Before discussing the diagnosis and management of thrombophilias in pregnancy, it is important to briefly review pertinent aspects of the coagulation pathway and physiologic changes that occur in pregnancy.

When vessel injury occurs, the repair process begins with the attachment of von Willebrand factor (VWF) to exposed subendothelium collagen. Platelets bind to VWF and release granule proteins, activating various signaling pathways, which encourage platelet aggregation and activation. Exposed platelet receptor sites form high-affinity bonds to nearby fibrinogen molecules, creating the framework of a platelet-fibrin plug. This structure is stabilized further when bound by other synergistic molecules such as thrombin and thromboxane A2 (TXA2). Activated factor VII (FVIIa) combines with tissue factor (TF) exposed on cell membranes. The TF-FVIIa complex activates factor X, which binds to factor Va forming a complex converting prothrombin to thrombin. Of note, factor Xa is only active when present at the site of vascular injury. As it diffuses away, it is inactivated by antithrombin in order to prevent further coagulation activation in remote vasculature.¹⁴ Thrombin goes on to convert fibrinogen to fibrin, as well as activate additional platelets as described before. An amplified positive feedback loop is maintained between these platelet and clotting factor activation pathways.

Avoidance of thrombosis and disseminated intravascular coagulation requires a synergistic balance between the coagulation cascade and local anticoagulation molecules, including antithrombin, protein C, and protein S. Although thrombin plays a critical role in initiating the coagulation reaction, it also functions as an anticoagulation molecule. Thrombin binds endothelial cells downstream from the initial clotting site and undergoes a conformational change allowing it to activate protein C. Once protein C is activated, its anticoagulant properties are reliant on protein S. The protein S and C complex inactivates factor Va and VIIIa, thus decreasing local coagulation effects.

Normal physiologic changes of pregnancy result in a prothrombotic state by affecting all aspects of Virchow triad (hypercoagulability, venous stasis, and tissue damage). Hormonal alterations create a hypercoagulable environment by increasing levels of VWF and clotting factors, decreasing anticoagulant properties of protein C, protein S, and antithrombin, all while increasing
plasminogen activator inhibitors 1 and 2, resulting in a decrease in fibrinolysis and platelet activation. Venous stasis occurs throughout pregnancy from progesterone-mediated vasodilation and peaks in the late third trimester.¹⁵ In addition, the gravid uterus applies pressure to the inferior vena cava and pelvic veins causing decreased flow in the lower extremities. Vessel injury from venous distention, surgery, trauma, and venipuncture can occur anytime but are especially prevalent around the time of delivery. Physiologic changes alter the coagulation pathway in favor of clotting with the purpose of limiting delivery-related blood loss, but it comes at the cost of predisposing women to VTE. Pregnancy-associated risk factors, such as obesity, immobilization, and the postsurgical state, can further increase risk of thromboembolic events peripartum.¹⁶

Screening for inherited thrombophilias is recommended when results will influence management decisions. Testing is not necessary when treatment is indicated for previously identified risk factors.¹⁷ All women with a personal history of VTE have exhibited prothrombotic tendencies. Clinical situations may be such that management would not be altered by a positive or negative thrombophilia result.

An evaluation for thrombophilia in pregnancy can be considered in the following clinical situations:

It is important to note that the same thrombophilic disorder can have variable penetrance among family members.¹⁹ As such, family history may not be as helpful as individual history in determining the risk of thrombosis.

An inherited thrombophilia evaluation includes testing for factor V Leiden (FVL) mutation, prothrombin G20210A mutation, antithrombin deficiency, protein C deficiency, and protein S deficiency (Table 2.1). It is best to postpone testing until 6 weeks after a VTE event and when the woman is not pregnant or on any anticoagulation or hormonal therapy.

