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Disorders of the hemostatic system can lead to both hemorrhage and thrombosis. The former can result from inherited and acquired defects in hemostasis and platelets, and the latter is greatly increased in the presence of inherited and acquired defects in the endogenous antico-agulant system.1,2 In addition to their association with thrombosis, the leading cause of maternal death in the United States, inherited and acquired thrombophilias as well as certain bleeding dyscrasias, have also been associated with adverse pregnancy outcomes. This chapter reviews the hemostatic system and its modulators and then discusses the various common inherited and acquired disorders of platelet function, coagulation, and anticoagulation and their impact on both mother and fetus.

The Hemostatic SystemThe hemostatic system is designed to ensure that hemorrhage is avoided in the setting of vascular injury while the fl uidity of blood is maintained in the intact circulation. After vascular injury, activation of the clotting cascade and simultaneous platelet adherence, activation, and aggregation are required to form the optimal fi brin-platelet plug and thus avoid bleeding. The system is held in check by a potent series of anticoagulant proteins as well as a highly regulated fi brinolytic system. Pregnancy presents an additional challenge to this system, because the risk of hemorrhage during placentation and in the third stage of labor is high, and the risk of thrombosis in the highly vulner-able uteroplacental and intervillous circulations is also great. Through a series of local and systemic adaptations, the vast majority of pregnant women are able to balance these paradoxical requirements and achieve uncomplicated pregnancies.

Platelet Plug FormationAfter vascular injury, platelets rolling and fl owing in the bloodstream are arrested at sites of endothelial disruption by the interaction of col-lagen with von Willebrand factor (vWF). Attachment to collagen exposes sites on the vWF molecule that permit it to bind to the platelet glycoprotein Ib/IX/V complex (GpIb-IX-V) receptor.3 Abnormal platelet adhesion and bleeding can result from mutations in GpIb-X-V (e.g., Bernard-Soulier disease) or from defects in the vWF gene (von Willebrand disease [vWD]). Platelets can also adhere to subendothelial collagen via their GpIa-IIa (α2β1 integrin) and GpVI receptors. Defi -ciencies in either receptor cause mild bleeding diatheses.

Adherent platelets are activated by collagen after binding to the GpVI receptor.4 This triggers receptor phosphorylation, leading to acti-

vation of phospholipase C, which causes the generation of inositol triphosphate and 1,2,-diacylglycerol. The former triggers a calcium fl ux, and the latter activates protein kinase C, which, in turn, triggers platelet secretory activity and activates various signaling pathways. Such signaling promotes activation of the GpIIb-IIIa (αIIBβ3 integrin) receptor, a crucial step in subsequent platelet aggregation (see later discussion). Thus, collagen serves to promote both platelet adhesion and platelet activation. However, maximal platelet activation requires binding of thrombin to platelet type 1 and 4 protease-activated recep-tors (PAR-1, PAR-4).5 Platelet activation is also mediated by receptor binding to thromboxane A2 (TXA2) and adenosine diphosphate (ADP), which are released by adjacent activated platelets. Collagen and these circulating agonists induce calcium-mediated formation of platelet pseudopodia, promoting further adhesion.

Platelet secretory activity includes the release of α-granules con-taining vWF, vitronectin, fi bronectin, thrombospondin, partially acti-vated factor V, fi brinogen, β-thromboglobulin, and platelet-derived growth factor. These factors either enhance adhesion or promote clotting. Secretory activity also includes the release of dense granules containing ADP and serotonin, which enhance, respectively, platelet activation and vasoconstriction in damaged vessels. Calcium fl ux pro-motes the synthesis of TXA2 by the sequential action of phospholipase A2, cyclooxygenase-1 (COX-1) and TXA2 synthase and its passive dif-fusion across platelet membranes to promote both vasoconstriction and, as noted, activation of adjacent platelets.4 Inherited disorders of α-granule homeostatic and release proteins result in gray platelet syn-drome, whereas defi ciencies in dense granule–related genes are associ-ated with Wiskott-Aldrich, Chediak-Higashi, Hermansky-Pudlak, and thrombocytopenia–absent radius syndrome. Inhibition of COX-1–mediated TXA2 synthesis by nonsteroidal anti-infl ammatory drugs (NSAIDs) also can also impair platelet function.

Platelet aggregation follows activation-induced conformational changes in the platelet membrane GpIIb-IIIa receptor, so-called inside-out signaling. The receptor forms a high-affi nity bond to divalent fi brinogen molecules. The same fi brinogen molecule is also able to bind to adjacent platelet GpIIb-IIIa receptors.6 Because these receptors are abundant (40,000 to 80,000 copies), large platelet rosettes quickly form, reducing blood fl ow and sealing vascular leaks.4 Mutations in the GpIIb-IIIa gene cause the bleeding dyscrasia known as Glanzmann thrombasthenia. Figure 40-1 presents a schematic review of platelet function.

Platelet activation and aggregation are prevented in intact endothe-lium via the latter’s elaboration of prostacyclin, nitric oxide, and ADPase as well as by active blood fl ow. Cyclic adenosine monophos-phate (cAMP) inhibits platelet activation, and this is the basis for the

Chapter 40

Coagulation Disorders in PregnancyCharles J. Lockwood, MD, and Robert M. Silver, MD

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826 CHAPTER 40 Coagulation Disorders in Pregnancy

therapeutic effects of dipyridamole. Normal pregnancy is associated with a modest decline in platelet number7 and with evidence of pro-gressive platelet activation.8

Fibrin Plug FormationEffective hemostasis requires the synergistic interaction of the clotting cascade with platelet activation and aggregation. This synergism is in part mechanical, because fi brin and platelets together form an effective hemostatic plug after signifi cant vascular disruption. However, bio-chemical synergism also occurs, because activated platelets contribute clotting factors and form an ideal surface for clot propagation. Con-versely, optimal platelet activation and subsequent aggregation require exogenous thrombin generation (see Fig. 40-1). Therefore, the avoid-ance of hemorrhage ultimately depends on the interplay between platelets and the coagulation cascade.

Understanding of the coagulation component of hemostasis has evolved rapidly in the past two decades. Clotting is no longer thought of as a seemingly infi nite cascade of enzymatic reactions occurring in the blood but rather as a highly localized cell surface phenomenon.9 Clotting is initiated when subendothelial (extravascular) cells express-ing tissue factor (TF), a cell membrane–bound glycoprotein, come into contact with circulating factor VII. Intrauterine survival is not possible in the absence TF.10 TF is primarily expressed on the cell membranes of perivascular smooth muscle cells, fi broblasts, and tissue parenchy-mal cells, but not on healthy endothelial cells. However, TF also circu-lates in the blood in very low concentrations, as part of cell-derived microparticles or in a truncated soluble form.8,11

After vascular disruption and in the presence of ionized calcium, perivascular cell TF comes into contact with plasma factor VII on negatively charged (anionic) cell membrane phospholipids. Factor VII

is unique in that it has low intrinsic clotting activity. In addition, it may autoactivate after binding to TF or be activated by thrombin or factors IXa or Xa.12 Activation of factor VII to VIIa increases its cata-lytic activity more than 100-fold, and its promiscuous activation 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 factor IX. Factor Xa remains active as long as it is bound to TF-VIIa in the cell membrane–bound prothrombinase complex. However, when factor Xa diffuses away from the site of vascular injury, it is 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 factor Xa itself or by thrombin. Partially activated factor Va can also be delivered to the site of clot initiation after its release from platelet α-granules (Fig. 40-2A).8 The Xa/Va complex catalyzes the conversion of prothrombin (factor II) to thrombin (factor IIa). Thrombin, in turn, converts fi brinogen to fi brin, and, as noted, activates platelets (see Fig. 40-2A).

Following this initial TF-mediated reaction, the clotting cascade is amplifi ed by clotting reactions that occur on adjacent activated platelets.9 Locally generated factor IXa diffuses to adjacent activated platelet membranes, or to perturbed endothelial cell membranes, where it binds to factor VIIIa. This cofactor is not only directly acti-vated by thrombin but is released from its vWF carrier molecule through the action of thrombin.9 The factor IXa/VIIIa complex can then generate factor Xa at these sites to further drive thrombin generation (see Fig. 40-2B). The signifi cant hemorrhagic sequelae of hemophilia underscore the vital role played by platelet surface factor IXa-VIIIa–mediated factor Xa generation in ensuring hemostasis.9

The clotting cascade can also be amplifi ed via the activation of factor XI to XIa by thrombin on activated platelet surfaces; factor XIa also activates factor IX (see Fig. 40-2C). The lack of signifi cant hem-orrhagic sequelae in patients with factor XI defi ciency emphasizes that this mechanism is of lesser importance in the maintenance of hemostasis. Factor XIa has been describing as serving a “booster function” in coagulation.9

A third, theoretical coagulation amplifi cation pathway may be mediated by circulating TF-bearing microparticles that bind to acti-vated platelets at sites of vascular injury through the interaction between P-selectin glycoprotein ligand-1 on the microparticles and P-selectin on activated platelets (see Fig. 40-2C).13 Taken together factor IXa, factor XIa, and TF-platelet surface events lead to additional factor Xa generation and thence to enhanced production of thrombin and fi brin. They also refl ect the synergism that exists between platelet acti-vation and the coagulation cascade.

The stable hemostatic plug is fi nally formed only when fi brin monomers self-polymerize and are cross-linked by thrombin-activated factor XIIIa (see Fig. 40-2D). This last reaction highlights the dominant role that thrombin plays in the coagulation cascade: Thrombin acti-vates platelets, generates fi brin, and activates the crucial clotting cofac-tors V and VIII, as well as the key clotting factors VII, XI, and XIII. This accounts for the primacy of antithrombin factors in preventing inappropriate intravascular clotting (i.e., thrombosis).

Prevention of Thrombosis: The Anticoagulant SystemAs noted, the hemostatic system not only must prevent hemorrhage after vascular injury but also must maintain the fl uidity of the circula-

Platelet Adhesion• GpIb/IX/V binding to vWF• GpIa/IIa binding to collagen

Platelet Aggregation• GpIIb/IIIa binding to fibrinogen and other large glycoproteins

Platelet Secretion• α-Granules contain fibrinogen, fibronectin, vitronectin, platelet factor 4, fibrinogen, vWF, thrombospondin, and platelet-derived growth factor, which enhance adhesion or clotting• Dense granules contain ADP and serotonin, which amplify platelet activation• Thromboxane A2, which promotes platelet activation and vasoconstriction

Platelet Activation• GpVI binding to collagen• PAR-1 and PAR-4 binding to thrombin• Receptor binding to ADP and TXA2

Platelet Plug Formation

FIGURE 40-1 Schematic review of platelet function. ADP, adenosine diphosphate; Gp, glycoprotein; PAR, protease-activated receptor; TXA2, thromboxane A2; vWF, von Willebrand factor.

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827CHAPTER 40 Coagulation Disorders in Pregnancy

tion in an intact vasculature. Indeed, thrombotic disease is a conse-quence of inappropriate and/or excess thrombin generation. As was the case with avoiding hemorrhage, avoidance of thrombosis is again dependent on the synergistic interaction of platelets and the coagulant system. As noted earlier, clotting is initiated locally at sites of vascular injury and amplifi ed by the arrival, adherence, and activation of plate-

lets. This local coagulation reaction is relatively protected from the dampening effects of circulating endogenous anticoagulants, both because of its intensity and because it is shielded by the initial layer of adherent and activated platelets. However, maximal platelet activation occurs only after stimulation by both subendothelial collagen and thrombin, so, as additional platelets aggregate on top of the initial layer

Vascular Injury

TF/VII(a)

II IIa

X IX

IXa

Fibrinogen Fibrin

Plateletactivation

Xa

Va

A

Vascular Injury

TF/VII(a)

II IIa

X IX

IXa

Fibrinogen

B

Fibrin

Plateletactivation

Xa

Va VIIIa � IXa

VIII

Vascular Injury

TF/VII(a)

II IIa

XIa

X IX

XI

IXa

Fibrinogen Fibrin

Plateletactivation

TF

Xa

Va

C

Vascular Injury

TF/VII(a)

II IIa

XIIIa

X IX

XIII

IXa

Fibrinogen Fibrinmonomers

Fibrinpolymers

Self-polymerization

Stablefibrin

polymers

Xa

Va

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 fi brinogen to fi brin and activates platelets. B, The clotting cascade is amplifi ed 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 fi nally formed when fi brin monomers self-polymerize and are cross-linked by thrombin-activated factor XIIIa.

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of platelets, they become progressively less activated, and their clotting reaction becomes more susceptible to the action of circulating inhibi-tors, thus attenuating the clotting cascade.9

Prevention of disseminated intravascular coagulation (DIC) ulti-mately requires the presence of inhibitor molecules (Fig. 40-3). The fi rst inhibitory molecule is TFPI which forms a complex with TF, VIIa, and Xa (the prothrombinase complex).14 As noted earlier, TFPI is most effective distal to the initial site of clotting, and it can be bypassed by the generation of factors IXa and XIa.

Paralleling its pivotal role in initiating the hemostatic reaction, thrombin also plays a central role in initiating the anticoagulant system. Thrombin binds to thrombomodulin, and the resultant conforma-tional change permits thrombin to activate protein C (PC) when bound to damaged endothelium or the endothelial protein C receptor (EPCR). Activated protein C (aPC) then binds to its cofactor, protein S (PS), to inactivate factors VIIIa and Va. However, this process is far less effi cient at blocking thrombin generation on activated platelets, possibly because platelet-derived, partially activated factor Va is resis-tant to aPC/PS inactivation.15 Therefore, additional anticoagulant reac-tions are required. Factor Xa can be effi ciently inhibited by the protein Z–dependent protease inhibitor (ZPI) when complexed to its cofactor, protein Z (PZ).16 ZPI also inhibits factor XIa in a process that does not require PZ. Defi ciencies of PZ can promote both intracerebral bleeding and systemic thrombosis, the latter predominating in the setting of coexistent inherited thrombophilias.

The most potent inhibitor of both factor Xa and thrombin is anti-thrombin (AT, previously known as antithrombin III or ATIII) (see Fig. 40-3). Antithrombin bound to vitronectin can bind thrombin or factor

Xa. The resultant conformational change facilitates AT binding to endothelial surface heparanoids or exogenous heparin, which aug-ments thrombin inactivation more than 1000-fold.17 Although throm-bin generated at the initial site of vascular injury is relatively “protected” from AT, thrombin produced more distally on the surface of activated platelets is readily susceptible.9 Similar inhibitory mechanisms utilize heparin cofactor II and α2-macroglobulin.

Restoration of Blood Flow: FibrinolysisFibrinolysis permits the restoration of circulatory fl uidity and serves as another barrier to thrombosis (Fig. 40-4). The cross-linked fi brin polymer is degraded to fi brin degradation products (FDPs) by the action of plasmin embedded in the fi brin clot.18 Plasmin is, in turn, generated by the proteolysis of plasminogen via tissue-type plasmino-gen activator (tPA), which is also embedded in fi brin. Endothelial cells also synthesize a second plasminogen activator, urokinase-type plas-minogen activator (uPA), whose primary function is cell migration and extracellular matrix remodeling.

Fibrinolysis is, in turn, modulated by a series of inhibitors. Plasmin is inhibited by α2-plasmin inhibitor, which, like plasmin and plasmino-gen, is bound to the fi brin clot, where it is positioned to prevent pre-mature fi brinolysis. Platelets and endothelial cells release type-1 plasminogen activator inhibitor (PAI-1) in response to thrombin binding to PARs. The PAI-1 molecule inhibits both tPA and uPA. In pregnancy, the decidua is also a very rich source of PAI-1,19 and the placenta can synthesize another antifi brinolytic molecule, PAI-2. Fibri-nolysis can also be inhibited by thrombin-activated fi brinolytic inhibi-tor (TAFI). This carboxypeptidase cleaves terminal lysine residues from fi brin to render it resistant to plasmin. TAFI is activated by the

Thrombomodulin

Fibrin monomer Fibrinogen

II IIa

PC

(�)

(�)

X

X

IX

TF/VIIa

TFPI

IXa

Xa�Va

VIIIa (�)

�AT

aPC � PS

EPCR

�AT

�PZ/ZPI

FXIII

Fibrin monomer Fibrinogen

Fibrin polymer

X-linked Fibrin

Plasmin Plasminogen

Thrombomodulin

tPA/uPA

��2 plasmininhibitor

� PAI-1� PAI-2� TAFI

FXIIIa

IIa(�)

FDPs

FIGURE 40-3 The anticoagulant system. Tissue factor pathway inhibitor (TFPI) binds with tissue factor (TF), factor VIIa, and factor Xa to form the prothrombinase complex. Thrombin, after binding to thrombomodulin, can activate protein C (PC) when bound to the endothelial protein C receptor (EPCR). Activated protein C (aPC) then binds to its cofactor, protein S (PS), to inactivate factors VIIIa and Va. Factor Xa is inhibited by the protein Z-dependent protease inhibitor (ZPI) when complexed to its cofactor, protein Z (PZ). Antithrombin (AT) potently inhibits both factor Xa and thrombin.

FIGURE 40-4 Fibrinolysis. The cross-linked fi brin polymer (X-linked Fibrin), which was stabilized by thrombin (factor IIa)-activated factor XIIIa, is degraded to fi brin degradation products (FDPs) by the action of plasmin, which is generated by the proteolysis of plasminogen via tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). To prevent excessive fi brinolysis, plasmin is inhibited by α2-plasmin inhibitor, and tPA and uPA are inhibited by plasminogen activator inhibitor type 1 (PAI-1) and type 2 (PAI-2). In addition, thrombin-activated fi brinolytic inhibitor (TAFI), which is activated by the thrombin-thrombomodulin complex, cleaves terminal lysine residues from fi brin to render it resistant to plasmin.

