Coagulation Disorders in Pregnancy

Acquired and inherited disorders of the hemostatic system can produce hemorrhage and thrombosis. ^, Inherited and acquired thrombophilias are associated with venous thromboembolism (VTE), a leading cause of maternal death in the United States, and may be associated with recurrent pregnancy loss and severe placenta-mediated pregnancy complications. The hemostatic system and its modulators are reviewed in this chapter. We discuss inherited and acquired disorders of platelet function, coagulation, and fibrinolysis and describe their impact on the mother and fetus. We provide an evidence-based approach to understanding the preventive and therapeutic alternatives for women challenged by these disorders in pregnancy.

Hemostatic System

The hemostatic system is designed to ensure that hemorrhage is avoided in the setting of vascular injury while the fluidity of blood flow is maintained in the intact circulation. After vascular injury, activation of the coagulation cascade and simultaneous platelet adhesion, activation, and aggregation are required to form the optimal fibrin-platelet plug to avoid or stop bleeding. The system is held in check by several factors. The endothelial cell lining covers a thrombogenic subendothelium and is vasodilatory. It is an active participant in preventing inappropriate platelet activation, as well as the anticoagulant and fibrinolytic systems. The hemostatic system is controlled by a potent series of circulating anticoagulant proteins and by a highly regulated fibrinolytic system.

Pregnancy introduces an additional challenge to this system because the risk of hemorrhage during delivery of the infant and placenta is high. On balance, the maternal hemostatic system has evolved to be prothrombotic. Nonetheless, through a series of local and systemic adaptations, most pregnant women can balance these paradoxical requirements and achieve uncomplicated pregnancies.

Platelet Plug Formation

After vascular injury, platelets rolling and flowing in the bloodstream are primarily arrested at sites of endothelial disruption by the interaction of collagen in the subendothelium with circulating von Willebrand factor (vWF). Fig. 53.1 schematically reviews platelet function. Attachment to collagen exposes sites on the vWF molecule that bind to platelet glycoprotein (Gp) Ib/IX/V complex (GpIb-IX-V) receptor, and vWF acts as glue connecting platelets with the subendothelium. Platelets can also adhere to subendothelial collagen through their glycoprotein Ia/IIa complex (GpIa-IIa; α ₂ β ₁ integrin) and GpVI receptors. Deficiencies or defects in either receptor cause mild bleeding diatheses.

Figure 53.1, Schematic review of platelet function.

Adherent platelets are activated by collagen after binding to the GpVI receptor. This triggers receptor phosphorylation, leading to activation of phospholipase C, which generates inositol triphosphate and 1,2-diacylglycerol. Inositol triphosphate triggers a calcium flux, and 1,2-diacylglycerol activates protein kinase C, which triggers platelet secretory activity and activates various signaling pathways. Signaling promotes activation of the glycoprotein IIb/IIIa complex (GpIIb-IIIa; α _IIB β ₃ integrin) receptor, a crucial step in subsequent platelet aggregation. Collagen promotes platelet adhesion and platelet activation. However, maximal platelet activation requires binding of thrombin to platelet protease-activated receptor types 1 and 4 (PAR-1 and PAR-4). Platelet activation is also mediated by thromboxane A ₂ (TXA ₂ ) binding to its receptor (TBXA2R) and adenosine diphosphate (ADP) binding to its receptors (P2Y12 and P2Y1). TXA ₂ and ADP are released by adjacent activated platelets. Collagen and these circulating agonists induce calcium-mediated formation of platelet pseudopodia, promoting further adhesion.

Platelet secretory activity includes release of α-granules containing vWF, vitronectin, fibronectin, thrombospondin, partially activated factor V, fibrinogen, β-thromboglobulin, and platelet-derived growth factor, which 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 TXA ₂ by the sequential action of phospholipase A ₂ , cyclo-oxygenase-1, and TXA ₂ synthase, and TXA ₂ ’s passive diffusion across platelet membranes promotes vasoconstriction and activation of adjacent platelets. Through an accumulation of activated platelets secreting platelet activators (e.g., ADP, TXA ₂ ) and by enhancing thrombin generation (a potent platelet activator), a storm of platelet accumulation and activation ensues. Inhibition of cyclooxygenase-1–mediated TXA ₂ synthesis by nonsteroidal antiinflammatory drugs (NSAIDs) and aspirin (acetylsalicylic acid [ASA]) can 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, which connect activated platelets. The same fibrinogen molecule is also able to bind to adjacent platelet GpIIb-IIIa receptors. Because these receptors are abundant (i.e., 40,000 to 80,000 copies), large platelet rosettes quickly form, reducing blood flow and sealing vascular leaks. Platelet activation and aggregation are prevented in intact endothelium by the latter’s elaboration of prostacyclin, nitric oxide, and ADPase and by active blood flow that dilutes platelet activators. Cyclic adenosine monophosphate inhibits platelet activation, which is the basis for the therapeutic effects of dipyridamole. Normal pregnancy is associated with a modest decline in platelet number ^, and with evidence of progressive platelet activation.

Coagulation: Fibrin Plug Formation

Effective hemostasis requires the synergistic interaction of the coagulation 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 coagulation factors and form an ideal surface for thrombin generation. Conversely, optimal platelet activation and subsequent aggregation require exogenous thrombin generation (see Fig. 53.1 ). 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 2 decades. Coagulation 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. Coagulation is initiated when subendothelial (extravascular) cells expressing tissue factor (TF), a cell membrane–bound glycoprotein, encounter a small concentration of circulating activated factor VII (VIIa). Tissue factor is encoded by the F3 gene and the protein is primarily expressed on the cell membranes of perivascular smooth muscle cells, fibroblasts, and tissue parenchymal cells, but it is not expressed 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. ^, Intrauterine survival is not possible in the absence of TF.

After vascular disruption and in the presence of ionized calcium, perivascular cell TF encounters plasma factor VIIa. Factor VIIa is unique in that it circulates in small quantities in activated form, which results from autoactivation after binding to TF or activation by factors IXa or Xa. Activation of factor VII to VIIa increases its catalytic activity more than 100-fold and ensures that factor VIIa is readily available to initiate coagulation when exposed to TF.

The TF and factor VIIa (TF/VIIa) complex activates both factor X and factor IX. Factor Xa remains active as long as it is bound to the TF-VIIa complex in the cell membrane–bound prothrombinase Xa/Va complex (Xa-Va). However, when factor Xa diffuses away from the site of vascular injury, it is rapidly inhibited by tissue factor pathway inhibitor (TFPI) or antithrombin. This prevents inappropriate propagation of the thrombus throughout the vascular tree. Factor Xa bound to its cofactor, Va, which is converted from its inactive form by factor Xa itself or by thrombin to form the Xa-Va complex. The latter actively catalyzes conversion of prothrombin (factor II) to thrombin (factor IIa). Partially activated factor Va also can be delivered to the site of coagulation initiation after its release from platelet α-granules ( Fig. 53.2A ). Thrombin converts fibrinogen to fibrin and activates platelets, as noted, by binding to PAR-1 and PAR-4 (see Fig. 53.2A ).

