Inherited Thrombophilia

Factor V Leiden

During normal hemostasis, protein C is activated by the thrombin–thrombomodulin complex to counterbalance the thrombotic role of thrombin. Activated protein C (APC) exerts its anticoagulant effects by inactivating factors Va and VIIIa, factors with significant regulatory roles in the coagulation cascade. ⁹ Protein C resistance, detected by a decreased response to exogenous APC, was initially identified in families with thrombophilia. ¹⁰ Although various forms of APC resistance, both inherited and acquired, have been identified, FVL accounts for the majority of cases. ^11,12 Factor Va is inactivated by APC once bound to the cleavage site at position 506 of factor V (R506Q). FVL results from a point mutation at the cleavage site due to a substitution of glutamine for arginine, leaving factor Va resistant to inactivation by APC. ¹² First described in 1994, FVL is the most common inherited thrombophilia. ^5,9 The incidence of FVL (heterozygosity) is as high as 5% of all caucasians but extremely rare (0.05%) among African and Asian descendants. ^9,13,14 It can be found in 20% of individuals with VTE and as many as 40% with VTE and clinical features suggesting a possible inheritable link (age less than 50, family history of VTE, recurrent VTE, or an idiopathic VTE). ^9,14 The prevalence of homozygosity in the general population is rare (0.02%) and found only in 3% of those with VTE. ¹ The relative risk of VTE is increased by 3- to 7-fold in those heterozygous and as much as 80-fold in those homozygous. ^{14 –16} The absolute risk in heterozygous carriers however remains low (0.1%-0.6% per year), with many individuals remaining asymptomatic until in the presence of additional risk factors for VTE. ^13,17,18

Prothrombin Mutation

Prothrombin mutation, also referred to as prothrombin G20210A, prothrombin variant, or factor II mutation, results from a point mutation at the 3′-untranslated region of the prothrombin gene leading to increased prothrombin levels and thus activation of thrombin. ⁶ First described in 1996, prothrombin mutation has been identified in 3% of caucasians, 0.06% of African and Asian descendants, and 7% to 18% of individuals with VTE. ^6,9 Heterozygosity for prothrombin mutation increases the relative risk of VTE by 3-fold, while estimates for homozygosity are not yet available. ⁶ As with FVL, the absolute risk of VTE with prothrombin mutation is low and often occurs in the presence of other predisposing factors. ¹³

Deficiencies in Natural Anticoagulants (AT, Protein C, and Protein S)

The first inherited thrombophilia to be identified were deficiencies in the natural anticoagulants. ⁴ In contrast to single-point mutations with FVL and prothrombin mutation, over 100 mutations have been identified with these disorders. ⁹ Deficiencies in the natural anticoagulants are rare, found in approximately 0.5% of the general population and 2% to 5% of individuals with VTE. ^2,9 Although usually thought to be genetic, there are certain conditions that can result in acquired deficiencies. ⁹

AT is a glycoprotein synthesized in the liver. Once bound to exogenous heparin or naturally occurring heparin-like substances, it is responsible for the inactivation of factors IIa and Xa as well as factors IXa, XIa, and XIIa. ¹⁹ Protein C and S are vitamin K-dependent glycoproteins synthesized in the liver. Protein C is activated by the thrombin–thrombomodulin complex and in the presence of free protein S, proteolytically inactivates both factor Va and factor VIIIa. ⁹

AT deficiency can be quantitative (type I) or qualitative (type II). In type I, both AT activity and antigen levels are decreased. In type II, AT activity is decreased; however, antigen levels may remain normal. Type II deficiency is further subdivided into type IIa or type IIb based on the location of the mutation and the assay used in the diagnosis, with type IIb being more common. ²⁰ Overall, more patients with AT deficiency have type II (88% vs 12% for type I). However, among those with VTE, type I predominates (60% vs 40% for type II). Identification of the specific subtype may have clinical utility as the risk of VTE in type II is lower when compared to other subtypes. ²¹ The overwhelming majority of patients are heterozygous as homozygosity usually results in death in utero. ²⁰