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thrombin-thrombomodulin complex.20 In the initial stages of clotting, platelets and endothelial cells release PAI-1, but, after a delay, endothe-lial cells release tPA and uPA to promote fi brinolysis. This biologic process permits sequential clotting followed by fi brinolysis to restore vascular patency.

The fi brinolytic system can also interact with the coagulation cascade. FDPs inhibit the action of thrombin, and this is a major source of hemorrhage in DIC. Moreover, PAI-1 bound to vitronectin and heparin also inhibits thrombin and factor Xa activity.21

The Effect of Pregnancy on HemostasisAs noted, pregnancy and delivery present unique and paradoxical chal-lenges to a woman’s hemostatic system. They also present one of the greatest risks for venous thromboembolism (VTE) that most young women will face. Profound alterations in both local uterine and sys-temic clotting, anticoagulant, and fi brinolytic systems are required to meet this enormously complex challenge. The uterine decidua is ideally positioned to regulate hemostasis during placentation and the third stage of labor. Progesterone augments expression of TF22 and PAI-119 on perivascular decidualized endometrial stromal cells. The crucial importance of the decidua in the maintenance of puerperal hemostasis is highlighted by the massive hemorrhage that accompanies obstetric conditions associated with impaired decidualization (e.g., ectopic and cesarean scar pregnancy, placenta previa, and accreta). That decidual TF plays the primary role in mediating puerperal hemostasis is demonstrated by the observation that transgenic TF knockout mice rescued by the expression of low levels of human TF have a 14% incidence of fatal postpartum hemorrhage despite far less invasive placentation.23

The extraordinarily high level of TF expression in human decidua can also serve a pathologic function if local hemostasis proves inade-quate to contain spiral artery damage and hemorrhage into the decidua occurs (i.e., abruption). This bleeding results in intense generation of thrombin and occasionally in frank hypofi brinogenemia and DIC. However, thrombin can also bind to decidual PAR-1 receptors to promote production of matrix metalloproteinases and cytokines, contributing to the tissue breakdown and infl ammation associated with abruptio placenta and preterm premature rupture of the membranes.24-27

Pregnancy also induces systemic changes in the hemostatic system. It is associated with a doubling in concentration of fi brinogen and increases of 20% to 1000% in factors VII, VIII, IX, and X as well as vWF.28 Levels of prothrombin and factor V remain relatively unchanged, and levels of factor XI decline modestly. The net effect is an increase in thrombin-generating potential. Pregnancy is also associated with 60% to 70% declines in free PS levels, which nadir at delivery due to hormonally induced increases in levels of its carrier protein, the com-plement 4B–binding protein.29 As a consequence, pregnancy is associ-ated with an increased resistance to aPC. These effects are exacerbated by cesarean delivery and infection, which drive further reduction in the concentration of free PS. Levels of PAI-1 increase threefold to fourfold during pregnancy, and plasma PAI-2 values, which are negli-gible before pregnancy, reach high concentrations at term.30 Thus, pregnancy is associated with increased clotting potential, decreased anticoagulant activity, and decreased fi brinolysis.30

Pregnancy is also associated with venous stasis in the lower extremi-ties resulting from compression of the inferior vena cava and pelvic veins by the enlarging uterus as well as a hormone-mediated increase in deep vein capacitance secondary to increased circulating levels of

estrogen and local production of prostacyclin and nitric oxide. Preg-nancy is also frequently associated with obesity, insulin resistance, and hyperlipidemia, all of which further increase levels of PAI-1.31

Disorders Promoting Thrombosis in PregnancyAcquired Thrombophilias: Antiphospholipid AntibodiesThe combination of VTE, obstetric complications, and antiphospho-lipid antibodies (APA) defi nes the antiphospholipid antibody syn-drome (APS).32 These antibodies are directed against proteins bound to negatively charged surfaces, usually anionic phospholipids. There-fore, APAs can be detected (1) by screening for antibodies that directly bind protein epitopes such as β2-glycoprotein-1, prothrombin, annexin V, aPC, PS, protein Z, ZPI, tPA, factor VII(a), and XII, the complement cascade constituents C4 and CH50, and oxidized low-density lipopro-teins, or (2) by indirectly assessing antibodies that react to proteins present in an anionic phospholipid matrix (e.g., cardiolipin, phospha-tidylserine), or (3) by assessing the downstream effects of these anti-bodies on prothrombin activation in a phospholipid milieu (i.e., lupus anticoagulants).33

The diagnosis of APS has been a controversial topic. A recent con-sensus conference proposed the criteria outlined in Table 40-1.34 In brief, APS requires the presence of at least one clinical criterion (confi rmed thrombosis or pregnancy morbidity) and one laboratory criterion (lupus anticoagulant [LA], anticardiolipin (ACA), or anti-β2-glycoprotein-1 antibody). However, the presence of thrombosis must take into account confounding variables that lessen the certainty of the diagnosis (see Table 40-1). Uteroplacental insuffi ciency may be recognized by the sequelae of nonreassuring fetal surveillance tests suggestive of fetal hypoxemia, abnormal Doppler fl ow velocimetry waveform analysis suggestive of fetal hypoxemia, oligohydramnios (amniotic fl uid index ≤5 cm), or birth weight less than the 10th per-centile. Classifi cation of APS should not be made if less than 12 wk or more than 5 years separates the positive APA test and the clinical manifestation.

Venous thrombotic events associated with APA include deep venous thrombosis (DVT) with or without acute pulmonary emboli; cerebral vascular accidents and transient ischemic attacks are the most common arterial events. At least half of patients with APA have systemic lupus erythematosus (SLE). A meta-analysis of 18 studies examining the thrombotic risk among SLE patients with LA, found odds ratios (OR) of 6.32 (95% confi dence interval [CI], 3.71 to 10.78) for a VTE episode and 11.6 (CI, 3.65 to 36.91) for recurrent VTE.35 By contrast, ACAs were associated with lower ORs of 2.50 (CI, 1.51 to 4.14) for an acute VTE and 3.91 (CI, 1.14 to 13.38) for recurrent VTE. A meta-analysis of studies involving more than 7000 patients in the general population identifi ed a range of ORs for arterial and venous thromboses in patients with LA: 8.6 to 10.8 and 4.1 to 16.2, respectively.33 The comparable numbers for ACA were 1 to 18 and 1 to 2.5. Therefore, there appears to be a consistently greater risk of VTE associated with LA compared with isolated ACA. Recurrence risks of up to 30% have been reported in affected patients, so long-term prophylaxis is required.36 The risk of VTE in pregnancy and the puerperium accruing to affected patients is poorly studied but may be as high as 5% despite treatment.37

As noted, APA are associated with obstetric complications includ-ing fetal loss, abruption, severe preeclampsia, and intrauterine growth

Ch040-X4224.indd 829 8/26/2008 4:07:57 PM


restriction (IUGR). LA are associated with fetal loss after the fi rst tri-mester, with ORs ranging from 3.0 to 4.8, and ACA display a wider range of ORs, 0.86 to 20.0.33 It is controversial whether APA are associated with recurrent (more than three) early (<10 weeks) sponta-neous abortions in the absence of stillbirth. At least 50% of pregnancy losses in patients with APA occur after the 10th week of gestation.38 Moreover, compared with patients who have unexplained fi rst-trimes-ter spontaneous abortions without APA, those with antibodies more often have demonstrable embryonic cardiac activity (86% versus 43%; P < .01).39

The association between APA and infertility also is uncertain. Increased levels of APA have been reported in women with infertil-ity.40,41 However, a meta-analysis of seven studies of affected patients undergoing in vitro fertilization found no signifi cant association between APA and either clinical pregnancy (OR, 0.99; CI, 0.64 to 1.53) or live birth rate (OR, 1.07; CI, 0.66 to 1.75).42 Finally, there is also no evidence that treating patients who have APA with anticoagulant medi-cations improves outcomes of in vitro fertilization.43

Women with APS who have pregnancies reaching viability are at increased risk for obstetric outcomes associated with abnormal placen-tation such as preeclampsia and IUGR. Up to 50% of pregnancies in women with APS develop preeclampsia, and one third have IUGR.37 Abnormal fetal heart rate tracings prompting cesarean delivery are also common. Conversely, most cases of preeclampsia and IUGR occur in women without APA. Although increased positive tests for APA have been reported in women with preeclampsia, especially in severe disease with onset before 34 weeks’ gestation44 and IUGR, most large retro-

spective and prospective studies have not found an association between these conditions and APA.45 This is not surprising, given the common occurrence of preeclampsia and IUGR and the relative infrequency of APS.

A myriad of mechanisms have been proposed for APA-mediated arterial and venous thrombosis. Direct inhibition of the anticoagulant effects of anionic phospholipid-binding proteins such as β2-glycopro-tein-1 and annexin V has been shown.46,47 In addition, APA appear to inhibit thrombomodulin, aPC, and AT activity; to induce TF, PAI-1, and vWF expression in endothelial cells; and to augment platelet acti-vation. Recently, APA induction of complement activation has been suggested to play a role in fetal loss, with heparin preventing such aberrant activation.48

Contemporary management of affected patients during pregnancy requires treatment with either unfractionated heparin or low-molecu-lar-weight heparin (LMWH) plus low-dose aspirin (LDA) at 50 to 80 mg/day. Rai and colleagues conducted a randomized, controlled trial among 90 APA-positive women with a history of recurrent fetal loss who received either LDA alone or LDA plus 5000 U of unfraction-ated heparin SQ every 12 hours until either recurrent loss or 34 weeks of gestation.39 The live birth rate was signifi cantly higher with com-bined heparin and LDA than with LDA alone: 71% (32/45) versus 42% (19/45) (OR, 3.37; CI, 1.40 to 8.10). Interestingly, 90% of the losses occurred in the fi rst trimester, and there was no difference in out-come between the two groups for women whose pregnancies advanced beyond 13 weeks’ gestation. Similar results were found in a nonrandomized trial by Kutteh.49 On the other hand, Farquharson and

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 confi rmed by objective, validated criteria (i.e., unequivocal fi ndings 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, orb. 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 insuffi ciency, orc. 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 Scientifi c 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 fulfi ll criteria should be stratifi ed 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 fi ltration 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.

Modifi ed from Miyakis S, Lockshin MD, Atsumi D, et al: International consensus statement on an update of the classifi cation criteria for defi nite

antiphospholipid syndrome (APS). J Thromb Haemost 4:295-306, 2006.

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coworkers found no advantage to adding LMWH to LDA.50 However, this latter study has been criticized because of the very low levels of APA present in affected patients as well as imperfect randomization. Meta-analysis found that unfractionated heparin plus LDA (two trials; N = 140) signifi cantly reduced pregnancy loss compared with LDA alone (relative risk [RR], 0.46; CI, 0.29 to 0.71) and that there was no advantage of high-dose over low-dose unfractionated heparin (one trial; N = 50).51 Another meta-analysis found that enoxaparin treat-ment resulted in an increased live birth rate, compared with LDA (RR, 10.0; CI, 1.56 to 64.20).52 Three studies of LDA alone versus placebo included in the meta-analysis showed no signifi cant reduction in preg-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 150 women treated with LDA and either unfractionated heparin (5000 U given SQ every 12 hours) or enoxaparin (20 mg daily) from the time of positive embryonic cardiac activity to either pregnancy loss or 34 weeks of gestation.53 The live birth rate was 71%. However, 27% of the patients miscarried (mostly in the fi rst trimester), and gesta-tional hypertension occurred in 17%, abruption in 7%, and IUGR in 15%.

Intravenous immune globulin (IVIG) has been reported to improve outcome in women with APS for whom treatment with heparin and LDA has failed.54 The effi cacy of the combination of LDA and LMWH in affected patients was compared with that of IVIG for the prevention of recurrent fetal loss in a study including 40 women,55 who were ran-domized to receive either LMWH (5700 IU/day SQ) and LDA or IVIG (400 mg/kg IV for 2 days, followed by 400 mg/kg every month). Although the clinical characteristics of the two groups were similar at the time of randomization, women receiving LMWH and LDA had a higher live birth rate (84%) than those receiving IVIG alone (57%). Moreover, IVIG plus heparin and LDA was also not superior to heparin and LDA alone in another small, randomized trial.56 Therefore, IVIG is not recommended as fi rst-line therapy for APS.

Given these small study sizes and heterogeneous therapies employed, recommendations for treatment are diffi cult to make. It is unlikely that a patient with no history of VTE who has repetitive early losses and borderline positive APA levels refl ects the same degree of risk or need for intense therapy as a patient with high levels of APA, prior VTE, and recurrent growth-retarded stillbirths. It is unclear whether the former

patient requires any therapy, but the latter patient needs therapeutic unfractionated heparin or LMWH with LDA.57 Tincani and associates reported on a survey of members of the International Advisory Board of the 10th International Congress on Antiphospholipid Antibodies. The consensus of the group was that treatment for APA-positive preg-nant patients should be LMWH and LDA.57 The dosage and frequency of LMWH depends on the situation, including the patient’s body weight and past history. Patients with previous thromboses should receive two injections per day. The use of IVIG should be restricted to patients with pregnancy losses despite conventional treatment (see later discussion for details of heparin dosing).

Inherited ThrombophiliasInherited thrombophilias have been linked to VTE. However, the occurrence of VTE in patients with an inherited thrombophilia is highly dependent on the presence of other predisposing factors, espe-cially a personal or family history of VTE. Even more controversial is the association between inherited thrombophilias and adverse preg-nancy outcomes.

Factor V Leiden MutationPresent in about 5% of the European population and 3% of African-Americans, factor V Leiden (FVL) is the most common of the serious heritable thrombophilias.58 The mutation is virtually absent in African blacks, Chinese, Japanese, and other Asians. The mutation causes a substitution of glutamine for arginine at position 506, the site of pro-teolysis and inactivation by aPC/PS, and FVL is the leading cause of aPC resistance. The heterozygous state is symptomatic, with a fi vefold increased risk of VTE, but homozygous patients have a 25-fold increased risk (Table 40-2). FVL is associated with about 40% of VTE events in pregnant patients.59 However, given the low prevalence of VTE in pregnancy (1/1400) and the high incidence of the mutation in the European-derived population, the risk of VTE among FVL hetero-zygotes without a personal history of VTE or an affected fi rst-degree relative is less than 0.3%.59 Nevertheless, the risk is at least 10% among pregnant women who have either a personal history of VTE or an affected fi rst-degree relative.60 Pregnant homozygous patients without a personal history of VTE or an affected fi rst-degree relative have a 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

Thrombophilia Relative Risk of VTE (95% CI)

Probability of VTE (%)

without or with a

Personal History of VTE

or a First-Degree

Relative with VTE

Ref. No.Without With

FVL (homozygous) 25.4 (8.8-66) 1.5 17 46FVL (heterozygous) 5.3 (3.7-7.6) 0.20-0.26 10 45, 46PGM (homozygous) NA 2.8 >17 46PGM (heterozygous) 6.1 (3.4-11.2) 0.37 >10 45, 46FVL/PGM (compound heterozygous) 84 (19-369) 4.7 NA 46Antithrombin defi ciency (<60% activity) 119 3.0-7.2 >40% 46, 47Protein S defi ciency (<55% activity) NA <1 6.6 46, 47Protein C defi ciency (<50% activity) 13.0 (1.4-123) 0.8-1.7 2-8 46, 47

CI, confi dence interval; FVL, factor V Leiden mutation; NA, not available; PGM, prothrombin gene mutation.

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of VTE, the risk is 17% (see Table 40-2). Screening can be done by assessing aPC resistance using a second-generation coagulation assay followed by genotyping for the FVL mutation if aPC resistance is found in a pregnant or nonpregnant woman. Alternatively, patients can simply be genotyped for FVL.

The College of American Pathologists Consensus Conference on Thrombophilia compared 16 case-control studies reporting a link between FVL and unexplained recurrent fetal loss and 6 studies failing to establish such an association and concluded that the latter studies were smaller and tended to include patients with early fi rst-trimester losses.61,62 In a meta-analysis of 31 studies, FVL was associated with early (<13 weeks) pregnancy loss, with an OR of 2.01 (CI, 1.13 to 3.58), but it was more strongly associated with late (>19 weeks), nonrecur-rent fetal loss, with an OR of 3.26 (CI, 1.82 to 5.83).63 A case-control study noted an even stronger link between FVL and recurrent fetal losses after 22 weeks’ gestation (OR, 7.83; CI, 2.83 to 21.67).64 Dudding and Attia conducted a meta-analysis and found no signifi cant associa-tion between FVL and fi rst-trimester loss but an OR of 2.4 (CI, 1.1 to 5.2) for isolated (nonrecurrent) third-trimester fetal loss, which increased to 10.7 (CI, 4.0 to 28.5) for two or more second- or third-trimester fetal losses.65 Similarly, Lissalde-Lavigne and associates reported the results of a case-control study nested in the 32,700 Nimes Obstetricians and Haematologists (NOHA) First study cohort.66 Mul-tivariate analysis revealed an association between FVL and pregnancy loss after 10 weeks (OR, 3.46; CI, 2.53 to 4.72) but not for losses occur-ring between 3 and 9 weeks. These studies strongly suggest that FVL is associated with fetal (>9 weeks) and not embryonic (<9 weeks) losses.

