Thromboembolic Disorders of Pregnancy



Thromboembolic Disorders of Pregnancy


Audrey A. Merriam

Christian M. Pettker

Michael J. Paidas



Introduction

Venous thromboembolism (VTE) poses significant maternal and fetal risks in pregnancy. It is estimated that VTE complicates 0.5 to 2 in 1000 pregnancies.1,2 Pregnancy has been associated with a sixfold higher incidence of VTE compared with age-matched nonpregnant women, and pulmonary embolism (PE) remains a leading cause of maternal mortality.3,4 In the United States, VTE leads to 9.3% of maternal deaths.5 Postpartum deep venous thrombosis (DVT) is more common than antepartum DVT, with reported rates of 0.61 in 1000 pregnancies compared to 0.13 in 1000 pregnancies, respectively.1,2,6 Timely diagnosis and treatment of DVT are essential as a quarter of patients with DVT develop PE. Initiation of anticoagulation once the diagnosis of DVT has been made significantly reduces both the risk of PE (5%) and the mortality rate (<1%).7


Pregnancy and the Hemostatic System: Clot Formation, Thrombin Regulation, and Fibrinolysis


Platelet Plug Formation: Adhesion, Activation, and Aggregation

Following vascular wall disruption, platelets adhere to subendothelial collagen, mediated by von Willebrand factor “bridges” anchored at one end to subendothelial collagen and at the other to the platelet Glib/IX/V receptor.8 Platelets also adhere to other subendothelial extracellular matrix proteins. Adherent platelets are then activated, and increases in phospholipase C activity promote the synthesis of thromboxane and the phosphorylation of key platelet proteins that promote granule release, including α-granules containing von Willebrand factor, thrombospondin, platelet factor 4, fibrinogen, beta-thromboglobulin, and platelet-derived growth factor, as well as dense granules containing adenosine diphosphate (ADP) and serotonin. ADP induces a conformational change in the GPIIb/IIIa receptor on the platelet membrane, resulting in platelet aggregation via high-affinity fibrinogen formation and other proteins.9

Alpha-granule release also promotes exteriorization of platelet factor 4, a chemokine with potent heparin-neutralizing activity, as well as other procoagulant factors, leading to thrombin generation. Thrombin binds to type 1 and type 4 protease-activated receptors (PAR-1, PAR-4) on the platelet membrane, serving as stimuli for platelet activation. Other factors, such as epinephrine and platelet activation factor, contribute to platelet activation. Platelet activation is limited by blood flow and agents elaborated by an intact endothelium, including prostacyclin, nitric oxide, and ADPase (Figure 37.1).


Fibrin Plug Formation: the Coagulation Cascade

Tissue factor (TF), a cell membrane-bound glycoprotein, is ultimately responsible for the initiation of adequate hemostasis, as platelet activation alone cannot generate an effective hemostatic plug.10 Intrauterine survival is not possible in the absence of TF, unlike the absence of either platelets or fibrinogen.11 TF is expressed on the cell membranes of perivascular smooth muscle cells, fibroblasts, and tissue parenchymal cells; TF also circulates in the blood in very low concentrations as part of cell-derived microparticles or in a truncated soluble form.11,12 These TF-bearing microparticles contribute to clotting by binding to platelets at sites of vascular injury through the interaction of P-selectin glycoprotein ligand-1 on microparticles with surface P-selectin on activated
platelets.13 In the presence of ionized calcium, perivascular cell- or platelet-bound TF comes into contact with plasma factor VII on negatively charged (anionic) cell membrane phospholipids (Figure 37.2).






Factor VII has low intrinsic clotting activity, autoactivates after binding to TF, and/or can be activated by thrombin, as well as factors IXa, Xa, or XIIa.10,11 The complex of TF/factor VII(a) can either directly activate factor X (extrinsic pathway) or generate factor Xa by initially activating factor IX. Factor IX complexes with its cofactor, factor VIIIa, to activate factor X (intrinsic pathway). Once activated, factor Xa complexes with its cofactor, factor Va, to convert factor II (prothrombin) to factor IIa (thrombin). The cofactors, factors V and VIII, can each be activated by either thrombin or factor Xa (Figure 37.1).

A second pathway of thrombin generation is available, which results from activation of factor XI by thrombin-activated factor XIIa, typically on the surface of activated platelets. Factor XII can be activated by the action of kallikrein and its cofactor, high-molecular-weight kininogen, and by plasmin. Factor IX activation can also occur via factor XIa.






