obstetric management enzymes assemble on the surface of the activatedis a crucial prognostic factor for the severity of PPH.5 platelet to form the tenase complex and to generate Many guidelines and ﬂowcharts have been published factor Xa, the prothrombinase complex is formed, andto optimize the management of PPH.6Y9 In these guide- thrombin generation takes places on the platelet sur-lines, conventional laboratory tests and vital parameters face. This process leads to generation of ﬁbrin fromare used to guide transfusion. The use of thromboelas- ﬁbrinogen.15,16tography (TEG) or thromboelastometry (ROTEM) in During pregnancy, plasma volume increases bymassive bleeding in nonobstetric patients is widely 40% and the erythrocyte count increases by 25%. As apracticed and has been proven to be cost-effective. result, hemoglobin levels and hematocrit decrease be-Current guidelines for the treatment of massive hemor- cause of this physiological hemodilution.17 In addition,rhage in patients with injury from trauma recommend platelet levels drop because of both hemodilution andthe use of TEG or TEM.10Y13 However, TEG/TEM increased consumption in the uteroplacental unit.17,18results in patients with injury from trauma cannot be In contrast, levels of many coagulation factors in-easily compared with those from women during labor crease during pregnancy, including vWF, factors Copyright © 2012 by Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
428 Obstetrical and Gynecological SurveyVII and VIII, as well as ﬁbrinogen and factor IX. The most common cause of PPH is uterine atony,Other factors, such as factors XII and V, remain un- which should be treated immediately by emptyingchanged.19,20 Natural coagulation inhibitors, such as the bladder and administering pharmacological agentsprotein S, decrease, and the ﬁbrinolytic system is such as oxytocin, ergometrine, or misoprostol.7 Othernegatively inﬂuenced by the increased plasminogen causes of blood loss, such as retained products ofactivator inhibitor and thrombin-activatable ﬁbrino- conception, uterine, or birth canal trauma, or pre-lysis inhibitor. Overall, these changes result in a state existing coagulation problems must be considered asof hypercoagulability and hypoﬁbrinolysis, which is well. Management should include the following steps:protective against excessive blood loss at delivery but (1) Laboratory evaluation: hemoglobin level, hemat-also leaves pregnant women more prone to throm- ocrit, platelet count, and ﬁbrinogen concentration, asboembolic events. well as PT and aPTT. (2) Volume resuscitation: ini- Fibrinogen levels rise signiﬁcantly from week 28 to tially ﬂuid resuscitation, followed if necessary bytwice the nonpregnant levels by term and remain el- transfusion of red blood cells to ensure rapid correc-evated throughout the ﬁrst postpartum days.17,18,21Y23 tion of oxygen carrying capacity. The risk of dilu-The rise in ﬁbrinogen levels is likely to be caused by tional coagulopathy due to ﬂuid resuscitation shouldan increase in synthesis due to hormonal changes, be considered. (3) Correction of coagulation factors:particularly elevated estrogen levels.24 depending on laboratory results and the clinical D-Dimer values increase progressively during preg- condition of the patient, fresh-frozen plasma (FFP),nancy, peaking at the ﬁrst day postpartum and de- ﬁbrinogen, platelets, or tranexamic acid can be ad-creasing thereafter. This rise in D-dimers occurs with ministered. The off-label use of recombinant activateda simultaneous increase in circulating ﬁbrinogen and factor VII should be considered only in refractory casesother procoagulant factors during pregnancy. Despite with ongoing bleeding after sufﬁcient correction of allhypoﬁbrinolysis, the excess ﬁbrin deposition results deﬁciencies has been achieved. (4) Surgical measures:in an increase in tissue plasminogen activator and evacuation of retained placental fragments, balloonhigher D-dimer values.17Y20,24,25 tamponade, selective embolization of the uterine artery, Despite these hemostatic alterations in pregnancy, uterine compression sutures (B-lynch), or hysterecto-laboratory studies show unchanged or only slightly my as necessary and as clinically indicated.6Y9decreased levels of activated partial thromboplastin Above all, it is important to note that massive PPHtime (aPTT), prothrombin time (PT), and interna- is potentially life threatening and requires a multi-tional normalized