Deficiencies in protein C may also be quantitative (type I) or qualitative (type II). In protein S deficiency, there is a qualitative deficiency (type II) along with 2 types of quantitative deficiencies (type I and type III). In type I, both total and free levels are reduced as opposed to type III where only free levels are affected. In contrast to AT deficiency, there does not appear to be any clinical utility in differentiating between the specific types of these disorders. ²²

In AT deficiency, the risk of VTE has been estimated to be increased by as much as 50–fold, with 50% of individuals experiencing an event by age 50. ^{20 –23} Type IIb is the exception, with an incidence of only 6%. ² The lifetime risk of VTE in protein C and protein S deficiencies is increased between 4- to 15-fold and 1- to 10-fold, respectively. ^2,23,24

Elevated Clotting Factors

Serum elevations in certain clotting factors have been associated with an increased risk of VTE. ^{3,25 –28} Factors VIII, IX, and XI function within the intrinsic pathway of the clotting cascade. When activated, factors VIII and XI result in activation of factor IX. Activated factor IX and factor VIII, also known as the tenase complex, stimulate the activity of factor X, which then activates thrombin. Increased thrombin generation activates a negative feedback mechanism through which fibrinolysis is inhibited. The increase in thrombin generation coupled with an inhibition of fibrinolysis leads to an increase in thrombus formation. ²⁸

Sustained elevations in factor VIII (defined as serum concentrations ≥ 150 IU/dL) are found in 11% of the general population and 25% of cases with VTE. ²⁷ These individuals have been found to have a relative risk of VTE 5 times that of those with levels <100 IU/dL. ²⁷ Although factor VIII and von Willebrand factor (vWF) circulate in the plasma as a complex, vWF appears to be responsible for elevated factor VIII levels in only 50% of incidences. ²⁵ Elevations consistently found among first-degree relatives suggest a hereditary link. ²⁶ A genetic polymorphism in the low-density lipoprotein receptor-related protein 1 (LRP1 663 C>T) was found to be associated with elevated levels of factor VIII in heterozygous patients. These patients were found to have a 3-fold increased the risk of VTE regardless of other known risk factors. ²⁹

Genetic variations in the factor XI gene have also been identified. Elevations are found in approximately 10% of the general population and determined to be an independent risk factor for VTE. ^28,30 The risk is increased by 2-fold in individuals with plasma levels of factor XI above the 90th percentile. ²⁸

Plasma levels of factor IX above the 90th percentile (>129 units/dL) have been associated with a 2- to 3-fold increased risk of VTE; however, data delineating factor IX as an independent risk factor for VTE are conflicting as are determinations of a genetic link. ^{30 –32}

Hyperhomocysteinemia

Impairment in the conversion of methionine to cysteine leads to increased levels of the intermediate product homocysteine. Hyperhomocysteinemia, which may be inherited or acquired, is defined as a serum homocysteine concentration of >15 μmol/L. It has been found in 5% of the general population, 7% of cases with VTE, and is estimated to increase the risk of VTE by 1.5- to 2-fold. ^1,33 Mutations in methylenetetrahydrofolate reductase (MTHFR) or cystathionine B-synthase are thought to be responsible for inherited forms of hyperhomocysteinemia while acquired deficiencies in folate, vitamin B₁₂, and vitamin B₆ have also been postulated as underlying causes. ^1,33 The mechanism by which hyperhomocysteinemia increases the risk of thrombosis is unclear but appears to be multifactorial. Postulated mechanisms include activation of factor V, inhibition of protein C, impairment of endothelial cell function, and others. ¹⁹

Anticoagulation Therapy

In nonpregnant patients with an acute VTE, the presence of an underlying inherited thrombophilia does not alter the choice or intensity of anticoagulation therapy. ^{8,34 –37} An exception to this may be with AT deficiency. These individuals may theoretically require larger doses of unfractionated heparin (UFH) and/or warrant monitoring of anti-Xa levels with low-molecular weight heparin (LMWH) use. This concern, however, has not been demonstrated clinically. ²⁰

