THROMBOPHILIA AND VENOUS THROMBOEMBOLISM IN PREGNANCY: DETECTION AND MANAGEMENT PARADIGM

About Authors:
Ritesh Shah*, Gaurav Chandawat, Rahul Jadav, Bhoomi Arora
Institute Of Clinical Research (India),
Ahmedabad, Gujarat-380013, India
*ritesh_shah99@yahoo.com

ABSTRACT
Venous thromboembolism (VTE) complicates approximately 1 to 2 of 1,000 pregnancies, with pulmonary embolism (PE) being a leading cause of maternal mortality and deep vein thrombosis (DVT) an important cause of maternal morbidity. The main reason for the increased risk of thromboembolism in pregnancy is hypercoagulability, which has likely evolved to protect women from the bleeding challenges of miscarriage and childbirth. Women are at a 4- to 5-fold increased risk of thromboembolism during pregnancy and the postpartum period compared with when they are not pregnant. Eighty percent of the thromboembolic events in pregnancy are venous, with an incidence of 0.61 to 1.72 per 1000 pregnancies.Includes a history of thrombosis, inherited and acquired thrombophilia, maternal age greater than 35, certain medical conditions, and various complications of pregnancy and childbirth.

Despite the increased risk of VTE during pregnancy and the postpartum period, most women do not require anticoagulation. The intensity of the anticoagulation will depend on the indication and the monitoring will depend on the intensity. At the time of delivery, anticoagulation should be manipulated to reduce the risk of bleeding complications while minimizing the risk of thrombosis. There are no large trials of anticoagulants in pregnancy, and recommendations are based on case series, extrapolations from nonpregnant patients and the opinion of experts. Nonetheless, anticoagulants are believed to improve the outcome of pregnancy for women who have, or have had, VTE.

Reference Id: PHARMATUTOR-ART-1371

INTRODUCTION
Information regarding the association of VTE with acquired and heritable thrombophilia and other high-risk conditions has greatly expanded during the last 2 decades, adding a new layer of complexity to decisions about thromboprophylaxis. In addition, updated guidelines regarding VTE and pregnancy have been published recently by the Royal College of Obstetricians and Gynaecologists (RCOG), the American College of Obstetricians and Gynecologists (ACOG), and the American College of Chest Physicians (ACCP) [1-3]. The objective of this review is to discuss which patients have a clinically important increased risk of VTE; of them, who needs thromboprophylaxis; and which management regimens to use in specific patient subgroups.

MECHANISM OF INCREASED VENOUS THROMBOEMBOLISM (VTE) RISK IN PREGNANCY AND EPIDEMIOLOGY
Pregnancy and the postpartum period carry an increased likelihood of VTE, with the frequency cited as 0.61 to 1.72 per1, 000 deliveries [4, 5]. Women are at an increased risk of both venous and arterial thromboembolism during pregnancy. Compared to women who are not pregnant, the risk of arterial thromboembolism (strokes and heart attacks) is increased 3- to 4-fold [6, 7] and the risk of venous thromboembolism (VTE) is increased 4- to 5-fold [8]. Postpartum, the risk is even higher (20-fold). Approximately 20% of these events are arterial, and the other 80% are venous [5, 6, 7]. VTE accounts for 1.1 deaths per 1,00,000 deliveries [6,7], or 10% of all maternal deaths. Approximately 80% of venous thromboembolic events during pregnancy are deep vein thrombosis (DVT) and 20% are pulmonary emboli [5] Approximately one third of pregnancy-related DVT and half of pregnancy-related pulmonary emboli occur after delivery [9, 10, 11]. Pelvic vein thromboses, which account for less than 1% of all cases of DVT, are rare outside of pregnancy or pelvic surgery yet account for approximately 10% of DVT during pregnancy and the postpartum period [10].

When DVT occurs during pregnancy, it is more likely to be proximal, massive, and in the left lower extremity [12]. proximal thromboses occurring under the influence of estrogen [13, 14]. This left-sided predominance is thought to be attributable to a relative stenosis of the left common iliac vein where it lies between the lumbar vertebral body and the right common iliac artery [15]. Pregnancy increases risk of VTE, in part, because all 3 elements of Virchow's Triad are present during gestation: stasis, vascular trauma, and hypercoagulability [4]. Increasing intra-abdominal pressure and compression of the vena cava by the enlarging uterus lead to decreased venous velocity and increased venous pressure in the lower extremities. Increased circulating levels of progesterone, along with local production of prostacyclin and nitric oxide, increase deep-vein capacitance [16]. These changes result in a relative venous stasis that increases with gestational age and tends to be worse in the left than in the right lower extremity [17-19]. In addition, venous distention is associated with endothelial damage and prothrombotic alterations in the endothelium that can persist, to some degree, for up to 6 weeks postpartum. Endothelial damage also can occur during operative or assisted deliveries or in association with conditions such as preeclampsia, which involves vascular endothelial activation [20].

Pregnant women are probably at an increased risk for VTE as a result of hormonally induced decreased venous capacitance and decreased venous outflow [21, 22].  possibly as a result of mechanical obstruction by the uterus [23], and questionably as a result of decreased mobility [24-27]. These factors, along with vascular injury, are important, especially during the postpartum period, but the risk of VTE is as high during the first trimester as it is during the second and third trimesters [9, 10]. Therefore, the risk of VTE increases before many of the anatomic changes of pregnancy take place, suggesting that, overall, the most important reason for the increased risk of VTE during pregnancy is hypercoagulability.