ratio (INR); all of these remain disciplinary approach, including all staff working at awithin reference limits for nonpregnant women.20 labor ward, anesthesia, and hematology. The Conﬁ-These overall hypercoaguable hemostatic changes dential Enquiry into Maternal and Child Health incontribute to the physiological preparation for deliv- the Netherlands strongly recommends the develop-ery and prevention of excessive blood loss postpar- ment of multidisciplinary massive hemorrhage guide-tum. An alteration in this equilibrium may inﬂuence lines, adapted to the hospital. Such protocols are widelythe course of PPH. used in trauma medicine to simplify and expedite the delivery of blood products to hemorrhagic patients.13,29,30 In obstetrics, there are few publica- tions regarding the implementation of massive hem- Deﬁnitions and Management of PPH orrhage guidelines in clinical practice.31Y34 However, Deﬁnitions for PPH vary. In general, PPH is deﬁned several publications report an improved maternalas blood loss of more than 500 mL within 24 hours outcome after the introduction of a multidisciplinaryafter vaginal delivery or 1000 mL after cesarean de- protocol and approach in PPH, despite more cases oflivery. Blood loss more than 1500 mL, a decline in PPH.35,36 The use of these protocols and regular localhemoglobin of 4 g/dL or more, transfusion of at least drill is recommended; review of procedures for4 units of red blood cells, or the need for a hemostatic management of PPH through regular courses can also(embolization) or operative intervention indicates be useful.7,34severe PPH. Massive blood loss is deﬁned as the lossof 1 blood volume, the loss of 50% of blood volumewithin 3 hours, or a loss rate of 150 mL/min.26 It is Coagulation Factors in PPHimportant to note that the amount of blood loss in PPHis very difﬁcult to assess clinically and is usually Primary coagulation disorders are not frequentlyunderestimated.27,28 identiﬁed as a cause of PPH, except in women on Copyright © 2012 by Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstetric Hemorrhage and Coagulation: Update & CME Review Article 429anticoagulation medication or with a known history of aPTT (to detect deﬁciencies of coagulation factorsbleeding disorders.5 Case series have shown a higher VIII, IX, XI, and/or XII) and PT (to detect deﬁcienciesincidence of PPH in women with inherited bleeding of coagulation factors X, VII, V, and II) only measuredisorders such as von Willebrand disease (risk ratio, the plasma component of the coagulation cascade and1.5Y3.0).37Y39 Other causes that have been indepen- were initially developed as laboratory tests to monitordently associated with a signiﬁcant risk of severe anticoagulant treatment, including heparin and vita-PPH include low levels of ﬁbrinogen (even without min K antagonists, respectively.reaching levels of deﬁciency), vWF antigen, factor Transfusion with ﬂuids, packed red blood cells, andXI, or platelet CD42b; TRAP-induced increase of FFP will aggravate dilutional coagulopathy as hasplatelet CD41a; nbd high values of serum residual been demonstrated in cardiac surgery.50 Such pro-prothrombin activity and blood group O. The presence ducts do not correct coagulation disorders completelyof 2 or more independent risk factors showed an odds because even FFP contains insufﬁcient amounts ofratio of 16.4 for severe PPH.40 coagulation factors. Most PPH protocols advocate the General screening of the pregnant population for transfusion of 4 FFP for every 6 units of packed reddisorders of coagulation would not be cost-effective blood cells or if PT/aPTT is greater than 1.5 timesor informative because of the low prevalence and normal, according to guidelines for management ofinsufﬁcient data on reference ranges in pregnancy, as bleeding after major trauma. In recent years, therewell as limited data on therapeutic algorithms based have been several publications that suggest a betteron such screening results. In women with clinical outcome and fewer transfusions when transfusingPPH, however, primary coagulation disorders should packed red blood cells and FFP on a 2:3 or even on abe considered. Most patients with PPH due to a coa- 1:1 ratio and early transfusion of FFP; however, suchgulopathy will have a history that points to bleeding studies are mainly retrospective.13,51Y53tendency (bruising, hematoma, bleeding with teeth In persistent PPH, ﬁbrinogen, coagulation factors,brushing, and/or heavy