The association between FVL and late, compared with early, preg-nancy losses was also demonstrated by a large European retrospective cohort study involving 571 women with thrombophilia having 1524 pregnancies, compared with 395 controls having 1019 pregnancies.67 There was a statistically signifi cant association between any inherited thrombophilia and stillbirth (OR, 3.6; CI, 1.4 to 9.4) but not spontane-ous abortion (OR, 1.27; CI, 0.94 to 1.71). The same trend was noted for FVL, with an OR for stillbirth of 2.0 (CI, 0.5 to 7.7) compared with 0.9 for spontaneous abortion (CI, 0.5 to 1.5). These same investigators then monitored a subset of 39 thrombophilic and 51 control patients who had no previous history of fetal loss and did not receive antico-agulation during the prospective follow-up aspect of the study.68 They reported a modestly increased overall risk of fetal loss in a subsequent pregnancy among women with thrombophilia (7/39 versus 7/51; RR, 1.4; CI, 0.4 to 4.7) and also among those with FVL (RR, 1.4; CI, 0.3 to 5.5). However, this study lacked power to exclude the usually reported twofold to threefold higher rates of loss associated with FVL, because there were only 21 patients. Nevertheless, given the trends, the authors concluded that “Women with thrombophilia appear to have an increased risk of fetal loss, although the likelihood of a positive outcome is high in both women with thrombophilia and in controls.”68

In a retrospective cohort study, Roque and colleagues evaluated 491 patients with a history of various adverse pregnancy outcomes for a variety of thrombophilias and reported that the presence of FVL was paradoxically protective against losses before 10 weeks of gestation (OR, 0.23; CI, 0.07 to 0.77) but was signifi cantly associated with losses after 14 weeks (OR, 3.71; CI, 1.68 to 8.23).69 Moreover, women who experienced only euploid losses were not more likely to have an identi-fi ed thrombophilia than women who experienced only aneuploid early losses (OR, 1.03; CI, 0.38 to 2.75). Consistent with this protective effect of FVL on early pregnancy is the observation that implantation rates after in vitro fertilization were substantially higher among FVL carriers than among noncarriers (90% versus 49%; P = .02).70

Early pregnancy is associated with a low-oxygen environment, with intervillous oxygen pressures of 17.9 ± 6.9 mm Hg at 8 to 10 weeks, rising to 60.7 ± 8.5 mm Hg at 12 to 13 weeks.71 Trophoblast plugging of the spiral arteries has been demonstrated in placental histologic studies before 10 weeks of gestation, and low Doppler fl ow is noted in the uteroplacental circulation before 10 weeks.72 Indeed, the undetectable levels of superoxide dismutase in trophoblast before 10 weeks of gesta-tion are consistent with a hypoxic state.73 Therefore, if FVL or other thrombophilias are associated with early pregnancy loss, it is most likely through mechanisms other than placental thrombosis. Also, because a majority of early pregnancy losses are associated with aneu-ploidy, thrombophilias are likely to play a far lesser role in such cases. In contrast, uteroplacental thrombosis after 9 weeks would be expected to reduce oxygen and nutrient delivery to a progressively larger embryo, accounting for the apparent link between FVL and the other maternal thrombophilias and later adverse pregnancy outcomes.

The correlation between FVL and other later adverse pregnancy events is more controversial. Kupferminc and associates studied 110 women and reported a link between FVL and severe preeclampsia (OR, 5.3; CI, 1.8 to 15.6).74 However, multiple case-control studies have failed to demonstrate a link between FVL and moderate or severe pre-eclampsia.75-77 Dudding and Attia’s meta-analysis estimated a 2.9-fold (CI, 2.0 to 4.3) increased risk of severe preeclampsia among FVL car-riers.65 Similarly, Lin and August conducted a meta-analysis of 31 studies involving 7522 patients and reported pooled ORs of 1.81 (CI, 1.14 to 2.87) for FVL and all preeclampsia and 2.24 (CI, 1.28 to 3.94) for FVL and severe preeclampsia.78 However, Kosmas and coauthors evaluated 19 studies involving 2742 hypertensive women and 2403 controls and reported that, whereas the studies published before 2000 found a modest association between FVL and preeclampsia (OR, 3.16; CI, 2.04 to 4.92), those published after 2000 did not (OR, 0.97; CI, 0.61 to 1.54).79 This suggests a reporting bias. Therefore, there is not suffi -cient evidence to conclude that FVL is associated with an increased occurrence of preeclampsia, although there is inadequate power to rule out an association between this thrombophilia and severe, early-onset preeclampsia.

Kupferminc and colleagues also reported a modest association between FVL and abruption (OR, 4.9; CI, 1.4 to 17.4).74 A second case-control study found that 17 of 27 patients with abruption had aPC resistance, compared with 5 of 29 control subjects (OR, 8.16; CI, 3.6 to 12.75), and 8 cases were found to have the FVL mutation, compared with one control.80 Prochazka and associates conducted a retrospective case-control study among 180 women with placental abruption and 196 controls and found a signifi cantly increased incidence of FVL car-riage among cases compared with controls (14.1% versus 5.1%; OR, 3.0; CI, 1.4 to 6.7).81 Alfi revic and coworkers conducted a meta-analysis that revealed a strong association between placental abruption and both homozygosity and heterozygosity for the FVL mutation (OR, 16.9; CI, 2.0 to 141.9, and OR, 6.7; CI, 2.0 to 21.6, respectively).82 Therefore, there appears to be evidence of an association between FVL carriage and placental abruption, although large case-control and ret-rospective cohort studies are needed to confi rm this link.

There is less consistent evidence for an association between FVL and IUGR. Martinelli and coauthors reported a strong association between FVL and IUGR (OR, 6.9; CI, 1.4 to 33.5).83 However, multiple, large case-control and cohort studies have reported no statistically signifi cant association between FVL and IUGR of less than the 10th or less than the 5th percentile.74,77,84 Howley and colleagues conducted a systematic review of studies describing the association between FVL and IUGR; among 10 case-control studies meeting selection criteria, there was a signifi cant association between FVL and IUGR (OR, 2.7;

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CI, 1.3 to 5.5).85 However, no association was found among fi ve cohort studies, of which three were prospective and two retrospective (RR, 0.99; CI, 0.5 to 1.9). The authors suggested that the putative association between IUGR and FVL was most likely driven by small, poor-quality studies that demonstrated extreme associations.

In summary, there appears to be a modest association between FVL and fetal loss after 10 weeks, and particularly with isolated losses after 22 weeks. There is a possible association between FVL and abruption. However, no clear association exists between FVL and either pre-eclampsia or IUGR, although studies have been underpowered to defi nitely exclude a link with severe early-onset preeclampsia or severe IUGR. It also is noteworthy that two prospective cohort studies found no association between FVL and any adverse obstetric outcome, including pregnancy loss, preeclampsia, and IUGR,86.87 but these studies were underpowered to draw fi rm conclusions. It is important to note that, although thrombophilia may be suffi cient to cause preg-nancy loss and perhaps abruption, most affected individuals without such prior obstetric complications are at low risk for subsequent adverse pregnancy outcomes.

Other Factor V MutationsOther mutations in the factor V gene have been variably linked to maternal VTE and adverse pregnancy outcomes. The factor V HR2 haplotype causes decreased factor V cofactor activity in the aPC-mediated degradation of factor VIIIa; however, a meta-analysis demonstrated no statistically signifi cant association between the HR2 haplotype and risk of VTE (OR, 1.15; CI, 0.98 to 1.36).88 There are confl icting reports about the linkage of the factor V HR2 haplotype and recurrent pregnancy loss. Zammiti and associates reported no association with losses before 8 weeks, but homozygosity for the factor V HR2 haplotype was associated with signifi cant and independent risks of pregnancy loss during weeks 8 and 9, which increased during weeks 10 to 12 and culminated after 12 weeks.89 In contrast, Dilley and colleagues found no association between carriage of the factor V HR2 haplotype and pregnancy loss.90 The sample sizes of these studies were too small to draw fi rm conclusions from, nor can conclusions be reached about the link between factor V HR2 haplotype and other adverse pregnancy outcomes.

Two other mutations in the factor V gene that occur at the second aPC cleavage site, factor V R306G Hong Kong and factor V R306T Cambridge, have also been described but do not appear to be strongly associated with VTE.91 There are inadequate data to assess any linkage between these mutations and adverse pregnancy outcomes.89

Prothrombin Gene MutationThe prothrombin G20210A polymorphism is a point mutation causing a guanine→adenine switch at nucleotide position 20210 in the 3′-untranslated region of the gene.58 This nucleotide switch results in increased translation, possibly due to enhanced stability of messenger RNA (mRNA). As a consequence, there are increased circulating levels of prothrombin. Although the mutation is present in only 2% to 3% of the European population, it is associated with 17% of VTEs in preg-nancy.59 However, as was the case with FVL, the risk of VTE in pregnant patients who are heterozygous for the prothrombin G20210A gene mutation (PGM) but who are without a personal or strong family history of VTE is less than 0.5%.59 Pregnant PGM-heterozygous patients with such a history have at least a 10% risk of VTE.60 PGM-homozygous patients without a personal or strong family history have a 2.8% risk for VTE in pregnancy, whereas such a history probably confers a risk of at least 20% (see Table 40-2). Because the combination of FVL and PGM has synergistic hypercoagulable effects, compound heterozygotes are at

greater thrombotic risk than either FVL or PGM homozygotes. Pregnant patients who are compound heterozygotes without a personal or strong family history have a 4.7% risk of VTE.59,60

The PGM has been associated with an increased risk of pregnancy loss in multiple case-control studies. One such study reported the pres-ence of the PGM in 7 of 80 patients with recurrent miscarriage, com-pared with 2 of 100 control patients (9% versus 2%; P = .04; OR, 4.7; CI, 0.9 to 23).92 Finan and associates also found an association between PGM and recurrent abortion, with an OR of 5.05 (CI, 1.14 to 23.2).93 However, other studies have failed to identify a link.94,95 A 2004 meta-analysis of seven studies evaluating the correlation between PGM and recurrent pregnancy loss, defi ned as two or more losses in the fi rst or second trimester, found a combined OR of 2.0 (CI, 1.0 to 4.0).96 Analo-gous to FVL, the association between PGM and pregnancy loss increases with increasing gestational age. In the meta-analysis by Rey and col-leagues, an association was reported between PGM and recurrent loss before 13 weeks’ gestation (OR, 2.3; CI, 1.2 to 4.79), but, as with FVL, a stronger association was observed between PGM and recurrent fetal loss before 25 weeks (OR, 2.56; CI, 1.04 to 6.29).63 Therefore, PGM appears to fi t the pattern displayed by FVL carriers of progressively greater risk of fetal loss with advancing gestation; however, these risks remain quite modest.

There are more limited data on the association between PGM and abruption. The case-control study of Kupferminc and associates found an association between the PGM and abruptio placenta (OR, 8.9; CI, 1.8 to 43.6),74 whereas Prochazka and colleagues found no such link.81 Meta-analyses suggested a strong link between PGM heterozygosity and placental abruption (OR, 28.9; CI, 3.5 to 236.7).82 It can be concluded that there is probably a link between the PGM and abruptio placentae.

The link between the PGM and other adverse pregnancy events is far less certain. Kupferminc and colleagues found an association between the PGM and IUGR of less than the 5th percentile (OR, 4.6; CI, 1 to 20) but no link between the PGM and severe preeclampsia.74 Martinelli and coworkers noted a strong association between PGM and IUGR in their case-control study (OR, 5.9; CI, 1.2 to 29.4).83 In con-trast, the large case-control study of Infante-Rivard and colleagues reported no link in heterozygotes between PGM and IUGR, with an OR of 0.92 (CI, 0.36 to 2.35).84 Similar results have been observed by other workers.74,80 A number of other case-control studies and meta-analyses have failed to establish a link between PGM and either pre-eclampsia or severe preeclampsia.77,78,97,98

Therefore, although most individual studies are limited by small sample size, case-control design, and the potential for selection biases (as was the case with FVL), there may be a weak association between the PGM and fetal loss as well as abruptio placenta. However, there does not appear to be a signifi cant link between PGM and IUGR or preeclampsia.

HyperhomocysteinemiaHyperhomocysteinemia can result from a number of mutations in the methionine metabolic pathway. Homozygosity for mutations in the methylene tetrahydrofolate reductase (MTHFR) gene is by far the most common cause. Homozygosity for the MTHFR C677T polymorphism is present in 10% to 16% of all Europeans, and that for the A1298C mutation occurs in 4% to 6%.99 Importantly, about 40% of whites are heterozygous for this polymorphism, and most heterozygotes have normal levels of homocysteine. Moreover, because homocysteine levels decrease in pregnancy and U.S. diets are replete with folic acid supple-mentation, hyperhomocysteinemia is extremely rare even among homozygotes. In addition, although hyperhomocysteinemia is a risk factor for VTE (OR, 2.5; CI, 1.8 to 3.5),100 MTHFR mutations per se

Ch040-X4224.indd 833 8/26/2008 4:07:58 PM


do not appear to convey an increased risk for VTE in either nonpreg-nant101 or pregnant women.102

As with thrombotic risk, meta-analyses suggest that elevated fasting homocysteine levels are more strongly associated with recurrent preg-nancy loss (<16 weeks) than are MTHFR mutations, with an OR of 2.7 (CI, 1.4 to 5.2) versus 1.4 (CI, 1.0 to 2.0), respectively.103 The Hordaland Homocysteine Study assessed the relationship between plasma homo-cysteine values in 5883 women and their prior 14,492 pregnancy out-comes.104 When the authors compared the upper with the lower quartile of plasma homocysteine levels, elevated levels trended toward an association with preeclampsia (OR, 1.32; CI, 0.98 to 1.77), very low birth weight (OR, 2.01; CI, 1.23 to 3.27), and stillbirth (OR, 2.03; CI, 0.98 to 4.21), although none of these associations reached statistical signifi cance.105 In contrast, a clear association was demonstrated between placental abruption and homocysteine levels greater than 15 μmol/L (OR, 3.13; CI, 1.63 to 6.03), and a weaker but signifi cant association was observed between homozygosity for the C677T MTHFR mutation and abruption (OR, 1.6; CI, 1.4 to 4.8). Indeed, a meta-analysis of these two risk factors found that hyperhomocystein-emia had a larger pooled OR for abruption (5.3; CI, 1.8 to 15.9) than did homozygosity for the MTHFR mutation (2.3; CI, 1.1 to 4.9).106

These studies strongly suggest that hyperhomocysteinemia, but not simply the presence of the MTHFR mutations, is linked to VTE and adverse pregnancy outcomes. Moreover, whereas homozygosity for MTHFR mutations is very common (10% to 20% in European popula-tions), hyperhomocysteinemia is quite rare. Therefore, screening for this disorder should be limited, requiring a fasting homocysteine level greater than 12 μmol/L to be considered positive in pregnant patients.146

Antithrombin Defi ciencyDefi ciency of AT is both the rarest and the most thrombogenic of the heritable thrombophilias. More than 250 mutations have been identi-fi ed in the AT gene, producing a highly variable phenotype. In general, disorders can be classifi ed into three types: type 1, those associated with reductions in both antigen and activity; type 2, those associated with normal levels of antigen but decreased activity; and type 3, the very rare homozygous defi ciency associated with little or no activ-ity.58,108 Complicating matters further, patients can develop acquired AT defi ciency due to liver impairment, increased consumption of AT associated with sepsis or DIC, or increased renal excretion in severe nephrotic syndrome. However, both inherited and acquired AT defi -ciencies are associated with VTE.

Because screening for AT defi ciency is done by assessing activity, its prevalence varies with the activity cutoff level employed, ranging from 0.02% to 1.1%. The recommended cutoff for “abnormality” is 50% activity, which is associated with a prevalence of 0.04% (1/2500 people).108 Although it increases the risk of VTE up to 25-fold in the nonpregnant state,108 because of its rarity AT defi ciency is associated with only 1% to 8% of VTE episodes.58 Pregnancy may increase its thrombogenic potential substantially (see Table 40-2). Moreover, use of a less stringent threshold yields a higher prevalence of AT defi ciency in patients with VTE. For example, in one study, 19.3% of pregnant women with VTE had less than 80% AT activity,59 but many of these cases may have been acquired due to clot-associated AT consumption. Conversely, the overall risk of VTE in pregnancy associated with AT defi ciency has been variably reported as 3% to 48%.30,60,109,110 The risk of VTE in pregnancy among AT-defi cient patients most likely varies also with a personal or family history (from 3% to 7% without such a history to as much as 40% with such a history).60

In the largest retrospective cohort study, AT defi ciency was associ-ated with a signifi cantly increased risk of stillbirth after 28 weeks’ gesta-

tion (OR, 5.2; CI, 1.5 to 18.1) but had a more modest association with miscarriage before 28 weeks (OR, 1.7; CI, 1.0 to 2.8).67 Given its rarity, there is a paucity of evidence concerning the link between AT defi -ciency and other adverse pregnancy outcomes. Roque and associates found it to be associated with increased risks of IUGR (OR, 12.93; CI, 2.72 to 61.45), abruption (OR, 60.01; CI, 12.02 to 300.46), and preterm delivery (OR, 4.72; CI, 1.22 to 18.26).69

Protein C Defi ciencyDefi ciency of PC results from more than 160 distinct mutations, pro-ducing a highly variable phenotype. As was the case with AT defi ciency, PC defi ciency can be associated with either reductions in both antigen and activity (type 1) or normal levels of antigen but decreased activity (type 2).58 The very rare homozygous PC defi ciency results in neonatal purpura fulminans and a requirement for lifelong anticoagulation.111 Activity levels can be ascertained by either a functional (clotting) or chromogenic assay.