Fibrinogen is cleaved by thrombin to produce fibrin. A stable hemostatic plug is created as fibrin monomers self-polymerize and are cross-linked by thrombin-activated factor XIIIa (Figure 37.2). Thus, thrombin is the ultimate arbiter of clotting
as it not only activates platelets and generates fibrin but, along with factor Xa, activates the crucial clotting cofactors, factors V and VIII, and mediates the aforementioned activation of factors VII, XII, and XIII (Figure 37.1).


The Anticoagulant System

The anticoagulant system provides balance in the hemostatic system to prevent excessive or inappropriate thrombin generation. The anticoagulant system consists of effector and inhibitor molecules (Figure 37.2). The first inhibitory molecule is tissue factor pathway inhibitor (TFPI), which forms a complex with TF, factor VIIa, and factor Xa (the prothrombinase complex).12 This block can be bypassed by the generation of factor XIa. Additionally, during the time period (10-15 seconds) before TFPI-mediated prothrombinase inhibition, a sufficient amount of factors Va, VIIIa, IXa, Xa, and thrombin can be generated to sustain clotting.

The protein C system plays a central role in regulating thrombin. Once thrombin is formed, it binds to thrombomodulin on the endothelial cell surface. A resultant conformational change permits thrombin to activate protein C when bound to damaged endothelium or to the endothelial protein C receptor. Activated protein C (APC) then binds to its cofactor, protein S (PS), to inactivate factors Va and VIIIa.13 Factor Va acts as a second cofactor in APC-mediated factor VIIIa inactivation.

Protein Z (PZ) is a 62-kDa, vitamin K-dependent plasma protein that serves as a cofactor for a PZ-dependent protease inhibitor (ZPI) of factor Xa.14,15 When ZPI is complexed to PZ, its inhibitory activity is enhanced 1000-fold.16 The ZPI molecule also inhibits factor XIa in a PZ-independent process. PZ is critical for regulation of factor Xa activity along with TFPI.16,17,18

The most active inhibitor of both factor Xa and thrombin is antithrombin. Antithrombin binds either thrombin or factor Xa and vitronectin. A conformational change facilitates binding to heparin, which augments antithrombin’s rate of thrombin inactivation 1000-fold.19 A similar inhibitory mechanism is initiated by heparin cofactor II and α-2 macroglobulin.


Fibrinolysis

Fibrinolysis is crucial to the prevention of thrombosis (Figure 37.2). Plasmin degrades fibrin, leading to fibrin degradation products. Plasmin is created by the proteolysis of plasminogen via tissue-type plasminogen activator (tPA) embedded in fibrin. Endothelial cells produce a second plasminogen activator, urokinase-type plasminogen activator (uPA). There is also a series of inhibitors of fibrinolysis (Figure 37.2). Plasmin is directly inhibited by α2-plasmin inhibitor, which can be bound to the fibrin clot to prevent premature fibrinolysis. Platelets and endothelial cells release type 1 plasminogen activator inhibitor (PAI-1) in response to thrombin binding to its PARs. The decidua is also a very rich source of PAI-1, while the placenta is the chief source of PAI-2.20 Thrombin-activatable fibrinolysis inhibitor, activated by the thrombin-thrombomodulin complex, is a fourth fibrinolysis inhibitor.21 The fibrinolytic system exerts anticoagulant effects. For example, fibrin degradation products inhibit thrombin action, a major source of hemorrhage in disseminated intravascular coagulation. In addition, PAI-1 bound to vitronectin and heparin directly inhibits thrombin and factor Xa activity.22


Clinical Presentation


Clinical Risk Factors for VTE in Pregnancy

Vascular stasis, hypercoagulability, and vascular trauma (Virchow triad) remain the three prime antecedents to thrombosis. Clinical risk factors specific to obstetrics that increase the risk for VTE include pregnancy, multiple gestation, preeclampsia, cesarean delivery, operative vaginal delivery, postpartum hemorrhage requiring transfusion (Table 37.1).24,25,26 Nonobstetric risk factors for VTE include age >35 years, infection, trauma, cancer, nephrotic syndrome, obesity, surgery, hyperviscosity syndromes, immobilization, congestive heart failure, prior VTE, and the presence of acquired and inherited thrombophilias. It can also be helpful to think about risk factors for VTE in terms of if the risk factor is reversible or not. For example, ovarian hyperstimulation syndrome, infection, immobility, long-distance travel (>4-6 hours), hyperemesis with associated dehydration, and hospital stay/bed rest are all potentially reversible risk factors for VTE.27 Hospital admission alone is associated with a 17-fold increase in VTE, which continues to remain elevated even 28 days after discharge.28

