The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies

Abstract

Factor V Leiden (FVL) and prothrombin G20210A mutation (PTM) are the two most common genetic polymorphisms known to predispose to a first episode of venous thromboembolism (VTE). However, whether these thrombophilic abnormalities are also risk factors for recurrent VTE is unclear. We conducted a systematic review of prospective studies to assess the risk of recurrent VTE associated with heterozygous carriage of each of these mutations. All randomized controlled trials and prospective cohort studies that reported the incidence of recurrent VTE in patients with and without FVL and PTM after discontinuation of anticoagulant treatment were collected and analyzed. The risk ratios (RR) and their 95% confidence intervals (CI) for recurrent VTE were calculated in heterozygous carriers of FVL or PTM and compared to those of noncarriers. Eleven studies fulfilled the inclusion criteria. Recurrent VTE occurred in 114 out of 557 heterozygous carriers of FVL (20.5%) as compared to 382 out of 2,646 non-carriers (14.4%); and in 38 out of 212 heterozygous carriers of PTM (17.9%) compared to 428 of 2,996 non-carriers (14.3%). The RR of VTE recurrence conferred by the heterozygous carriage of FVL and PTM was 1.39 (95% CI, range 1.15 to 1.67) and 1.20 (range 0.89 to 1.61), respectively, using the Mantel-Haenszel fixed-effects model; 1.45 (1.13 to 1.85) and 1.36 (1.02 to 1.82), respectively, using the Der Simonian and Laird random effects method. In symptomatic patients with VTE, heterozygous carriage of FVL is clearly associated with a definitely increased risk of recurrent thromboembolism. The risk is lower with PTM and is difficult to interpret since it varies according to the assessment method used.Key words: venous thromboembolism, thrombophilia, anticoagulation, factor V Leiden, prothrombin G20210A. ollowing the discovery of factor V Leiden (FVL) and prothrombin G20210A mutation (PTM) in the first half of the 1990s, numerous case-control, cross-sectional, and family studies have provided the convincing evidence that heterozygosity for either mutation is associated with a significantly increased risk of venous thromboembolism (VTE).1-3 This risk is higher in homozygous carriers and in carriers of double heterozygosity. While it is widely acknowledged that these mutations confer an increased risk of thrombosis, it is controversial whether patients who are heterozygous carriers of either mutation and develop a thrombotic episode have an increased risk of recurrent events in comparison with non-carriers.1-3 As a consequence, it is still not known whether detection of these abnormalities, which are highly prevalent in western countries, has the potential to identify a subgroup of patients who might benefit from the adoption of individually adjusted prevention strategies following their first thrombotic episode.4,5 Available literature dealing with this issue includes both prospective and retrospective investigations. By definition, prospective studies are methodologically stronger, as they imply the formation of an appropriate inc...

Pathophysiology of Post-Thrombotic Syndrome: The Effect of Recurrent Venous Thrombosis and Inherited Thrombophilia

“…The risk of recurrence is higher among patients with permanent risk factors including inherited prothrombotic abnormalities than among patients who have suffered trauma or underwent surgery [32]. Factor V-Leiden, prothrombin G 20210 A mutation, and MTHFR mutation leading to hyperhomocysteinemia are the most commonly observed prothrombotic genetic abnormalities associated with venous recurrence [41,42]. Ipsilateral recurrence has been strongly associated with PTS [28,33,39,43].…”

Thrombophilia States and Markers of Coagulation Activation in the Prediction of Pediatric Venous Thromboembolic Outcomes: A Comparative Analysis with Respect to Adult Evidence

“…36 By comparison, early retrospective data with variable followup duration in a small number of FV Leiden homozygotes suggested a more substantial increase in risk of recurrent VTE relative to heterozygotes and non-carriers, 32 and was subsequently confirmed by prospective findings of an approximately 2-fold increase in risk for recurrent VTE at 2 years (cumulative probability of recurrence at that time of 20% among homozygotes as compared to less than 10% in non-carriers). 37 Increased procoagulant factor activity The factor II (i.e., prothrombin) G20210A polymorphism (PT G20210A), 38 found in approximately 2% of Caucasians, is associated with elevated prothrombin levels and appears to confer a 2-fold increase in risk of first-episode VTE based upon epidemiologic studies.…”

“…38,39 Currently, the risk of recurrent VTE among patients heterozygous or homozygous for PT G20210A polymorphism remains unclear; one prospective study found no increase in risk for recurrent VTE among prothrombin polymorphism heterozygotes as compared to non-carrier controls, and was not able to assess the recurrence risk for homozygotes due to their absence in the study population. 36 While one recent metaanalysis found no increase in risk of recurrent VTE among PT G20210A heterozygotes, 37 another suggested a mild increase in recurrence risk of 1.4-fold. 40 Elevated plasma factor VIII (FVIII) activity has been defined in adult studies as a common thrombophilia state (found in approximately one-third of VTE patients) that in many instances appears to reflect constitutively increased expression not due to acute phase response, with a tendency to be familial.…”

“…The risk of recurrent VTE among patients heterozygous for FV Leiden remains unclear [30][31][32][33][34][35][36] but may be modestly increased according to a recent meta-analysis. 36 By comparison, early retrospective data with variable followup duration in a small number of FV Leiden homozygotes suggested a more substantial increase in risk of recurrent VTE relative to heterozygotes and non-carriers, 32 and was subsequently confirmed by prospective findings of an approximately 2-fold increase in risk for recurrent VTE at 2 years (cumulative probability of recurrence at that time of 20% among homozygotes as compared to less than 10% in non-carriers).…”

Inactivation of Thrombomodulin by Ionizing Radiation in a Cell-Free System: Possible Implications for Radiation Responses in Vascular Endothelium

“…On the other hand, there is significant human data suggesting that a dysfunction of the TM-thrombin-protein C system is considerably more sensitive to perturbation. For example, studies of mutations in the TM-thrombin-protein C system show that heterozygous carriers of mutations in TM (30), heterozygous carriers of mutations in protein C (31), and individuals heterozygous for factor V Leiden (32), where activated factor V is resistant to inhibition by activated protein C, all exhibit increased thrombophilia. Therefore, a decrease in TM cofactor function of the magnitude reported here may well be biologically significant, particularly in a situation with fractionated radiation where accumulation of damage may occur.…”