During pregnancy, testing is reliable for FVL mutation, prothrombin G20210A mutation, protein C deficiency, and antithrombin deficiency. Screening for FVL can be completed using a “second-generation” functional assay for activated protein C resistance or via DNA analysis. Prothrombin G20210A testing is completed by DNA analysis. Testing for protein C and antithrombin deficiency is completed via activity level assays, with levels <65% and <60% being diagnostic, respectively.²⁰

Women should not be evaluated for protein S deficiency during pregnancy as plasma levels drop significantly. If it is absolutely necessary to screen for protein S deficiency in pregnancy, activity assay levels less than 30% and 24% in the second and third trimesters, respectively, are suggestive of deficiency.²⁰ Outside of pregnancy, an activity level less than 55% is consistent with a diagnosis of protein S deficiency.²⁰

Antithrombin, protein C, and protein S levels are all reduced during an acute thrombotic event or when on anticoagulation therapy. Antithrombin concentration is affected by heparin,²¹ and as protein C and S are vitamin K dependent, their concentrations are altered by warfarin.²²

Experts typically classify thrombophilias as low or high risk based predominantly on the likelihood of the patient developing a VTE. The exact threshold
that should be utilized to classify a thrombophilia as high risk is a matter of debate. Yet, from a practical standpoint, the classification of thrombophilias into low and high risk for VTE is important as it often impacts clinical management. For example, women with low-risk thrombophilias may undergo clinical surveillance with no pharmacologic prophylaxis or may qualify for only postpartum pharmacologic prophylaxis. In contrast, women with high-risk thrombophilias may require antepartum prophylaxis and increased doses of pharmacologic prophylaxis (eg, intermediate or adjusted dose), especially in the setting of prior VTE or other risk factors.

Recommendations are limited by the quality of evidence, which is highly reliant on case-controlled studies. Decisions for anticoagulation use should always be individualized and influenced by multiple risk factors, such as a personal history of VTE, a family history of VTE, severity of thrombophilia, as well as factors such as obesity and cesarean delivery.

In 2016, experts formed the Anticoagulation Forum, where guidelines from the American College of Obstetricians and Gynecologists (ACOG), Society of Obstetricians and Gynaecologists of Canada (SOGC), Royal College of Obstetricians and Gynaecologists (RCOG), and American College of Chest Physicians (ACCP) were reviewed in an effort to clarify the current clinical recommendations. A consensus was reached that pharmacologic prophylaxis should be recommended for a patient with a VTE risk of 3% or greater antepartum and postpartum.²³

Factor V is a procoagulant protein that is inactivated by the activated form of protein C (APC). In those with FVL mutation, a single amino acid substitution causes factor V to become resistant to inactivation by APC, leading to increased thrombin generation downstream. FVL is the most common inherited thrombophilia, accounting for approximately 50% of all individuals with a thrombophilia.²⁵ Its prevalence is highest among Caucasians, with the heterozygote form occurring in 3% to 8%.²⁶ Among individuals with their first VTE episode, the prevalence of factor V mutation is 10% to 20%.²⁷ In pregnancy, this low-risk thrombophilia accounts for approximately 40% of VTE episodes; however, in women with no history of VTE (identified by family history), the annual VTE risk in pregnancy is only 0.2% to 2.1%.^28,29 Croles and colleagues conducted a meta-analysis and found women heterozygous for FVL without personal or family history had an absolute relative risk of pregnancy-associated VTE of 1.1% (95% confidence interval [CI], 0.3-1.9).³⁰ There was a 0.4% absolute risk in the antepartum period and 2.0% absolute risk postpartum.³⁰ These findings were upheld by another meta-analysis completed by Bates et al who found a similar absolute VTE risk of 1.2% in asymptomatic pregnant women.²³

Prothrombin is a procoagulant protein that becomes activated into thrombin by the factor Xa/Va complex. Those with PGM (G220210A) have undergone a point mutation on the prothrombin gene that causes increased rates of translation. This single nucleotide switch thus results in increased levels of circulating prothrombin in these individuals.

The prevalence of heterozygosity for PGM in Caucasian populations is 1% to 3%.²⁷ Among women presenting with their first VTE episode, the prevalence is 5% to 6%.²⁷ In women with no personal history of VTE, the annual VTE risk in pregnancy is 0.5%.²⁸ The overall absolute risk of women with no prior or family history of VTE and who are heterozygous for PGM was found to be 0.9%.³⁰ This finding was confirmed by a separate meta-analysis that found the absolute risk to be 1.0%.²³