menstrual bleeding).41 and tranexamic acid are often administered. Tra- Severe PPH may result in secondary coagulopathy, nexamic acid has an antiﬁbrinolytic effect and acts bysimilar to what is seen in massive blood loss in blocking the conversion of plasminogen to plasma. Itpatients with injury from trauma. This may be due to is effective in reducing perioperative and postopera-the consumption of coagulation factors, dilution, ac- tive blood loss54,55 and in reducing heavy menstrualidosis, or hypothermia. Resuscitation with crystalloid bleeding.56 During delivery of the placenta, there isﬂuids in large amounts may induce dilutional acido- rapid degradation of ﬁbrinogen and ﬁbrin, as well assis, formation of interstitial edema, and impairment of activation of plasminogen activators and productionmicrocirculation.42 Colloid ﬂuids, in particular syn- of ﬁbrin degradation products due to the activation ofthetic colloids such as hydroxyethyl starch solutions the ﬁbrinolytic system. The antiﬁbrinolytic effect of(HESs), may impair clot formation and therefore in- tranexamic acid could theoretically reduce blood losscrease blood loss.43,44 Even new-generation medium- in the third stage of labor, although at present, there ismolecular-weight HES disturbs ﬁbrin polymerization insufﬁcient evidence to support its use in this set-in patients undergoing spine surgery, and the presence ting.57 In addition, a study by Charbit et al found noof HES or gelatin solutions in patients with ﬁbrino- evidence of hyperﬁbrinolysis in patients with PPHlysis leads to faster clot disintegration.45,46 Progressive because of severe uterine atony.48 The WOMAN Trialdilutional coagulopathy, hypothermia, and metabolic (World Maternal Antiﬁbrinolytic Trial), a randomizedacidosis have been referred to as the lethal triad in controlled trial in which tranexamic acid is comparednonpregnant patients with massive blood loss.47,48 to placebo in women with PPH, might resolve this In current guidelines for management of severe issue.58PPH, transfusion of packed cells, FFP, and platelets, The off-label use of procoagulative agents such asin addition to uterotonic therapy, ﬂuid resuscitation, recombinant factor VIIa is only indicated and effec-and surgical measures, is regarded as ﬁrst-line ther- tive in the presence of adequate substrate for coagu-apy.6Y9 In most cases, therapy of PPH cannot be lation (ﬁbrinogen and platelets) and is not withoutbased on the actual hemostatic competence because risk; a meta-analysis reported signiﬁcantly more ar-regular conventional coagulation tests typically re- terial thrombotic events in patients receiving recom-quire 45 to 60 minutes for results to be available and binant factor VIIa.59,60 Possible adverse effects ofare nonspeciﬁc.49 One logistical challenge is the time uncontrolled administration of blood products andneeded to prepare plasma from anticoagulant whole factor concentrates also include thrombosis and vol-blood samples. Another clinical challenge is that ume overload. Copyright © 2012 by Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
430 Obstetrical and Gynecological Survey The absence of quick and speciﬁc laboratory tests vere bleeding. Although data are limited, resultsto monitor PPH and assess the development of a consistently favor the early administration of ﬁbrin-secondary coagulopathy can result in excessive and ogen over FFP in bleeding patients.66avoidable usage of blood products. A preferred ap-proach would be the selective administration of bloodproducts and clotting factors according to deple- Principles of TEG and TEMtion.61,62 The general protocols and guidelines used Both TEG and ROTEM are so-called dynamic,for the nonpregnant patient are likely not adequate or viscoelastic coagulation tests, which represent theappropriate for peripartum women. In pregnancy, the whole coagulation process from the initiation of clotrelative hypercoagulable state makes uncontrolled formation through ﬁbrinolysis. The tests are per-treatment potentially more dangerous. In addition, formed on whole blood instead of plasma, whichthere are no clear therapeutic thresholds deﬁned for saves time and means that these tests represent theperipartum women. It is unclear whether treatment interaction between cellular and plasma clotting fac-should be aimed at achieving minimal levels de- tors. These point-of-care devices have several sepa-scribed for nonpregnant subjects or whether preg- rate channels, allowing multiple samples to be runnancy normal values should be the goal. Evaluation of simultaneously or sequentially.