The common, VTE-protective, G haplotype of F5 increases factor V-short, TFPI function, and risk of bleeding.

The G haplotype is a group of co-inherited single nucleotide variants in the F5 gene that reduce venous thromboembolism (VTE) risk. Even though seven percent of the population is homozygous for the G haplotype (F5-G/G), the underlying mechanism of VTE protection is poorly understood. Using RNA-seq data from 4,651 blood donors in the INTERVAL study we detected a rare excision event at the FV-short splice sites in 5% of F5-G/Gs as compared with 2.16% of homozygotes for the F5 reference sequence (F5-ref) (p=0.003). Highly elevated (~10-fold) FV-short, an FV isoform lacking most of the B-domain, has been linked with increased tissue factor inhibitor alpha (TFPIα) levels in rare hemorrhagic diathesis including East Texas Bleeding Disorder. To ascertain whether the enhanced FV-short splicing seen in F5-G/G INTERVAL participants translated to increased plasma FV-short levels we analyzed plasma samples from 7 F5-G/G and 13 F5-ref individuals in a recall-by-genotype study. A ~2.2-fold higher amount of FV-short was found in a plasma pool from F5-G/G participants as compared with F5-refs (p=0.029), but no difference in total FV levels. Whilst no significant difference in TFPI levels were found, F5-G/Gs showed a ~1.4-fold TFPI-dependent increase in lag time to thrombin generation compared to F5-refs (p=0.0085). Finally, in an analysis of 117,699 UK Biobank participants we discovered that, while being protective against VTE, the G haplotype also confers an increase in bleeding episodes (p=0.011). Our study provides evidence that the effect of the common G haplotype is mediated by the FV-short/TFPI pathway.

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