Factor V Leiden paradox in Factor V Leiden homozygotes – a retrospective cohort study

Introduction In heterozygous carriers of the Factor V Leiden (FVL) mutation, the risk of pulmonary embolism (PE) is lower than the risk of deep vein thrombosis (DVT), a phenomenon that has been described as the FVL paradox. Whether FVL homozygotes exhibit the FVL paradox is a matter of debate. It has been hypothesized that the second FVL allele counteracts the FVL paradox. To evaluate the FVL paradox in FVL homozygotes, we investigated the odds to suffer from PE for FVL homozygotes compared with FVL wildtype carriers and FVL heterozygotes.

Method In a retrospective cohort study, we recruited 100 consecutive FVL homozygotes with venous thromboembolism who visited the Departments of Haemostasis of the University Hospital Gießen & Marburg GmbH and the University Hospital Frankfurt a.M. between 2007 and 2020. Age- and sex-matched FV wildtype carriers (n=100) and FVL heterozygotes (n=100) were enclosed as controls. Logistic regression analysis was applied to calculate the Odds Ratio (OR) for PE.

Results The cohort encompassed more females (60%) than men and the median age of the participants was about 46 years. FVL homozygotes suffered significantly less often from PE compared with FV wildtype carriers (16% vs. 44%, p<0,001) and FVL heterozygotes (16% vs. 39%, p<0,001). By contrast, isolated DVT was more common in FVL homozygotes than in wildtype carriers (84% vs. 56%, p<0,001) and heterozygotes (84% vs. 61%, p<0,001). The odds to suffer from PE was 76% lower for FVL homozygotes compared with wildtype carriers (Odds Ratio, OR, 0,24, 95% CI 0,13-0,47, p<0,001) and 70% lower than for FVL heterozygotes (OR 0,30, 95% CI 0,15-0,58, p<0,001). In stratified analyses, we found no effect modification for the DVT localisation (proximal vs. distal leg vein thrombosis), a high BMI (≥30 vs. <30), and hormone-associated (oral contraceptives, pregnancy, puerperium) vs. non-hormone-associated VTE in women. Proximal DVT was not significantly more common in FVL homozygotes than in FV wildtype carriers (48,9% vs. 43,5%, OR 1,24, 95% CI 0,66-2,34, p=0,502) and FVL heterozygotes (48,9% vs. 63,3%, OR 0,55, 95% CI 0,30-1,03, p=0,062).

Conclusion FVL homozygotes suffer more often from isolated DVT but less often from PE compared with FVL wildtype carriers and FVL heterozygotes. FVL homozygotes exhibit the FVL paradox and the paradox is even more pronounced in FVL homozygotes than in heterozygotes.

Publication History

Article published online:
20 February 2023