Estimates of prevalence and thrombotic risk refl ect the cutoff values employed. Most laboratories use activity cutoff values of 50% to 60%, which are associated with prevalence estimates of 0.2% to 0.3% and RRs for VTE of 6.5 to 12.5.58,68,108. The risk of VTE in pregnancy among PC-defi cient patients has been reported to range from 2% to 8%.30,112,113 Because of its rarity, there are few reports linking PC defi -ciency to adverse pregnancy outcomes, and those that exist involve too few patients to draw any fi rm conclusions. In their case-control study, Roque and colleagues reported a strong link between PC defi ciency and abruption (OR, 13.9; CI, 2.21 to 86.9) and between PC defi ciency and preeclampsia (OR, 6.85; CI, 1.09 to 43.2).69 A meta-analysis also reported a strong association of this defi ciency and preeclampsia/eclampsia (OR, 21.5; CI, 1.1 to 414.4) but not stillbirth.82 It is biologi-cally plausible that PC defi ciency should pose risks of fetal loss and abruption analogous to those associated with FVL. However, given the very small sample sizes, no fi rm conclusions can be drawn regarding the link between PC defi ciency and either preeclampsia or IUGR.

Protein S Defi ciencyMore than 130 mutations have been linked to defi ciency of PS.58 The great majority of affected patients can be characterized as having low levels of both total and free PS antigen (type 1) or as having only a low free PS level due to enhanced binding to the complement 4B–binding protein (type 2a). The latter condition is frequently caused by a serine 460 to proline mutation (protein S Heerlen), which has been associated with either FVL or PC mutation in about half of affected patients.114 As with PC defi ciency, homozygous PS defi ciency results in neonatal purpura fulminans.111

Screening for PS defi ciency can be done with an activity assay, but this approach is associated with substantial interassay and intra-assay variability, in part because of frequently changing physiologic levels of complement 4B–binding protein.115 Detection of free PS antigen levels lower than 55% in a nonpregnant woman is consistent with the diag-nosis.115 However, Paidas and colleagues found far lower levels in normal pregnancy, with suggested cutoff levels for free PS of 29% for the fi rst and second trimesters and 23% for the third trimester.29 With such criteria, the prevalence of true PS defi ciency is low (0.03% to 0.13%) in the nonpregnant state and rises up to 3% in the pregnant state, but its degree of thrombogenicity is modest (OR, 2.4; CI, 0.8 to 7.9).29,58,115 Among those patients with PS defi ciency and a strong family history of VTE, the risk of VTE in pregnancy is 6.6% (see Table 40-2).112

The meta-analysis by Rey and colleagues reported an association between PS defi ciency and recurrent late (>22 weeks or <25 weeks)

Ch040-X4224.indd 834 8/26/2008 4:07:58 PM


fetal loss (OR, 14.7; CI, 1.0 to 2181) as well as nonrecurrent fetal losses at greater than 22 weeks (OR, 7.4; CI, 1.3 to 43).63 A second meta-analysis suggested an even stronger link between PS defi ciency and stillbirth (OR, 16.2; CI, 5.0 to 52.3), IUGR (OR, 10.2; CI, 1.1 to 91.0), and preeclampsia/eclampsia (OR, 12.7; CI, 4 to 39.7), but not abrup-tion.82 Again, the small sample sizes limit the ability to draw fi rm conclusions.

Protein Z-Dependent Protease Inhibitor and

Protein Z Defi ciencyTwo nonsense mutations in the coding region of the ZPI gene have been identifi ed to occur more often in patients with VTE (4.4%) than in controls (0.8%) (OR, 5.7; CI, 1.25 to 26.0).116 Defi ciency of PZ (activity <5th percentile) has been associated with strokes but not with VTE.117 PZ defi ciency was linked to late fetal loss (10 to 16 weeks’ gesta-tion) in one study (OR, 6.7; CI, 3.1 to 14.8)118 but not in another.119 Paidas and associates prospectively compared PZ levels in 103 patients with subsequent normal pregnancy outcome and 106 women with various adverse pregnancy outcomes including fetal loss, IUGR, pre-eclampsia, and abruption; they noted lower fi rst-trimester PZ levels among the patients with subsequent adverse outcomes (1.81 ± 0.7 versus 2.21 ± 0.8 μg/mL; P < .001).29 There were also lower PZ levels in affected patients in the second trimester (1.5 ± 0.4 versus 2.0 ± 0.5 μg/mL; P < .0001) and in the third trimester (1.6 ± 0.5 versus 1.9 ± 0.5 μg/mL; P < .0002). However, it is unclear whether low PZ levels were causative or whether PZ was reduced as a result of other throm-bophilias or the ongoing uteroplacental pathologic processes. Although PZ defi ciency may have its own pathogenic potential, its presence with other thrombophilic mutations in patients with prior fetal loss may also confer resistance to heparin therapy.119

Mutations in Fibrinolytic Pathway GenesTwo polymorphisms, 675 4G/5G and A844G, in the promoter region of the PAI-1 gene have been described.120 Homozygosity for the 4G/4G allele in the PAI-1 gene results in the presence of four instead of fi ve consecutive guanine nucleotides in the promoter region, producing a site that is too small to permit repressor binding. Conversely, the A844G polymorphism affects a consensus sequence binding site for the regulatory protein Ets, enhancing PAI-1 gene transcription. The preva-lence of the 4G/4G genotype in the general population is high, ranging from 23.5% to 32.3%.121,122 Moreover, most studies have not found any independent relationship between the 4G/4G polymorphism and the development of VTE in unselected patients.123-125 However, the 4G/4G genotype has been linked to a further increased risk for VTE when it is present in patients with PS defi ciency or FVL, suggesting that it plays an additive but not independent role in the genesis of VTE.126,127 No relationship has been demonstrated between the A844G polymor-phism and VTE.123

There are limited data on the association between the 4G/4G allele and adverse pregnancy outcomes. No statistically signifi cant associa-tion was found between isolated homozygosity for the 4G/4G muta-tion and recurrent spontaneous abortion in several small studies.128,129 However, endothelial expression of PAI-1 is induced by angiotensin II, 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 signifi cant increase in the combination of the PAI-1 4G/4G and ACE D/D genotypes among patients with recurrent spontaneous abortion compared with controls (13.6% versus 4.7%; OR, 3.2; P = .01).121

Moreover, a possible association exists between the 4G/4G allele and later adverse pregnancy outcomes. Yamada and coworkers

described a modest association between 4G/4G homozygosity and the occurrence of severe preeclampsia (OR, 1.62; CI, 1.02 to 2.57).130 Glueck and colleagues conducted a case-control study and observed that compared to patients with either the 5G/5G or the 4G/5G allele, those who were homozygous for the 4G/4G allele had greater rates of prematurity (14% versus 3%; P = .001), second- and third-trimester deaths (9% versus 2%; P = .004), and IUGR (4% versus 0.4%; P = .012).131 However, caution must be exercised in the interpretation of these data, because the occurrence of adverse outcomes was lower in the control group than would be expected in the general population, and 30% of patients who were homozygous for the 4G/4G mutation had coexisting thrombophilias.131 As was the case for the association between 4G/4G homozygosity and VTE, this mutation may be more likely to be linked with adverse pregnancy outcomes when it occurs simultaneously with other thrombophilic disorders or with triggers of increased PAI-1 expression such as the ACE D/D genotype and disor-ders linked to insulin resistance (e.g., obesity, type 2 diabetes, hyper-lipidemia, polycystic ovary syndrome).

Polymorphisms have been described in the TAFI and tPA genes, but no clear link has been established for either with increased VTE risk or adverse pregnancy outcomes.

Other Thrombophilic MutationsThe -455GtoA polymorphism in the fi brinogen β gene leads to increased plasma fi brinogen levels but an unclear thrombotic risk.132 Both the apolipoprotein B R3500Q and E2/E3/E4 polymorphisms and the platelet receptor gene polymorphisms GpIIIa L33P and GpIa 807CtoT also offer an uncertain VTE risk, although they may contrib-ute to coronary and cerebral artery thrombosis, particularly in the presence of other risk factors such as smoking, hypertension, obesity, and diabetes. The common hereditary hemochromatosis gene (HFE gene C282Y mutation) does not appear to be a risk factor for VTE, even when it is present in patients with FVL.133 An analysis of links between fetal loss and β-fi brinogen -455GtoA, between apolipoprotein B R3500Q and E2/E3/E4, and between GpIIIa L33P and HFE C282Y found no signifi cant associations.134

Polymorphisms have also been described in the thrombomodulin, TFPI, and endothelial PC receptor genes, but they are of no or unknown thrombogenic potential.58 The Val34Leu polymorphism in the factor XIII gene is associated with increased activation by thrombin and a potentially thrombotic phenotype135 but confers uncertain risks for VTE and adverse pregnancy outcome.

SummaryA great number of potentially thrombophilic polymorphisms are being uncovered, at an ever-increasing pace. Although most of these muta-tions do not appear to be highly thrombogenic when present in isola-tion, they may exert an additive or even a synergistic effect on the thrombogenicity of other disorders. This might account for the fi nding of a very modest association between a given thrombophilic state (e.g., FVL, PS defi ciency) and the isolated occurrence of VTE or adverse pregnancy outcomes in low-risk populations together with a far higher concordance rate within certain families.

Screening for Thrombophilias

Screening and Prevention of

Venous ThromboembolismThe presence of a known thrombophilia increases the recurrence risk of VTE among pregnant women. Brill-Edwards and associates pro-

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spectively evaluated 125 pregnant women with a prior VTE, 95 of whom were tested for acquired and inherited thrombophilias (includ-ing APAs, FVL, and PGM) and for PC, PS and AT defi ciencies.136 Antenatal heparin was withheld in all patients, but postpartum anti-coagulation was provided. The overall antepartum recurrence rate for VTE was 2.4% (CI, 0.2% to 6.9%), but no recurrences were observed in the 44 women who had no evidence of thrombophilia and whose previous episode of thrombosis was associated with temporary risk factors that included pregnancy itself. Among the 51 women who had a thrombophilia or whose previous VTE was considered idiopathic, the antepartum recurrence rate was 5.9% (CI, 1.2% to 16.2%), and among the 25 thrombophilic patients the recurrence risk was 16% (4 patients) (OR, 6.5; CI, 0.8 to 56.3). Therefore, there appears to be evidence-based justifi cation to test pregnant patients with a prior history of VTE associated with temporary and reversible risk factors (e.g., fractures, prolonged immobilization, cancer), because the presence of a throm-bophilic state would be an indication for antepartum as well as post-partum thromboprophylaxis. Conversely, women with a prior VTE associated with a nonrecurring risk factor who are without thrombo-philia or other current major risk or susceptibility factors (e.g., need for prolonged bed rest, obesity, current superfi cial thrombophlebitis) may not need antepartum prophylactic heparin therapy during preg-nancy.136 However, because thrombotic events during pregnancy in such women have been reported on rare occasions,110 the risks and benefi ts of antepartum thromboprophylaxis should be discussed with the patient. Also, such patients should receive postpartum prophylaxis, because most pregnancy-associated fatal pulmonary embolisms occur in the postpartum period. In this setting, knowledge of the thrombo-philic state affects management.

The 7th American College of Chest Physicians Guidelines for the Antenatal and Peripartum Management of Thrombophilia suggest that the occurrence of VTE in nonpregnant patients who are receiving estrogen-containing contraceptives is comparable with such events occurring in pregnancy. In either case they would recommend ante-partum and postpartum prophylaxis in a subsequent pregnancy, regardless of thrombophilia status in women who had a VTE during a prior pregnancy or while taking estrogen-containing contraceptives.137 Similarly, consideration should also be given to screening of pregnant women who have a strong family history (i.e., affected fi rst-degree relative) of VTE. Given the greater than 10% risk of VTE in pregnancy among patients with such a history and a thrombophilia (see Table 40-2), thromboprophylaxis, although of unproven effi cacy, is a reason-able option. Cost-effective screens should be initially limited to the most common and most thrombogenic disorders, including FVL and PGM. Negative results should lead to evaluation of fasting homocys-teine levels and PC, PS, and AT defi ciencies.

The dosing regimen to be employed varies with the severity of the thrombophilia, the patient’s family history, and the nature of the prior VTE episodes. In general, for patients with a personal or strong family history of VTE and a lesser thrombogenic thrombophilia (e.g., FVL, PGM, hyperhomocysteinemia refractory to folate therapy, PC or PS defi ciency), antepartum prophylaxis with either mini-dose unfraction-ated heparin or low-dose LMWH is effective in preventing DVT in pregnant patients at risk. The standard regimen of unfractionated heparin used in pregnancy consists of 5000 units administered SQ every 12 hours, increased by 2500 units in the second and third tri-mesters. However, Barbour and associates observed that this standard unfractionated heparin regimen was inadequate to achieve the desired anti-factor Xa therapeutic range in 5 of 9 second-trimester pregnancies and in 6 of 13 third-trimester pregnancies.138 Therefore, assessment of anti-factor Xa levels may be important.

Alternatively, prophylaxis can employ LMWH. Regimens can include dalteparin 5000 U SQ, given every 12 hours or once a day, or enoxaparin 30 mg SQ, every 12 hours or 40 mg SQ once a day. Whereas monitoring of anti-factor Xa levels is not necessary in nonpregnant patients, given the absence of data in pregnancy, the greater variability in heparin binding, and the increased volume of distribution and/or metabolism and excretion in pregnancy, we recommend serial mea-surements of anti-factor Xa levels, with a goal of 0.1 to 0.2 U/mL at 4 hours after each injection.

For patients with highly thrombogenic thrombophilias (e.g., homo-zygotes or compound heterozygotes for FVL and PGM, patients with AT defi ciency or APS with prior VTE) who have a personal or strong family history of VTE, and for patients with recurrent VTE, therapeutic (high-dose) unfractionated heparin or LMWH should be used. The goal of unfractionated heparin therapy is to obtain and maintain an activated partial thromboplastin time (aPTT) of 1.5 to 2.5 times control values or a plasma heparin concentration of 0.2 to 0.4 U/mL, or an anti-factor Xa concentration of 0.4 to 0.7 U/mL. The aPTT should not be used to guide unfractionated heparin therapy in patients with prolonged aPTT due to LAs. Therapeutic LMWH therapy consists of enoxaparin 1 mg/kg SQ twice daily or a comparable dose of dalte-parin (e.g., 10,000 U SQ every 12 hours). Barbour and colleagues evaluated whether the standard therapeutic doses of dalteparin main-tained peak therapeutic levels of anticoagulation during pregnancy and reported that 85% (11/13) of patients required an upward dosage adjustment.139 Therefore, we recommend titrating either agent to maintain factor Xa levels at 0.6 to 1.0 U/mL 4 hours after injection. For patients with highly thrombogenic thrombophilias in the absence of a personal or strong family history of VTE, we recommend using an intermediate or “high prophylactic” dose of LMWH, titrating the dose to maintain factor Xa levels at 0.4 to 0.6 U/mL.

Regardless of whether the patient is receiving prophylactic, thera-peutic, or high prophylactic doses of LMWH, we recommend switch-ing to the comparable dose of unfractionated heparin at 36 weeks, to permit application of neuraxial anesthesia if desired or indicated during labor or delivery. Both heparin and LMWH are associated with an increased risk for osteopenia. Although of unproven benefi t, it seems prudent to advise axial skeleton weight-bearing exercise and calcium supplementation. These medications also increase the risk for heparin-induced thrombocytopenia, which paradoxically is associated with thrombosis. With therapeutic doses of LMWH and with any dose of unfractionated heparin, platelet counts should be obtained after 3 to 4 days of therapy and intermittently for the fi rst 3 weeks of treatment.140

Postpartum thromboprophylaxis is also required. Warfarin is con-sidered safe to take while breast feeding. Warfarin is started within 24 hours of commencing heparin therapy. Doses are determined by moni-toring the international normalized ratio (INR). To avoid paradoxical thrombosis and skin necrosis from warfarin’s early, predominantly anti-PC effect, it is critical to maintain these women on therapeutic doses of unfractionated heparin or LMWH for a minimum of 5 days and until the INR is in the therapeutic range (2.0 to 3.0) for 2 consecu-tive days.

Screening and Prevention of Adverse

Pregnancy OutcomesAs can be discerned from the preceding review, there appears to be a modest and consistent association between the major inherited throm-bophilias (including FVL, PGM, elevated fasting homocysteine levels and PC, PS, and AT defi ciency) and fetal loss after 10 weeks, and par-ticularly isolated losses after 22 weeks. There is also a possible associa-

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tion between these thrombophilic states and abruption. However, no clear association exists between FVL or the other major thrombophil-ias and either preeclampsia or IUGR, although studies have been underpowered to defi nitely exclude a link with severe early-onset pre-eclampsia and/or severe (<5th percentile) IUGR.

There are few studies examining the effectiveness of anticoagula-tion therapy in patients harboring inherited thrombophilias who have experienced recurrent fetal loss or other adverse pregnancy outcomes. Kupferminc and associates treated pregnant thrombophilic women who had a prior history of severe preeclampsia, abruption, IUGR, or stillbirth with enoxaparin 40 mg/day and LDA, plus folate supplemen-tation for those patients found to be homozygous for the MTHFR mutation.141 They reported that, compared to their prior pregnancies, patients receiving LMWH plus LDA had an increased mean gestational age at delivery (32.1 [±5.0] versus 37.6 [±2.3] weeks) and also increased birth weight of their infants (1175 [±590] versus 2719 [±526] g) (P < .0001 for both comparisons).

In a prospective cohort study, Folkeringa and colleagues assessed the effects of anticoagulant drugs on fetal loss in women with AT, PC, or PS defi ciency.142 Of 37 women with a defi ciency, 26 (70%) received thromboprophylaxis during pregnancy, with no fetal losses, compared to 45% fetal loss in defi cient women not receiving thromboprophylaxis (P = .001). The adjusted RR of fetal loss with versus without throm-boprophylaxis was 0.07 (CI, 0.001 to 0.7).

