Thromboembolic Disorders in Pregnancy

Vasoconstriction and Platelet Action

Vasoconstriction and platelet activity play a primary initial role in limiting blood loss following vascular disruption and endothelial damage. Vasoconstriction limits blood flow and also limits the size of thrombus necessary to repair the defect. Platelet adherence to damaged vessels is mediated by the formation of von Willebrand factor (vWF) “bridges” anchored at one end to subendothelial collagen and at the other to the platelet glycoprotein Ib (GP Ib)/factor IX/V receptor. Platelet adhesion stimulates release of α-granules that contain vWF, thrombospondin, platelet factor 4, fibrinogen, β-thromboglobulin, and platelet-derived growth factor as well as dense granules that contain adenosine diphosphate (ADP) and serotonin. These latter molecules, when combined with the release of thromboxane A ₂ (TXA ₂ ), contribute to further vasoconstriction and platelet activation. In addition, ADP causes a conformational change in the platelet GP IIb/IIIa receptor that promotes aggregation by forming interplatelet fibrinogen, fibronectin, and vitronectin bridges.

Coagulation Cascade

Platelet action alone is insufficient to provide adequate hemostasis in the face of a substantial vascular insult; in this setting, the coagulation cascade—with resultant fibrin plug formation—is required to restore hemostasis . Tissue factor (TF), a cell membrane-bound glycoprotein, is the primary initiator of the coagulation cascade. It is expressed constitutively by epithelial, stromal, and perivascular cells throughout the body and in abundance by endometrial stromal cells and the pregnant uterine decidua. TF is also present in low concentrations in the blood, on activated platelets, and in high levels in amniotic fluid, which accounts for the coagulopathy seen in amniotic fluid embolism. It is interesting to note that although intrauterine survival is possible in the absence of platelets or fibrinogen, it is not possible in the absence of TF. Clotting is initiated by the binding of TF to factor VII, the only clotting factor with intrinsic coagulation activity in its zymogenic form ( Fig. 50.1 ).

Following endothelial injury and in the presence of ionized calcium, perivascular cell- or platelet-bound TF comes into contact with factor VII on anionic cell membrane phospholipids. Factor VII has low intrinsic clotting activity but can be autoactivated after binding to TF, or it can be activated by thrombin or activated factors such as IXa, Xa, or XIIa. The TF–activated factor VII (VIIa) complex initiates the elements of the coagulation cascade by activating both factors IX and X. Activated factor IX (IXa) complexes with its cofactor VIIIa to indirectly activate X. Once generated, Xa binds with its cofactor Va to convert prothrombin (factor II) to thrombin (factor IIa). Cofactors V and VIII can be activated by either thrombin or Xa, and XIIa activates XI on the surface of activated platelets, which provides an alternative route to IX activation. Factor XII can be activated by kallikrein/kininogen as well as by plasmin. The key event of hemostasis occurs when thrombin cleaves fibrinogen to produce fibrin. Fibrin monomers self-polymerize and are cross-linked by thrombin-activated factor XIIIa. Although TF is the initiator of hemostasis, thrombin is the ultimate arbiter of clotting; it not only activates platelets and generates fibrin, it also activates critical clotting factors and cofactors (V, VII, VIII, XI, and XIII). Fig. 50.1 provides a diagram of the interaction of the various components of the coagulation cascade.

Anticoagulant System

The risk of thrombosis, the inappropriate and excessive activation of the clotting cascade, is restrained by the anticoagulant system (see Fig. 50.1 ). Evidence shows that the coagulation system “idles” like a car engine to quickly respond to vascular injury, and thus the anticoagulant system performs the critical role of preventing the inappropriate acceleration of clotting. Tissue factor pathway inhibitor (TFPI) binds to the prothrombinase complex (factor Xa/TF/factor VIIa) to stop TF-mediated clotting. However, as noted, factor XIa generation can bypass this block. Moreover, in the 10 to 15 seconds before TFPI-mediated prothrombinase inhibition, sufficient quantities of factors Va, VIIIa, IXa, and Xa and thrombin are generated to sustain clotting for some time. As a result, additional physiologic anticoagulant molecules are required to maintain blood fluidity.

Paradoxically, thrombin also plays a pivotal role in the anticoagulant system by binding to thrombomodulin, which causes a conformation change that allows it to activate protein C. The activated protein C (APC) molecule binds to anionic endothelial cell membrane phospholipids on damaged vessels or to the endothelial cell protein-C receptor (EPCR) to inactivate factors Va and VIIIa. Protein S is an important cofactor in this process because it enhances APC activity. Factor Va is also a cofactor in APC-mediated factor VIIIa inactivation.