ﬁbrinogen levels presents a good example of this Thromboelastography was introduced by Hartertissue; Charbit et al63 investigated different coagula- in 1948 in a trial setting. Clinically, it was ﬁrst used intion parameters during PPH and found that PT, INR, 1985 in hepatic and cardiothoracic surgery. The TEGaPTT, ﬁbrinogen, D-dimer, prothrombin, and factor V mechanism consists of a plastic pin attached to awere signiﬁcantly lower in a group of women with torsion wire that is immersed in a rotating cup. Aftersevere PPH compared to women with milder PPH. In clot formation, an electrical signal is traced as a curveboth groups, however, the ﬁbrinogen values were over time (Fig. 1). The outcome of a TEG tracing iswithin the reference range for nonpregnant subjects presented as 5 parameters:(2Y4 g/L). In the peripartum period, however, normalﬁbrinogen values are above what is considered normal & R: Period from initiation of the test to the initialand vary from 3.5 to 6.5 g/L.20 Consequently, values ﬁbrin formation and pin movement (seconds)used to guide interventions might differ from non- & K: Time from the beginning of clot formationpregnant levels. until the amplitude of the TEG reaches 20 mm Fibrinogen is of importance in forming a ﬁrm clot (seconds)and is the ﬁrst parameter to decrease during massive & > angle: Angle between the line in the middle ofbleeding, due to increased ﬁbrinogen consumption as the TEG tracing and the line tangential to thewell as hemodilution resulting from ﬂuid adminis- developing ‘‘body’’ of the TEG (degrees)tration. Fibrinogen is the only parameter that has been & Maximal amplitude (MA) = Greatest amplitudeshown to be signiﬁcantly lower and independently of the TEG tracing (mm)associated with progress toward severe bleeding. Fi- & LY30 = Rate of amplitude reduction 30 minutesbrinogen levels of 2 g/L or lower have been reported to after MAhave a positive predictive value of 100% and thereforecould be an early predictor of severe PPH.63 Gayatet al64 published a retrospective cohort on the pre-dictors of severe PPH; in a univariate analysis, ﬁ-brinogen levels less than 2 g/L and prothrombin timeless than 50% were signiﬁcant predictors of severePPH, whereas in the multivariate analysis only ﬁ-brinogen levels less than 2 g/L remained signiﬁcant.Bell et al65 presented 6 cases of obstetric hemorrhageassociated with hypoﬁbrinogenemia (all ﬁbrinogenlevels G1.5 g/L) that was treated with ﬁbrinogen; co-agulation test results rapidly normalized and severehemorrhage improved. Notably, however, all patientsalso received platelets, FFP, and packed red blood cells. In contrast to obstetrics, many surgical specialtiesuse early administration of ﬁbrinogen in cases of se- Fig. 1. Result of TEG. Copyright © 2012 by Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstetric Hemorrhage and Coagulation: Update & CME Review Article 431 Alterations of the normal TEG pattern and varia- ferentiate between the related pathways (extrinsictions in the different parameters provide information and intrinsic pathway respectively).regarding alterations in the dynamic coagulation 2. Insufﬁcient substrate for clot formation due toprocess. Alterations in the R value are related to co- platelet and ﬁbrinogen deﬁciency: CT is normal,agulation factor activation, K and > angle parameters CFT is slightly prolonged, and the clot amplitudeare related to coagulation factor ampliﬁcation, MA (CA) and MCF are reduced. Platelets are inhibitedreﬂects platelet aggregation, and LY30 reﬂects ﬁbri- in FIBTEM, implying that FIBTEM evaluates thenolysis at different points in time (LY30 is 30 minutes speciﬁc ﬁbrinogen component.after maximum amplitude is reached). 