Gris and colleagues conducted a randomized trial of anticoagula-tion in 160 women who had had one unexplained fetal loss after 10 weeks of gestation and who were heterozygous for FVL, PGM, or PS defi ciency.119 All patients were given 5 mg folic acid daily before con-ception; once pregnant, they were randomized to receive either LDA (100 mg daily) or enoxaparin (40 mg daily) beginning in the 8th week. Uncomplicated live births were noted in 28.8% of the LDA group and in 86.2% of the enoxaparin group (P < .0001; OR, 15.5; CI, 7 to 34). Enoxaparin proved superior to LDA among FVL patients. PZ defi -ciency and/or positive anti-PZ antibodies was associated with poorer outcomes. Although these results are impressive, this study has been criticized because of its lack of blinding and the high loss rate in the LDA-only group.

In summary, observational, prospective cohort, and randomized, controlled trials all suggest that LMWH with or without LDA reduces the recurrence risk of fetal loss in thrombophilic patients. Based on these fi ndings, the following recommendations can be made:

1. Women with hyperhomocysteinemia should receive folic acid supplementation regardless of their antecedent VTE or obstetric history, given its low toxicity. For those with a history of VTE or recurrent fetal loss in whom folate does not correct the meta-bolic disorder, prophylactic unfractionated heparin or LMWH should be considered.

2. As noted earlier, patients in the highly thrombogenic thrombo-philia group (AT defi ciency, homozygous or compound hetero-zygous FVL or PGM), regardless of their obstetric history, should be offered “high prophylactic” doses of LMWH, with the dose titrated to maintain factor Xa levels at 0.4 to 0.6 U/mL (if there is no personal or strong family history of VTE) or to maintain therapeutic doses of LMWH (if there is such a history).

3. Pregnant women with less thrombogenic thrombophilias (e.g., heterozygous FVL or PGM, PC or PD defi ciency, hyperhomo-cysteinemia unresponsive to folate therapy) who have no per-sonal or strong family history of VTE but unexplained fetal loss after 9 weeks can be offered antepartum prophylaxis after full

informed consent is obtained regarding the unproven effi cacy of this treatment. They should receive postpartum thrombopro-phylaxis if they require a cesarean delivery, because most fatal acute pulmonary emboli occur during this period.

4. It is unclear whether patients with recurrent abruption in the absence of other known risk factors (e.g., smoking, renal disease, hypertension, uterine anomalies) should be offered antepartum prophylaxis.

5. At this time, there appears to be no justifi cation for offering antepartum thromboprophylaxis to asymptomatic, otherwise low-risk women with lesser thrombophilias who have recurrent preeclampsia or IUGR. However, given the possible association between inherited thrombophilias and later adverse pregnancy outcomes, it is reasonable to consider close maternal/fetal sur-veillance appropriate in this population. Fetal growth may be monitored with serial ultrasound examinations (every 4 to 6 weeks) beginning at 20 weeks’ gestation. Doppler fl ow studies of the umbilical artery may be used as a fetal assessment tool in the setting of IUGR. Nonstress testing and biophysical profi les may be appropriate at 36 weeks or earlier, as clinically indicated. Early delivery may be indicated for deteriorating maternal or fetal condition. Surveillance can be decreased if there is no evi-dence of placental insuffi ciency.

Acquired Platelet Disorders

Idiopathic Thrombocytopenic PurpuraAlso known as primary immune or autoimmune thrombocytopenic purpura, idiopathic thrombocytopenic purpura (ITP) is a syndrome of immunologically mediated thrombocytopenia that is characterized by increased platelet destruction. Immunoglobulin G (IgG) antibody binds to platelets, rendering them more susceptible to sequestration and premature destruction in the reticuloendothelial system, espe-cially the spleen. The rate of destruction exceeds the compensatory ability of the bone marrow to produce new platelets, leading to thrombocytopenia.

In adults, ITP is usually chronic. It may coexist with pregnancy, because the disease usually manifests in the second to third decade of life and has a female preponderance of 2 : 1.143 In fact, ITP is the most common autoimmune bleeding disorder encountered during preg-nancy. The overall course of ITP is not consistently infl uenced by pregnancy (although, rarely, women experience repeated fl ares with each pregnancy); however, pregnancy may be adversely affected by ITP, and the primary risk is hemorrhage in the peripartum period. Because the placenta selectively transports maternal IgG antiplatelet anti-bodies into the fetal circulation, fetal thrombocytopenia also may occur.

DIAGNOSISMost women with ITP have a history of petechiae, ecchymoses, easy

bruising, menorrhagia, or other bleeding manifestations. The diagno-sis is primarily one of exclusion and is based on the history, physical examination, complete blood count (CBC), and examination of the peripheral blood smear.144 The CBC is normal except for thrombocy-topenia (platelet count <100,000/μL), and the smear may show an increased proportion of slightly enlarged platelets. The history and physical examination usually exclude other causes of thrombocytope-nia. Rarely, a bone marrow biopsy is required to clarify the diagnosis. Typical bone marrow fi ndings include increased numbers of immature megakaryocytes. Although the issue is controversial, many authorities

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do not routinely perform this procedure in typical cases of ITP, espe-cially in women younger than 40 years of age.143

It can be diffi cult to distinguish ITP from other causes of maternal thrombocytopenia. The condition most commonly confused with ITP is incidental thrombocytopenia of pregnancy, also known as “essential” or “gestational” thrombocytopenia. Incidental thrombocytopenia of pregnancy is mild (platelets >70,000 cells/μL), asymptomatic, and often fi rst noted by the clinician after a CBC obtained as part of a routine automated prenatal screening test.145,146 In contrast to ITP, incidental thrombocytopenia of pregnancy is common. It occurs in up to 5% of pregnant women and accounts for more than 70% of mater-nal thrombocytopenia.146,147 Individuals with incidental thrombocyto-penia have no prior history of thrombocytopenia and are not at risk for bleeding complications or fetal thrombocytopenia. No special care is required for these women. Other causes of maternal thrombocyto-penia that should be considered are preeclampsia, pseudothrombocy-topenia due to laboratory artifact, SLE, APS, human immunodefi ciency virus (HIV) or hepatitis C virus infection, drug-induced thrombocy-topenia, thrombotic thrombocytopenia, immunodefi ciency states, hereditary thrombocytopenias, and DIC.

Numerous direct and indirect assays of antiplatelet antibodies have been developed to confi rm the diagnosis of ITP. Most patients with ITP have platelet-associated immunoglobulin, and many also have circulating unbound antiplatelet antibodies. Levels of direct (platelet-associated) IgG have a strong inverse correlation with the maternal platelet count and intravascular platelet life span.148 Nonetheless, a negative result does not exclude a diagnosis of ITP.149 Concentrations of indirect (circulating) antiplatelet antibodies less reliably predict maternal platelet counts. Although assays for direct and indirect anti-platelet antibodies are widely available, they are not recommended for the routine evaluation of maternal thrombocytopenia or ITP.144 Assays for antiplatelet antibodies are hampered by a variety of problems, including the use of several different assays, a large degree of interlabo-ratory variation, and a high background rate of platelet-associated IgG. Furthermore, women with ITP cannot be distinguished from those with incidental thrombocytopenia of pregnancy on the basis of anti-platelet antibody testing.150

MATERNAL CONSIDERATIONSThe goal of maternal therapy during pregnancy is to minimize the

risk of hemorrhage and to restore a normal platelet count. Asympto-matic pregnant women with ITP and platelet counts greater than 50,000/μL do not require treatment. In nonpregnant patients, most authorities recommend treatment if the platelet count is lower than 10,000/μL or in the presence of bleeding, but it is controversial whether a particular platelet count (e.g., <50,000/μL or <30,000/μL) is suffi -cient indication for therapy during pregnancy in asymptomatic women. A reasonable approach is to aim for a platelet count greater than 30,000/μL throughout pregnancy and greater than 50,000/μL near term.

The American Society of Hematology ITP Practice Guideline Panel151 recommends treating pregnant women with platelet counts between 10,000 and 30,000/μL during the second or third trimester. More aggressive treatment is often pursued close to the estimated due date, in anticipation of potential bleeding, surgery, or need for regional anesthesia. Some anesthesiologists may require a platelet count greater than 80,000/μL before deeming the woman’s condition safe for place-ment of an epidural catheter.152

Glucocorticoid Drugs. Glucocorticoid drugs have been the cor-nerstone of ITP therapy in pregnancy. Prednisone, 1 to 1.5 mg/kg/day, or the therapeutic equivalent, is the initial treatment of choice.

Improvement usually occurs within 3 to 7 days and reaches a maximum within 2 to 3 weeks. Some increase in the platelet count occurs in 50% to more than 70% of patients, depending on the duration and intensity of therapy.144 Complete remission has been reported in 5% to 30% of cases.144 If platelet counts become normal, the steroid dose can be tapered by 10% to 20% per week until the lowest dosage required to maintain the platelet count higher than 50,000/μL is reached.

It is uncertain how steroids improve platelet counts and decrease bleeding in patients with ITP. Proposed mechanisms of action153 include increased platelet production, decreased production of anti-platelet antibodies and platelet-associated IgG, decreased clearance of antibody-coated platelets by the reticuloendothelial system, and decreased capillary fragility. Adverse effects of steroid use in pregnancy are well known and include glucose intolerance, osteoporosis, hyper-tension, psychosis, and moon facies. Accordingly, the dose and dura-tion of therapy should be minimized.

Intravenous Immune Globulin. IVIG is used in cases of ITP refractory to corticosteroids as well as in urgent circumstances, such as preoperatively, in the peripartum period, or when the platelet count is less than 10,000/μL (or <30,000/μL in a bleeding patient). IVIG is a pooled concentrate of immunoglobulins collected from many donors. High doses of IVIG (1000 mg/kg/day for 2 to 5 days) usually induce a peak platelet count within 7 to 9 days. More than 80% of patients treated with this regimen will have a peak platelet count greater than 50,000/μL, and in 30% of patients the duration of the response lasts for more than 30 days.154,155 Although the mechanism of action is unclear, it seems to involve depression of antiplatelet antibody produc-tion, interference with antibody attachment to platelets, inhibition of macrophage receptor-mediated immune complex clearance, and blockage of Fc receptors in the reticuloendothelial system.155-157 In responders, only 2 or 3 days of IVIG therapy may be needed, and higher doses of 800 or 1000 mg/kg may suffi ce as a single or double infusion.158

Although IVIG had previously been associated with occasional hepatitis C transmission, the current purifi cation process eliminates the risk of blood-borne infections. HIV transmission has never been associated with IVIG use. Untoward effects of IVIG include headache, chills, nausea, liver dysfunction, alopecia, transient neutropenia, fl ush-ing, autoimmune hemolytic anemia, and anaphylactic reactions in patients with IgA defi ciencies.159 There are no known adverse fetal effects. IVIG is extremely expensive, and for that reason its use is best reserved for urgent cases and for ITP refractory to corticosteroids. Examples include a platelet count less than 5000/μL despite treatment with steroids for several days, active bleeding, and extensive and pro-gressive purpura.143

Platelet Transfusions. Platelet transfusions should be considered only as a temporary measure to control life-threatening hemorrhage or to prepare a patient for cesarean delivery or other surgery. Survival of transfused platelets is decreased in patients with ITP, because anti-platelet antibodies also bind to platelets. Therefore, the usual elevation in platelets of approximately 10,000/μL per unit of platelet concentrate is not achieved in patients with ITP. A transfusion of 8 to 10 packs is suffi cient in most cases.

Splenectomy. Complete remission is obtained in 80% of patients with ITP who undergo splenectomy. This operation, which removes the major sites of platelet destruction and antiplatelet antibody pro-duction, is usually avoided during pregnancy because of risks to the fetus and technical diffi culties with the procedure. Nonetheless, sple-nectomy can be safely accomplished during pregnancy if necessary, ideally in the second trimester. It also has been combined with cesarean delivery at term without reported morbidity. Splenectomy (during

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pregnancy) is appropriate for women with platelet counts lower than 10,000/μL who are bleeding and have not responded to IVIG and steroids.144

Rhesus Immune Globulin. Anti-Rh(D) immune globulin has been successfully used to treat ITP in RhD-positive individuals. Indeed, immune globulin against Rh(D) (75 μg per kilogram of maternal weight) works as well as corticosteroids at initial presentation.160 It is more costly than steroids but has fewer side effects. Anti-Rh(D) is not typically used during pregnancy because of a theoretic risk of fetal erythrocyte destruction, although it would most likely bind maternal red blood cells before reaching the fetal circulation. Cases of successful and safe use of anti-Rh(D) during pregnancy (in RhD-positive women) have been reported.161

Other drugs used to treat ITP, such as vinca alkaloids, colchicine, cyclophosphamide, and danazol, are best avoided in pregnancy because of the potential for adverse effects on the fetus. Azathioprine may be considered in refractory cases.

FETAL CONSIDERATIONSBecause the placenta is permeable to circulating maternal antiplate-

let IgG, fetal thrombocytopenia may occur with maternal ITP. Occa-sionally, this results in minor clinical bleeding, such as purpura, ecchymoses, hematuria, or melena. In rare cases, fetal thrombocytope-nia can lead to intracranial hemorrhage (ICH), resulting in severe neurologic impairment or death. Indeed, concern for ICH and its avoidance has become the central issue in the obstetric management of ITP.

Clinicians have tried a variety of strategies intended to minimize fetal bleeding problems in women with ITP. It is now clear that mater-nal medical therapies such as IVIG162 and steroids162-164 do not reliably prevent fetal thrombocytopenia. On the basis of reports of ICH associ-ated with vaginal birth,165 some clinicians recommended cesarean delivery for women with ITP.166 Others have proposed that cesarean delivery be reserved for fetuses with platelet counts lower than 50,000/μL.167 This tactic was prompted by observations that hemorrhagic complications are extremely rare in infants with platelet counts greater than 50,000/μL, and the risk of fetal bleeding is inversely proportional to the platelet count.163.168 With this plan, however, a method is needed to determine which fetuses are thrombocytopenic—ideally, one that is noninvasive, reproducible, and sensitive in identifying at-risk fetuses. No such test is available.

Maternal characteristics and serologic fi ndings, including throm-bocytopenia, previous splenectomy, and platelet-associated antibodies, do not correlate strongly with neonatal thrombocytopenia.146,169 Fetal thrombocytopenia is uncommon in the absence of circulating antiplatelet antibodies,170 but exceptional cases have been reported.171 In addition, positive results have a low positive predictive value,170 and assays for indirect antiplatelet antibodies can be diffi cult to perform.

Good correlation has been reported between neonatal platelet counts and the platelet count of infants born previously to a woman with ITP.164 However, older siblings are not always available for com-parison, and concordance among sibling platelet counts is imperfect.164 Furthermore, discordant platelet counts have been detected in twin gestations complicated by ITP.169,172 Therefore, no historical factor or maternal blood test can accurately predict the fetal platelet count in all cases.

Some investigators have advocated the use of fetal scalp sampling during labor to directly measure the fetal platelet count.167,173 Vaginal delivery is permitted if the platelet count is greater than 50,000/μL; otherwise, the birth is by cesarean delivery. This method is attractive

because it involves negligible risk to mother and fetus and uses an assay (platelet count) that is widely available and inexpensive. Indeed, fetal scalp sampling has allowed 80% of fetuses with platelet counts greater than 50,000/μL to safely deliver vaginally.169 The major drawback is the occasional occurrence of falsely low platelet counts, resulting in unnec-essary cesarean deliveries.174-176 Further, fetal scalp sampling cannot always easily be accomplished if there is limited cervical dilation or a high presenting part.

These problems can be circumvented with the use of cordocentesis to determine the fetal platelet count. This method results in accurate platelet counts and can be performed before labor.162,177.178 The proce-dure is usually deferred until fetal maturity is present. As with scalp sampling, the delivery route is based on the fetal platelet count. However, cordocentesis cannot always be accomplished in the late third trimester,177,178 the skills required are not available in all centers, and the procedure is expensive. Cordocentesis also may result in serious complications.176 Hemorrhage at the puncture site, cord hematoma, and cord spasm with fetal bradycardia contribute to an overall associ-ated mortality rate of 2.7%.179 Procedure-related complications have been reported in about 4% to 5% of cordocenteses in patients with presumed ITP.180 In several instances, fetuses with normal platelet counts were delivered by cesarean section or incurred serious morbid-ity. Bleeding is more likely in the presence of severe thrombocytope-nia.181,182 The true incidence of complications may be even higher: procedure-related complications often go unreported, and reporting centers tend to have the most expertise with the procedure and are likely to have lower complication rates than other facilities.179

Problems with fetal scalp sampling and cordocentesis have prompted reevaluation of the effi cacy of these procedures in the man-agement of pregnancies complicated by ITP.163,183,184 In addition, several reports have suggested that hemorrhagic complications in thrombo-cytopenic neonates are unrelated to the route of delivery.163,168,176,185 In a review of 474 neonates born to mothers with ITP, 29% of thrombo-cytopenic infants delivered vaginally suffered clinically apparent bleed-ing, compared with 30% of those delivered by cesarean section.163 A careful analysis of the literature also suggests that no case of ICH has been directly attributable to intrapartum events.176,184

Another important consideration is the relative infrequency of ICH in infants born to mothers with ITP. For example, in a comprehensive population-based study of almost 16,000 pregnancies complicated by ITP, there were no cases of ICH.147 The only three infants with ICH had alloimmune, not autoimmune, thrombocytopenia. These observa-tions were confi rmed in retrospective analyses of ITP in pregnancy. The proportion of infants with platelet counts lower than 50,000/μL is about 15%, and this may be an overestimate of the risk because of publication bias. Serious bleeding complications occurred in 22 of 688 neonates,180 and only 6 (0.87%) had ICH. None of the cases of ICH were clearly demonstrated to be caused by intrapartum events. In one review of 288 ITP pregnancies wherein fetal platelet counts were deter-mined at the time of delivery, there were no cases of ICH or perinatal death.168

In summary, obstetric management of ITP remains controversial, but most investigators now believe that fetal scalp sampling, cordocen-tesis, and cesarean delivery contribute to cost and morbidity without preventing neonatal bleeding complications. Therefore, it is recom-mended that ITP be managed without determination of the fetal plate-let count and that cesarean delivery be reserved for the usual obstetric indications.163,168,176,184 In contrast, others have found that the potential 1% risk of ICH warrants cesarean delivery in selected cases.144,186 Those clinicians who favor interventional management use fetal scalp sam-pling to determine the fetal platelet count in pregnancies most at risk

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for thrombocytopenia (e.g., when there is a sibling with severe throm-bocytopenia). The use of cordocentesis in the obstetric management of ITP is diffi cult to justify.