After the initial TF-mediated reaction, the coagulation cascade is amplified in a propagation phase by an explosive positive feedback loop of coagulation reactions that occur on adjacent activated platelets. 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 directly activated by thrombin and is released from its vWF carrier molecule through the action of thrombin. The activated factor IXa/VIIIa complex (IXa-VIIIa; tenase complex) can then generate large amounts of factor Xa at these sites to further drive thrombin generation (see Fig. 53.2B ). The significant hemorrhagic sequelae of hemophilia underscore the vital role of tenase complex–mediated factor Xa generation in ensuring a sufficient thrombin burst for adequate hemostasis.

The coagulation cascade is also amplified by the activation of factor XI to XIa by thrombin on activated platelet surfaces; factor XIa also activates factor IX (see Fig. 53.2C ). The lack of significant hemorrhagic sequelae in patients with factor XI deficiency emphasizes that this mechanism has a less important role in the maintenance of hemostasis. Factor XIa has been described as having a “booster function” in coagulation.

A third, putative 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. Together, the factor IXa, factor XIa, and TF-platelet surface events lead to additional factor Xa generation and 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 formed only when fibrin monomers self-polymerize and are cross-linked by thrombin-activated factor XIIIa (see Fig. 53.2D ). This 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 (e.g., thrombosis, disseminated intravascular coagulation [DIC]).

Prevention of Thrombosis: the Anticoagulant System

The hemostatic system must prevent hemorrhage after vascular injury and maintain the fluidity of the circulation in an intact vasculature. Thrombotic disease is a consequence of inappropriate or excess thrombin generation. As in preventing hemorrhage, avoidance of thrombosis depends on the synergistic interaction of platelets and the coagulation system. Coagulation 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 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 subendothelial collagen and thrombin. As additional platelets aggregate on top of the initial layer of platelets, they become progressively less activated, and the coagulation reaction becomes more susceptible to the action of circulating inhibitors, attenuating the coagulation cascade.

Prevention of DIC ultimately requires the presence of inhibitor molecules ( Fig. 53.3 ). The first inhibitory molecule is TFPI, which forms a complex with TF, VIIa, and Xa (i.e., prothrombinase complex). TFPI is most effective distal to the initial site of clotting, and it can be bypassed by the generation of factors IXa and XIa.

Paralleling its pivotal role in initiating the hemostatic reaction, thrombin also plays a central role in initiating the anticoagulant system. Thrombin binds to thrombomodulin on intact downstream endothelial cells. The resultant conformational change permits thrombin to activate protein C, in effect converting thrombin from a procoagulant molecule to an anticoagulant molecule. Protein C activation is enhanced when it is presented on the cell surface by the endothelial protein C receptor (PROCR, formerly designated EPCR), which is abundant in some circulatory compartments but not others. Activated protein C then inactivates factors Va and VIIIa, thereby limiting coagulation. The latter reactions are enhanced by protein S, the cofactor of activated protein C.

Thrombomodulin also dampens coagulation by binding thrombin and removing it from participating in procoagulant reactions. The most potent inhibitor of factor Xa and thrombin is antithrombin (AT, also known as antithrombin III [ATIII]) (see Fig. 53.3 ). AT can bind thrombin and factors Xa, IXa, and XIa and can inactivate them. AT binding to endothelial surface heparinoids or exogenous heparin results in a conformational change that augments its thrombin inactivation potential more than 1000-fold. 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.

Restoration of Blood Flow: Fibrinolysis

Fibrinolysis permits the restoration of circulatory fluidity and serves as another barrier to widespread thrombosis ( Fig. 53.4 ). The cross-linked fibrin polymer is degraded to fibrin degradation products, including d -dimer, by the action of plasmin embedded in the fibrin clot. Plasmin is generated by proteolysis of plasminogen by tissue-type plasminogen activator (tPA), which is released by intact endothelial cells. Endothelial cells also synthesize a second plasminogen activator, urokinase-type plasminogen activator (uPA), the primary function of which is cell migration and extracellular matrix remodeling.

Fibrinolysis is inhibited by serpins, including plasminogen activator inhibitor-1 (PAI-1) and α ₂ -antiplasmin (α ₂ -AP), and a non-serpin inhibitor, thrombin-activated fibrinolysis inhibitor (TAFI). Platelets and endothelial cells release PAI-1 in response to thrombin binding to protease-activated receptors (PARs) PAR-1 and PAR-4. The PAI-1 molecule inhibits tPA and uPA. In pregnancy, the decidua is also a very rich source of PAI-1, ¹⁸ and the placenta can synthesize another antifibrinolytic molecule, plasminogen activator inhibitor-2 (PAI-2). Plasmin is inhibited by α2-AP. TAFI is activated by the thrombin-thrombomodulin complex, which cleaves terminal lysine residues from fibrin to render it resistant to plasmin. 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 interact with the coagulation cascade. Fibrin degradation products inhibit the action of thrombin, which is a major source of hemorrhage in DIC. Moreover, PAI-1 bound to vitronectin and heparin inhibits thrombin and factor Xa activity.

Effect of Pregnancy on Hemostasis

Pregnancy and delivery present unique and paradoxical challenges to a woman’s hemostatic system and constitute one of the greatest risks for venous thrombotic events (VTE) that most young women will face. Until the 17th century, more than 10% of women died of hemorrhage at delivery, and peripartum hemorrhage remains the leading cause of maternal mortality in the developing world. This created enormous evolutionary selection pressure, which likely prompted development of the maternal prothrombotic state.

The causal link between pregnancy and VTE is best explained by the Virchow triad, a framework that categorizes elements of the pathophysiology of VTE as venous stasis, vascular damage, and hypercoagulability. Venous stasis, which begins in the first trimester and peaks at 36 weeks, is thought to be caused by progesterone-induced venodilation, pelvic venous compression by the gravid uterus, and pulsatile compression of the left iliac vein by the right iliac artery. The latter accounts for the marked propensity for left leg deep venous thrombosis (DVT) in pregnancy (>80%). DVT in pregnancy commonly arises from proximal veins (iliac and femoral) rather than calf veins, as is the usual pattern in nonpregnant patients, leading to a higher propensity for isolated iliac vein thrombosis and iliofemoral thrombosis in pregnant patients with DVT. As a consequence of the tendency for more proximal location of thromboses during pregnancy, they are more likely to be associated with long-term postphlebitic syndrome.

During pregnancy, vascular damage to the pelvic vessels can be caused by venous distention. Vascular damage can occur after all types of deliveries.