3. Hyperﬁbrinolysis: Formation and strength are Thromboelastometric tests can be run in native normal, but the clot lysis index is increased. Thiswhole blood. However, it is common to use activators can be conﬁrmed by the APTEM12,68,69 (Fig. 2).to speed up the process and standardize the tests and tosimulate different pathways of activation. Tissue Use of TEG or ROTEM in Obstetricsfactor and kaolin can be incorporated into the TEGcuvette, and heparinase and platelet GpIIb/IIIa inhi- There have been several publications on the use ofbitors can also be used to provide more detailed in- TEG and less on the use of ROTEM in pregnancy.formation in speciﬁc clinical settings67 (Fig. 1). Some studies have compared pregnant women to Thromboelastometry is based on the same princi- nonpregnant subjects, conﬁrming the hypercoaguableples as TEG, but its mechanism is a rotating plastic pin state of parturients with TEG.70,71 Other studies fo-ﬁxed on a steel axis that is immersed into a cup. The cused on speciﬁc situations during pregnancy andmovement of the pin is converted to an optical signal delivery. In this review, we focus on normal preg-and transferred to a graphical display. The outcome of nancy, normal delivery, and PPH.a TEM tracing is very similar to the TEG with resultsalso presented as 5 parameters: Comparing Pregnant With Nonpregnant Women & Clotting time (CT): Time from start of mea- Armstrong et al72 compared the TEM coagulation surement until initiation of clotting (seconds) parameters of healthy pregnant women to healthy non- & Clot formation time (CFT): Time from initiation pregnant female controls and clearly demonstrated the of clotting until a clot ﬁrmness of 20 mm is hypercoaguable state of normal pregnancy. Although detected (seconds) it was concluded that ROTEM could be a helpful ad- & > angle: Angle between the line in the middle of junct to conventional laboratory testing in reducing the TEM tracing and the line tangential to the delays in instituting appropriate treatment, reference developing ‘‘body’’ of the TEM (degrees) values for pregnant women were lacking. Huissoud & Maximum clot ﬁrmness (MCF): Firmness of the et al73 showed a signiﬁcant increase in MCF, clot clot (mm) amplitude at 5 seconds (CA5) and clot amplitude at & Maximum lysis (ML): Reduction of the clot 15 seconds (CA15) (INTEM, EXTEM, and FIBTEM) ﬁrmness after MCF in relation to MCF (%) in the second and third trimesters in healthy pregnant Different coagulation activators (reagents) are used women. This is again in concordance with and conﬁrmsto catalyze the process. In the INTEM assay Ca2+, the hypercoaguable state of pregnancy. The CT andphospholipids and ellagic acid are used to activate and clot lysis index at 30 (CLI30) do not change duringassess the coagulation process via the intrinsic path- pregnancy. There is a signiﬁcant correlation betweenway. Tissue factor is used in EXTEM assays for ac- thromboelastometric and conventional coagulationtivation and assessment of the extrinsic pathway.Besides TF, a platelet inhibitor (cytochalasin) isadded to the blood sample in the FIBTEM assay todifferentiate between platelet dysfunction and the ﬁ-brin polymerization process. In APTEM, a ﬁbrino-lysis inhibitor (aprotinin) is used together with TF toconﬁrm or to rule out hyperﬁbrinolysis. Abnormali-ties can occur in 3 areas:1. Initial clotting abnormality due to clotting factor deﬁciency: CT and CFT are prolonged and the angle of the curve is reduced. EXTEM and INTEM dif- Fig. 2. Result of ROTEM. Copyright © 2012 by Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
432 Obstetrical and Gynecological Surveytests, and a strong correlation between ﬁbrinogen to a control group from a preliminary study and showedconcentration and clot amplitude in the FIBTEM that in ROTEM, the FIBTEM- clotting amplitudes wereanalysis was found. These data combined with the signiﬁcantly lower in the PPH group compared withresults of Charbit et al suggested that TEG could be the control group without abnormal bleeding. Aused as a rapid diagnostic tool to detect a decrease in limitation of the publication is that it is not completelyﬁbrinogen in cases of severe bleeding.63 clear at what time the blood samples were taken and Oudghiri et al74 deﬁned reference values for TEM the degree of blood loss at that moment. A strongparameters in the postpartum period in uncomplicated and signiﬁcant correlation between ﬁbrinogen levelsdeliveries. As was previously shown, a strong corre- and the FIBTEM parameters is presented for the PPHlation between thromboelastometric and conventional group as well as for the control group. The ﬁbrinogencoagulation parameters was found, especially be- threshold of 2 g/L corresponded to a CA5-FIBTEM oftween ﬁbrinogen concentration and FIBTEM CA5. 