Delivery should be accomplished in a setting in which platelets, fresh-frozen plasma, and IVIG are available. A neonatologist or pedia-trician familiar with the disorder should be present to promptly treat any hemorrhagic complications in the neonate. The platelet count of the affected newborn usually falls after delivery, and the lowest platelet count is not reached for several days.187 Most infants are asymptomatic, and the thrombocytopenia is self-limited. Nonetheless, daily platelet counts should be obtained for several days. Although breastfeeding early in the puerperium may theoretically cause neonatal thrombocy-topenia, many women with ITP have done so without clinical sequelae.

Neonatal Alloimmune ThrombocytopeniaIn contrast to the minimal fetal risks in maternal ITP, fetal/neonatal alloimmune thrombocytopenia (NAIT) is a serious and potentially life-threatening condition that affects 0.2 to 1.0 of every 1000 live births in white people.188-190 Rates vary by ethnicity, and African Americans appear to be affected less frequently.191 The disorder occurs as the result of maternal alloimmunization against fetal platelet antigens that are lacking on the mother’s own platelets; it is analogous to the hemolytic anemia caused by maternal alloimmunization against fetal erythrocyte antigens.

Several polymorphic, diallelic platelet antigen systems are respon-sible for NAIT. Many of these antigen systems were simultaneously identifi ed in different parts of the world and given several names. To minimize confusion, uniform nomenclature has been adopted to describe these antigen systems as human platelet antigens (e.g., HPA-1), with alleles designated as “a” or “b.”192 The most frequent cause of NAIT in whites is sensitization against HPA-1a, also known as PLAT or Zwa. The antigens HPA-1a (PLAl) and HPA-lb (PLA2) are the product of polymorphic alleles that differ by a single base-pair change in the gene encoding the platelet glycoprotein GpIIIa (integrin β3).193 In turn, this causes a substitution of proline for leucine in the protein, resulting in antigenically distinct conformations. Of all white people, 97% are HPA-1a positive; 69% are homozygous HPA-1a, and 28% are heterozygous.194 Several other antigens, including HPA-lb, HPA-5b (Br), HPA-3b (Bak), and HPA-4b (Yuk), also may cause NAIT (Table 40-3). In Asians, sensitization against HPA-4 is the most common cause of NAIT.

Although approximately 1 in 42 pregnancies is incompatible for HPA-1a, NAIT develops in only 1 of every 20 to 40 of these cases. In some instances,195 the disorder remains subclinical because the anti-platelet antibodies are not potent enough to induce thrombocytopenia in the infant.196 In addition to antigen exposure, there appears to be a need for an immunologic susceptibility to HPA-la sensitization. The human leukocyte antigen (HLA) class II determinant, Dw52a, appears to be a requirement for the development of antibodies against HPA-1a.197 Associations between sensitization to other platelet antigens and HLA phenotypes are less well characterized, although DR6 has been linked to anti-HPA-5.198 In contrast to rhesus isoimmunization, NAIT can occur during a fi rst pregnancy without prior exposure to the offending antigen. The diagnosis is usually made after birth in an infant with unexplained severe thrombocytopenia, often associated with ecchymoses or petechiae.188,199 The most serious bleeding compli-cation is ICH, which occurs in 10% to 20% of infants with NAIT.199,200 Fetal ICH due to NAIT can occur in utero,201 and 25% to 50% of cases of ICH are detected by sonography before delivery.201 Characteristic sonographic fi ndings include evidence of intracranial hematoma or

hemorrhage and porencephalic cysts. Obstructive hydrocephalus also may be present. As with red cell alloimmunization, the condition tends to worsen throughout pregnancy, as well as in subsequent pregnan-cies.200,202,203 NAIT should be suspected in cases of otherwise unex-plained fetal or neonatal thrombocytopenia, in utero or ex utero ICH, or porencephaly. Serologic evaluation should be performed in an expe-rienced laboratory with special interest and expertise in NAIT.

In most cases, the diagnosis of NAIT can be determined by testing the parents; testing of fetal or neonatal blood is confi rmatory and occasionally helpful. Appropriate assays include serologic confi rmation of maternal antiplatelet antibodies that are specifi c for paternal or fetal/neonatal platelets. In addition, individuals should undergo plate-let typing with zygosity testing. This can be determined serologically or with DNA-based tests, because the genes and polymorphisms for HPAs recognized to cause NAIT are well characterized. This is particu-larly useful for obstetric management, because fetal HPA typing can be accomplished with amniocytes.204 Chorionic villus sampling should be avoided, because it may exacerbate the alloimmune reaction.

TABLE 40-3 PLATELET-SPECIFIC ALLOANTIGENS THAT ARE ASSOCIATED WITH ALLOIMMUNE THROMBOCYTOPENIA

HPA System Name Antigen Familiar Name

Polymorphisms of GpIIIa

HPA-1 HPA-1a P1A1, ZwªHPA-1b P1A1, Zwb

HPA-4 HPA-4a Pena, Yukb

HPA-4b Penb, Yuka

HPA-6 HPA-6bw Ca, TuHPA-7 HPA-7bw MoHPA-8 HPA-8w Sr-aHPA-10 HPA-10bw La(a)HPA-11 HPA-11bw Gro(a)HPA-14 HPA-14bw Oe(a)HPA-16 HPA-16bw Duv(a)

Polymorphisms of GpIIb

HPA-3 HPA-3a Baka, LekHPA-3b Bakb

HPA-9 HPA-9bw Maxa

Polymorphisms of GpIa

HPA-5 HPA-5a Brb, ZavbHPA-5b Bra, Zava

HPA-13 HPA-13bw Sit(a)

Polymorphisms of GpIb

HPA-2 HPA-2b Koa, Sib-aHPA-12 HPA-12bw Ly(a)

Other probable platelet alloantigen specifi cities

HPA-15 HPA-15a Gov aHPA-15b Gov b

Gp, glycoprotein; HPA, human platelet antigen.

Modifi ed from Mark E. Brecher (ed): Platelet and granulocyte antigens

and antibodies. In Technical Manual, 15th ed. Bethesda, MD: American

Association of Blood Banks. Reprinted with permission from

Berkowitz RL, Bussel JB, McFarland JG: Alloimmune

thrombocytopenia: State of the art 2006. Am J Obstet Gynecol

195:907-13.a, 2006.

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Occasionally, results are ambiguous, and in some cases, an antigen incompatibility cannot be identifi ed. The management of such diffi cult cases is best individualized and underscores the need for consultation with physicians and laboratories familiar with the disorder.

The natural history of NAIT is diffi cult to ascertain, because it is usually unrecognized during fi rst affected pregnancies, and subsequent pregnancies are infl uenced by therapeutic interventions. Nonetheless, several observations can be made from a large cohort of 107 fetuses with NAIT (97 with HPA-la incompatibility) who were followed with serial cordocenteses to determine the fetal platelet count:205

1. The recurrence risk of NAIT is extremely high and is 100% if the fetus has the HPA-la antigen in sensitized HPA-la-negative mothers.

2. Fetal thrombocytopenia caused by HPA-la sensitization is often severe and can occur early in gestation. Of the patients studied, 50% had initial platelet counts of less than 20,000/μL. This included 21 (46%) of 46 fetuses tested before 24 weeks’ gestation.

3. A history of a sibling with antepartum ICH is a risk factor for the development of severe thrombocytopenia. However, neither a sibling platelet count nor a sibling with ICH recognized after delivery reliably predicts the initial fetal platelet count.

4. Thrombocytopenia uniformly worsens in untreated fetuses. Seven fetuses in this cohort had initial platelet counts higher than 80,000/μL and were not treated. All demonstrated rapid and substantial decreases in their platelet counts.

NAIT associated with antigens other than HPA-la is less well studied. In the large series reported by Bussel and colleagues, throm-bocytopenia associated with anti-HPA-la was more severe than NAIT caused by other antigen incompatibilities.205 Therefore, data regarding HPA-la incompatibility cannot be generalized to other causes of NAIT.

The explicit goal of the obstetric management of pregnancies at risk for NAIT is to prevent ICH and its associated complications. As with ITP, antepartum management is controversial and few randomized data are available to guide therapy. In contrast to ITP, however, the dramatically higher frequency of ICH associated with NAIT justifi es more aggressive interventions. Also, therapy must be initiated antena-tally because of the risk of in utero ICH. If the diagnosis is uncertain, the risk of NAIT should be confi rmed by documentation of platelet incompatibility or maternal antiplatelet antibodies specifi c for paternal or fetal platelets. It is unnecessary to repeat testing in a family with a case of previously confi rmed NAIT. Antibody titers are poorly predic-tive of risk to the current pregnancy and need not be obtained once the diagnosis is secure. If the father is heterozygous for the offending antigen, fetal genotyping should be accomplished with amniocytes. This strategy can prevent additional expensive and risky interventions in approximately 50% of cases.

If the fetus is considered to be at risk, most investigators recom-mend cordocentesis to determine the fetal platelet count. This strategy avoids treatment of fetuses with normal platelet counts and provides feedback about treatment response in cases of thrombocytopenia. The drawback is the modest but clinically important risk of fetal hemor-rhage after cordocentesis in the setting of severe NAIT.182,191 Because of this risk, a case could be made to initiate therapy without knowledge of the fetal platelet count. It is controversial whether the benefi ts of fetal blood sampling outweigh the risks in most cases. Many clinicians now transfuse between 5 and 15 mL of packed, washed, and irradiated maternal platelets (obtained by plateletpheresis) at the time of cordo-

centesis.182 Although the effi cacy of this approach is unproved, it may decrease the risk of bleeding complications at the time of the proce-dure. It is important to distinguish this use of platelets from platelet transfusions intended as primary therapy (see later discussion).

The optimal timing of the initial cordocentesis is controversial. ICH can occur early in gestation,206 prompting some authorities to recom-mend fetal blood sampling as soon as the procedure is technically fea-sible (18 to 20 weeks). Such cases are rare, however, and the consequences of bleeding complications from cordocentesis are potentially more grave at previable gestational ages. Fetal blood sampling can probably be safely delayed until 24 to 26 weeks in most cases. Further studies should resolve some of these issues. Meanwhile, it seems prudent to individualize the management of each case, depending on the perti-nent antigen and the severity of NAIT during previously affected pregnancies.

Proposed therapies to increase the fetal platelet count and prevent ICH include maternal treatment with steroids and IVIG,189,207-210 fetal treatment with IVIG,211-213 and fetal platelet transfusions.203 However, no therapy is effective in all cases.

The administration of IVIG directly to the fetus has not consistently raised fetal platelet counts216; however, because only a small number of patients have been treated, lack of effi cacy has not been proved. Platelet transfusions are effective,217 but the short half-life of transfused plate-lets necessitates weekly procedures. The potential risks involved with multiple transfusions and the potential for increased sensitiza-tion191,217,218 limit the attractiveness of this treatment. Platelet transfu-sions are perhaps best reserved for severe cases refractory to other therapies.

Administration of IVIG to the mother appears to be the most consistently effective antenatal therapy for NAIT. Bussel and colleagues demonstrated that weekly infusions of 1 g/kg maternal weight of IVIG often stabilize or increase the fetal platelet count.189,207,209 In a study of 55 women with NAIT and thrombocytopenic fetuses, between 62% and 85% of fetuses responded to IVIG therapy, depending on how “response” was defi ned.207 No fetus suffered ICH. In fact, ICH is extremely rare in pregnancies treated with IVIG, occurring in only 1 of more than 100 cases managed by Bussel and his collaborators.202 The mechanism of action is uncertain but may be related to placental Fc receptor blockade preventing active transport of antiplatelet antibod-ies across the placenta.219

Bussel and coworkers207 also showed that low-dose dexamethasone therapy does not improve fetal platelet counts beyond the effect achieved with IVIG. Fetal platelet counts increased to a similar degree in NAIT patients randomized to treatment with either IVIG alone or IVIG plus 1.5 mg/day of dexamethasone.207 In contrast, 5 of 10 patients with no response to IVIG had increased fetal platelet counts after the addition of 60 mg/day of prednisone.207 They also noted that fewer than half of fetuses with platelet counts lower than 20,000/μL responded to the initial dose of IVIG.

This led to a subsequent parallel set of randomized trials, in which patients were stratifi ed by level of risk for severe thrombocytopenia and ICH. The fi rst trial, conducted in 40 women with either a prior infant with ex utero ICH or a current fetus with a platelet count of less than 20,000/μL, randomized treatment IVIG 1 g/kg/wk plus predni-sone 1 mg/kg/day versus IVIG 1 mg/kg/wk alone, after a cordocentesis at 20 weeks.220 IVIG and steroids increased the mean platelet count over 3 to 8 weeks by 67,100/μL, compared with 17,300/μL for IVIG alone (P < .001). Moreover, the difference in treatment was more pro-found in the subgroup of cases with initial fetal platelet counts lower than 10,000/μL. In these cases, IVIG and prednisone increased the platelet count in 82% of cases, compared with 18% for IVIG alone.200

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Thirty-nine women at lower risk for fetal ICH (i.e., no prior infant with ICH and current fetal platelet count >20,000/μL) were random-ized to treatment with IVIG (1 g/kg/wk) or lower-dose prednisone (0.5 mg/kg/day). There was no signifi cant difference in fetal response to these two regimens.200 The same group also treated 15 women who had prior infants with in utero ICH with IVIG, 1 or 2 g/kg/wk, begin-ning at 12 weeks’ gestation. Therapy was intensifi ed (increased IVIG and/or adding steroids) if there was severe thrombocytopenia at 20 weeks. All fetuses responded adequately to intensifi ed therapy, except one that had in utero ICH at 19 weeks’ gestation.189

Berkowitz, Bussel, and colleagues reported further results of a recent randomized clinical trial comparing outcome in “standard risk (no prior infant with ICH)” pregnancies for NAIT treated with IVIG 2 g/kg/wk versus IVIG 1 g/kg/wk plus 0.5 mg/kg/day of prednisone.200 Outcomes were similar and excellent in both groups, with no cases of ICH. Empiric therapy was started at 20 weeks’ gestation, and cordo-centesis was done once at 32 weeks. Salvage therapy (either adding steroids or increasing the dose of IVIG) was done if the platelet count was lower than 50,000/μL.200

Most authorities recommend cesarean delivery for fetuses with platelet counts of less than 50,000/μL.191 As discussed in the section on ITP, vaginal delivery has never been shown to cause ICH, and cesarean delivery has never prevented it. Furthermore, the use of 50,000/μL as a cutoff is entirely arbitrary. Nonetheless, the substantial rate of ICH probably justifi es cesarean delivery in pregnancies with severe NAIT.

In summary, according to the available current data, it seems appro-priate to stratify treatment based on the level of risk for NAIT. In families with prior in utero ICH, empiric treatment early in pregnancy is advised. In women who previously delivered infants with ex utero ICH, or who currently have a fetus with a platelet count lower than 20,000/μL, appropriate treatment is IVIG and glucocorticoids. However, lower doses of IVIG (or glucocorticoids) may be used in lower-risk cases. It is controversial whether the information obtained from assessment of fetal platelet count by cordocentesis justifi es the risk of that procedure.191,220,221 There appears to be value in adjusting the initial treatment based on fetal platelet count—increasing the dose of IVIG or adding glucocorticoids, or both—in cases of treatment failure.191,207,220 Therefore, we consider assessment of the fetal platelet count between 24 and 32 weeks’ gestation in fetuses at risk based on genotyping or paternal testing. The procedure can usually be safely delayed until the fetus reaches viability. Cordocentesis may be espe-cially helpful in cases that are not caused by HPA-1a, because the recurrence risk is less and the clinical course less predictable. The fetal platelet count may be again determined at term to guide the route of delivery, as outlined, if vaginal birth is desired. Alternatively, a platelet count of greater than 100,000/μL at 32 weeks can be used as a threshold to allow vaginal delivery at term.200 This strategy usually limits the number of cordocenteses to no more than two or three per pregnancy. Empiric treatment without cordocentesis also is a reasonable option, and care should be individualized after appropriate counseling regard-ing pros and cons of cordocentesis.

There are no data to support population-wide screening for poten-tial HPA incompatibility.191 Studies are ongoing to address the effi cacy and cost-effectiveness of such programs. Another clinical dilemma is the patient whose sister has had a pregnancy with NAIT. It may be worthwhile to assess platelet antigen incompatibility, HLA phenotype, and (in cases at risk based on these tests) fetal platelet count in such patients. However, we have not found such testing to be useful. Instead, we reassure such women that their prospective risk of NAIT is low and that we are unsure about the clinical relevance of such testing.