Factor Xa can also be inhibited by the protein Z–dependent protease inhibitor (ZPI). When ZPI forms a complex with its cofactor, protein Z, its inhibitory activity is enhanced a thousand-fold, although ZPI can also inhibit factor XIa independent of protein Z. Deficiencies of protein Z can promote both bleeding and thrombosis, although the latter predominates particularly in the presence of other thrombophilias.

Thrombin activity is modulated by a number of serine protease inhibitors—such as heparin cofactor II, α-2 macroglobulin, and antithrombin—which serve to inactivate thrombin and Xa . The most active inhibitor within this group is antithrombin, which binds to either thrombin or factor Xa and then to heparin or other glycosaminoglycans, augmenting antithrombin's rate of thrombin inactivation more than a thousand-fold. The other two inhibitors work in a similar fashion to inhibit thrombin.

Clot Lysis and Fibrinolysis

Fibrinolysis is a further critical element in preventing overwhelming thrombosis (see Fig. 50.1 ). Tissue-type plasminogen activator (tPA), an endothelial enzyme metabolized by the liver, becomes embedded in fibrin and cleaves plasminogen to generate plasmin, which in turn cleaves fibrin into fibrin degradation products; the latter are indirect measures of fibrinolysis. These fibrin degradation products can also inhibit thrombin action, a favorable effect when production is limited but a contributor to disseminated intravascular coagulation (DIC) when production is excessive. A second plasminogen activator, urokinase-type plasminogen activator (uPA), is produced by endothelial cells. A series of fibrinolysis inhibitors also prevent hemorrhage from premature clot lysis. The α-2 plasmin inhibitor is bound to the fibrin clot, where it prevents premature fibrinolysis. Platelets and endothelial cells release type 1 plasminogen activator inhibitor (PAI-1), an inactivator of tPA. In pregnancy, the decidua is also a rich source of PAI-1, whereas the placenta produces mostly type 2 (PAI-2). The thrombin-activatable fibrinolysis inhibitor (TAFI) is another fibrinolytic inhibitor that is also activated by the thrombin-thrombomodulin complex. TAFI modifies fibrin and renders it resistant to inactivation by plasmin.

Antiphospholipid Syndrome

Overall, antiphospholipid syndrome (APS) is responsible for approximately 14% of thromboembolic events in pregnancy . The diagnosis of APS requires the presence of prior or current vascular thrombosis or characteristic obstetric complications together with at least one of the following laboratory criteria: anticardiolipin antibodies (immunoglobulin G [IgG] or IgM greater than 40 GPL [1 GPL unit is 1 µg of IgG antibody] or 40 MPL [1 MPL unit is 1 µg of IgM antibody] or greater than the 99th percentile), anti–β-2 glycoprotein-I (IgG or IgM greater than the 99th percentile), or lupus anticoagulant.

The antiphospholipid antibodies (APAs) are a class of self-recognition immunoglobulins whose epitopes are proteins bound to negatively charged phospholipids. These antibodies must be present on two or more occasions at least 12 weeks apart for diagnosis and are present in 2.2% of the general obstetric population. Most affected patients have uncomplicated pregnancies. Thus providers should use caution when ordering and interpreting tests in the absence of APS-qualifying clinical criteria.

APS has been associated with both venous (DVT, PE) and arterial vascular events (stroke). A meta-analysis of 18 studies has shown elevated risk of DVT, PE, and recurrent VTE among patients with systemic lupus erythematous (SLE) who test positive for antiphospholipid antibodies. Overall, when compared to those SLE patients who do not test positive for either test, those with lupus anticoagulants and anticardiolipin antibodies have a respective sixfold and twofold increased risk of venous thrombosis. These antibodies also pose a risk to patients without SLE. The lifetime prevalence of arterial or venous thrombosis in affected non-SLE patients is approximately 30%, with an event rate of 1% per year . The risks of thromboembolic events are highly dependent on the presence of other predisposing factors that include pregnancy, estrogen exposure, immobility, surgery, and infection. As noted above, APS has also been associated with adverse pregnancy outcome and accounts for 14% of VTE in pregnancy. In fact, the risk of a thrombotic event in pregnancy is 5% even with prophylaxis. All patients who present with VTE in pregnancy or in the postpartum period should have an appropriate APS workup.

