Abstract
BACKGROUND: A high level of plasma coagulation factor (F)VIII is an established and likely causal risk factor for venous thromboembolism (VTE). Procoagulant phospholipids (PPLs) facilitate FVIII activity in coagulation. OBJECTIVES: To assess the association between plasma levels of FVIII and risk of future VTE according to PPL clotting time (PPL(CT)), an inverse surrogate measure of plasma PPL activity. METHODS: A population-based nested case-control study comprising 278 incident VTE cases and 593 randomly selected age- and sex-matched controls were derived from the Tromsø cohort. Exposures were determined from data collected at the cohort baseline. Logistic regression was used to estimate odds ratios (ORs) with 95% CIs for VTE across tertiles of FVIII and PPL(CT). RESULTS: High (tertile 3) vs low (tertile 1) FVIII antigen levels resulted in an age- and sex-adjusted OR of 1.53 (95% CI, 0.78-3.00) in those with high PPL(CT) (low PPL activity), while the corresponding OR for those with low PPL(CT) (high PPL activity) was 1.88 (95% CI, 0.96-3.66). In the biological interaction analysis, participants with both high FVIII and PPL activity had an OR of 1.86 (95% CI, 0.97-3.57) compared with those with low FVIII and PPL activity. In the joint exposure group, 10% (95% CI, -55% to 75%) of VTEs could be attributable to the interaction between FVIII and PPL activity. Results remained similar after further adjustment for body mass index, C-reactive protein, arterial cardiovascular disease, and cancer. CONCLUSION: The effect of high FVIII levels on VTE risk was particularly augmented in those with high PPL activity, suggesting that the effect of FVIII on VTE risk might be partially dependent on PPL activity.