Chapter 40 – Coagulation Disorders in Pregnancy

Transcription

Chapter 40 – Coagulation Disorders in Pregnancy
Charles J. Lockwood, MD,
Robert M. Silver, MD
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 anticoagulant 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 System
The hemostatic system is designed to ensure that hemorrhage is avoided in the setting of vascular injury while the fluidity 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 fibrin-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 fibrinolytic 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 vulnerable 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 Formation
After vascular injury, platelets rolling and flowing in the bloodstream are arrested at sites of endothelial disruption by the
interaction of collagen 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. Deficiencies in either
receptor cause mild bleeding diatheses.
Update: New Content Added
Date Added: 13 August 2009
Coagulation disorders in pregnancy
Charles Lockwood,
Robert Silver
Summary
Similarly, Rudick et al. found an unexpectedly low prevalence of factor V Leiden in patients undergoing in vitro fertilization,
and noted that the mutation had a positive association with pregnancy.
References
1. Rudick B, Irene Su H, Sammel MD, et al: Is factor V Leiden mutation a cause of in vitro fertilization failure?. Fertil
Steril 2009; May 20 [Epub ahead of print]:.
Date Added: 06 August 2009
Charles Lockwood,
Robert Silver
Summary
Similarly, Rudick et al. found an unexpectedly low prevalence of factor V Leiden in patients undergoing in vitro fertilization
and noted that the mutation had a positive association with pregnancy.
References
1. Rudick B, Irene H, Sammel MD, et al: Is factor V Leiden mutation a cause of in vitro fertilization failure?. Fertil
Steril 2009; May 20 [Epub ahead of print]:.
Adherent platelets are activated by collagen after binding to the GpVI receptor.[4] This triggers receptor phosphorylation, leading
to activation of phospholipase C, which causes the generation of inositol triphosphate and 1,2,-diacylglycerol. The former
triggers a calcium flux, 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
receptors (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 calciummediated formation of platelet pseudopodia, promoting further adhesion.
Platelet secretory activity includes the release of α-granules containing vWF, vitronectin, fibronectin, thrombospondin, partially
activated factor V, fibrinogen, 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 flux promotes the synthesis of TXA2 by the
sequential action of phospholipase A2, cyclooxygenase-1 (COX-1) and TXA2 synthase and its passive diffusion 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 syndrome, whereas deficiencies in dense granule–related genes are
associated with Wiskott-Aldrich, Chediak-Higashi, Hermansky-Pudlak, and thrombocytopenia–absent radius syndrome. Inhibition
of COX-1–mediated TXA2 synthesis by nonsteroidal anti-inflammatory 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-affinity bond to divalent fibrinogen molecules. The same fibrinogen 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 flow 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.
FIGURE 40-1 Schematic review of platelet function. ADP, adenosine diphosphate; Gp, glycoprotein; PAR, protease-activated receptor; TXA2, thromboxane
A2; vWF, von Willebrand factor.
Platelet activation and aggregation are prevented in intact endothelium via the latter's elaboration of prostacyclin, nitric oxide,
and ADPase as well as by active blood flow. Cyclic adenosine monophosphate (cAMP) inhibits platelet activation, and this is the
basis for the therapeutic effects of dipyridamole. Normal pregnancy is associated with a modest decline in platelet number[7] and
with evidence of progressive platelet activation. [8]
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Fibrin Plug Formation
Effective hemostasis requires the synergistic interaction of the clotting cascade with platelet activation and aggregation. This
synergism is in part mechanical, because fibrin and platelets together form an effective hemostatic plug after significant vascular
disruption. However, biochemical synergism also occurs, because activated platelets contribute clotting factors and form an ideal
surface for clot propagation. Conversely, optimal platelet activation and subsequent aggregation require exogenous thrombin
generation (see Fig. 40-1). Therefore, the avoidance 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 infinite 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 expressing 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, fibroblasts, and tissue parenchymal
cells, but not on healthy endothelial cells. However, TF also circulates 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 catalytic 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 antithrombin (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 fibrinogen to fibrin, and, as noted, activates platelets (see Fig.
40-2A).
FIGURE 40-2 Fibrin plug formation. A, After vascular disruption, plasma factor VII binds to tissue factor (TF) to form the TF/VII(a) complex, which activates both
factor X and factor IX. Factor Xa binds to factor Va, which has been activated by thrombin (factor IIa) or released from platelet α-granules. The Xa/Va complex
catalyzes the conversion of prothrombin (factor II) to thrombin, which, in turn, converts fibrinogen to fibrin and activates platelets. B, The clotting cascade is
amplified by clotting reactions that occur on adjacent activated platelets. Locally generated factor IXa binds to factor VIIIa, which is activated by thrombin. The
factor IXa/VIIIa complex then generates factor Xa. C, Coagulation is further boosted by the thrombin-mediated activation of factor XI to factor XIa, which also
activates factor IX. Circulating TF-bearing microparticles may also bind to activated platelets at sites of vascular injury. D, The stable hemostatic plug is finally
formed when fibrin monomers self-polymerize and are cross-linked by thrombin-activated factor XIIIa.
Following this initial TF-mediated reaction, the clotting cascade is amplified 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 activated 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 significant 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 amplified 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 significant hemorrhagic sequelae in patients with factor XI deficiency
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 amplification pathway may be mediated by circulating TF-bearing microparticles that bind to
activated 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 fibrin. They also
reflect the synergism that exists between platelet activation and the coagulation cascade.
The stable hemostatic plug is finally formed only when fibrin monomers self-polymerize and are cross-linked by thrombinactivated factor XIIIa (see Fig. 40-2D). This last reaction highlights the dominant role that thrombin plays in the coagulation
cascade: Thrombin activates platelets, generates fibrin, and activates the crucial clotting cofactors 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 System
As noted, the hemostatic system not only must prevent hemorrhage after vascula r injury but also must maintain the fluidity of the
circulation in an intact vasculature. Indeed, thrombotic disease is a consequence 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
amplified by the arrival, adherence, and activation of platelets. 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 of platelets, they become
progressively less activated, and their clotting reaction becomes more susceptible to the action of circulating inhibitors, thus
attenuating the clotting cascade.[9]
Prevention of disseminated intravascular coagulation (DIC) ultimately requires the presence of inhibitor molecules (Fig. 40-3).
The first 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.
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.