Thrombotic Thrombocytopenic Purpura and

Hemolytic Uremic SyndromeThrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are thrombotic microangiopathies that are charac-terized by thrombocytopenia, hemolytic anemia, and multisystem organ failure. They are rare entities, but they may occur during preg-nancy, are life-threatening, and can be diffi cult to distinguish from the HELLP syndrome (hemolysis, elevated liver enzymes, and low plate-lets). The incidence is estimated to be 1 : 25,000 births.222 Early diag-nosis and treatment are critical, because mortality may be reduced by 90%.223

TTP is characterized by central nervous system (CNS) abnormali-ties, severe thrombocytopenia, and intravascular hemolytic anemia. The most common CNS abnormalities are headache, altered con-sciousness, seizures, and sensory-motor defi cits. Renal dysfunction and fever also may occur. Individuals with HUS have renal involvement as the major fi nding, as well as thrombocytopenia and hemolytic anemia. The conditions are diffi cult to distinguish from each other, because up to 50% of patients with HUS have CNS abnormalities, and renal dys-function may occur in up to 80% of those with TTP. For this reason, the two disorders are often considered as a single entity.224,225

The pathophysiology of both conditions is abnormal and profound intravascular platelet aggregation leading to multiorgan ischemia. In HUS, this occurs predominantly in the kidney. The inciting event in TTP is uncertain. One possibility is an abnormal immune response, because the condition is associated with several autoimmune disorders. It is more common in women, consistent with many other autoim-mune conditions. Other possibilities are medications such as chemo-therapy agents, viral infection, and perhaps pregnancy itself, although many individuals have no risk factors. Larger than average vWF mul-timers appear to contribute to the pathophysiology, promoting abnor-mal platelet aggregation.226 A plasma enzyme termed ADAMTS13 cleaves these vWF multimers, thereby preventing the formation of platelet clumps. ADAMTS13 activity may be absent in patients with TTP, making it a risk factor for the condition.227 Defi ciency in ADAMTS13 may be congenital,228 or it may be acquired through the development of autoantibodies.229 HUS is most often seen in children after a diarrheal illness caused by Escherichia coli. Hemolysin from Shiga toxin–negative E. coli O26 attaches to receptors in renal epithe-lium, leading to endothelial injury, platelet activation/aggregation, and ischemia.230 In adults, HUS is often precipitated by pregnancy, chemo-therapy, or bone marrow transplantation. The recurrence risk is higher in adults and in patients who do not have infectious diarrhea as an inciting event.

The diagnosis of these conditions is clinical, because there is no laboratory “gold standard.” CBC and peripheral blood smear confi rms thrombocytopenia and microangiopathic hemolytic anemia (schisto-cytes, helmet cells, and burr cells). Lactate dehydrogenase and bilirubin are elevated, indicating hemolysis. Serum creatinine and blood urea nitrogen may be elevated, especially in HUS. Clotting studies are typi-cally normal early in the disease process. However, secondary DIC may occur after tissue necrosis. Large multimers of vWF may be present in cases of TTP, and renal biopsy may show microvascular occlusions and intraglomerular platelet aggregates in HUS. ADAMTS13 activity may be decreased in both TTP and HUS.227 However, in many centers, results may not be available in a timely fashion.231 Both disorders are hard to distinguish from preeclampsia.231,232 Potential clinical signs and laboratory tests to differentiate these conditions are shown in Table 40-4.233 The distinction between preeclampsia and TTP or HUS is

Ch040-X4224.indd 842 8/26/2008 4:08:00 PM


critical, because the former will improve with delivery, but TTP and HUS require additional therapy.

Plasmapheresis has been reported to substantially increase the sur-vival rate with TTP to about 80%.234,235 Effi cacy is less certain for HUS, but good outcomes have been reported.233,235 The mechanism of action is unclear but may involve removal of platelet-aggregating agents, such as large vWF multimers, or autoantibodies against ADAMTS13. Addi-tional treatment includes infusion of platelet-poor or cryoprecipitate-poor fresh-frozen plasma (30 mL/kg/day), which may replace ADAMTS13, thus reducing vWF multimer size and reducing platelet aggregation. Platelet transfusions should be avoided, because it may precipitate the disease.223 However, red blood cell transfusion is often necessary. Glucocorticoids or other immunosuppressive therapy may be useful (potentially to reduce antibodies to ADAMTS13) and is rec-ommended for patients who do not respond immediately to plasma exchange.227 Effi cacy is uncertain. Treatment should continue for several days after recovery. Refractory cases may benefi t from cytotoxic immunosuppressive agents. These therapies are generally accepted for TTP. Therapy is similar for HUS, although effi cacy is less certain. Individuals with HUS often require dialysis as well.

About 10% to 25% of TTP cases occur during pregnancy or the postpartum period. Indeed, pregnancy is considered to be a risk factor for TTP and HUS, perhaps because of physiologic reduction in ADAMTS13 levels, general hypercoagulability, and synergistic features with preeclampsia.236,237 HUS is more likely to occur in the peripartum

or postpartum period. If TTP or HUS manifests during pregnancy, there is a risk of up to 33% for fetal mortality.238,239 Fetal death is caused by previable delivery, severe maternal illness, and placental insuffi -ciency. If TTP or HUS occurs early in gestation, aggressive treatment with plasma infusions, plasmapheresis, and steroids should be initi-ated. Delivery of the fetus should be considered in refractory cases, because improvement has been reported in sporadic cases.233 At later gestational ages, delivery becomes a more attractive option. It is impor-tant to consider TTP and HUS in cases of apparent preeclampsia or HELLP syndrome that do not improve without 48 to 72 hours after delivery.

It also is important to counsel women about the recurrence risk for these conditions. In a small series of women with TTP or HUS in pregnancy, half had a least one recurrence.222 Long-term morbidity and mortality were substantial. However, good outcomes have been reported in subsequent pregnancies in women with prior TTP or HUS associated with pregnancy.240,241 Serial and prophylactic plasma exchange may be useful in women with prior TTP or HUS and persis-tent severely reduced ADAMTS13 activity.241

Drug-Induced Thrombocytopenia and

Functional Platelet DefectsSome drugs, such as heparin and quinidine, can cause thrombocyto-penia. Functional platelet defects occur when there are normal numbers of platelets that do not function properly. Drugs are a common cause of this condition. Examples include aspirin, NSAIDs, antimicrobial agents such as carbenicillin, and glyceryl guaiacolate, which is present in some cold remedies.

Congential Platelet Disorders

Von Willebrand DiseasevWD occurs in 1.3% of individuals, making it the most common inherited bleeding disorder.242,243 The condition is caused by abnormal platelet adhesion resulting from defi ciencies or abnormalities in vWF. There are three types. Type I, the most common variety, accounts for 80% of cases; it is usually inherited in an autosomal dominant fashion and is characterized by defi ciencies in structurally normal factor VIII and vWF. In type I vWD, platelets fail to aggregate in the presence of ristocetin. Type II vWD is less common and may be transmitted in an autosomal recessive fashion. There are several subtypes of type II vWD, which is notable for vWF that does not function normally. Type IIA involves a defi ciency of normal high-molecular-weight multimers of vWF, with consequent decreased affi nity for platelets. Type IIB is char-acterized by vWF with an increased affi nity for platelets due to an increased affi nity for GpIb. The clinical disorder is similar to that caused by pseudo-vWD, which results from defective GpIb and also leads to hyperactive platelet binding to vWF. Type IIM is notable for morphologically and qualitatively abnormal vWF with reduced inter-action with GpIb. Type IIN is caused by vWF with impaired binding to factor VIII. Type III also is an autosomal recessive trait and is the least common of the three types. Individuals with type III vWD have severe defi ciencies of vWF/factor VIII. vWD and its subtypes may be diagnosed with a variety of laboratory studies, as summarized in Table 40-5.244,245

A primary treatment for many women with vWD is desmopressin (DDAVP), which increases plasma factor VIII and vWF levels (Table 40-6).246,247 Response to DDAVP is highly variable among women with vWD, although most of those with type I disease have a favorable

TABLE 40-4 CLINICAL CHARACTERISTICS AND LABORATORY FINDINGS IN TTP, HUS, AND SEVERE PREECLAMPSIA/HELLP SYNDROME

TTP HUS Preeclampsia/HELLP

Neurologic symptoms +++ +/− +/−Fever ++ +/− −Hypertension +/− +/− +/−Renal dysfunction +/− +++ +/−Skin lesions (purpura) + − −Platelets ↓↓↓ ↓↓ ↓PT/PTT ↔ ↔ ↓ or ↔Fibrinogen ↔ ↔ ↓ or ↔BUN/Cr ↑ ↑↑↑ ↑AST/ALT ↔ ↔ ↑LDH ↑↑↑ ↑↑↑ ↑Multimeric forms of vWF + + −ADAMTS13 activity ↓↓↓ ↓↓↓ ??? −

+ = mild symptoms present; ++ = moderate symptoms present;

+++ = severe symptoms present; +/− = mild or no symptoms present;

- = no symptoms present; Ø = mildly decreased; ØØ = moderately

decreased; ØØØ = severely decreased; ≠ = mild elevation; ≠≠≠ = severe

elevation; ´ = no change.

ADAMTS13, von Willebrand factor–cleaving protease; ALT, alanine

aminotransferase; AST, aspartate aminotransferase; BUN, blood urea

nitrogen; Cr, creatinine; HELLP, hemolysis, elevated liver enzymes, and

low platelets; HUS, hemolytic uremic syndrome; LDH, lactate

dehydrogenase; PT, prothrombin time; PTT, partial thromboplastin

time; TTP, thrombotic thrombocytopenic purpura; vWF, von Willebrand

factor.

Modifi ed from Esplin MS, Branch DW: Diagnosis and management of

thrombotic microangiopathies during pregnancy. Clin Obstet Gynecol

42:360, 1999.

Ch040-X4224.indd 843 8/26/2008 4:08:00 PM


response. Some women with type IIA vWD also respond well to DDAVP. However, the drug should be avoided in women with type IIB disease, because it may cause thrombocytopenia.248 Patients with type III disease rarely respond. Ideally, an individual’s response to DDAVP should be tested under nonurgent circumstances. A typical dose is 0.3 μg/kg to a maximum of 20 μg SQ or diluted in 50 to 100 mL of normal saline and given intravenously over 30 minutes. If the patient is not pregnant, the drug may be administered on day 1 of menses. A subjective decrease in fl ow is considered a positive response. If the patient is pregnant or not bleeding, the response is gauged by assessing a change in platelet count and vWF:ristocetin cofactor (RCoF) peak activity at 90 minutes after the administration of DDAVP. Adverse effects of DDAVP include headache, fl ushing, changes in blood pres-sure, fl uid retention, and hyponatremia. The drug is pregnancy cate-gory B.

Replacement of clotting factors is the other standard treatment for VWD. In cases with factor VIII:c or vWF levels less than 50 IU/dL, prophylactic treatment should be given to cover invasive procedures and delivery.247 Patients with low vWF levels and either known positive responses to DDAVP or type I disease should be given prophylactic treatment with a single dose of DDAVP, either 60 minutes before anticipated delivery or at the time of cord clamping.247 Additional doses are of uncertain benefi t and may be harmful. Special attention must be given to the possibility of fl uid retention and hyponatremia

when using DDAVP near the time of childbirth.243 Women who do not respond to DDAVP may be treated with factor VIII/vWF plasma con-centrate in the form of plasma, cryoprecipitate, Humate-P, and Koate. These products are typically labeled with vWF:Ac concentrations indi-cating functional activity: 1 IU/kg of vWF:Ac increases the plasma level by 2.0 U/dL. Ideally, vWF:Ac levels should be 50% of normal (50 IU/dL) in prophylactic settings; 100% of normal is the goal in cases of bleeding or surgery. This level should be maintained for at least 3 days after vaginal delivery or 5 days after cesarean delivery.247 Tranexamic acid also may be useful in controlling or preventing postpartum hemorrhage.247

Pregnancy is not contraindicated in women with vWD, but they should be informed of the potential for bleeding.243,244 A recent large epidemiologic study estimated the OR of postpartum hemorrhage for women with vWD to be 1.5 (CI, 1.1 to 2.0).249 The OR for needing a blood transfusion was 4.7 (CI, 3.2 to 7.0), and 5 of 4067 women died (a rate 10-fold higher than in the general population).249 The antepar-tum period is an ideal time to characterize the type of vWD and the response to DDAVP. If possible, a multidisciplinary team including a hematologist, obstetrician, and anesthesiologist should coordinate care and a management plan.247 Prenatal diagnosis is possible in many cases, and genetic counseling should be offered to affected families (Table 40-7). This is especially pertinent for patients who are at risk of having a fetus with severe type III disease. At times, genetic testing of amnio-

TABLE 40-5 CONGENITAL BLEEDING AND PLATELET DISORDERS

Disorders Defi nition Diagnostic Assays

Hemophilia A Severe Factor VIII <2% Prolonged aPTT, low factor VIII Mild Factor VIII 2-25% Prolonged aPTT, low factor VIII Carrier Factor VIII ≈50% aPTT usually normal, low factor VIIIHemophilia B Severe Factor IX <2% Prolonged aPTT, low factor IX Mild Factor IX 2-25% Prolonged aPTT, low factor IX Carrier Factor IX ≈50% aPTT usually normal, low factor IXFactor VII defi ciency Low factor VII Prolonged INR, low factor VIIFactor X defi ciency Low factor X Prolonged aPTT, prolonged INR, low factor XFactor XI defi ciency Low factor XI Prolonged aPTT, low factor XIIFactor XII defi ciency Low factor XII Prolonged aPTT, low factor XIIFactor XIII defi ciency Low factor XIII Normal aPTT and INR, low factor XIIIHypofi brinogenemia Low fi brinogen Low fi brinogen vWD Types I and III Defi cient (type I) or absent (type III) vWF Absent vWF:RCoF and RIPA; platelets aggregate with

bovine plasma Type IIA Qualitatively abnormal vWF: lack of HMW multimers Multimeric analysis Type IIB Qualitatively abnormal vWF; spontaneously binds

platelets; lack of HMW multimersPlatelets aggregate to 0.5 mg/mL of ristocetin;

multimeric analysis ↓ plateletsPseudo-vWD Platelets spontaneously bind GpIb-IX-V complex Absent vWF:RCoF activity; differentiated from vWD

by no clumping to bovine plasmaBernard-Soulier syndrome Platelet GpIb is defective Absent vWF:RCoF activity; differentiated from vWD

by no clumping to bovine plasmaSecretion defects Arachidonic acid and prostaglandin pathway

abnormalitiesAspirin/NSAIDs are common causes; abnormal

response to collagen, arachidonic acid; normal primary wave only

Storage pool defi ciencies Abnormal function or component defi ciency of platelet granules (α, δ, or both)

Primary wave only; decreased collagen assay; variable arachidonic acid assay; mepacrine labeling

Glanzmann thrombasthenia GpIIb-IIIa is absent, present in minimal amounts, or qualitatively abnormal

Platelets not activated by ADP, collagen, or arachidonic acid

ADP, adenosine diphosphate; aPTT, activated partial thromboplastin time; Gp glycoprotein; HMW, high molecular weight; INR, international

normalized ratio; NSAIDs, nonsteroidal anti-infl ammatory drugs; RCoF, ristocetin cofactor; RIPA, ristocetin-induced platelet agglutination; vWD, von

Willebrand disease; vWF, von Willebrand factor.

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cytes or chorionic villi is possible in cases of known mutations or restriction fragment length polymorphisms.250,251 Also, cordocentesis to perform functional assays on fetal blood may be diagnostic, although results can be unreliable due to variable penetrance, and the risk of bleeding at cordocentesis is increased in affected cases.252,253 It may be helpful to assess levels of vWF antigen (vWF:Ag), vWF:Ac, and factor VIII:c on a serial basis (e.g., on the initial visit, at 28 and 34 weeks’ gestation, and before invasive procedures and delivery).247 VIII/vWF concentrates, DDAVP, skilled anesthesia personnel, and hematology consultation should be available at delivery.

Neuraxial anesthesia is considered to be contraindicated in most women with vWD, but safe use of regional anesthesia has been reported in a few women with mild type I disease.254,255 Regional anesthesia is thought to be safe if factor VIII and vWF:RCoF levels are greater than 50 IU/dL, although this is unproven.243,247 Cesarean delivery has been advised by some authorities in an attempt to avoid fetal bleeding.256 However, the procedure is of unproven effi cacy and bleeding has been reported in affected infants born by cesarean.256 Given the unproven effi cacy and the risk of maternal hemorrhage, elective cesarean delivery is not routinely advised in cases of vWD.244,247 However, traumatic delivery, such as vacuum or rotational forceps, should be avoided. Neonates born to mothers with vWD should be tested to determine their vWF status. There is an increased risk of hemorrhage after deliv-ery, even several weeks later. Frequent patient contact, monitoring of

vFW levels, and prolonged prophylaxis may reduce this risk, but this also is unproven.243

Bernard-Soulier SyndomeBernard-Soulier syndrome is usually transmitted in an autosomal recessive fashion; therefore, a family history is rare, although a variant appears to be autosomal dominant. Affected individuals have muco-cutaneous bleeding due to a defect or defi ciency in the platelet glyco-proteins (GpIb-IX-V) that form a transmembrane complex that binds vWF.257 The result is platelets that cannot bind to subendothelial surface. Laboratory diagnosis includes a decreased number of relatively large platelets, absent ristocetin response, a failure of platelets to aggre-gate in response to bovine plasma, and decreased platelet GpIb-IX-V complex density as measured by fl ow cytometry.258 Successful treat-ment requires platelet transfusion.

