Introduction: Factor V Leiden mutation and prothrombin G20210A mutation are the most common causes of an inherited thrombophilia and together account for 50 to 60 percent of diagnoses. Traditionally, patients have been treated with oral warfarin therapy or injectable low molecular weight heparin (LMWH), which requires frequent laboratory monitoring or self-injections. The difficulty with administration and monitoring of traditional therapy has made direct oral anticoagulants (DOACs) increasingly favored for treatment of VTE. However, the efficacy and bleeding complication of DOAC use in inherited thrombophilia has not been well studied.

Methods: We designed a retrospective analysis of patients with Factor V Leiden mutation and prothrombin G20210A mutation at the University of Virginia who were treated with a DOAC (rivaroxaban, apixaban, edoxaban, or dabigatran) for treatment of VTE or atrial fibrillation from January 28th, 2011 to May 30th, 2017. Adult patients with presence of either homozygous or heterozygous mutation for either Factor V Leiden mutation or prothrombin mutation were included. All patients were required to be treated for at least 48 hours with a documented follow-up of adverse events. Medical charts were reviewed for age, gender, weight, presence of Factor V Leiden mutation and/or prothrombin G20210A mutation, DOAC dose, and frequency, bleeding events, and recurrent thrombotic events. Our primary outcomes were efficacy defined as development of a recurrent VTE and safety defined as occurrence of any bleeding event. Efficacy was compared to the post-hoc sub-group analysis that was conducted on the data from the RE-MEDY trial, in which VTE/VTE-related deaths were observed to be 1.5% with patients taking dabigatran compared to 2.3% with patients taking warfarin (p=0.2277) (Skelley, et al. J Throm Thrombolysis, 2017). Major and minor events were defined per International Society of Thrombosis and Hemostasis (ISTH) anticoagulation committee guidelines.

Results: Fifty eight patients were eligible for analysis. The median age was 52.7 ± 16.7 years with 39 (67.2%) females. Baseline patient characteristics, type of thrombophilia, and indication for DOAC therapy are represented in Table 1. Median length of time on a DOAC was 24 months.

Four patients developed a recurrent VTE however on further analysis, 3 patients were found to be non-compliant with DOAC therapy. Excluding the noncompliant patients, the rate of a recurrent VTE was 1.7% (Table 2).

Nine (15.5%) patients suffered a bleeding event, of which 4 were major and 5 were minor (Table 2). Of the 4 major bleeding events, 3 were gastrointestinal (GI). One patient bled due to arterio-venous malformations, the second patient developed a bleed at the esophagectomy site, and the third patient had biliary drainage from ischemic liver disease post liver transplant. One patient suffered an intracranial hemorrhage; this patient was concurrently taking aspirin and clopidogrel while on therapeutic apixaban. The minor bleeding events included epistaxis (n=1), hemoptysis (n=1) and GI (n=3). Hemoptysis was discovered simultaneously with the diagnosis of lung cancer. Three of the patients with minor bleeding events were taking ASA, including one who was also taking dual antiplatelet therapy with clopidogrel.

Conclusion: DOACs have been shown to have similar efficacy and safety compared to warfarin in many patient populations. However, there are limited studies evaluating use of DOACs in patients with inherited thrombophilia. Substantial evidence supporting widespread DOAC use in these patients is lacking. Our study confirmed the efficacy of DOACs in this patient population with a thrombosis event of only 1.7% which is favorable compared to the warfarin historical control rate of 2.3% (Skelley, et al. J Throm Thrombolysis, 2017). There was a higher than expected rate of bleeding complications, however many patients were on dual antiplatelet therapy or had other risk factors for bleeding. It would be imprudent to attribute these bleeding events solely to DOAC use. Though this is the only study of its kind, it is limited by small numbers and retrospective design. Further studies are needed to evaluate the use of DOACs compared to warfarin and LMWH. We plan to conduct further analysis utilizing a control group of inherited thrombophilia patients on warfarin compared to those on DOACs.


No relevant conflicts of interest to declare.

Author notes


Asterisk with author names denotes non-ASH members.