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 conformational 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 efficient at blocking thrombin
generation on activated platelets, possibly because platelet-derived, partially activated factor Va is resistant to aPC/PS
inactivation.[15] Therefore, additional anticoagulant reactions are required. Factor Xa can be efficiently 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. Deficiencies 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 antithrombin (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 augments thrombin inactivation more than 1000-fold. [17]
Although thrombin 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: Fibrinolysis
Fibrinolysis permits the restoration of circulatory fluidity and serves as another barrier to thrombosis (Fig. 40-4). The crosslinked fibrin polymer is degraded to fibrin degradation products (FDPs) by the action of plasmin embedded in the fibrin clot.[18]
Plasmin is, in turn, generated by the proteolysis of plasminogen via tissue-type plasminogen activator (tPA), which is also
embedded in fibrin. Endothelial cells also synthesize a second plasminogen activator, urokinase-type plasminogen activator
(uPA), whose primary function is cell migration and extracellular matrix remodeling.
FIGURE 40-4 Fibrinolysis. The cross-linked fibrin polymer (X-linked Fibrin), which was stabilized by thrombin (factor IIa)-activated factor XIIIa, is degraded to
fibrin 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 fibrinolysis, 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 fibrinolytic inhibitor (TAFI), which is activated by the thrombinthrombomodulin complex, cleaves terminal lysine residues from fibrin to render it resistant to plasmin.
Fibrinolysis is, in turn, modulated by a series of inhibitors. Plasmin is inhibited by α2-plasmin inhibitor, which, like plasmin and
plasminogen, is bound to the fibrin clot, where it is positioned to prevent premature fibrinolysis. 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
antifibrinolytic molecule, PAI-2. Fibrinolysis can also be inhibited by thrombin-activated fibrinolytic inhibitor (TAFI). This
carboxypeptidase cleaves terminal lysine residues from fibrin to render it resistant to plasmin. TAFI is activated by the thrombinthrombomodulin complex.[20] In the initial stages of clotting, platelets and endothelial cells release PAI-1, but, after a delay,
endothelial cells release tPA and uPA to promote fibrinolysis. This biologic process permits sequential clotting followed by
fibrinolysis to restore vascular patency.
The fibrinolytic 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 Hemostasis
As noted, pregnancy and delivery present unique and paradoxical challenges 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 systemic clotting, anticoagulant, and fibrinolytic 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 TF[22] and PAI-1[19] 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
inadequate 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 hypofibrinogenemia 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 inflammation 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
fibrinogen 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 complement 4B–binding protein.[29] As a consequence, pregnancy is
associated 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 negligible before pregnancy, reach high concentrations at term.[30] Thus, pregnancy is associated with
increased clotting potential, decreased anticoagulant activity, and decreased fibrinolysis.[30]
Pregnancy is also associated with venous stasis in the lower extremities 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. Pregnancy is also frequently
associated with obesity, insulin resistance, and hyperlipidemia, all of which further increase levels of PAI-1.[31]
Disorders Promoting Thrombosis in Pregnancy
Acquired Thrombophilias: Antiphospholipid Antibodies
The combination of VTE, obstetric complications, and antiphospholipid antibodies (APA) defines the antiphospholipid antibody
syndrome (APS).[32] These antibodies are directed against proteins bound to negatively charged surfaces, usually anionic
phospholipids. Therefore, 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 lipoproteins, or (2) by indirectly assessing antibodies that react to proteins
present in an anionic phospholipid matrix (e.g., cardiolipin, phosphatidylserine), or (3) by assessing the downstream effects of
these antibodies on prothrombin activation in a phospholipid milieu (i.e., lupus anticoagulants). [33]
The diagnosis of APS has been a controversial topic. A recent consensus conference proposed the criteria outlined in Table
40-1.[34] In brief, APS requires the presence of at least one clinical criterion (confirmed 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 insufficiency may be recognized by the sequelae of nonreassuring fetal surveillance tests suggestive of fetal
hypoxemia, abnormal Doppler flow velocimetry waveform analysis suggestive of fetal hypoxemia, oligohydramnios (amniotic fluid
index ≤5 cm), or birth weight less than the 10th percentile. Classification 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.
TABLE 40-1 -- REVISED CLASSIFICATION CRITERIA FOR DIAGNOSIS OF THE ANTIPHOSPHOLIPID ANTIBODY
SYNDROME (APS)[*]
Clinical Criteria
1.
Vascular thrombosis[†]: One or more clinical episodes of arterial, venous, or small-vessel thrombosis, in any tissue or
organ confirmed by objective, validated criteria (i.e., unequivocal findings of appropriate imaging studies or
histopathology).
2.
Pregnancy morbidity:
a. One or more unexplained deaths of a morphologically normal fetus at or beyond 10 weeks of gestation, with
normal fetal morphology documented by ultrasound or by direct examination of the fetus, or
b. One or more premature births of a morphologically normal neonate before the 34th week of gestation because
of (i) eclampsia or severe preeclampsia or (ii) recognized uteroplacental insufficiency, or
c. Three or more unexplained consecutive euploid spontaneous abortions before 10 weeks of gestation, with
maternal anatomic or hormonal abnormalities and paternal and parental chromosomal causes excluded.
Laboratory Criteria[‡]
1.
Lupus anticoagulant (LA) present in plasma, on two or more occasions at least 12 wk apart, detected according to the
guidelines of the ISTH Scientific Subcommittee on Lupus Anticoagulants/Phospholipid-Dependent Antibodies.
2.
Anticardiolipin antibody (aCL) of IgG and/or IgM isotype in serum or plasma, present in medium or high titer (i.e., >40
GPL or MPL, or >99th percentile), on two or more occasions, at least 12 wk apart, measured by a standardized ELISA.
3.
Anti-β2-glycoprotein-1 antibody of IgG and/or IgM isotype in serum or plasma (in titer >99th percentile), present on two
or more occasions, at least 12 wk apart, measured by a standardized ELISA, according to recommended procedures.
Modified from Miyakis S, Lockshin MD, Atsumi D, et al: International consensus statement on an update of the classification
criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 4:295-306, 2006.
APA, antiphospholipid antibody; BMI, body mass index; ELISA, enzyme-linked immunosorbent assay; GFR, glomerular filtration
rate; GPL, IgG phospholipid units; HDL, high-density lipoprotein; IgG, immunoglobulin G; IgM, immunoglobulin M; ISTH,
International Society on Thrombosis and Hemostasis; LDL, low-density lipoprotein; MPL, IgM phospholipid units.
* APS is present if at least one clinical criterion and one laboratory criterion are met.
† Coexisting inherited or acquired factors for thrombosis are not reasons for excluding patients from APS trials. However, two subgroups of APS patients should
be recognized, according to (1) the presence or (2) the absence of additional risk factors for thrombosis. Indicative (but not exhaustive) of such factors are age
(>55 yr in men, >65 yr in women); presence of any of the established risk factors for cardiovascular disease (hypertension, diabetes mellitus, elevated LDL or low
HDL cholesterol, cigarette smoking, family history of premature cardiovascular disease, BMI ≥30 kg/m2, microalbuminuria, estimated GFR <60 mL/min),
inherited thrombophilias, oral contraceptive use, nephrotic syndrome, malignancy, immobilization, and surgery. Patients who fulfill criteria should be stratified
according to contributing causes of thrombosis.