Prenatal diagnosis is possible in many cases and should be offered to families with a prior affected child. Because of previous platelet transfusions, affected mothers often are at risk for NAIT. Cesarean delivery is controversial and should be reserved for obstetric indica-tions.244,259 Regional anesthesia is considered to be contraindicated. Prophylactic platelet transfusion before delivery in this setting is also controversial because of the risk of alloimmune thrombocytopenia. This risk must be weighed against frequent hemorrhagic complications related to delivery, especially postpartum complications.259 The use of

TABLE 40-6 TREATMENT OF CONGENITAL BLEEDING AND PLATELET DISORDERS

Disorder Threshold for Treatment Treatment

Hemophilia A Bleeding; before delivery/procedures if factor VIII level <50 IU/dL

Factor VIII concentrate, cryoprecipitate, DDAVP

Hemophilia B Bleeding; before delivery/procedures if factor IX level <50 IU/dL

Factor IX concentrate, cryoprecipitate

Factor VII defi ciency Bleeding; before delivery/procedures if factor VII level <50 IU/dL

rFVIIa, factor VII concentrate

Factor X defi ciency Bleeding; possibly before delivery/procedures Factor IX concentrate, FFPFactor XI defi ciency Bleeding; before delivery/procedures if factor

XI level <15 IU/dLFactor XI concentrate, FFP (do not exceed peak factor XI

levels of 70 IU/dL)Factor XII defi ciency ? ?Factor XIII defi ciency Bleeding; pregnancy Factor XIII concentrate, FFP, cryoprecipitate (keep XIIIa

antigen or activity >10% of normal)Hypofi brinogenemia Bleeding; fi brinogen <150 mg/dL; pregnancy FFP, cryoprecipitate (keep fi brinogen >100 mg/dL)vWD Type I Bleeding DDAVP (if favorable response), tranexamic acid, FFP,

cryoprecipitate, Humate-P, Koate (goals are >50 IU/dL of vWF:Ac)

Type IIA Bleeding; operative delivery; procedures DDAVP (if favorable response), transexamic acid, FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of vWF:Ac)

Type IIB Bleeding; operative delivery; procedures FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of vWF:Ac); DDAVP is contraindicated

Type IIN Bleeding; operative delivery; procedures FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of vWF:Ac)

Type IIM Bleeding; operative delivery; procedures FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of vWF:Ac)

Type III Bleeding; all deliveries; procedures FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of vWF:Ac); DDAVP is not effective

Bernard-Soulier syndrome Bleeding (prophylaxis for delivery is controversial)

Platelet transfusion (possibly DDAVP, transexaminic acid, immune suppression, rFVIIa)

Storage pool defi ciencies Bleeding (prophylaxis for delivery is controversial)

Platelet transfusion; ? DDAVP

Glanzmann thrombasthenia Bleeding; delivery; procedures Platelet transfusion, rFVIIa

DDAVP, desmopressin; FFP, fresh-frozen plasma; rFVIIa, recombinant activated factor VII; vWD, von Willebrand disease; vWF, von Willebrand factor.

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HLA and platelet antigen–matched platelets may reduce this risk. Several other strategies may reduce the risk of bleeding, or may be used to treat bleeding after delivery, in women with Bernard-Soulier syn-drome. These include DDAVP, antifi brinolytic therapy with tranexamic acid, immune suppression to prolong platelet survival, and recombi-nant activated factor VII (rFVIIa).259-262 The optimal dose of rFVIIa is uncertain, but a dose of 90 to 120 μg/kg body weight, repeated every 2 hours (if there is a good response), has been recommended.259

Disorders of Platelet SecretionDisorders of platelet secretion include several rare conditions charac-terized by platelet storage pool defi ciencies. These disorders involve defi cient or abnormal platelet granules or their contents.

GRAY PLATELET SYNDROMEGray platelet syndrome is caused by a defi ciency of α-granules in

platelets and megakaryocytes. Platelet α-granules contain vWF, platelet factor 4, and platelet-derived growth factor. Characteristic gray-appear-ing platelets are noted on peripheral smear or marrow aspirate after

staining with Romanowsky solution. Treatment includes platelet trans-fusion. Good pregnancy outcome was reported in a patient with gray platelet syndrome after platelet transfusion.263

DELTA STORAGE POOL DISEASEDelta (δ) storage pool disease involves a defi ciency in dense gran-

ules (δ granules) in platelets containing ADP. Diagnosis is made by electron microscopy or by an adenosine triphosphate (ATP)-to-ADP ratio greater than 3 : 1 in inactive platelets. Other syndromes associated with δ storage pool disease include the Chediak-Higashi, Wiskott-Aldrich, thrombocytopenia with absent radii (TAR), and Hemansky-Pudlak syndromes. Most patients with δ-storage pool diseases respond to platelet transfusion, although some may respond to DDAVP. Rarely, individuals have congenital or acquired abnormalities of d and a gran-ules, termed αδ storage pool disease. A case of an uncomplicated pregnancy without treatment was reported in a patient with Chediak-Higashi syndrome.264 Wiscott-Aldrich syndrome is an X-linked immu-nodefi ciency syndrome that is associated with early mortality. Prenatal diagnosis is possible and should be offered to affected families.265

TABLE 40-7 PRENATAL DIAGNOSIS OF CONGENITAL BLEEDING AND PLATELET DISORDERS*

Disorder Tissue Required Tests Comment

Hemophilia A Amniocytes, fetal blood

Fetal gender; factor VIII mutation analysis, linkage analysis (if family mutation is known); cord blood factor VIII levels

Because of the risk of bleeding, cordocentesis is reserved for cases in which genetic testing is nondiagnostic.

Hemophilia B Amniocytes, fetal blood

Fetal gender; factor IX mutation analysis, linkage analysis (if family mutation is known); cord blood factor IX levels


Factor VII defi ciency Amniocytes, fetal blood

Factor VII mutation analysis, linkage analysis (if family mutation is known); cord blood factor VII levels


Factor X defi ciency Amniocytes, fetal blood

Factor X mutation analysis, linkage analysis (if family mutation is known); cord blood factor X levels


vWD (types I and III) Amniocytes or fetal blood

Mutation analysis, linkage analysis if family mutation known; vWF:RCoF


vWD (type II) Amniocytes or fetal blood

Mutation analysis, linkage analysis if family mutation known; vWF:RCoF


Bernard-Soulier syndrome

Amniocytes or fetal blood

Mutation analysis, linkage analysis if family mutation known; vWF:RCoF; bovine plasma

Because of the risk of bleeding, cordocentesis is reserved for cases in which genetic testing is nondiagnostic. Cordocentesis is extremely hazardous if fetus is positive for the mutation.

Glanzmann thrombasthenia

Amniocytes or fetal blood

Mutation analysis, linkage analysis if family mutation known; functional assays; anti-GpIIb-IIIa antibody binding

Because of the risk of bleeding, cordocentesis is reserved for cases in which genetic testing is nondiagnostic. Cordocentesis is extremely hazardous if fetus is positive for the mutation.

Gray platelet syndrome Fetal blood Microscopic analysis Normal fetal platelets have α-granules.Wiscott-Aldrich

syndromeAmniocytes or

fetal bloodMutation analysis, linkage analysis if

family mutation known; platelet size/volume


Chediak-Higashi syndrome

Fetal blood Peroxidase stain of neutrophils Proven successful in feline model.

Hermansky-Pudlak syndrome

Amniocytes Mutation analysis, linkage analysis if family mutation known

—

*Genes and some mutations have been identifi ed for defi ciencies of factors X, XI, XII, XIII, and fi brinogen. Therefore, prenatal diagnosis using

amniocytes may be possible. Cordocentesis also may be informative through the direct measurement of factor levels.

Gp, glycoprotein; RCoF, ristocetin cofactor; vWD, von Willebrand disease; vWF, von Willebrand factor.

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Thrombocytopenia associated with TAR typically resolves at 1 year of life. Prenatal diagnosis of the syndrome has been reported.266 Several pregnancies have been reported in women with Hermansky-Pudlak syndrome.267,268 This autosomal recessive condition is characterized by oculocutaneous albinism, platelet storage pool defi ciency, and the accumulation of ceroid (a yellow, granular substance) in reticuloendo-thelial cells. It is common in some areas of Puerto Rico.267,268

GLANZMANN THROMBASTHENIAGlanzmann thrombasthenia is an abnormality in the quantity or

quality (or both) of the platelet membrane glycoprotein, GpIIb-IIIa.269 The disease is transmitted in an autosomal dominant fashion and has been reported to occur most often in Iraqi-Jewish and Arab popula-tions in Israel, in Southern India, and among European Gypsies.270,271 Patients with type 1 Glanzmann thrombasthenia lack detectable GpIIb-IIIa, whereas those with type 2 disease have only 10% to 20% of normal platelet surface GpIIb-IIIa.

These patients are at lifelong risk for bleeding, often requiring fre-quent platelet transfusions. Accordingly, many develop alloimmune antibodies against platelet antigens, causing their pregnancies to be at risk for NAIT (see earlier discussion).272 Women with a history of multiple platelet transfusions should undergo evaluation for parental platelet antigen incompatibility and the presence of specifi c anti-plate-let antibodies for fetal antigens. Cordocentesis has been particularly risky in affected pregnancies and is best avoided if possible. This makes prenatal diagnosis more diffi cult. In cases of known mutations, fetal genotype may be obtained from amniocytes or chorionic villi (avoid chorionic villus sampling if the patient has antibodies).

The primary intrapartum treatment for Glanzmann thrombasthe-nia is platelet transfusion.273,274 If possible, type-specifi c platelets should be used to avoid platelet alloimmunization. If pooled platelets must be used in sensitized women, immunosuppressive therapy may prolong the lifespan and effectiveness of the platelets. Cesarean delivery should be reserved for the usual obstetric indications, including alloimmune thrombocytopenia. Postpartum hemorrhage is common. Hormonal treatment and prolonged use of uterotonic agents may reduce the risk of this complication, although this approach is of unproven effi cacy. The use of rFVIIa appears to be safe and relatively effective in patients with Glanzmann thrombasthenia,274-276 and it may prove to be an important tool for the treatment of this disease during pregnancy.

Bleeding DisordersAcquired Bleeding Disorders

Factor VIII InhibitorsThe development of antibodies against factor VIII is a rare but serious acquired bleeding disorder. The inciting event is unknown, but the condition often manifests in the postpartum period.277 Clinical fea-tures are similar to those seen in hemophilia. Diagnosis is made by prolonged clotting times that do not normalize in response to mixing studies with normal plasma. Demonstration of a specifi c factor VIII inhibitor and documentation of low levels of factor VIII in the plasma confi rm the diagnosis. Hemorrhage may be severe and may respond to activated prothrombin complex concentrate or rFVIIa.276,277 Mild cases often respond to DDAVP and factor VIII concentrates.277 Plasma-pheresis may be helpful in refractory cases. The disease typically regresses spontaneously over time. Although IgG antibodies to factor VIII may develop, infants are rarely affected. The condition usually

remits spontaneously, with or without the use of immunosuppressive therapy.277

Congenital Bleeding Disorders

Hemophilia A (Factor VIII Defi ciency) and

Hemophilia B (Factor IX Defi ciency)Hemophilia A and B are caused by congenital defi ciencies of factor VIII and IX, respectively. They are inherited in an X-linked recessive fashion. Therefore, affected females are uncommon. Heterozygous carriers are usually asymptomatic. Rarely, a heterozygous female has clinical symp-toms of bleeding, perhaps because of skewed X inactivation of the X chromosome containing the normal gene. Symptoms tend to be mild, and serious hemorrhage during labor and delivery is rare. Treatment may be accomplished with factor VIII concentrate or cryoprecipitate for hemophilia A and factor IX concentrate or fresh-frozen plasma for hemophilia B.247

Pregnancy issues often focus on the fetus/neonate, because 50% of male offspring born to female carriers will be affected. Carrier detec-tion of hemophilia A may be accomplished using assays for factor VIII and is reliable during pregnancy. Prenatal diagnosis is feasible through factor VIII and IX gene mutation analysis or linkage analysis (or both).251 Rarely, cordocentesis may be used to detect an affected fetus by testing levels of factors VIII and IX (which are normally lower in a fetus than in an adult). However, this approach is reserved for cases in which genetic testing is not diagnostic, because the procedure is risky.247

Levels of factor VIII or IX, or both, should be assessed at the initial pregnancy visit, at 28 and 34 weeks of gestation, and again at deliv-ery.247 Recombinant factor VIII and IX should be used as the treatment of choice in pregnant carriers of hemophilia A and B, respectively. Treatment should be initiated in the setting of bleeding or factor VIII or IX levels lower than 50 IU/dL.247 DDAVP may be helpful in women with hemophilia A, but not in those with hemophilia B. Regional anesthesia should be safe in women with normal coagulation studies and factor levels greater than 50 IU/dL. Vaginal delivery has not been shown to increase bleeding in affected male infants. However, fetal scalp electrodes, operative vaginal delivery, and circumcision should be avoided in male infants born to carriers of hemophilia A. Postnatal diagnosis may be established in newborns through assays of maternal and cord blood. Carriers of hemophilia B are detected by factor IX assay. Levels of factor IX in carriers are usually decreased, although they may be normal. Delivery issues with hemophilia B are similar to those for hemophilia A.

Other Factor Defi cienciesDefi ciencies of factors VII, X, XI, and XIII are uncommon hereditary bleeding disorders. Factor VII, X, and XIII defi ciencies are probably autosomal recessive traits, whereas factor XI defi ciency appears to be an incompletely autosomal-recessive trait. Replacement with rFVIIa is the treatment of choice for women with factor VII defi ciency.278 Factor X–defi cient women may be treated with fresh-frozen plasma or factor IX concentrates to treat active bleeding.279,280 Prophylactic transfusion may be useful before vaginal or cesarean delivery.279,281 Individuals who are homozygous for factor XI defi ciency have levels less than 20% of normal, whereas heterozygotes have levels that are 30% to 65% of normal.282 Bleeding does not always correlate with factor XI concentra-tions, and heterozygotes may have minor bleeding problems. Most women do not experience hemorrhage during delivery,283,284 and it may be possible to stratify patients with the condition into bleeding and

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nonbleeding phenotypes.284 Prophylactic treatment is not required for all deliveries, and treatment may be reserved for excessive bleeding.283,284 This may be accomplished with fresh-frozen plasma given as a 10 mL/kg load followed by 5 mL/kg per day, or through direct replacement with factor XI concentrate.

Factor XIII defi ciency is rare but can lead to severe bleeding such as ICH after minor trauma and abnormal wound healing. Life-threat-ening umbilical cord stump hemorrhage has occurred in affected new-borns. An increased risk of recurrent pregnancy loss also has been reported in women with factor XIII defi ciency.285 This is thought to be the result of decidual bleeding, and successful pregnancy rarely occurs without treatment. Diagnosis is made by assessment of factor XIII (A and S subunits) or by dissolution of clot in 5-molar urea. Treatment includes transfusion with factor XIII concentrate, fresh-frozen plasma, cryoprecipitate, and/or whole blood. Small amounts of plasma may provide adequate factor XIII for hemostasis. Although of uncertain effi cacy, maintenance of XIIIA-antigen (Ag) or XIII-activity (act) at 10% is advised.285 This may require the administration of 1 vial of XIIIA concentrate (250 IU) every 7 days in early pregnancy, followed by 2 vials every 7 days after 23 weeks gestation.285,286 Extra replacement (e.g., 4 vials) may be helpful at the time of delivery.285

Hypofi brinogenemia/Afi brinogenemiaCongenital hypofi brinogenemia is a rare, autosomal-dominant condi-tion characterized by bleeding as well as obstetric problems such as abruption, postpartum hemorrhage, and recurrent pregnancy loss.287,288 The condition is defi ned as the presence of structurally normal fi brino-gen in concentrations of less than 150 mg/dL.287 Miscarriage at mid-gestation appears to be caused by perigestational hemorrhage.288 This is supported by data from transgenic mice lacking fi brinogen, who suffer uniform pregnancy loss at day 10.289 Pregnancy loss in these mice is corrected by the addition of fi brinogen. Dysfi brinogenemia has been weakly associated with hypercoagulability, rather than hypocoagulabil-ity. Successful pregnancies in women with hypofi brinogenemia have been reported with the use of fresh-frozen plasma or cryoprecipitate to maintain fi brinogen levels greater than 100 to 150 mg/dL.287,288 Each unit of cryoprecipitate contains about 300 mg of fi brinogen, which raises the plasma concentration by approximately 6 mg/dL.

Factor XII defi ciencyFactor XII is involved in both coagulation and fi brinolysis, and defi -cient individuals have been reported to be at increased risk for both bleeding and thrombosis. However, it is not clear that this condition increases the risk for either bleeding or thrombosis.290 The condition is of interest because it is associated with recurrent pregnancy loss.291,292

Plasminogen Activator Inhibitor 1 Defi ciencyIndividuals with elevated levels of PAI-1 are at increased risk for thrombosis and possibly for pregnancy loss. In contrast, defi ciency of PAI-1 has been reported to be associated with an increased risk of bleeding.293 The condition often manifests as menorrhagia and may be responsive to aminocaproic acid.293 Indeed, low PAI-1 activity has been reported in 23% of patients referred for evaluation of bleeding diathesis, compared with 10% of controls (OR, 2.75; CI, 1.39 to 5.42).294 It may prove to be an important cause of abnormal bleeding. There are few data regarding pregnancy in women with PAI-1 defi ciency.

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