Normal pregnancy is accompanied by increased concentrations of factors VII, VIII, X, and von Willebrand factor and by pronounced increases in fibrinogen [28]. Factors II, V, and IX are relatively unchanged [28]. Free protein S, the active, unbound form, is decreased during pregnancy secondary to increased levels of its binding protein, the complement component C4b [28]. Plasminogen activator inhibitor type 1 (PAI-1) levels increase 5-fold [28].  Levels of PAI-2, produced by the placenta, increase dramatically during the third trimester [29]. Markers of thrombin generation such as prothrombin F1+2 and thrombin-antithrombin (TAT) complexes are increased [30-33]. These changes, which may not completely return to baseline until more than 8 weeks postpartum, begin with conception. So does the risk of thrombosis.

The hypercoagulability of pregnancy has likely evolved to protect women from hemorrhage at the time of miscarriage or childbirth. Indeed, in the developing world, the leading cause of maternal death is still hemorrhage, but in Western Europe and the United States, where hemorrhage is successfully treated or prevented, the leading cause of maternal death is thromboembolic disease [34].

Thrombophilia, an acquired or inherited tendency to develop thrombosis, in a pregnant woman increases the risk of thrombosis from 1.72 in 1,000 births to as high as 1 in 2 [35-37]. The utero-placental-fetal as well as the maternal circulation may be affected. Women with thrombophilia are more likely to experience placental abruption, preeclampsia, fetal growth restriction, stillbirth, and, possibly, recurrent miscarriage [38-40]. Thromboprophylaxis for pregnant women with thrombophilia has been shown to reduce maternal morbidity and mortality [41] and improve pregnancy outcome in those with the antiphospholipid syndrome [42] and those with inherited thrombophilia and a history of fetal loss [43]. Thromboprophylaxis for the treatment or prevention of VTE in pregnancy, however, is not without risk, to both the mother and the fetus, especially with agents that cross the placenta barrier.Finally, normal pregnancy is accompanied by procoagulant changes in the hemostatic system. The activities of most clotting factors increase, levels of some anticoagulants decrease, and fibrinolytic activity decreases.

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RISK FACTORS FOR THROMBOSIS IN PREGNANCY
The most important risk factor for VTE in pregnancy is a history of thrombosis. Fifteen to 25% of thromboembolic events in pregnancy are recurrent events. The risk of recurrent VTE in pregnancy is also increased 3- to 4-fold relative risk 3.5 (95% confidence interval 1.6, 7.8) [44]. In recent studies, the rate of recurrent VTE in women who did not receive anticoagulation has been reported to range from 2.4% to12.2% [45-47]. In women who did receive anticoagulation, the rate of recurrent VTE has been reported to range from 0 to 2.4% [45, 48, 49].

Besides a history of thrombosis, the most important risk factor for VTE in pregnancy is thrombophilia [5]. Other medical conditions that increase the risk of VTE are heart disease, sickle cell disease, lupus, obesity, anemia, diabetes, hypertension, and smoking. Pregnancy and delivery complications that increase the risk are multiple gestation, hyperemesis, disorders of fluid, electrolyte and acid-base balance, antepartum hemorrhage, caesarean delivery, postpartum infection, postpartum hemorrhage, and transfusion [5]. Odds ratios for these conditions were obtained from an analysis of 14,335 records from the Nationwide Inpatient Sample [5] and are summarized in Table 1. In the same analysis, older age and black race were also found as risk factors for VTE. The odds ratio (OR) for women age 35 and older was found to be 2.1 (2.0, 2.3) [5]. After controlling for age, the OR for black women was still found to be 1.4 (1.2, 1.6) [5]. Thrombophilia is present in 20% to 50% [47, 50, 51] of women who experience VTE during pregnancy and the postpartum period. Both acquired and inherited thrombophilia increase the risk. The absolute risk of VTE conferred by type of thrombophilia was systematically reviewed by Robertson et al [52] and is summarized in Table 2.

In addition, all current guidelines recognize a limited number of thrombophilias as important risk factors (Table 1). The ACOG practice bulletin specifically recommends testing for antiphospholipid antibodies (APS) and inherited thrombophilias in women with a history of thrombosis who have not had a complete evaluation of possible underlying aetiologies [2, 53]. Note that this "complete" evaluation includes testing only for APA and well-characterized inherited thrombophilias. Testing for methylene tetrahydrofolate reductase (MTHFR) mutations or homocysteine levels is not recommended [53]. According to the RCOG guideline, women with 3 or more current or persistent risk factors listed in Table 1 (other than thrombophilia or previous VTE, which carry their own recommendations) are at sufficiently increased risk for VTE that antenatal treatment with prophylactic heparin should be considered [1]. Of course, an obstetric patient may develop 1 or more risk factors for VTE during pregnancy or the postpartum period, as shown in Table 2. Of these, probably the most important are surgical procedures during pregnancy or in the first 6 weeks postpartum, including caesarean [3]

Table 1: Pre-existing risk factors for venous thromboembolism (VTE) in pregnancy

Table 2: Obstetric or new-onset risk factors for VTE in pregnancy

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