‡ Investigators are strongly advised to classify APS patients in studies into one of the following categories: I, more than one laboratory criteria present (any
combination); IIa, LA present alone; IIb, aCL antibody present alone; IIc, Anti-β2 glycoprotein-1 antibody present alone.
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% confidence 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 identified 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 including fetal loss, abruption, severe preeclampsia, and intrauterine
growth restriction (IUGR). LA are associated with fetal loss after the first trimester, 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) spontaneous 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 first-trimester 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
infertility.[40,41] However, a meta-analysis of seven studies of affected patients undergoing in vitro fertilization found no significant
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 medications 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
placentation 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' gestation[44] and IUGR, most large
retrospective 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-glycoprotein-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 activation. 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-molecular-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 unfractionated heparin SQ every 12 hours until either recurrent loss or 34 weeks of gestation.[39] The live
birth rate was significantly higher with combined 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 first trimester, and there was no difference in outcome
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 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) significantly 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 treatment
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 significant reduction in pregnancy 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 first trimester), and gestational 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 efficacy 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 randomized 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 first-line therapy for APS.
Given these small study sizes and heterogeneous therapies employed, recommendations for treatment are difficult to make. It is
unlikely that a patient with no history of VTE who has repetitive early losses and borderline positive APA levels reflects 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
pregnant 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 Thrombophilias
Inherited 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, especially a personal or family history of VTE. Even more
controversial is the association between inherited thrombophilias and adverse pregnancy outcomes.
Factor V Leiden Mutation
Present 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 proteolysis and inactivation by aPC/PS, and
FVL is the leading cause of aPC resistance. The heterozygous state is symptomatic, with a fivefold 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 heterozygotes without a personal history of VTE or an affected firstdegree 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 first-degree relative.[60] Pregnant homozygous patients without a personal history of VTE or an
affected first-degree relative have a 1.5% risk for VTE in pregnancy; if there is a personal or family history 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.
TABLE 40-2 -- INHERITED THROMBOPHILIAS AND THEIR ASSOCIATION WITH VENOUS THROMBOEMBOLISM
IN PREGNANCY
Probability of VTE (%) without or with a Personal History of VTE or
a First-Degree Relative with VTE
Relative Risk of VTE
Thrombophilia
(95% CI)
Without
With
FVL (homozygous)
25.4 (8.8-66)
1.5
17
FVL (heterozygous)
5.3 (3.7-7.6)
0.20-0.26
10
PGM (homozygous)
NA
2.8
>17
PGM (heterozygous)
6.1 (3.4-11.2)
0.37
>10
FVL/PGM (compound
84 (19-369)
4.7
NA
heterozygous)
Antithrombin deficiency
119
3.0-7.2
<40%
(<60% activity)
Protein S deficiency (<55%
NA
<1
6.6
activity)
Protein C deficiency (<50% 13.0 (1.4-123)
0.8-1.7
2–8
activity)
(VTE)
Ref.
No.
46
45, 46
46
45, 46
46
46, 47
46, 47
46, 47
CI, confidence interval; FVL, factor V Leiden mutation; NA, not available; PGM, prothrombin gene mutation.
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 first-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), nonrecurrent 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 significant association between FVL and first-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] Multivariate
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 occurring 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, pregnancy 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 significant association between any inherited thrombophilia and stillbirth (OR, 3.6;
CI, 1.4 to 9.4) but not spontaneous 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
anticoagulation 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 significantly 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 identified
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 flow is noted in the uteroplacental circulation before
10 weeks.[72] Indeed, the undetectable levels of superoxide dismutase in trophoblast before 10 weeks of gestation 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 aneuploidy, 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 preeclampsia.[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 carriers.[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 sufficient
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.
Date Added: 19 November 2009
Charles Lockwood,
Robert Silver
Summary
Kahn et al. conducted a prospective multicenter cohort study of 5337 pregnant women, of whom 113 developed
preeclampsia, and noted that inherited thrombophilias including FVL were present in only 14% of cases and 21% of controls
(adjusted logistic regression OR 0.6, 95% CI 0.3-1.3).
References
1. Kahn SR, Platt R, McNamara H, et al: Inherited thrombophilia and preeclampsia within a multicenter cohort: The
Montreal Preeclampsia Study. Am J Obstet Gynecol 2009; 200(2):151.e1-151.e9-discussion e1-e5.
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 significantly increased incidence of FVL carriage among cases compared with controls (14.1% versus
5.1%; OR, 3.0; CI, 1.4 to 6.7).[81] Alfirevic 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 retrospective cohort studies are needed to confirm this link.
Date Added: 12 November 2009
Charles Lockwood,
Robert Silver
Summary
This update is intended to be read immediately following the sentence, “Therefore, there appears to be evidence of an
association between FVL carriage and placental abruption, although large case-control and retrospective cohort studies are
needed to confirm this link.”
Facco et al. conducted a meta-analysis of case-control and cohort studies examining the relationship between IUGR and
FVL and reported an OR of 1.23 (95% CI 1.04-1.44), but they observed that this linkage was mainly driven by case-control
studies, suggesting a publication bias.
References
1. Facco F, You W, Grobman W, et al: Genetic thrombophilias and intrauterine growth restriction: A
meta-analysis. Obstet Gynecol 2009; 113(6):1206-1216.
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 significant 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 significant association between FVL and IUGR (OR, 2.7;
CI, 1.3 to 5.5).[85] However, no association was found among five 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 preeclampsia or IUGR, although studies have been underpowered to definitely 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 firm conclusions. It is important to note that, although thrombophilia may be sufficient to cause
pregnancy loss and perhaps abruption, most affected individuals without such prior obstetric complications are at low risk for
subsequent adverse pregnancy outcomes.
Other Factor V Mutations
Other 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 aPCmediated degradation of factor VIIIa; however, a
meta-analysis demonstrated no statistically significant association between the HR2 haplotype and risk of VTE (OR, 1.15; CI,
0.98 to 1.36).[88] There are conflicting 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 significant 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 firm 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 Mutation
The 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 pregnancy.[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 presence of the PGM in 7 of 80 patients with recurrent miscarriage, compared 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, defined as two or more
losses in the first or second trimester, found a combined OR of 2.0 (CI, 1.0 to 4.0).[96] Analogous to FVL, the association
between PGM and pregnancy loss increases with increasing gestational age. In the meta-analysis by Rey and colleagues, 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 fit 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 contrast, 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
preeclampsia 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 significant link between PGM and IUGR or preeclampsia.