Hypercoagulability occurs as the hemostatic system is progressively altered to prepare pregnant women for the hemostatic challenges of delivery. The modern consequence of this maternal hypercoagulable state is an increased risk of VTE. Two changes to the hemostatic system constitute the biologic mechanisms driving the maternal hypercoagulable state. First, anticoagulant activity of protein S is reduced and activated protein C resistance increases. Procoagulant activity is increased through higher levels of factors VII, VIII, and X, fibrinogen, and von Willebrand factor, leading to increased thrombin production, as measured by increased thrombin-antithrombin complex, soluble fibrin, and prothrombin fragment 1+2 levels. Second, thrombus dissolution is reduced through decreased fibrinolysis accruing increased PAI-1 and PAI-2 activity and decreased tPA activity. During the postpartum period, defined as the 6-week interval after delivery, the procoagulant maternal hemostatic system gradually returns to the nonpregnant state as evidenced by progressive normalization of markers of coagulation activation to prepregnancy levels. ^,

Profound alterations occur in local uterine coagulation, anticoagulant, and fibrinolytic systems to meet this hemostatic challenge. Uterine decidua is ideally positioned to regulate hemostasis during placentation and the third stage of labor. Progesterone augments expression of TF and PAI-1 on perivascular decidualized endometrial stromal cells. The crucial importance of the decidua in maintaining 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, placenta accreta). Decidual TF plays the primary role in mediating puerperal hemostasis. 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.

The extraordinarily high level of TF expression in human decidua can have 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. Moreover, thrombin can also bind to decidual PAR-1 receptors to promote production of matrix metalloproteinases and inflammatory cytokines, contributing to the tissue breakdown and inflammation associated with abruptio placentae and preterm premature rupture of the membranes. Thrombin also inhibits decidual cell progesterone receptor expression through activation of the Erk1/2 pathway ^, and induces myometrial contractions and prostaglandin production to promote preterm birth.

Disorders Promoting Thrombosis in Pregnancy

Acquired Thrombophilias: Antiphospholipid Syndrome

Antiphospholipid Antibodies

Antiphospholipid antibodies (aPLAs) are a heterogeneous group of autoantibodies recognizing epitopes expressed by negatively charged phospholipids, proteins, or a phospholipid-protein complex. It is unclear which epitopes these antibodies bind to in vivo, but the most relevant appears to be β ₂ -glycoprotein-1, which has an affinity for negatively charged phospholipids and plays a regulatory role in coagulation. There are numerous aPLAs, and there has been controversy regarding the best assays. There have been problems with interlaboratory variation, poor quality control, and a lack of standardization. Most of these problems have been addressed through a series of workshops, and most commercially available aPLA assays are validated and reliable. The three best characterized and standardized aPLA assays are the lupus anticoagulant (LA), anticardiolipin antibodies (ACAs), and anti–β ₂ -glycoprotein-1 antibodies.

“Lupus anticoagulant” is a misnomer for an antibody found in patients who need not have lupus and are not anticoagulated. The name was derived from the fact that the antibody interferes with phospholipid-dependent clotting assays, prolonging the assay clotting time and making it appear that the individual is anticoagulated. It was initially recognized in patients with lupus, accounting for the poor nomenclature. It can be detected by any of several phospholipid-dependent clotting tests, including the activated partial thromboplastin time (aPTT), dilute Russell viper venom time, kaolin clotting time, and plasma clotting time. It is necessary to do confirmatory testing because there are reasons other than LA for prolonged clotting times, such as a clotting factor deficiency or specific inhibitor. The assay for LA is interpreted as being present or absent.

ACAs are detected by a more traditional immunoassay. Results are reported as level of antibody for immunoglobulin G (IgG) in IgG phospholipid (GPL) units, or level of antibody for immunoglobulin M (IgM) in IgM phospholipid (MPL) units. Medium or high positive levels of IgG antibodies are most strongly associated with the clinical disorders of antiphospholipid syndrome (APS). This is typically at 40 GPL or higher, which is about the 99th percentile for normal populations. The same is true for anti–β ₂ -glycoprotein-1 antibodies, which are reported in standard IgG β ₂ -glycoprotein units (SGUs) and standard IgM β ₂ -glycoprotein units (SMUs). Similar to ACAs, levels greater than 99% are clinically meaningful. As performed in most US laboratories, LA is the aPLA most specifically associated with APS. In fact, a large recent cohort study noted that LA but not other aPLAs was associated with adverse pregnancy outcomes. However, most authorities advise testing for all three antibodies if APS is suspected, and being positive for all three antibodies also is associated with the highest risk of obstetric complications. Positive results for aPLAs may be transient, especially in the setting of infection. Testing should be repeated in 12 weeks to confirm the finding.

Antiphospholipid Syndrome

In a manner similar to that for systemic lupus erythematosus (SLE), the diagnosis of APS requires specific clinical features and supportive laboratory testing ( Box 53.1 ). ^, APS requires the presence of at least one clinical criterion (i.e., confirmed thrombosis or pregnancy morbidity) and one laboratory criterion (i.e., LA, ACA, or anti–β ₂ -glycoprotein-1 antibody). However, the finding of thrombosis must take into account risk factors that lessen the certainty of the diagnosis (see Box 53.1 ). Uteroplacental insufficiency may be recognized by the sequelae of abnormal fetal surveillance tests suggesting fetal hypoxemia, abnormal Doppler velocimetry suggesting fetal hypoxemia, oligohydramnios (i.e., amniotic fluid index ± 5 cm), or birth weight less than the 10th percentile in the absence of other causes for poor fetal growth. Diagnosis of APS should not be made if less than 12 weeks or more than 5 years separate the positive aPLA test result and the clinical manifestation.

Box 53.1

Revised Classification Criteria for Diagnosis of the Antiphospholipid Syndrome

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. 2006;4:295–306.

ACAs, Anticardiolipin antibodies; APS, antiphospholipid syndrome; 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; LDL, low-density lipoprotein; MPL, IgM phospholipid (units).

Clinical Criteria ^a

a A diagnosis of APS requires at least one clinical criterion and one laboratory criterion to be met.

1.
Vascular thrombosis ^b

b Coexisting inherited and acquired factors for thrombosis are not reasons for excluding patients from APS trials. However, two subgroups of patients with APS should be recognized according to (1) the presence or (2) the absence of additional risk factors for thrombosis. Risk factors include older age (>55-year-old men, >65-year-old women); any risk factor for cardiovascular disease (e.g., hypertension, diabetes mellitus, elevated LDL or low HDL cholesterol, cigarette smoking, family history of premature cardiovascular disease, BMI ≥30 kg/m ² , microalbuminuria, estimated GFR <60 mL/min); inherited thrombophilias; oral contraceptive use; nephrotic syndrome; malignancy; immobilization; and surgery. Patients who fulfill these criteria should be stratified according to contributing causes of thrombosis.

: One or more clinical episodes of arterial, venous, or small-vessel thrombosis; 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’ 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 34 weeks’ 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’ gestation, with maternal anatomic or hormonal abnormalities and paternal and parental chromosomal causes excluded

Laboratory Criteria ^c

c Investigators are strongly advised to classify patients with APS in studies as follows: I, more than one laboratory criterion present (any combination); IIa, lupus anticoagulant present alone; IIb, ACA present alone; IIc, anti–β ₂ -glycoprotein-1 antibody present alone.

