Key result
Genetically lower F2 levels linked to ~56% lower VTE risk without increasing bleeding.
Why the study?
Anticoagulant therapy carries a persistent and cumulative bleeding risk during prolonged treatment, creating a need for new, safer anticoagulant targets.
Do genetically predicted reductions in coagulation factors F2 and F11 reduce VTE and stroke risk without increasing bleeding risk?
Observational (n=891,384)
Mendelian randomization
Yes
Do genetically predicted reductions in coagulation factors F2 and F11 reduce VTE and stroke risk without increasing bleeding risk?
Effect estimate: OR 0.44 (95% CI 0.38-0.51)
p-value: p=2.6E-28
Genetic evidence suggests that targeting coagulation factors II and XI may safely prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.
Supports F2/F11 inhibition for VTE and cardioembolic stroke prevention without bleeding risk; extends MR evidence to guide targeted trials.
Background Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed. Methods We performed two-sample Mendelian randomization (MR) and genetic colocalization to prioritize anticoagulant targets with the strongest efficacy (venous thromboembolism [VTE] prevention) and safety (low bleeding risk) profiles. We leveraged three large-scale plasma protein datasets (deCODE, n=35,559; Fenland n = 10,708; ARIC n= 7,213) and one liver gene expression dataset (n =246) to evaluate evidence for a causal effect of 26 coagulation cascade plasma proteins on VTE from a new genome-wide association meta-analysis of 44,232 VTE cases and 847,152 controls (from the UK Biobank, FinnGen and Estonian Biobank), stroke subtypes (from UK Biobank and International Stroke Genetics consortium 73,652 cases and 1,234,808 controls), bleeding outcomes (FinnGen, n=309,154) and over one million parental lifespans (UK Biobank and LifeGen consortium). Results Genetically predicted reductions in F2 blood levels were associated with lower VTE risk (OR [odds ratio] per 1 standard deviation [SD] lower F2=0.44, 95% CI=0.38-0.51, p=2.6E-28) and cardioembolic stroke risk (OR = 0.55, 95% CI=0.39-0.76, p=4.2e-04) but not with bleeding (OR = 1.13, 95% CI=0.93-1.36, p=2.2e-01). Genetically predicted F11 reduction were associated with lower risk of VTE (OR = 0.61, 95% CI=0.58-0.64, p=4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI=0.69-0.86, p=4.1e-06), but not with bleeding (OR = 1.01, 95% CI=0.95-1.08, p=7.5e-01) (Figure 3). These MR associations were concordant across the three blood protein datasets and the hepatic gene expression dataset as well as three different MR and colocalization analyses. Conclusion These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.
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Gagnon et al. (2023) conducted an observational in Venous thromboembolism, stroke, and bleeding (n=891,384). Genetically predicted reduction in F2 blood levels vs. Baseline genetic levels was evaluated on Venous thromboembolism (VTE) risk (OR 0.44, 95% CI 0.38-0.51, p=2.6E-28). Genetically predicted reductions in F2 blood levels were associated with a 56% lower risk of venous thromboembolism (OR 0.44) and lower cardioembolic stroke risk without increasing bleeding risk.
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