Hyperhomocysteinemia
Hyperhomocysteinemia 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
supplementation, 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 do not appear to convey
an increased risk for VTE in either nonpregnant[101] or pregnant women.[102]
As with thrombotic risk, meta-analyses suggest that elevated fasting homocysteine levels are more strongly associated with
recurrent pregnancy 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 homocysteine values in 5883
women and their prior 14,492 pregnancy outcomes.[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 significance.[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 significant 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 hyperhomocysteinemia 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 populations), 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 Deficiency
Deficiency of AT is both the rarest and the most thrombogenic of the heritable thrombophilias. More than 250 mutations have
been identified in the AT gene, producing a highly variable phenotype. In general, disorders can be classified 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 deficiency associated with little or no activity.[58,108] Complicating
matters further, patients can develop acquired AT deficiency 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
deficiencies are associated with VTE.
Because screening for AT deficiency 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 deficiency 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 deficiency 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 deficiency has been variably reported as 3% to 48%.[30,60,109,110] The risk of VTE in pregnancy among
AT-deficient 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 deficiency was associated with a significantly increased risk of stillbirth after 28
weeks' gestation (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 deficiency 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 Deficiency
Deficiency of PC results from more than 160 distinct mutations, producing a highly variable phenotype. As was the case with AT
deficiency, PC deficiency 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 deficiency 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 reflect 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-deficient patients has been reported to range from 2% to 8%.[30,112,113] Because of its
rarity, there are few reports linking PC deficiency to adverse pregnancy outcomes, and those that exist involve too few patients
to draw any firm conclusions. In their case-control study, Roque and colleagues reported a strong link between PC deficiency
and abruption (OR, 13.9; CI, 2.21 to 86.9) and between PC deficiency and preeclampsia (OR, 6.85; CI, 1.09 to 43.2).[69] A
meta-analysis also reported a strong association of this deficiency and preeclampsia/eclampsia (OR, 21.5; CI, 1.1 to 414.4) but
not stillbirth.[82] It is biologically plausible that PC deficiency should pose risks of fetal loss and abruption analogous to those
associated with FVL. However, given the very small sample sizes, no firm conclusions can be drawn regarding the link between
PC deficiency and either preeclampsia or IUGR.
Protein S Deficiency
More than 130 mutations have been linked to deficiency 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
deficiency, homozygous PS deficiency results in neonatal purpura fulminans.[111]
Screening for PS deficiency 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 diagnosis.[115] However, Paidas and
colleagues found far lower levels in normal pregnancy, with suggested cutoff levels for free PS of 29% for the first and second
trimesters and 23% for the third trimester.[29] With such criteria, the prevalence of true PS deficiency 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 deficiency 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 deficiency and recurrent late (>22 weeks or <25
weeks) 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 deficiency 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 abruption.[82] Again, the small
sample sizes limit the ability to draw firm conclusions.
Protein Z-Dependent Protease Inhibitor and Protein Z Deficiency
Two nonsense mutations in the coding region of the ZPI gene have been identified 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] Deficiency of PZ (activity <5th percentile) has been associated
with strokes but not with VTE.[117] PZ deficiency was linked to late fetal loss (10 to 16 weeks' gestation) 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,
preeclampsia, and abruption; they noted lower first-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 thrombophilias or the ongoing
uteroplacental pathologic processes. Although PZ deficiency 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 Genes
Two 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 five 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 prevalence 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
deficiency 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 polymorphism and VTE.[123]
There are limited data on the association between the 4G/4G allele and adverse pregnancy outcomes. No statistically significant
association was found between isolated homozygosity for the 4G/4G mutation 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 significant 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 disorders linked to
insulin resistance (e.g., obesity, type 2 diabetes, hyperlipidemia, 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 Mutations
The −455GtoA polymorphism in the fibrinogen β gene leads to increased plasma fibrinogen 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 contribute 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-fibrinogen −455GtoA, between apolipoprotein B
R3500Q and E2/E3/E4, and between GpIIIa L33P and HFE C282Y found no significant 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 phenotype[135] but confers uncertain risks for VTE and adverse pregnancy outcome.
Summary
A great number of potentially thrombophilic polymorphisms are being uncovered, at an ever-increasing pace. Although most of
these mutations do not appear to be highly thrombogenic when present in isolation, they may exert an additive or even a
synergistic effect on the thrombogenicity of other disorders. This might account for the finding of a very modest association
between a given thrombophilic state (e.g., FVL, PS deficiency) 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 Thromboembolism
The presence of a known thrombophilia increases the recurrence risk of VTE among pregnant women. Brill-Edwards and
associates prospectively evaluated 125 pregnant women with a prior VTE, 95 of whom were tested for acquired and inherited
thrombophilias (including APAs, FVL, and PGM) and for PC, PS and AT deficiencies.[136] Antenatal heparin was withheld in all
patients, but postpartum anticoagulation 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 justification 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
thrombophilic state would be an indication for antepartum as well as postpartum thromboprophylaxis. Conversely, women with a
prior VTE associated with a nonrecurring risk factor who are without thrombophilia or other current major risk or susceptibility
factors (e.g., need for prolonged bed rest, obesity, current superficial thrombophlebitis) may not need antepartum prophylactic
heparin therapy during pregnancy.[136] However, because thrombotic events during pregnancy in such women have been
reported on rare occasions,[110] the risks and benefits 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 thrombophilic 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 antepartum 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 first-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 efficacy, is a
reasonable 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 homocysteine levels and PC, PS, and AT
deficiencies.
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 deficiency), antepartum
prophylaxis with either mini-dose unfractionated 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 trimesters. 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 secondtrimester 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 measurements 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., homozygotes or compound heterozygotes for FVL and PGM,
patients with AT deficiency 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 dalteparin (e.g., 10,000 U SQ every 12 hours). Barbour and
colleagues evaluated whether the standard therapeutic doses of dalteparin maintained 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, therapeutic, or high prophylactic doses of LMWH, we recommend
switching 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 benefit, 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 first 3 weeks of treatment.[140]
Postpartum thromboprophylaxis is also required. Warfarin is considered safe to take while breast feeding. Warfarin is started
within 24 hours of commencing heparin therapy. Doses are determined by monitoring 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 consecutive days.