These reversible and irreversible risk factors increase clotting potential through a variety of mechanisms, including increases in TF, clotting factors, and PAI-1; decreases in PS levels; increasing stasis; and vascular injury. Pregnant women with a
history of a thrombophilia and those with a prior history of thromboembolism have the highest risks of thromboembolism (Table 37.2).29









Hemostatic Changes in Pregnancy

Substantial changes must occur in local (decidual) and systemic coagulation, anticoagulant, and fibrinolytic systems to meet the hemostatic challenges of pregnancy, including avoidance of hemorrhage at implantation, placentation, and the third stage of labor. Progesterone augments perivascular decidual cell TF and PAI-1 expression.20,30 Transgenic TF knockout mice rescued by the expression of low levels of human TF have been found to have a 14% incidence of fatal postpartum hemorrhage, underscoring the importance of decidual TF.31 Obstetric conditions associated with impaired decidualization (eg, ectopic and cesarean scar pregnancy, placenta previa and accreta) are associated with potential lethal hemorrhage in humans.








Pregnancy is associated with significant elevations of a number of clotting factors. Fibrinogen concentration is doubled, and 20% to 1000% increases are seen in factors VII, VIII, IX, X, XII, and von Willebrand factor, with maximum levels reached at term.32 Prothrombin and factor V levels remain unchanged, while levels of factors XIII and XI decline modestly. The net effect of these changes is to increase thrombin-generating potential. Coagulation activation markers in normal pregnancy are elevated, as evidenced by increased thrombin activity, increased soluble fibrin levels (9.2-13.4 nmol/L), increased thrombin-antithrombin
(TAT) complexes (3.1-7.1 µg/L), and increased levels of fibrin D-dimer (91-198 µg/L).23 Fifty percent of women had elevated TAT levels (11/22), and 36% of women had elevated levels of D-dimers (9/25) in the first trimester.

Significant changes in the natural anticoagulant and fibrinolytic systems occur in normal pregnancy. PS levels decrease significantly in normal pregnancy. Mean free PS antigen levels have been reported to be 38.9% ± 10.3% and 31.2% ± 7.4% in the second and third trimesters, respectively.33 In a follow-up study, free PS antigen levels in the first trimester were found to be 39% (SD 10.5), compared with the reference range in nonpregnancy of 88% (SD 19), P < .05.34 The PS carrier molecule, complement 4B-binding protein, is increased in pregnancy and is one explanation for the diminished PS levels in pregnancy. These diminished PS levels result in a resistance to APC.32,33 Levels of PAI-1 increase three- to fourfold during pregnancy; plasma PAI-2 values are low prior to pregnancy and reach concentrations of 160 µg/L at term. Table 37.3 summarizes the relevant pregnancy-associated changes in the hemostatic system.23,35,36 The prothrombotic hemostatic changes are exacerbated by pregnancy-associated venous stasis in the lower extremities because of 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 the local production of prostacyclin and nitric oxide. The most significant pregnancy-related prothrombotic factors are listed in Table 37.4.

















Acquired Thrombophilia

The well-characterized antiphospholipid antibody syndrome (APLS) is defined by the combination of VTE, obstetric complications, and antiphospholipid antibodies (APAs).37 By definition APA-related thrombosis can occur in any tissue or organ except superficial veins, while accepted associated obstetric complications include at least one fetal death at or beyond the 10th week of gestation, or at least one premature birth at or before the 34th week, or at least three consecutive spontaneous abortions before the 10th week. All other causes of pregnancy morbidity must be excluded. APAs must be present on two or more occasions at least 12 weeks apart.38 APAs are detected by screening for antibodies that:



  • directly bind these protein epitopes (eg, anti-β2-glycoprotein-1, prothrombin, annexin V, APC, PS, PZ, ZPI, high- and low-molecular-weight kininogens, tPA, factors Vila and XII, the complement cascade constituents, C4 and CH, and oxidized low-density lipoprotein antibodies); or


  • are bound to proteins present in an anionic phospholipid matrix (eg, anticardiolipin and phosphatidylserine antibodies); or


  • exert downstream effects on prothrombin activation in a phospholipid milieu (ie, lupus anticoagulants).39

Anti-β2-glycoprotein-1, anticardiolipin, and lupus anticoagulants are used when screening for APLS. A positive test occurs with detection of immunoglobulin (Ig)G and/or IgM to one of three APAs. Positive test results are as follows: anticardiolipin antibodies (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.40 Clinicians should use caution when ordering and interpreting tests in the absence of the APLS-qualifying clinical criteria listed above.