1.
Lupus anticoagulant present in plasma on two or more occasions at least 12 weeks apart, detected according to the guidelines of the ISTH (Scientific Subcommittee on Lupus Anticoagulants/Phospholipid-Dependent Antibodies)
2.
ACAs of the IgG or IgM isotype in serum or plasma, present in medium or high titers (i.e., >40 GPL or MPL, or >99th percentile), on two or more occasions at least 12 weeks apart as measured by a standardized ELISA
3.
Anti–β2-glycoprotein-1 antibody or IgG or IgM isotype in serum or plasma (in a titer >99th percentile), present on two or more occasions at least 12 weeks apart as measured by a standardized ELISA according to recommended procedures

As with all syndromes, the relevance of a positive laboratory test in the absence of clinical features of the syndrome is uncertain. Some aPLAs, especially low levels of the IgM isotype of ACAs, can be found in a small percentage of healthy individuals. Many patients with APS also have SLE and are considered to have secondary APS. APS in the absence of another autoimmune condition is primary APS.

Clinical Features of APS

Medical Complications

A characteristic feature of thromboses associated with aPLAs is that they can be venous or arterial. Approximately two-thirds of events are venous, and the most common site is deep in the lower extremity. Up to 50% of venous thromboses are pulmonary emboli, but thromboses in unusual locations also are common. It is estimated that aPLAs are present in about 2% of individuals with unexplained thromboembolism. Arterial thromboses also are common; the most frequent type of arterial thrombosis in patients with APS is a cerebrovascular accident. Symptoms may include transient ischemic attacks and amaurosis fugax. Coronary occlusions and arterial thromboses in atypical sites also may occur. About 4% to 5% of cerebrovascular accidents in patients younger than 50 years of age are associated with aPLAs. ^,

A meta-analysis of 18 studies examining the thrombotic risk among SLE patients with LA found an odds ratio (OR) of 6.32 (95% confidence interval [CI], 3.71 to 10.78) for a venous thrombosis and an OR of 11.6 (95% CI, 3.65 to 36.91) for recurrent venous thrombosis. In contrast, ACAs were associated with lower ORs of 2.50 (95% CI, 1.51 to 4.14) for an acute VTE and 3.91 (95% CI, 1.14 to 13.38) for recurrent venous thrombosis. 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. The comparable numbers for ACAs were 1 to 18 and 1 to 2.5. There appears to be a consistently greater risk of VTE associated with LA compared with isolated ACAs. Recurrence risks of up to 30% have been reported for affected patients, and long-term prophylaxis is required. The risk of VTE in pregnancy and the puerperium for women with APS is uncertain but is estimated to be between 5% and 12%. ^,

Autoimmune thrombocytopenia is a frequent medical complication of APS, occurring in almost one-half of cases. The condition is hard to distinguish from immune thrombocytopenia and is treated in a similar fashion. Other medical disorders associated with aPLAs include autoimmune hemolytic anemia, livedo reticularis, chorea gravidarum, transverse myelitis, pyoderma-like leg ulcers, and cardiac valve disease. Some individuals have a life-threatening systemic illness—catastrophic APS—that is caused by multiple thromboses of the small and large vessels. Characterized by cardiopulmonary insufficiency, renal failure, and fever, catastrophic APS often occurs after delivery. ^,

Obstetric Complications

aPLAs are associated with numerous obstetric complications, including recurrent pregnancy loss, fetal death, preeclampsia, fetal growth restriction (FGR), abruption, and abnormal fetal test results. These conditions increase the risk of medically indicated preterm birth. In untreated patients, LA is associated with an OR for fetal loss after the first trimester of 3.0 to 4.8. The ORs for fetal loss for women with ACAs range from 0.86 to 20.0. Detection of aPLAs is more strongly associated with fetal death after 10 weeks’ gestation than with early pregnancy loss (e.g., implantation failures, preembryonic losses, embryonic demises). At least 50% of pregnancy losses for patients with aPLAs occur after the 10th week of gestation. In women with unexplained first-trimester pregnancy losses, those with aPLAs are more likely to have embryonic cardiac activity (86% versus 43%; P < .01) than those without aPLAs. aPLAs are strongly associated with stillbirth (losses after 20 weeks’ gestation). A large case-control study noted an OR of 5.3 for nongenetic, nonobstetric stillbirth in women with IgG ACAs (95% CI, 2.39 to 11.76).

It is clear that aPLAs are not associated with sporadic early pregnancy loss. This is expected because most such losses are caused by genetic abnormalities. There is some association between aPLAs and recurrent and otherwise unexplained early pregnancy loss, but whether patients with recurrent early pregnancy loss truly have APS remains controversial.

The association between aPLAs and infertility is uncertain. Increased levels of aPLAs have been reported in women with infertility. ^, However, a meta-analysis of seven studies of affected patients undergoing in vitro fertilization found no significant association between aPLAs and clinical pregnancy (OR = 0.99; 95% CI, 0.64 to 1.53) or live birth rate (OR = 1.07; 95% CI, 0.66 to 1.75). There is no evidence that treating patients who have aPLAs with anticoagulant medications improves the outcomes of in vitro fertilization.

Women with APS who have pregnancies reaching viability are at increased risk for obstetric outcomes associated with abnormal placentation, such as preeclampsia and FGR. Up to 50% of pregnant women with APS develop preeclampsia, and one-third of pregnancies have FGR. Abnormal fetal heart rate tracings prompting cesarean delivery are also common. Conversely, most cases of preeclampsia and FGR occur in women without aPLAs. Although increased positive test results for aPLAs have been reported for women with preeclampsia, especially for those with severe disease with onset before 34 weeks’ gestation and FGR, most large retrospective and prospective studies have not found an association between these conditions and APS. This is not surprising, given the common occurrence of preeclampsia and FGR and the relative infrequency of APS.

Pathophysiology

The mechanisms of thrombosis and pregnancy loss associated with aPLAs are uncertain. Many pathways have been proposed for aPLA-mediated arterial and venous thrombosis. For example, aPLAs directly inhibit the anticoagulant effects of anionic phospholipid-binding proteins such as β ₂ -glycoprotein-1 and annexin V. ^, The aPLAs appear to inhibit thrombomodulin, activated protein C, and AT activity; to induce TF, PAI-1, and vWF expression in endothelial cells; and to augment platelet activation. These mechanisms may play a role in the pathophysiology of pregnancy complications. Although it is an oversimplification, thrombosis in the uteroplacental circulation may lead to placental infarction and insufficiency. Inflammation in the placenta appears to make an important contribution to abnormal pregnancy in women with APS. The activation of complement by aPLAs was critical for aPLA-induced pregnancy loss and FGR in a murine model. ^, Complement activation also has been reported in humans with APS.