Screening and Prevention of Adverse Pregnancy Outcomes
As can be discerned from the preceding review, there appears to be a modest and consistent association between the major
inherited thrombophilias (including FVL, PGM, elevated fasting homocysteine levels and PC, PS, and AT deficiency) and fetal
loss after 10 weeks, and particularly isolated losses after 22 weeks. There is also a possible association between these
thrombophilic states and abruption. However, no clear association exists between FVL or the other major thrombophilias and
either preeclampsia or IUGR, although studies have been underpowered to definitely exclude a link with severe early-onset
preeclampsia and/or severe (<5th percentile) IUGR.
There are few studies examining the effectiveness of anticoagulation 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 supplementation 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 deficiency.[142] Of 37 women with a deficiency, 26 (70%) received thromboprophylaxis during pregnancy, with no
fetal losses, compared to 45% fetal loss in deficient women not receiving thromboprophylaxis (P = .001). The adjusted RR of
fetal loss with versus without thromboprophylaxis was 0.07 (CI, 0.001 to 0.7).
Gris and colleagues conducted a randomized trial of anticoagulation in 160 women who had had one unexplained fetal loss after
10 weeks of gestation and who were heterozygous for FVL, PGM, or PS deficiency.[119] All patients were given 5 mg folic acid
daily before conception; 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 deficiency 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 findings, 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 metabolic disorder, prophylactic unfractionated heparin or LMWH should be considered.
2.
As noted earlier, patients in the highly thrombogenic thrombophilia group (AT deficiency, homozygous or compound
heterozygous 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 deficiency,
hyperhomocysteinemia unresponsive to folate therapy) who have no personal 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 efficacy of this treatment. They should receive postpartum thromboprophylaxis if they require a
cesarean delivery, because most fatal acute pulmonary emboli occur during this period.
4.
5.
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.
At this time, there appears to be no justification 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 surveillance appropriate in this population. Fetal growth may be monitored with serial ultrasound
examinations (every 4 to 6 weeks) beginning at 20 weeks' gestation. Doppler flow studies of the umbilical artery may be
used as a fetal assessment tool in the setting of IUGR. Nonstress testing and biophysical profiles 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 evidence of placental insufficiency.
Acquired Platelet Disorders
Idiopathic Thrombocytopenic Purpura
Also 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, especially 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 pregnancy. The overall course of ITP is not consistently influenced by pregnancy (although, rarely, women
experience repeated flares 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 antibodies into the
fetal circulation, fetal thrombocytopenia also may occur.
DIAGNOSIS
Most women with ITP have a history of petechiae, ecchymoses, easy bruising, menorrhagia, or other bleeding manifestations.
The diagnosis 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 thrombocytopenia (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 thrombocytopenia. Rarely, a bone marrow biopsy is required to clarify the diagnosis. Typical bone
marrow findings include increased numbers of immature megakaryocytes. Although the issue is controversial, many authorities
do not routinely perform this procedure in typical cases of ITP, especially in women younger than 40 years of age.[143]
It can be difficult 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 first 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 maternal thrombocytopenia.
[146,147] Individuals with incidental thrombocytopenia 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
thrombocytopenia that should be considered are preeclampsia, pseudothrombocytopenia due to laboratory artifact, SLE, APS,
human immunodeficiency virus (HIV) or hepatitis C virus infection, drug-induced thrombocytopenia, thrombotic thrombocytopenia,
immunodeficiency states, hereditary thrombocytopenias, and DIC.
Numerous direct and indirect assays of antiplatelet antibodies have been developed to confirm 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
antiplatelet 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 interlaboratory 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 antiplatelet antibody
testing.[150]
MATERNAL CONSIDERATIONS
The goal of maternal therapy during pregnancy is to minimize the risk of hemorrhage and to restore a normal platelet count.
Asymptomatic 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 sufficient 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 Panel[151] 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 placement of an epidural
catheter.[152]
Glucocorticoid Drugs.
Glucocorticoid drugs have been the cornerstone 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
action[153] include increased platelet production, decreased production of antiplatelet 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, hypertension, psychosis, and
moon facies. Accordingly, the dose and duration 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 production, 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 suffice as a single or double infusion.[158]
Although IVIG had previously been associated with occasional hepatitis C transmission, the current purification 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, flushing, autoimmune hemolytic anemia,
and anaphylactic reactions in patients with IgA deficiencies.[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
progressive 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
antiplatelet 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 sufficient 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 production, is usually avoided during pregnancy because of risks to the
fetus and technical difficulties with the procedure. Nonetheless, splenectomy 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 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 CONSIDERATIONS
Because the placenta is permeable to circulating maternal antiplatelet IgG, fetal thrombocytopenia may occur with maternal ITP.
Occasionally, this results in minor clinical bleeding, such as purpura, ecchymoses, hematuria, or melena. In rare cases, fetal
thrombocytopenia 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
maternal medical therapies such as IVIG[162] and steroids[162–164] do not reliably prevent fetal thrombocytopenia. On the basis of
reports of ICH associated 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 findings, including thrombocytopenia, 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 difficult 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 comparison, 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.
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
unnecessary cesarean deliveries.[174–176] Further, fetal scalp sampling cannot always easily be accomplished if there is limited
cervical dilation or a high presenting part.
[167,173]
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 procedure 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 associated 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 morbidity. Bleeding is more likely in
the presence of severe thrombocytopenia.[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 efficacy of these procedures in the
management of pregnancies complicated by ITP.[163,183,184] In addition, several reports have suggested that hemorrhagic
complications in thrombocytopenic 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 thrombocytopenic infants delivered vaginally suffered clinically apparent bleeding, 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 observations were confirmed 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 determined 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,
cordocentesis, and cesarean delivery contribute to cost and morbidity without preventing neonatal bleeding complications.
Therefore, it is recommended that ITP be managed without determination of the fetal platelet 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
sampling to determine the fetal platelet count in pregnancies most at risk for thrombocytopenia (e.g., when there is a sibling with
severe thrombocytopenia). The use of cordocentesis in the obstetric management of ITP is difficult to justify.
Delivery should be accomplished in a setting in which platelets, fresh-frozen plasma, and IVIG are available. A neonatologist or
pediatrician 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 thrombocytopenia,
many women with ITP have done so without clinical sequelae.
Neonatal Alloimmune Thrombocytopenia
In 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 responsible for NAIT. Many of these antigen systems were
simultaneously identified 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.
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, Zwa
HPA-1b
P1A1, Zwb
HPA-4
HPA-4a
Pena, Yukb
HPA-4b
Penb, Yuka
HPA-6
HPA-6bw
Ca, Tu
HPA-7
HPA-7bw
Mo
HPA-8
HPA-8w
Sr-a
HPA-10
HPA-10 bw 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, Lek
HPA-3b
Bakb
HPA-9
HPA-9bw
Maxa
Polymorphisms of GpIa
HPA-5
HPA-5a
Brb, Zavb
HPA-5b
Bra, Zava
HPA-13
HPA-13bw Sit(a)
Polymorphisms of GpIb
HPA-2
HPA-2b
Koa, Sib-a
HPA-12
HPA-12bw Ly(a)
Other probable platelet alloantigen specificities
HPA System Name
HPA-15
Antigen
Familiar Name
HPA-15a
Gov a
HPA-15b
Gov b
Modified 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.