6 mm and a CA15 of 8 mm, both with 100% sensi-Unfortunately, the study excluded women with PPH, tivity and with 87% and 84% speciﬁcity, respectively.making the data of uncertain applicability to that In an unpublished study by Dr Doucloy-Boutersgroup, and also lacked an adequate sample size. et al (expert meeting, Munich, April 2010), the cutoff values for the FIBTEM were evaluated at 30 minutes Dilution postpartum in a small number of women (12 PPH and The effect of dilution on thromboelastometric 30 controls). Again, it is not clear what the degree ofparameters in both nonpregnant and pregnant women blood loss was at the time of the blood sample. Fi-has been studied. In pregnant women, most studies brinogen levels less than 4 g/L and MCF less than 19were done before elective cesarean delivery, that is, mm were seen in 10 of 12 patients in the PPH groupbefore the occurrence of any peripartal changes and and ﬁbrinogen levels of 4 g/L or greater and MCFbefore the onset of any blood loss. Butwick and greater than 19 mm in 25 of 30 patients in the controlCarvalho75 demonstrated that preloading with 500 mL group, which led them to conclude that one must beof HES resulted in mild coagulation effects in R and aware of the risk of PPH when the ﬁbrinogen level isK time when measured with TEG, whereas no effect less than 4 g/L or FIBTEM MCF is less than 19 mm.was observed after preloading with 1500 mL of lac- Furthermore, ﬁbrinogen values less than 2 g/L andtated Ringer’s solution. Turker et al76 showed a mild correlating MCF values lower than 12 mm may behypocoaguable effect on TEG parameters (shorter R high-risk cases.time and lower MA, the > angle was only signiﬁcantly Another small study by Bauters et al80 compareddecreased after preloading with HES) in healthy laboratory results of 23 patients with PPH and 31parturients after preload with HES or succinylated women without PPH. They deﬁned PPH as blood lossgelatin before elective cesarean delivery, although the more than 800 mL, and the ﬁrst blood sample wasresults were not signiﬁcant. Ansari and Riad77 dem- obtained at the moment of diagnosis, another sampleonstrated that in vitro dilution to 60% with lactated was obtained 2 hours later. In patients with PPH, theyRinger’s or lactated Ringer’s solution/HES causes observed a decrease in FIBTEM A15 values 2 hourssigniﬁcant changes in all coagulation parameters earlier than the decrease in ﬁbrinogen, suggesting ameasured by TEM, with the latter solution causing a coagulopathy that was conﬁrmed 2 hours later by ﬁ-more pronounced effect. brinogen decrease. There are no studies available in PPH patients that assess or deﬁne cutoff values that can be used for Use of TEG or ROTEM in guiding therapy. The lack of predeﬁned TEG/TEM Obstetric Hemorrhage target values hampers its routine use in the clinical A number of studies have assessed the utility of setting. Testing without proper guidance on how toTEG or metric testing in pregnancy. Butwick et al78 interpret the results can therefore not be recom-assessed the correlation between TEG parameters and mended outside a research setting.blood loss in elective cesarean delivery. They showeda weak association between clot strength (maximum Limitationsamplitude) and blood loss and a modest reduction inthe degree of maternal hypercoagulability in the early As with any laboratory test, TEG and ROTEMpostpartum period. have some limitations. Adequate training and quality In a prospective observational study focused on controls are required for the successful performancePPH, Huissoud et al79 compared 51 women with PPH of these tests. Furthermore, thromboelastometric tests Copyright © 2012 by Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Obstetric Hemorrhage and Coagulation: Update & CME Review Article 433are not useful in patients on platelet aggregation in- 2) study different cutoff values for intervention to de-hibitor treatment. The added coagulation activators termine whether treatment should start at FIBTEMinduce thrombin formation, which may conceal the (with correlating ﬁbrinogen levels) for nonpregnantextent of inhibition of antithrombotic medication on subjects or at lower values for pregnant women, andplatelet aggregation.81 Thus, it is not possible to dis- 3) study the effectiveness and the cost-effectivenesscriminate between thrombocytopenia and disorders of of TEG/ROTEMYbased care compared with cur-platelet function.82,83 Also, treatment with ﬁbrinogen rent care in PPH.may increase MCF in INTEM and EXTEM and dis-guise thrombocytopenia.84 Another limitation is temperature. Both TEG and REFERENCESTEM analyses are routinely performed at 37-C;therefore, the effect of hypothermia might not be 1. 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