Obstetric Management

The first consideration in the medical management of APS during pregnancy is whether the patient has had a prior thrombosis. Most individuals with APS and a history of thrombosis should undergo lifelong anticoagulation, typically with vitamin K antagonists (e.g., warfarin). They should be treated with therapeutic anticoagulant doses of unfractionated heparin (UH) or low-molecular-weight heparin (LMWH) for the entire pregnancy, and anticoagulation with vitamin K antagonists is reinitiated after delivery. The optimal treatment for women with APS but no prior thrombosis is less clear. Most authorities advise using a thromboprophylactic dose of UH or LMWH during pregnancy and through 6 weeks after delivery, although some experts advise low-dose ASA alone. This approach is used to reduce the risk of thrombosis and to improve the obstetric outcome. Appropriately designed trials have never been conducted with women who had medical and obstetric APS. Given the small study sizes, weak study designs, lack of contemporary controls, and heterogeneity of the enrollment criteria and therapies employed, it is difficult to make definitive, evidence-based recommendations for treatment. It is noteworthy that a recent meta-analysis found a small increase in live births and a small reduction in preeclampsia in women taking heparins, with or without aspirin. However, the weaknesses of the studies included limit the certainty of these findings. Hydroxychloroquine may improve obstetric outcomes in APS pregnancies, but proof of efficacy is lacking. Preliminary data suggest improved outcomes in women treated with hydroxychloroquine in addition to standard therapy, even in refractory cases. ^, Ongoing randomized trials should provide high-quality data regarding the efficacy of hydroxychloroquine and APS. Good outcomes also have been reported with the use of other adjunctive treatments for “difficult” obstetric APS including pravastatin and plasma exchange, but quality data are lacking.

Patients with APS and no prior thromboses are at long-term increased risk for thromboembolism. Most authorities advise against the use of estrogen-containing contraceptives in women with APS. Progestin-containing agents are not contraindicated. The risks for nonobstetric complications such as thrombocytopenia and SLE also are increased. Counseling regarding nonobstetric issues and referral to an internist with expertise in APS is advised after delivery.

Inherited Thrombophilias

Inherited thrombophilias are associated with VTE. However, the incidence of VTE among patients with an inherited thrombophilia depends on the potency of the thrombophilia and exposure to other external risk factors (e.g., surgery, casts, immobilization, exogenous estrogen). Because thrombophilias predispose to the development of thrombosis in the slow-flow circulation of leg veins, the hypothesis that thrombophilias may lead to thrombosis in the slow-flow circulation of the placenta and to the consequent placenta-mediated complications appears plausible. However, this concept remains controversial, and its application unclear for most thrombophilias and most pregnancy complications.

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’ gestation and rising to 60.7 ± 8.5 mm Hg at 12 to 13 weeks. Trophoblast plugging of the spiral arteries has been demonstrated in placental histologic studies before 10 weeks’ gestation, and low Doppler flow is observed in the uteroplacental circulation before 10 weeks. The undetectable levels of superoxide dismutase in trophoblasts before 10 weeks’ gestation are consistent with a hypoxic state. If inherited thrombophilias are associated with early pregnancy loss, it is most likely through mechanisms other than placental thrombosis. Because most early pregnancy losses are associated with aneuploidy and other genetic abnormalities, thrombophilias are unlikely to play a role. 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 maternal thrombophilias and adverse pregnancy outcomes.

As noted, thrombin plays a central role in hemostasis. It also appears that thrombin is necessary in normal placental development. TF, the most important initiator of coagulation, is constitutively expressed on almost all cells other than endothelial cells. The maternal-fetal placental interface develops as the fetal-derived trophoblasts invade endometrial tissue. The placental end-product includes fetal trophoblastic tissue in direct contact with maternal blood in the intervillous space, which is fed by the spiral arteries that are offshoots of the maternal uterine artery.

Isermann and colleagues demonstrated that knockout mice that do not express thrombomodulin on trophoblasts have inadequate placentation, which leads to embryonic lethality early in gestation. This embryonic lethality depends on TF expression on the trophoblast cells and thrombin generation. In thrombomodulin-deficient mice, embryonic lethality does not depend on fibrinogen and cannot be ameliorated with heparin. Giant trophoblast cells apoptose when exposed to fibrin degradation products, and trophoblast cell growth is arrested after engagement of PAR-2 and PAR-4. Because embryonic thrombomodulin deficiency is not associated with fibrin deposition in the developing placenta or placental thrombosis, mechanisms other than overt placental thrombosis must be responsible for embryonic lethality. Li and coworkers showed that the embryonic lethality associated with deletion of the PROCR gene, which encodes an endothelial cell surface protein receptor for activated protein C that enhances activation of the protein, can be rescued by PROCR gene expression on trophoblasts and by genetically modifying TF expression. Sood and associates showed that PAR-4 deficiency in the mother or platelet deficiency can partially rescue thrombomodulin-deficient mice.

The net effect appears to be an autocrine loop whereby placental growth is enhanced by contact of maternal blood and fetal cells through the intermediary of the hemostatic system. Trophoblasts may constitutively express TF ^, (unlike endothelial cells) and clearly have abundant thrombomodulin, PAR-1, and PROCR, and they are in contact with maternal blood. It is likely that thrombin binds to trophoblast thrombomodulin, leading to the generation of activated protein C and its binding to PROCR. This complex then activates G protein–coupled receptors PAR-1 and PAR-2, leading to cell signaling that promotes trophoblast cell growth and differentiation. Thrombin can also bind to PAR-4 on maternal platelets and, through an unknown mechanism, influence trophoblast cell growth and differentiation. Placental development and maternal hemostasis are intimately tied, but much remains to be discovered before it is appropriate to extrapolate this knowledge to clinical practice.

Factor V Leiden Mutation

Occurring in about 5% of Europeans and 0.8% of African Americans, factor V Leiden (FVL) mutation is the most common inheritable thrombophilias. ^, The mutation is rare in African Blacks, Chinese, Japanese, and other Asians. The mutation leads to a substitution of glutamine for arginine at position 506 at the site of proteolysis and inactivation by activated protein C. The FVL mutation is the leading cause of activated protein C resistance. The heterozygous state leads to a fivefold increased risk of VTE with a lifetime incidence of about 35%, whereas homozygous patients have a 25-fold increased risk with a lifetime VTE incidence of about 65% ( Table 53.1 ). FVL is associated with approximately 40% of the VTE events among pregnant patients. However, given the low prevalence of VTE in pregnancy and during the puerperium (1 case per 1400) and the high incidence of the mutation in the European-derived population, the risk of pregnancy-associated VTE among FVL heterozygotes without a personal history of VTE or an affected first-degree relative is less than 0.3%. The risk appears to be at least 10% among pregnant women who have a personal history of VTE or an affected first-degree relative. Pregnant homozygous patients without a personal history of VTE or an affected first-degree relative have an approximately 1.5% risk of VTE in pregnancy; if there is a personal or family history of VTE, the risk was 17% in one study (see Table 53.1 ). Screening can be done by assessing activated protein C resistance using a second-generation coagulation assay, followed by genotyping for the FVL mutation if the resistance is found in a pregnant or nonpregnant woman. Alternatively, patients can be genotyped for the FVL mutation.

