Associations between plasma levels of coagulation factors VIII and IX and incident cardiovascular disease and mortality: systematic review and meta-analysis

Background:
Associations of plasma levels of coagulation factors VIII (FVIII) and IX (FIX) with incident cardiovascular disease (CVD) and mortality remain uncertain.

Objective:
To clarify associations of FVIII and FIX with CVD and mortality in a meta-analysis in general population prospective studies.

Methods:
We conducted a systematic literature review up to 19 July 2024, of PubMed and Cochrane databases, reporting estimates (and measures of variability) of associations of plasma levels of FVIII or FIX with risks of incident CVD. Pooled risk ratios (RRs), adjusted for age, sex, systolic blood pressure, total cholesterol, smoking and diabetes, were estimated in a random effects meta-analysis for effects of FVIII and FIX levels on incident CVD, and CVD and total mortality.

Results:
In 7 studies (8888 cases in 32,123 participants) for FVIII and 4 studies (2273 cases in 6951 participants) for FIX the pooled RRs (95% confidence interval) for incident CVD per 1 SD higher were 1.12 (1.09, 1.14) and 1.05 (1.00, 1.12), respectively. Corresponding CVD mortality and total mortality RRs for FVIII were 1.17 (1.07, 1.28) and 1.16 (1.12, 1.19), and for FIX;1.14 (1.06, 1.22) and 1.13 (1.07, 1.18), respectively. Comparing factor levels above versus below the 90th percentile, pooled RRs were 1.34 (1.25, 1.44) for FVIII; and 1.02 (0.85, 1.22) for FIX.

Conclusions:
Risks of CVD, CVD mortality and total mortality increase across higher population distributions of FVIII levels. Risks of CVD mortality and total mortality also increase across FIX levels, but no evidence of an independent effect for incident CVD risk.