Gp, glycoprotein; HPA, human platelet antigen.
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 antiplatelet 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 first 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 complication 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 findings 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 pregnancies.[200,202,203] NAIT should be suspected in cases of otherwise unexplained fetal or neonatal
thrombocytopenia, in utero or ex utero ICH, or porencephaly. Serologic evaluation should be performed in an experienced
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 confirmatory
and occasionally helpful. Appropriate assays include serologic confirmation of maternal antiplatelet antibodies that are specific
for paternal or fetal/neonatal platelets. In addition, individuals should undergo platelet 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 particularly 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.
Occasionally, results are ambiguous, and in some cases, an antigen incompatibility cannot be identified. The management of
such difficult cases is best individualized and underscores the need for consultation with physicians and laboratories familiar with
the disorder.
The natural history of NAIT is difficult to ascertain, because it is usually unrecognized during first affected pregnancies, and
subsequent pregnancies are influenced 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-lanegative 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,
thrombocytopenia 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 justifies more aggressive interventions. Also,
therapy must be initiated antenatally because of the risk of in utero ICH. If the diagnosis is uncertain, the risk of NAIT should be
confirmed by documentation of platelet incompatibility or maternal antiplatelet antibodies specific for paternal or fetal platelets. It
is unnecessary to repeat testing in a family with a case of previously confirmed NAIT. Antibody titers are poorly predictive 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 recommend 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 hemorrhage 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 benefits 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 cordocentesis.[182] Although the efficacy of this approach is unproved, it may decrease the risk of bleeding complications at
the time of the procedure. 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
recommend fetal blood sampling as soon as the procedure is technically feasible (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 pertinent 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 counts[216]; however, because only a
small number of patients have been treated, lack of efficacy has not been proved. Platelet transfusions are effective,[217] but the
short half-life of transfused platelets necessitates weekly procedures. The potential risks involved with multiple transfusions and
the potential for increased sensitization[191,217,218] limit the attractiveness of this treatment. Platelet transfusions 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 defined.[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
antibodies across the placenta.[219]
Bussel and coworkers[207] 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 stratified by level of risk for severe
thrombocytopenia and ICH. The first 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 prednisone 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 profound 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]
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
randomized to treatment with IVIG (1 g/kg/wk) or lower-dose prednisone (0.5 mg/kg/day). There was no significant 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, beginning at 12 weeks' gestation. Therapy was intensified (increased IVIG and/or adding steroids) if there
was severe thrombocytopenia at 20 weeks. All fetuses responded adequately to intensified 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 cordocentesis 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 justifies cesarean delivery
in pregnancies with severe NAIT.
In summary, according to the available current data, it seems appropriate 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 justifies 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 especially 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 regarding pros and cons of cordocentesis.
There are no data to support population-wide screening for potential HPA incompatibility.[191] Studies are ongoing to address the
efficacy 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 Syndrome
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are thrombotic microangiopathies that are
characterized by thrombocytopenia, hemolytic anemia, and multisystem organ failure. They are rare entities, but they may occur
during pregnancy, are life-threatening, and can be difficult to distinguish from the HELLP syndrome (hemolysis, elevated liver
enzymes, and low platelets). The incidence is estimated to be 1 : 25,000 births.[222] Early diagnosis and treatment are critical,
because mortality may be reduced by 90%.[223]
TTP is characterized by central nervous system (CNS) abnormalities, severe thrombocytopenia, and intravascular hemolytic
anemia. The most common CNS abnormalities are headache, altered consciousness, seizures, and sensory-motor deficits.
Renal dysfunction and fever also may occur. Individuals with HUS have renal involvement as the major finding, as well as
thrombocytopenia and hemolytic anemia. The conditions are difficult to distinguish from each other, because up to 50% of
patients with HUS have CNS abnormalities, and renal dysfunction 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 autoimmune conditions. Other possibilities are medications such as chemotherapy agents, viral
infection, and perhaps pregnancy itself, although many individuals have no risk factors. Larger than average vWF multimers
appear to contribute to the pathophysiology, promoting abnormal 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] Deficiency 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 epithelium, leading to
endothelial injury, platelet activation/aggregation, and ischemia.[230] In adults, HUS is often precipitated by pregnancy,
chemotherapy, 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
confirms thrombocytopenia and microangiopathic hemolytic anemia (schistocytes, 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 typically 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 critical, because the former will improve with delivery, but TTP and HUS require
additional therapy.
TABLE 40-4 -- CLINICAL CHARACTERISTICS AND LABORATORY FINDINGS IN TTP, HUS, AND SEVERE
PREECLAMPSIA/HELLP SYNDROME
TTPHUS
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
↓↓↓ ↓↓↓ ???−
Modified from Esplin MS, Branch DW: Diagnosis and management of thrombotic microangiopathies during pregnancy. Clin
Obstet Gynecol 42:360, 1999.
+ = mild symptoms present; ++ = moderate symptoms present; +++ = severe symptoms present; +/− = mild or no symptoms
present; − = no symptoms present; ↓ = mildly decreased; ↓↓ = moderately decreased; ↓↓↓ = 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.
Plasmapheresis has been reported to substantially increase the survival rate with TTP to about 80%.[234,235] Efficacy 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. Additional 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 recommended for patients who do not respond
immediately to plasma exchange.[227] Efficacy is uncertain. Treatment should continue for several days after recovery.
Refractory cases may benefit from cytotoxic immunosuppressive agents. These therapies are generally accepted for TTP.