Although the mainstay for VTE treatment has been initial parenteral anticoagulation transitioned to oral warfarin, the development of target-specific oral anticoagulants (TSOACs) is challenging current practice. ⁸ Rivaroxaban, an oral anti-Xa inhibitor, is the only TSOAC currently approved for the treatment of VTE in the United States. In the EINSTEIN-DVT study, rivaroxaban was found to be noninferior to standard therapy (enoxaparin–warfarin) with no statistical difference detected in regard to incidence of major bleeding. Of the 1731 subjects in the rivaroxaban group and 1718 subjects in the standard therapy group, there were 6.2% and 6.8%, respectively, with a known thrombophilia. ³⁸ Within this subgroup, recurrent VTE occurred in 1 patient receiving rivaroxaban and 3 patients receiving standard therapy. ³⁹ In the continued treatment arm of this trial, the incidence of known thrombophilia was 8.1% for subjects continued on rivaroxaban as well as those receiving placebo after initial therapy for 6 to 12 months; however, there was no subgroup analysis for outcomes based on thrombophilia status. ³⁸ In the EINSTEIN-PE trial, 5.7% of the 2419 subjects in the rivaroxaban group and 5% of the 2413 subjects receiving standard therapy (enoxaparin-warfarin) were included with a known thrombophilia. ⁴⁰ During the treatment period, 2 patients in each group with a known thrombophilia experienced a recurrent VTE. ⁴¹

Apixaban, an oral anti-Xa inhibitor currently approved for stroke prophylaxis in patients with nonvalvular atrial fibrillation, has been studied for the treatment of VTE. ^42,43 In the AMPLIFY trial, apixaban was found to be noninferior to standard therapy (enoxaparin–warfarin) for VTE recurrence and superior to standard therapy regarding occurrence of major bleeding (0.6% vs 1.8%, 95% confidence interval [CI] 0.17-0.55). The incidence of known thrombophilia was lower in this trial (2.8% in the apixaban group and 2.2% in the standard therapy group) and there was no subgroup analysis regarding thrombophilia status. ⁴² There was a similar incidence (∼4%) of known thrombophilia in each arm of the apixaban extension study although again subgroup analysis for thrombophilia status was not available. ⁴³

Dabigatran, a direct thrombin inhibitor, although not currently approved for VTE treatment in the United States, has been evaluated for VTE treatment. ^44,45 Thrombophilia status was not addressed in the RECOVER trial in which dabigatran was found to be noninferior to standard therapy (enoxaparin–warfarin). ⁴⁴ However, in the REMEDY extension study, 18% of subjects in both the dabigatran and the standard therapy groups were reported to have a known thrombophilia. ⁴⁵

The overall number of individuals with an identified thrombophilia in the TSOAC trials was small; however, it should be noted that routine screening was not conducted. ^{38 –45} With as many as 50% of patients with VTE testing positive for an underlying thrombophilia in other trials when screened, it is likely the number of individuals with thrombophilia was higher and well represented in the above-mentioned trials. ^1,7 Therefore, although direct evidence to support the use of TSOACs in patients with thrombophilia is lacking, there is no evidence to suggest inherited thrombophilia requires a varying intensity of anticoagulation other than that provided by standard therapy. The decision on whether or not to use these agents in patients with VTE should always include a discussion of the risks and benefits. In individuals with known thrombophilia, the discussion should include the lack of direct evidence with known thrombophilia until additional data are available.