Inherited Thrombophilias

The inherited thrombophilias are a heterogeneous group of genetic disorders associated with arterial and venous thrombosis as well as fetal loss. As with APAs, the occurrence of a thromboembolic event is highly dependent on other predisposing factors such as pregnancy, exogenous estrogens, immobility, obesity, surgery, infection, trauma, and the presence of other thrombophilias. However, the most important risk modifier is a personal or family history of venous thrombosis. Table 50.1 presents the prevalence and risk of venous thrombosis among pregnant patients with and without a personal or family history of venous thrombosis. As noted, the thrombophilias are divided into high and low risk based on the overall risk of VTE. The screening for and management of inherited thrombophilias during and around the time of pregnancy has been addressed by American College of Obstetricians and Gynecologists (ACOG). All patients who present with VTE in pregnancy or postpartum should be considered for an appropriate workup for inherited thrombophilias.

Recent prospective studies have suggested that lower-risk inherited thrombophilias may have an even weaker association with maternal thrombosis than that reported by the retrospective studies cited in Table 50.1 . For example, a prospective study of 4885 low-risk women screened in the first trimester of pregnancy noted that 134 (2.7%) carried the factor V Leiden mutation, but none had a thromboembolic event during pregnancy or the in puerperium (95% confidence interval [CI], 0% to 2.7%). In two other prospective studies that involved 584 pregnant Irish and 4250 British women, again screened for factor V Leiden early in pregnancy, no thrombotic episodes were noted among carriers. Said and associates blindly tested 1707 Australian nulliparous women for factor V Leiden, the prothrombin gene G20210A mutation, and a thrombomodulin polymorphism prior to 22 weeks, and reported an expected prevalence of heterozygosity for the factor V Leiden and prothrombin G20210A gene mutations and homozygosity for the thrombomodulin polymorphism of 5.39%, 2.38%, and 3.51%, respectively; again, none of the patients developed VTEs. However, one prospective study of 2480 women tested for activated protein-C resistance/factor V Leiden early in pregnancy and observed that affected patients had an eightfold increase in VTE. Thus, the true risk of thrombosis in patients with low-risk inherited thrombophilias is probably lower than that suggested by retrospective case-control and cohort studies and is likely also dependent on the presence of concomitant risk factors such as a strong family history, obesity, and surgery.

Risk Factors and Associations

Virchow triad—vascular stasis, hypercoagulability, and vascular trauma—describes the three classic antecedents to thrombosis, and many of the physiologic changes of pregnancy contribute to these criteria . Other pregnancy-specific risk factors for thrombosis include increased parity, multiple gestation, preeclampsia, postpartum endomyometritis, postpartum hemorrhage requiring transfusion, operative vaginal delivery, and cesarean delivery. The latter is associated with a fourfold increase in VTE risk compared with vaginal delivery, with emergent cesarean delivery increasing the risk of VTE even further. Risk factors not unique to pregnancy include age greater than 35 years, obesity (body mass index ≥30 kg/m ² ), trauma, paralysis, smoking, nephrotic syndrome, hyperviscosity syndromes, cancer, surgery (particularly orthopedic procedures), and a history of DVT or PE ( Table 50.2 ). There are also reversible risk factors that can increase the risk of VTE in pregnancy including ovarian hyperstimulation syndrome, infection, immobility, long-distance travel (>4 to 6 hours), hyperemesis with associated dehydration and hospital stay/bedrest. Admission to the hospital in pregnancy may be associated with a 17-fold increased risk for VTE compared with a nonhospitalized cohort, with this risk remaining high (sixfold) for the 28 days after admission . In vitro fertilization (IVF) has been shown to increase the risk for VTE in the first trimester in a cross-sectional study in Sweden, although the overall absolute risk is still rather low.

Complications

Thromboembolism is associated with serious complications that include arrhythmia, hypoxia, pulmonary hypertension, heart failure, and postthrombotic syndrome of the extremities. Thromboembolism is a major cause of death worldwide; thus prompt diagnosis and treatment is a priority. When confronted with the signs and symptoms suggestive of VTE, rapid initiation of the workup and treatment is essential to avoid complications. Complications of anticoagulation, such as bleeding or thrombocytopenia, are also a reality and should be avoided.

Considerations in the Management of Pregnant Women

Pregnancy and the postpartum period are considered high-risk periods for thromboembolism. Key considerations in the workup and management of pregnant women include the selection of appropriate diagnostic tools and anticoagulation regimens with special concern regarding pregnancy-related changes and fetal exposures.