TABLE 53.1

Inherited Thrombophilias Associated With Venous Thromboembolism in Pregnancy

Thrombophilia	Relative Risk of VTE (95% Cl)	Probability (%) of VTE Without or With a Personal History of VTE or a First-Degree Relative With VTE		References
Thrombophilia	Relative Risk of VTE (95% Cl)	Without	With	References
FVL (homozygous)	25.4 (8.8–66)	1.5	17	96, 97
FVL (heterozygous)	5.3 (3.7–7.6)	0.26	10	96, 97, 394
PGM (homozygous)	NA	2.8	>17	96, 97
PGM (heterozygous)	9.5 (2.1–66.7) or 6.1 (3.4–11.2)	0.37	>10	96, 97
FVL/PGM (double heterozygous)	84 (19–369)	4.7	>10	96, 97
Antithrombin deficiency (<60% activity)	119 (NA) or 10.4 (2.2–62.5)	7	>10–40	96, 97, 394
Protein S deficiency (<55% activity)	3.2 (1.3–8.0)	<1	7–22	96, 97
Protein C deficiency (<50% activity)	13.0 (1.4–123)	0.2-0.8	2–17	96, 97

CI, Confidence interval; FVL, factor V Leiden mutation; NA, not available; PGM, prothrombin gene mutation; VTE, venous thromboembolism.

The link between FVL and early and late pregnancy loss is controversial. In a meta-analysis of predominantly retrospective studies with significant heterogeneity, FVL was associated with early (<13 weeks’ gestation) pregnancy loss (OR = 2.01; 95% CI, 1.13 to 3.58), but it was more strongly associated with late (>19 weeks), nonrecurrent fetal loss (OR = 3.26; 95% CI, 1.82 to 5.83). Similarly, multivariate analysis of a nested case-control study revealed an association between FVL thrombophilia and pregnancy loss after 10 weeks (OR = 3.46; 95% CI, 2.53 to 4.72) but not for losses occurring between 3 and 9 weeks. These results suggest that FVL thrombophilia is associated with fetal (>9 weeks) but not embryonic (<9 weeks) losses. A case-control study noted an association between stillbirth and homozygous (OR = 87.44; 95% CI, 7.88 to 970.92) but not heterozygous FVL, although these results should be interpreted with caution due to extremely small numbers.

In contrast, a prospective study by the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network found no increase in the incidence of fetal loss among women heterozygous for FVL. A subsequent meta-analysis of seven prospective cohort studies to estimate the risk of pregnancy loss in women with or without the FVL mutation found a pooled OR estimate of 1.52 (95% CI, 1.06 to 2.19) for a total of 16,959 women with an observed FVL mutation prevalence of 4.7%. There was substantial statistical heterogeneity ( I ² = 51.0%; P =.06) across all seven studies. Overall, the aforementioned studies suggest that FVL status is likely weakly associated with pregnancy loss after the first trimester. Yet, it is reassuring that the absolute risk of pregnancy loss in women with FVL is low (4.2%) and is only slightly higher than the rate in women without FVL (3.2%).

The correlation between FVL status and other adverse pregnancy events is even more controversial. In the late 1990s, Kupferminc and associates studied 110 women and reported a link between FVL carriage and severe preeclampsia (OR = 5.3; 95% CI, 1.8 to 15.6). However, multiple case-control studies failed to confirm a link between FVL positivity and moderate or severe preeclampsia. Dudding and Attia’s meta-analysis estimated a 2.9-fold (95% CI, 2.0 to 4.3) increased risk of severe preeclampsia among FVL mutation carriers. Similarly, Lin and August conducted a meta-analysis of 31 studies involving 7522 patients and reported pooled ORs of 1.81 (95% CI, 1.14 to 2.87) for FVL and all forms of preeclampsia and 2.24 (95% CI, 1.28 to 3.94) for FVL and severe preeclampsia. Kosmas and coauthors evaluated 19 studies involving 2742 women with hypertension and 2403 controls. Whereas the studies published before 2000 found a modest association between FVL thrombophilia and preeclampsia (OR = 3.16; 95% CI, 2.04 to 4.92), those published after 2000 did not (OR = 0.97; 95% CI, 0.61 to 1.54). This suggests a reporting bias.

Kahn and colleagues conducted a prospective multicenter cohort study of 5337 pregnant women, 113 of whom developed preeclampsia, and found that inherited thrombophilias, including FVL, occurred in only 14% of cases and 21% of controls (adjusted logistic regression OR = 0.6; 95% CI, 0.3 to 1.3). Moreover, a meta-analysis of 10 prospective cohort studies found that FVL did not significantly increase the risk of preeclampsia (estimated pooled OR = 1.23; 95% CI, 0.89 to 1.70) in 21,833 total women among whom the prevalence of FVL was 4.9%. The absolute risk of preeclampsia in FVL-positive women was 3.8%, compared with 3.2% for FVL-negative women. The cohorts were homogeneous across studies, and the definition of the outcome (preeclampsia) was consistent across the studies. This meta-analysis had more than 90% power to detect an absolute increase of 2% (from control value of 3.2% to FVL value of 3.2% + 2% = 5.2%) in the rate of preeclampsia among women with the FVL mutation, but it did not detect an increased risk. This information should provide reassurance to women with the FVL mutation that they are not at significantly increased risk for preeclampsia.

There is even less consistent evidence for an association between the FVL mutation and FGR. A small case-control study reported a strong association between the FVL variant and FGR (OR = 6.9; 95% CI, 1.4 to 33.5) with a very wide CI, reflecting the fact that there were only eight cases with the FVL mutation. However, multiple large case-control and cohort studies have reported no statistically significant association between the FVL mutation and FGR of less than the 10th percentile or less than the 5th percentile. ^, ^, Howley and colleagues conducted a systematic review of studies describing the association between the FVL mutation and FGR; among 10 case-control studies meeting the selection criteria, there was a significant association between the FVL mutation and FGR (OR = 2.7; 95% CI, 1.3 to 5.5). However, no association was found when combining two prospective cohort studies (relative risk = 0.99; 95% CI, 0.5 to 1.9). The investigators suggested that the putative association between FGR and FVL was most likely driven by small, poor-quality studies that demonstrated extreme associations. Facco and colleagues also conducted a meta-analysis of case-control and cohort studies that examined the relationship between FGR and carrying an FVL mutation and reported an OR of 1.23 (95% CI, 1.04 to 1.44), but they observed that this linkage was mainly driven by the case-control studies, suggesting a publication bias.

In the meta-analysis of prospective cohort studies previously described, seven studies reported information on small-for-gestational-age (SGA) births and FVL. Occurrence of the FVL mutation did not significantly increase the risk of SGA (estimated pooled OR = 1.0; 95% CI, 0.80 to 1.25) among 20,654 total women with FVL prevalence of 6.0%. The absolute risk of SGA births below the 10th percentile among women with FVL was 6.5%, compared with 7.4% for FVL-negative women. This finding should allow clinicians to provide reassurance to women positive for the FVL mutation that they are not at increased risk for giving birth to an SGA child.