The optimal duration of therapy after an initial VTE is uncertain. The benefit of reducing VTE recurrence must be balanced with the hemorrhagic risk associated with continued therapy. ⁸ Because the benefit of anticoagulation is lost once therapy is discontinued, consideration for an extended duration past the initial 3 months of therapy is suggested in individuals at a substantial risk of recurrence in the absence of a high risk of bleeding. ^{8,46 –48} Although the presence of a thrombophilia suggests an increased risk that would warrant extended or indefinite therapy, this has not been demonstrated definitively in clinical trials. ^{49 –57} For the most common thrombophilia (heterozygosity for FVL and prothrombin mutation), trials have reported either a small increase in risk of recurrence or have failed to find an increased risk. ^{36,49,54 –56,58,59} Although the risk of recurrence appears to be increased in individuals homozygous for either FVL or prothrombin mutation or with more than one thrombophilia and potentially with deficiencies in the natural anticoagulants, the rarity of these conditions questions the utility of routine screening in order to guide decisions related to treatment duration. ^{36,49,54,55,57,60}

The most recent guidelines published by the American College of Chest Physicians for the prevention and treatment of thromboembolic events do not consider the presence of inherited thrombophilia as a major determinant in determining duration of therapy but rather location (distal vs proximal) and cause (provoked vs unprovoked) of the event. ⁸ Prandoni et al followed 1626 individuals for up to 10 years after an initial VTE. The rates of recurrence were significantly higher after initial idiopathic events than that provoked; 15% versus 6.6% at 1 year, 40.8% versus 16.1% at 5 years, and 52.6% and 22.5% at 10 years. ⁶¹ In an earlier trial by Prandoni et al, the risk of recurrence was reduced in VTE provoked by surgery (hazard ratio [HR] 0.36; 95% CI 0.21-0.62) or secondary to recent trauma or fracture (HR 0.51; 95% CI 0.32-0.87). ⁵⁷ Similar results were reported in a trial by Hansson et al for the risk of recurrence in VTE provoked by surgery (relative risk [RR] 0.27; 95% CI 0.13-0.55). ⁶² Boutitie et al also reported a lower risk of recurrence after initial events that were provoked as compared to unprovoked (HR 0.55, 95% CI 0.41-0.74). ⁶³ In addition, the latter 2 trials found location to be an independent risk of recurrence. ^62,63 Hanson et al reported an increased risk with proximal events (RR 2.4, 95% CI 1.48-3.88) while Boutitie et al reported a lower incidence with distal events (HR 0.49, 95% CI 0.34-0.71). ^62,63 The current guidelines therefore suggest consideration for extended therapy in all patients with an unprovoked, proximal event due to the increased risk of recurrence in these individuals, regardless of thrombophilia status. ⁸ A patient's individual risk of bleeding as well as personal preference must be taken into consideration when determining the most appropriate duration of therapy. The patient should always be a part of the decision on whether or not to continue therapy. It is also important to continually reassess the risks and benefits, as this may change over time. ⁸

Vitamin Replacement in Hyperhomocysteinemia

Although vitamin B supplementation may reduce the levels of plasma homocysteine by as much as 30% in individuals with hyperhomocysteinemia, this has failed to show a reduction in VTE. ^64,65 In the Heart Outcomes Prevention Evaluation-2 (HOPE-2) trial, 5522 patients with either cardiovascular disease or diabetes and at least 1 additional risk factor for vascular disease were randomized to receive either supplementation (folic acid 2.5 mg, pyridoxine 50 mg, and cyanocobalamin 1 mg daily) or placebo. Patients were followed for 5 years after which time there were no differences found in the incidence of VTE between the groups. There were also no benefits of treatment seen in patients with baseline homocysteine levels in the highest quartile or >13.8 μmol/L. ⁶⁴ The Vitamins and Thrombosis (VITRO) study investigated the incidence of recurrent thrombosis in 701 individuals without other known factors for VTE based on homocysteine levels either above or below the 75th percentile. Patients were randomized to receive vitamin B supplementation (folic acid 5 mg daily, pyridoxine 50 mg daily, and cyanocobalamin 0.4 mg) daily or placebo. After 2.5 years of follow-up, the incidence of symptomatic VTE did not differ significantly between the groups despite significant decreases in homocysteine levels with supplementation. ⁶⁵ Although hyperhomocysteinemia appears to be a biomarker for increased risk of VTE, treatment with vitamin supplementation is not recommended at this time.