The risk of major bleeding in patients with factor V Leiden or prothrombin G20210A gene mutation while on extended anticoagulant treatment for venous thromboembolism.

BACKGROUND: Thrombophilia predisposes to venous thromboembolism (VTE) because of acquired or hereditary factors. Among them, it has been suggested that gene mutations of the factor V Leiden (FVL) or prothrombin G20210A mutation (PGM) might reduce the risk of bleeding, but little data exist for patients treated using anticoagulants. OBJECTIVES: To assess whether thrombophilia is protective against bleeding. METHODS: This multicentre, multinational, prospective cohort study evaluated adults receiving long-term anticoagulants after a VTE event. We analyzed the incidence of major bleeding as the primary outcome, according to the genotype for FVL and PGM (wild-type and heterozygous/homozygous carriers). RESULTS: Of 2260 patients with genotype testing, during a median follow-up of 3 years, 106 patients experienced a major bleeding event (17 intracranial and 7 fatal). Among 439 carriers of FVL, 19 experienced major bleeding and there were no differences between any mutation vs wild-type (hazard ratio [HR], 0.89 [0.53-1.49]; p = .66). The comparison of major bleeding events between the 158 patients with any-PGM mutation (heterozygous or homozygous) vs wild-type also showed a nonstatistically significant difference with HR of 0.53 (0.19-1.43), p = .21. However, multivariate analysis demonstrated that major bleeds or clinically relevant nonmajor bleeding were statistically less likely for patients with either FVL and/or PGM compared with patients with both wild-type factor V and prothrombin genes (HR, 0.73; 95% CI = 0.55-0.97; p = .03). CONCLUSION: This study demonstrates that thrombophilia, defined as the presence of either FVL or the prothrombin G20210A mutation, is related with a lower rate of major/clinically relevant nonmajor bleeding while on anticoagulants in the extended treatment for VTE.

Predicting major bleeding during extended anticoagulation for unprovoked or weakly provoked venous thromboembolism.

No clinical prediction model has been specifically developed or validated to identify patients with unprovoked venous thromboembolism (VTE) who are at high risk of major bleeding during extended anticoagulation. In a prospective multinational cohort study of patients with unprovoked VTE receiving extended anticoagulation after completing ≥3 months of initial treatment, we derived a new clinical prediction model using a multivariable Cox regression model based on 22 prespecified candidate predictors for the primary outcome of major bleeding. This model was then compared with modified versions of 5 existing clinical scores. A total of 118 major bleeding events occurred in 2516 patients (annual risk, 1.7%; 95% confidence interval [CI], 1.4-2.1). The incidences of major bleeding events per 100 person-years in high-risk and non-high-risk patients, respectively, were 3.9 (95% CI, 3.0-5.1) and 1.1 (0.8-1.4) using the newly derived creatinine, hemoglobin, age, and use of antiplatelet agent (CHAP) model; 3.3 (2.6-4.1) and 1.0 (0.7-1.3) using modified ACCP score, 5.3 (0.6-19.2) and 1.7 (1.4-2.0) using modified RIETE score, 3.1 (2.3-3.9) and 1.1 (0.9-1.5) using modified VTE-BLEED score, 5.2 (3.3-7.8) and 1.5 (1.2-1.8) using modified HAS-BLED score, and 4.8 (1.3-12.4) and 1.7 (1.4-2.0) using modified outpatient bleeding index score. Modified versions of the ACCP, VTE-BLEED, and HAS-BLED scores help identify patients with unprovoked VTE who are at high risk of major bleeding and should be considered for discontinuation of anticoagulation after 3 to 6 months of initial treatment. The CHAP model may further improve estimation of bleeding risk by using continuous predictor variables, but external validation is required before its implementation in clinical practice.