Therapy is similar for HUS, although efficacy 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 insufficiency. If TTP or HUS occurs early in gestation, aggressive treatment with plasma
infusions, plasmapheresis, and steroids should be initiated. 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 important 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 persistent severely reduced
ADAMTS13 activity.[241]
Drug-Induced Thrombocytopenia and Functional Platelet Defects
Some drugs, such as heparin and quinidine, can cause thrombocytopenia. 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 Disease
vWD 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 deficiencies 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 deficiencies
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 deficiency of normal high-molecular-weight multimers of
vWF, with consequent decreased affinity for platelets. Type IIB is characterized by vWF with an increased affinity for platelets
due to an increased affinity 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 interaction 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 deficiencies 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]
TABLE 40-5 -- CONGENITAL BLEEDING AND PLATELET DISORDERS
Disorders
Definition
Diagnostic Assays
Hemophilia A
Factor VIII <2%
Prolonged aPTT, low factor VIII
Severe
Factor VIII 2-25%
Prolonged aPTT, low factor VIII
Mild
Factor VIII ≈50%
aPTT usually normal, low factor VIII
Carrier
Hemophilia B
Factor IX <2%
Prolonged aPTT, low factor IX
Severe
Factor
IX
2-25%
Prolonged
aPTT, low factor IX
Mild
Factor IX ≈50%
aPTT usually normal, low factor IX
Carrier
Factor VII deficiency Low factor VI
Prolonged INR, low factor VII
Factor X deficiency
Low factor X
Prolonged aPTT, prolonged INR, low factor X
Factor XI deficiency Low factor XI
Prolonged aPTT, low factor XII
Factor XII deficiency Low factor XII
Prolonged aPTT, low factor XII
Factor XIII deficiency Low factor XIII
Normal aPTT and INR, low factor XIII
Hypofibrinogenemia
Low fibrinogen
Low fibrinogen
Absent vWF:RCoF and RIPA; platelets aggregate with
vWD Types I and II Deficient (type I) or absent (type III) vWF
bovine plasma
Qualitatively abnormal vWF: lack of HMW
Multimeric analysis
Type IIA
multimers
Qualitatively abnormal vWF; spontaneously Platelets aggregate to 0.5 mg/mL of ristocetin; multimeric
Type IIB
binds platelets; lack of HMW multimers
analysis ↓ platelets
Pseudo-vWD
Platelets spontaneously bind GpIb-IX-V
Absent vWF:RCoF activity; differentiated from vWD by no
complex
clumping to bovine plasma
Bernard-Soulier
Platelet GpIb is defective
Absent vWF:RCoF activity; differentiated from vWD by no
syndrome
clumping to bovine plasma
Secretion defects
Arachidonic acid and prostaglandin pathway Aspirin/NSAIDs are common causes; abnormal response
abnormalities
to collagen, arachidonic acid; normal primary wave only
Storage pool
Abnormal function or component deficiency Primary wave only; decreased collagen assay; variable
deficiencies
of platelet granules (α, δ, or both)
arachidonic acid assay; mepacrine labeling
Glanzmann
GpIIb-IIIa is absent, present in minimal
Platelets not activated by ADP, collagen, or arachidonic
thrombasthenia
amounts, or qualitatively abnorma
acid
ADP, adenosine diphosphate; aPTT, activated partial thromboplastin time; Gp glycoprotein; HMW, high molecular weight; INR,
international normalized ratio; NSAIDs, nonsteroidal anti-inflammatory drugs; RCoF, ristocetin cofactor; RIPA, ristocetin-induced
platelet agglutination; vWD, von Willebrand disease; vWF, von Willebrand factor.
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 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 flow 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,
flushing, changes in blood pressure, fluid retention, and hyponatremia. The drug is pregnancy category B.
TABLE 40-6 -- TREATMENT OF CONGENITAL BLEEDING
Disorder
Threshold for Treatment
Hemophilia A
Bleeding; before delivery/procedures if
factor VIII level <50 IU/dL
Hemophilia B
Bleeding; before delivery/procedures if
factor IX level <50 IU/dL
Factor VII deficiency Bleeding; before delivery/procedures if
factor VII level <50 IU/dL
Factor X deficiency
Bleeding; possibly before
delivery/procedures
Factor XI deficiency Bleeding; before delivery/procedures if
factor XI level <15 IU/dL
Factor XII deficiency ?
Factor XIII deficiency Bleeding; pregnancy
Hypofibrinogenemia
vWD
Type I
Type IIA
Type IIB
Type IIN
Type IIM
Type III
Bernard-Soulier
syndrome
Storage pool
deficiencies
Glanzmann
thrombasthenia
Bleeding; fibrinogen <150 mg/dL;
pregnancy
Bleeding
AND PLATELET DISORDERS
Treatment
Factor VIII concentrate, cryoprecipitate, DDAVP
Factor IX concentrate, cryoprecipitate
rFVIIa, factor VII concentrate
Factor IX concentrate, FFP
Factor XI concentrate, FFP (do not exceed peak factor XI evels
of 70 IU/dL)
?
Factor XIII concentrate, FFP, cryoprecipitate (keep XIIIa
antigen or activity >10% of normal)
FFP, cryoprecipitate (keep fibrinogen >100 mg/dL)
DDAVP (if favorable response), tranexamic acid, FFP,
cryoprecipitate, Humate-P, Koate (goals are >50 IU/dL of
vWF:Ac)
Bleeding; operative delivery; procedures DDAVP (if favorable response), transexamic acid, FFP,
cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of vWF:Ac)
Bleeding; operative delivery; procedures FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of
vWF:Ac); DDAVP is contraindicated
vWF:Ac)
vWF:Ac)
Bleeding; all deliveries; procedures
FFP, cryoprecipitate, Humate-P, Koate (goal is >50 IU/dL of
vWF:Ac); DDAVP is not effective
Bleeding (prophylaxis for delivery is
Platelet transfusion (possibly DDAVP, transexaminic acid,
controversial)
immune suppression, rFVIIa)
Bleeding (prophylaxis for delivery is
Platelet transfusion; ? DDAVP
controversial)
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.
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
benefit and may be harmful. Special attention must be given to the possibility of fluid 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
concentrate in the form of plasma, cryoprecipitate, Humate-P, and Koate. These products are typically labeled with v WF: Ac
concentrations indicating functional activity: 1 IU/kg of v WF: Ac increases the plasma level by 2.0 U/dL. Ideally, v WF: 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 antepartum 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 amniocytes 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), v WF: 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.
TABLE 40-7 -- PRENATAL DIAGNOSIS OF CONGENITAL BLEEDING AND PLATELET DISORDERS[*]
Tissue
Disorder
Required
Tests
Comment
Hemophilia A
Amniocytes,
Fetal gender; factor VIII mutation
Because of the risk of bleeding, cordocentesis is
fetal blood
analysis, linkage analysis (if family
reserved for cases in which genetic testing is
mutation is known); cord blood factor nondiagnostic.
VIII levels
Hemophilia B
Amniocytes,
Fetal gender; factor IX mutation
fetal blood
analysis, linkage analysis (if family
mutation is known); cord blood factor nondiagnostic.
IX levels
Factor VII
Amniocytes,
Factor VII mutation analysis, linkage Because of the risk of bleeding, cordocentesis is
deficiency
fetal blood
analysis (if family mutation is known); reserved for cases in which genetic testing is
cord blood factor VII levels
nondiagnostic.
