Impact of double heterozygosity for Factor V Leiden and Prothrombin G20210A on the thrombotic phenotype

• Published in: Thrombosis research 2021-04, Vol.200, p.121-127
• Main Authors: Luxembourg, Beate, Henke, Franziska, Kirsch-Altena, Anette, Sachs, Ulrich, Kemkes-Matthes, Bettina
• Format: Article
• Language: English
• Subjects: Compound heterozygous; Double heterozygous; Factor V - genetics; Factor V Leiden; Factor V Leiden paradox; Female; FIIG20210A; Humans; Phenotype; Prothrombin - genetics; Retrospective Studies; Risk Factors; Thrombophilia - genetics; Thrombosis; Venous thrombosis
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/j.thromres.2021.01.022

Because of the rarity of double heterozygosity for Factor V Leiden (FVL) and Prothrombin (FII) G20210A, little is known about the thrombotic phenotype in double heterozygotes. In a retrospective cohort study of patients referred for a thrombophilia work-up, we investigated whether double heterozygotes (n = 138) exhibit a more severe thrombotic phenotype compared with single FVL or FIIG20210A heterozygotes, single FVL homozygotes, or wildtype carriers. The risk of venous thromboembolism (VTE) was higher for female but not male double heterozygotes compared with single heterozygotes (FVL: 2.51, 95%CI 1.55–4.08, FIIG20210A: 1.75, 95%CI 1.14–2.68) and wildtype carriers (HR 2.53, 95%CI 1.58–4.05) but not compared with FVL homozygotes (HR 1.31, 95%CI 0.94–1.83). Female double heterozygotes developed VTE nearly a decade earlier than wildtype carriers and FVL heterozygotes (mean 44.2 vs. 52.6 and 52.2 years), most often in association with oral contraceptives. Spontaneous VTE and arterial thromboembolic events were not more frequent in double heterozygotes compared with the other genotype groups. Deep vein thrombosis (DVT) of the lower limb was the predominant VTE location in double heterozygotes, atypical vein thrombosis was rare. A phenomenon that has been described as the FVL paradox, a higher proportion of isolated DVT than pulmonary embolism, was also found for double heterozygotes. The thrombotic phenotype in double heterozygotes resembles the appearance of the thrombotic phenotype in FVL carriers but the thrombotic risk is aggravated by women-specific risk factors. •Spontaneous VTE is not more frequent in double heterozygotes than in single heterozygotes or FVL homozygotes.•Female but not male double heterozygotes have a higher risk of VTE than single heterozygotes.•The Factor V Leiden paradox also applies to double heterozygotes.•Arterial thromboembolism is not more common in double heterozygotes than in single heterozygotes or FVL homozygotes.