Venous thrombotic events associated with APA include DVT with or without acute pulmonary embolus, whereas the most common arterial events include cerebral vascular accidents and transient ischemic attacks. At least half of patients with APA have systemic lupus erythematosus (see Chapter 40). Anticardiolipin antibodies are associated with an odds ratio (OR) of 2.17 (1.51-3.11; 14 studies) for any thrombosis, 2.50 (1.51-4.14) for DVT and PE, and 3.91 (1.14-13.38) for recurrent VTE.41 The lifetime prevalence of arterial or venous thrombosis in affected patients with APA is about 30%, with an event rate of 1% per year.39 These antibodies are present in up to 20% of individuals with VTE.42 A review of 25 prospective, cohort and case-control studies involving more than 7000 patients observed an OR range for arterial and venous thromboses in patients with lupus anticoagulants of 8.65 to 10.84 and 4.09 to 16.2, respectively, and 1.0 to 18.0 and 1.0 to 2.51 for anticardiolipin antibodies.39

There is a 5% risk of VTE during pregnancy and the puerperium among patients with APA despite treatment.43 Recurrence risks of up to 30% have been reported in APA-positive patients with a prior VTE; thus, long-term prophylaxis is required in patients with APLS and a prior VTE. A severe form of APS is termed catastrophic APS, or CAPS, which is defined as a potentially life-threatening variant with multiple vessel thromboses leading to multiorgan failure.44 In the Euro-Phospholipid Project Group44 (13 countries included), DVT, thrombocytopenia, stroke, PE, and transient ischemic attacks were found in 31.7%, 21.9%, 13.1%, 9.0%, and 7.0% of cases, respectively.

APAs are associated with obstetric complications in about 15% to 20% of cases including fetal loss after 9 weeks’ gestation, abruptio placentae, severe preeclampsia, and intrauterine/fetal growth restriction (FGR). Reported ORs for lupus anticoagulant-associated fetal loss range from 3.0 to 4.8, whereas anticardiolipin antibodies display a wider range of reported ORs of 0.86 to 20.0.39 It is unclear whether APAs are also associated with recurrent (>3) early spontaneous abortion in the absence of stillbirth. Fifty percent or more of pregnancy losses in APA
patients occur after the 10th week.45 Patients with APA more often display initial fetal cardiac activity compared with patients with unexplained first trimester spontaneous abortions without APA (86% vs 43%; P < .01).46 APAs have been commonly found in the general obstetric population, with one survey demonstrating that 2.2% of such patients have either IgM or IgG anticardiolipin antibodies, with most such women having relatively uncomplicated pregnancies.47 Other factors may play a role in the pathogenesis of APA. Potential mechanism(s) by which APA induce arterial and venous thrombosis as well as adverse pregnancy outcomes include APA-mediated impairment of endothelial thrombomodulin and APC-mediated anticoagulation; induction of endothelial TF expression; impairment of fibrinolysis and antithrombin activity; augmented platelet activation and/or adhesion; and impairment of the anticoagulant effects of the anionic phospholipid binding proteins β2-glycoprotein-1 and annexin V.48,49 APA induction of complement activation has been suggested to play a role in fetal loss, with heparin preventing such aberrant activation.50


Inherited Thrombophilias

Inherited thrombophilias are a heterogeneous group of disorders associated with varying degrees of increased thrombotic risk. The occurrence of a thromboembolic event, even in pregnant women with an inherited thrombophilia is highly dependent on other predisposing risk factors such as pregnancy, immobility, obesity, surgery, infection, etc. The most important risk modifier is a personal or family history of venous thrombosis. Any woman who presents with VTE (DVT or PE) during pregnancy or postpartum period should undergo an appropriate workup for inherited thrombophilias.

Factor V Leiden mutation is a relatively common mutation is present in 5% of American Caucasians, 1% of African-Americans, and 5% to 9% of Europeans, but is rare in Asian and African populations.51,52 The factor V mutation is associated with resistance to APC and is inherited primarily in an autosomal-dominant fashion.52,53 Heterozygosity is found in 20% to 40% of nonpregnant patients with thromboembolic disease, whereas homozygosity confers a >100-fold risk of thromboembolic disease.52

Prospective studies suggest lower-risk inherited thrombophilias may have an even weaker association with maternal thrombosis than was once thought. A study of 4885 low-risk women were screened in the first trimester for thrombophilias and 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%-2.7%).54 Another two studies screening for factor V Leiden in early pregnancy found no thrombotic episodes in women found to carry heterozygous mutations.55,56

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Jun 19, 2022 | Posted by in OBSTETRICS | Comments Off on Thromboembolic Disorders of Pregnancy

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