Similarly, there is inconsistent evidence for an association between the FVL mutation and placental abruption. Kupferminc and colleagues reported a modest association between positive FVL status and abruption (OR = 4.9; 95% CI, 1.4 to 17.4). A second case-control study found that 17 of 27 patients with abruption had activated protein C resistance, compared with 5 of 29 control subjects (OR = 8.16; 95% CI, 3.6 to 12.75), and 8 patients were found to have the FVL mutation, compared with 1 control. Procházka 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; 95% CI, 1.4 to 6.7). Alfirevic and coworkers conducted a meta-analysis that revealed a strong association between placental abruption and homozygosity and heterozygosity for the FVL mutation (OR = 16.9; 95% CI, 2.0 to 141.9 and OR = 6.7; 95% CI, 2.0 to 21.6, respectively). However, in the previous meta-analysis of prospective cohort studies, five studies evaluated the association between FVL and placental abruption. These studies included 12,308 women with a pooled FVL mutation prevalence of 5.1%. The absolute risk of placental abruption in FVL-positive women was 1.3%, compared with 0.9% for FVL-negative women. The pooled OR estimate for placental abruption among women with the FVL mutation (homozygous or heterozygous) was 1.85 (95% CI, 0.92 to 3.70). The moderate statistical heterogeneity ( I ² = 33%) identified may be attributable to the inconsistent and unclear definition of placental abruption across studies. The meta-analysis had inadequate power to detect a doubling of risk of placental abruption among women with FVL due to small sample sizes and low event rates, limiting conclusions regarding an association between FVL and placenta abruption. Further research is required to determine whether FVL status is truly associated with placental abruption.

In summary, there appears to be a weak association between the FVL and pregnancy loss. However, no clear association exists between FVL status and preeclampsia, FGR, SGA, or placental abruption. Although FVL is associated with pregnancy loss, most affected individuals without prior obstetric complications are at low risk for subsequent adverse pregnancy outcomes. FVL should be thought of as a risk factor for, rather than a cause of, pregnancy loss and possibly other severe adverse outcomes, similar to risk factors such as maternal age and obesity.

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 (A4070G) decreases factor V cofactor activity in the activated protein C–mediated degradation of factor VIIIa; however, a meta-analysis demonstrated no association between the HR2 haplotype and the risk of VTE (OR = 1.15; 95% CI, 0.98 to 1.36). 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 independent risks of pregnancy loss during weeks 8 and 9, which increased during weeks 10 to 12 and culminated after 12 weeks. In contrast, Dilley and colleagues found no association between carriage of the factor V HR2 haplotype and pregnancy loss. The study sample sizes were too small to allow firm conclusions 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 activated protein C cleavage site, factor V R306G Hong Kong and factor V R306T Cambridge, have been described but do not appear to be strongly associated with VTE. Data are inadequate to assess any link between these mutations and adverse pregnancy outcomes.

Prothrombin Gene Mutation

The prothrombin G20210A polymorphism is a point mutation causing a guanine-to-adenine switch at nucleotide position 20,210 in the 3′-untranslated region of the F2 gene. This nucleotide switch results in increased translation, possibly due to enhanced stability of messenger RNA. Consequently, there are increased circulating levels of prothrombin. Although the mutation occurs in only 2% to 3% of Europeans, it is associated with 17% of VTEs during pregnancy. As was the case with FVL, the risk of VTE in pregnant patients who are heterozygous for the G20210A prothrombin gene mutation (PGM) but who do not have a personal or strong family history of VTE is less than 0.5%. Pregnant PGM-heterozygous patients with a history of VTE have at least a 10% risk of VTE. PGM-homozygous patients without a personal or strong family history have a 2.8% risk of VTE in pregnancy, whereas such a history probably confers a risk of at least 20% (see Table 53.1 ). Because the combination of FVL and PGM has synergistic hypercoagulable effects, patients heterozygous for both mutations are likely at comparable thrombotic risk to either FVL or PGM homozygotes. Pregnant patients who are double heterozygotes without a personal or strong family history have a 4.7% risk of VTE. ^,

PGM has been associated with an increased risk of pregnancy loss in multiple case-control studies. One study reported PGM in 7 of 80 patients with recurrent pregnancy loss, compared with 2 of 100 control patients (9% versus 2%; P = .04; 95% OR = 4.7; CI, 0.9 to 23). Finan and coworkers also found an association between PGM and recurrent pregnancy loss, with an odds ratio of 5.05 (95% CI, 1.14 to 23.2). However, other studies failed to identify a link. ^, 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 odds ratio of 2.0 (95% CI, 1.0 to 4.0). 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; 95% 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; 95% CI, 1.04 to 6.29). It is noteworthy that a recent large case-control study found no relationship between PGM and stillbirth. In a meta-analysis of prospective cohort studies, only four studies evaluated the association of PGM and pregnancy loss; they reported a pooled OR estimate of 1.13 and wide 95% CIs (0.64 to 2.01). However, the meta-analysis was underpowered to detect small differences in the absolute risk of pregnancy loss among women with PGM.

Other case-control studies and meta-analyses have failed to establish a link between PGM and preeclampsia or severe preeclampsia. ^, ^, ^, ^, In the meta-analysis of prospective cohort studies, six studies evaluated PGM status and preeclampsia and did not report a significant association between PGM (heterozygous or homozygous) and preeclampsia (pooled OR = 1.25; 95% CI, 0.79 to 1.99) among 14,254 women with a PGM prevalence of 4.1%. The absolute risk of preeclampsia among women with PGM was 3.5%, compared with 3.0% for PGM-negative women. This finding should reassure women with these thrombophilias that they are not at increased risk for preeclampsia.

A link between PGM and SGA birth appears to have been excluded. Despite two small, positive studies, ^, the large case-control study of Infante-Rivard and colleagues reported no link in heterozygotes between PGM and FGR (OR = 0.92; 95% CI, 0.36 to 2.35). Similar results have been observed by others. In the meta-analysis of prospective cohort studies, five studies reported PGM status and SGA births below the 10th percentile among 17,287 total women with a PGM prevalence of 5.1%. The absolute risk of SGA births below the 10th percentile among women with PGM (heterozygous or homozygous) was 5.4%, compared with 5.7% for PGM-negative women. There was no association between PGM (heterozygous or homozygous) and SGA status below the 10th percentile (pooled OR = 1.25; 95% CI, 0.92 to 1.70). The pooled OR estimate of three studies reporting SGA births below the 5th percentile and PGM was 1.46 (95% CI, 0.81 to 2.62) among a total of 6285 women, with a prevalence of 3.3% for PGM. The prevalence of SGA births below the 5th percentile among women with PGM was 5.7%, compared with 4.3% for PGM-negative women. This information should provide reassurance to women with PGM that they are not more likely to give birth to an SGA child.