Factor X
Amniocytes,
Factor X mutation analysis, linkage
deficiency
fetal blood
analysis (if family mutation is known); reserved for cases in which genetic testing is
cord blood factor X levels
nondiagnostic.
vWD (types I and Amniocytes or Mutation analysis, linkage analysis if Because of the risk of bleeding, cordocentesis is
III)
fetal blood
family mutation known; vWF:RCoF
nondiagnostic.
vWD (type II)
Amniocytes or Mutation analysis, linkage analysis if Because of the risk of bleeding, cordocentesis is
fetal blood
family mutation known; vWF:RCoF
nondiagnostic.
Bernard-Soulier Amniocytes or Mutation analysis, linkage analysis if Because of the risk of bleeding, cordocentesis is
syndrome
fetal blood
family mutation known; vWF:RCoF;
bovine plasma
nondiagnostic. Cordocentesis is extremely hazardous
if fetus is positive for the mutation.
Glanzmann
thrombasthenia
fetal blood
family mutation known; functional
assays; anti-GpIIb-IIIa antibody
nondiagnostic. Cordocentesis is extremely hazardous
binding
if fetus is positive for the mutation.
Gray platelet
Fetal blood
Microscopic analysis
Normal fetal platelets have α-granules.
syndrome
Wiscott-Aldrich
syndrome
fetal blood
family mutation known; platelet
size/volume
nondiagnostic.
Chediak-Higash Fetal blood
Peroxidase stain of neutrophils
Proven successful in feline model.
syndrome
Tissue
Disorder
Required
HermanskyAmniocytes
Pudlak syndrome
Tests
Mutation analysis, linkage analysis if
family mutation known
Comment
—
* Genes and some mutations have been identified for deficiencies of factors X, XI, XII, XIII, and fibrinogen. Therefore, prenatal diagnosis using
amniocytes may be possible. Cordocentesis also may be informative through the direct measurement of factor levels. Gp, glycoprotein; RCoF,
ristocetin cofactor; vWD, von Willebrand disease; vWF, von Willebrand factor.
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 efficacy and bleeding has been reported in affected
infants born by cesarean.[256] Given the unproven efficacy 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 delivery, 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 Syndome
Bernard-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 mucocutaneous bleeding due to a defect or deficiency in
the platelet glycoproteins (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 aggregate in response to bovine plasma, and decreased platelet GpIb-IX-V complex density
as measured by flow cytometry.[258] Successful treatment 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 indications.[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 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 syndrome. These include DDAVP, antifibrinolytic therapy
with tranexamic acid, immune suppression to prolong platelet survival, and recombinant 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 Secretion
Disorders of platelet secretion include several rare conditions characterized by platelet storage pool deficiencies. These
disorders involve deficient or abnormal platelet granules or their contents.
GRAY PLATELET SYNDROME
Gray platelet syndrome is caused by a deficiency of α-granules in platelets and megakaryocytes. Platelet α-granules contain
vWF, platelet factor 4, and platelet-derived growth factor. Characteristic gray-appearing platelets are noted on peripheral smear
or marrow aspirate after staining with Romanowsky solution. Treatment includes platelet transfusion. Good pregnancy outcome
was reported in a patient with gray platelet syndrome after platelet transfusion.[263]
DELTA STORAGE POOL DISEASE
Delta (δ) storage pool disease involves a deficiency in dense granules (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 granules,
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 immunodeficiency syndrome that is associated with
early mortality. Prenatal diagnosis is possible and should be offered to affected families.[265] 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 deficiency, and the accumulation of ceroid (a yellow, granular substance) in
reticuloendothelial cells. It is common in some areas of Puerto Rico.[267,268]
GLANZMANN THROMBASTHENIA
Glanzmann thrombasthenia is an abnormality in the quantity or quality (or both) of the platelet membrane glycoprotein, GpIIbIIIa.[269] The disease is transmitted in an autosomal dominant fashion and has been reported to occur most often in Iraqi-Jewish
and Arab populations 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 frequent 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 specific anti-platelet antibodies for fetal antigens. Cordocentesis has been particularly risky in affected
pregnancies and is best avoided if possible. This makes prenatal diagnosis more difficult. 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 thrombasthenia is platelet transfusion.[273,274] If possible, type-specific
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
efficacy. 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 Disorders
Acquired Bleeding Disorders
Factor VIII Inhibitors
The 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 features 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
specific factor VIII inhibitor and documentation of low levels of factor VIII in the plasma confirm 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] Plasmapheresis 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 Deficiency) and Hemophilia B (Factor IX Deficiency)
Hemophilia A and B are caused by congenital deficiencies 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 symptoms 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 detection 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 delivery.[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 Deficiencies
Deficiencies of factors VII, X, XI, and XIII are uncommon hereditary bleeding disorders. Factor VII, X, and XIII deficiencies are
probably autosomal recessive traits, whereas factor XI deficiency appears to be an incompletely autosomal-recessive trait.
Replacement with rFVIIa is the treatment of choice for women with factor VII deficiency.[278] Factor X–deficient 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 deficiency 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 concentrations, 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 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 deficiency is rare but can lead to severe bleeding such as ICH after minor trauma and abnormal wound healing.
Life-threatening umbilical cord stump hemorrhage has occurred in affected newborns. An increased risk of recurrent pregnancy
loss also has been reported in women with factor XIII deficiency.[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 efficacy, 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]
Hypofibrinogenemia/Afibrinogenemia
Congenital hypofibrinogenemia is a rare, autosomal-dominant condition characterized by bleeding as well as obstetric problems
such as abruption, postpartum hemorrhage, and recurrent pregnancy loss.[287,288] The condition is defined as the presence of
structurally normal fibrinogen 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 fibrinogen, who suffer uniform
pregnancy loss at day 10.[289] Pregnancy loss in these mice is corrected by the addition of fibrinogen. Dysfibrinogenemia has
been weakly associated with hypercoagulability, rather than hypocoagulability. Successful pregnancies in women with
hypofibrinogenemia have been reported with the use of fresh-frozen plasma or cryoprecipitate to maintain fibrinogen levels
greater than 100 to 150 mg/dL.[287,288] Each unit of cryoprecipitate contains about 300 mg of fibrinogen, which raises the plasma
concentration by approximately 6 mg/dL.
Factor XII deficiency
Factor XII is involved in both coagulation and fibrinolysis, and deficient 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 Deficiency
Individuals with elevated levels of PAI-1 are at increased risk for thrombosis and possibly for pregnancy loss. In contrast,
deficiency 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 deficiency.
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Chapter 40 – Coagulation Disorders in Pregnancy

Transcription

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