| Title: | The common VTE-protective G haplotype of F5 increases factor V-short, TFPI function, and risk of bleeding |
| Journal: | Blood Advances |
| Published: | 31 Dec 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39365993/ |
| DOI: | https://doi.org/10.1182/bloodadvances.2024014020 |
Publication 13587
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Abstract
ABSTRACT: The G haplotype is a group of co-inherited single nucleotide variants in the F5 gene that reduce venous thromboembolism (VTE) risk. Although 7% of the population is homozygous for the G haplotype (F5-G/G), the underlying mechanism of VTE protection is poorly understood. Using RNA sequencing data from 4651 blood donors in the INTERVAL study, we detected a rare excision event at the factor V (FV)-short splice sites in 5% of F5-G/Gs carriers as compared with 2.16% of homozygotes for the F5 reference sequence (F5-ref; P = .003). Highly elevated (∼10-fold) FV-short, a FV isoform that lacks most of the B-domain, has been linked with increased tissue factor inhibitor α (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 when compared with the pool of F5-refs (P = .029), but there was no difference in the total FV levels. Although 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 than F5-refs (P = .0085). Finally, in an analysis of 117 699 UK Biobank participants, we discovered that, although being protective against VTE, the G haplotype also confers an increase in bleeding episodes (P = .011). Our study provides evidence that the effect of the common G haplotype is mediated by the FV-short/TFPI pathway.</p>
11 Keywords
- Factor V
- Female
- Genetic Predisposition to Disease
- Haplotypes
- Hemorrhage
- Humans
- Lipoproteins
- Male
- Polymorphism, Single Nucleotide
- Risk Factors
- Venous Thromboembolism
28 Authors
- Matthew C. Sims
- Magdalena Gierula
- Jonathan C. Stephens
- Alex Tokolyi
- Luca Stefanucci
- Elodie Persyn
- Luanluan Sun
- Janine H. Collins
- Emma E. Davenport
- Emanuele Di Angelantonio
- Kate Downes
- Michael Inouye
- Dirk S. Paul
- Will Thomas
- Alexander Tolios
- NIHR BioResource
- Sofie Ashford
- Jyoti Khadake
- Rachel Linger
- Paul Roberts
- Hannah Stark
- Hannah Williams
- Willem H. Ouwehand
- Nicholas S. Gleadall
- James T. B. Crawley
- Adam S. Butterworth
- Mattia Frontini
- Josefin Ahnström
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