There are limited data on the association between PGM and abruption. The case-control study of Kupferminc and coworkers found an association between PGM and abruptio placentae (OR = 8.9; 95% CI, 1.8 to 43), whereas Procházka and colleagues found no such link. One meta-analysis suggested a strong link between PGM heterozygosity and placental abruption (OR = 28.9; 95% CI, 3.5 to 236). In contrast, in the meta-analysis of prospective cohort studies, the pooled OR estimate for placental abruption in women with PGM (homozygous or heterozygous) was 2.02 (95% CI, 0.81 to 5.02), with moderate heterogeneity across studies. The latter meta-analysis was underpowered to detect a doubling of risk of placental abruption in women with the PGM.

In summary, there may be a weak association between PGM and pregnancy loss and placental abruption in case-control studies, but further prospective cohort studies are required to confirm this association. However, there does not appear to be a significant link between PGM and SGA or preeclampsia.

Hyperhomocysteinemia

Serum homocysteine levels are sensitive to dietary vitamin intake and are reduced by increased intake of folic acid and vitamin B ₁₂ . Hyperhomocysteinemia can result from several 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 occurs in 10% to 16% of all Europeans, and homozygosity for the A1298C mutation occurs in 4% to 6%. About 40% of Whites are heterozygous for the C677T polymorphism, and most heterozygotes have normal levels of homocysteine. Moreover, because homocysteine levels decrease in pregnancy and US dietary flour is fortified with folic acid supplementation, hyperhomocysteinemia is rare even among homozygotes. Although hyperhomocysteinemia is a weak risk factor for VTE (OR = 2.5; 95% CI, 1.8 to 3.5), MTHFR mutations by themselves do not appear to convey an increased risk for VTE in nonpregnant or pregnant women.

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 (95% CI, 1.4 to 5.2) versus 1.4 (95% CI, 1.0 to 2.0), respectively. The Hordaland Homocysteine Study assessed the relationship between plasma homocysteine values in 5883 women and their prior 14,492 pregnancy outcomes. When the investigators compared the upper with the lower quartile of plasma homocysteine levels, elevated levels trended toward modest associations with preeclampsia (OR = 1.32; 95% CI, 0.98 to 1.77), very low birth weight (OR = 2.01; 95% CI, 1.23 to 3.27), and stillbirth (OR = 2.03; 95% CI, 0.98 to 4.21), with various degrees of statistical significance determined by the method of analysis. In contrast, a clear association was demonstrated between placental abruption and homocysteine levels greater than 15 μmol/L (OR = 3.1; 95% CI, 1.6 to 6.0), and a weaker but significant association was observed between homozygosity for the C677T MTHFR mutation and abruption (OR = 2.6; 95% CI, 1.4 to 4.8). A meta-analysis of these two risk factors found that hyperhomocysteinemia had a larger pooled OR for abruption (5.3; 95% CI, 1.8 to 15.9) than did homozygosity for the MTHFR mutation (2.3; 95% CI, 1.1 to 4.9).

Even though these studies suggest that hyperhomocysteinemia may be linked to VTE and adverse pregnancy outcomes, it is unclear whether high homocysteine levels truly have a causal effect. The observation that lowering of homocysteine levels did not reduce VTE rates suggests that homocysteine may simply be a marker of increased risk. As such, screening for MTHFR polymorphism or measurement of homocysteine levels is not recommended by either the American College of Obstetricians and Gynecologists or the American College of Medical Genetics and Genomics. ^,

Antithrombin Deficiency

AT deficiency is the least common and the most thrombogenic of the inherited thrombophilias. More than 250 mutations have been identified in the AT gene, producing a highly variable phenotype. Disorders can be classified as type 1, those associated with reductions in antigen and activity; type 2, those associated with normal levels of antigen but decreased activity; and type 3, the rare homozygous deficiency associated with little or no activity. ^, Complicating matters further, patients can acquire an AT deficiency due to liver impairment, increased consumption of AT associated with sepsis or DIC, or increased renal excretion in persons with severe nephrotic syndrome. 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 (range, 0.02% to 1.1%). The recommended cutoff for abnormality is 50% activity, which is associated with a prevalence of 0.04% (1 of 2500 people). Although AT deficiency increases the risk of VTE up to 25-fold in the nonpregnant state, because of its rarity, it is associated with only 1% to 8% of VTE episodes during pregnancy. ^, Hemostatic changes of pregnancy that decrease antithrombin levels may substantially increase its thrombogenic potential. Moreover, use of a less stringent threshold yields a higher prevalence of AT deficiency among patients with VTE. For example, in one study, 19.3% of pregnant women with VTE had less than 80% AT activity, but many of these cases might have been acquired due to clot-associated AT consumption. Conversely, the overall fraction of VTE in pregnancy associated with AT deficiency has been reported as 3% to 48%. ^, The risk of VTE in pregnancy among patients with AT deficiency most likely varies with a personal or family history (3% to 7% without such a history and up to 40% with such a history) (see Table 53.1 ). A systematic review on the risk of VTE in asymptomatic pregnant women (with a family history but no personal history of thrombosis) with AT deficiency or in the postpartum period resulted in an estimated OR of 6.09 (95% CI, 1.58 to 23.43) for thrombosis. This supports the classification of AT deficiency as a high-risk thrombophilia.

In the largest retrospective cohort study, AT deficiency was associated with an increased risk of stillbirth after 28 weeks’ gestation (OR = 5.2; 95% CI, 1.5 to 18.1) but had a more modest association with loss before 28 weeks (OR = 1.7; 95% CI, 1.0 to 2.8). Because of its rarity, there is a paucity of evidence concerning the link between AT deficiency and other adverse pregnancy outcomes. In a selected referral population, Roque and associates found that it was associated with increased risks of FGR (OR = 12.9; 95% CI, 2.7 to 61), abruption (OR = 60; 95% CI, 12 to 300), and preterm delivery (OR = 4.7; 95% CI, 1.2 to 18).

Protein C Deficiency

Deficiency of protein C results from more than 160 distinct mutations, producing a highly variable phenotype. As with AT deficiency, protein C deficiency can be associated with reductions in antigen and activity (type 1) or normal levels of antigen but decreased activity (type 2). The rare homozygous protein C deficiency results in neonatal purpura fulminans and a requirement for lifelong anticoagulation. Activity levels can be determined by a functional (clotting) or chromogenic assay.

Estimates of prevalence reflect the cutoff values employed. Most laboratories use activity cutoff values of 50% to 60%, which are associated with prevalence estimates of 1.5%. The reported risk of VTE in pregnancy among protein C–deficient patients with a personal or family history of VTE is 2% to 8%. ^, ^, Because of its rarity, there are few reports linking protein C deficiency to adverse pregnancy outcomes. In a selected referral population, Roque and associates found that protein C deficiency was associated with increased risks of abruption (OR = 13.9; 95% CI, 2.2 to 86.9) and preeclampsia (OR = 6.85; 95% CI, 1.09 to 43.2). Although it is biologically plausible that protein C deficiency may result in adverse pregnancy outcomes, small sample sizes prevent firm conclusions.

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