Combined effect of high factor VIII levels and high mean platelet volume on the risk of future incident venous thromboembolism.

BACKGROUND: High factor VIII (FVIII) levels and large platelets, as reflected by a high mean platelet volume (MPV), are separately associated with increased risk of venous thromboembolism (VTE). Whether the combination of high FVIII levels and large platelets has a supra-additive effect on VTE risk is unknown. OBJECTIVES: We aimed to investigate the joint effect of high FVIII levels and large platelets, as reflected by high MPV, on the risk of future incident VTE. METHODS: A population-based nested case-control study with 365 incident VTE cases and 710 controls was derived from the Tromsø study. FVIII antigen levels and MPV were measured in blood samples drawn at baseline. Odds ratios with 95% CIs were estimated across FVIII tertiles (<85%, 85%-108%, and ≥108%) and within predefined MPV strata (<8.5, 8.5-9.5, and ≥9.5 fL). RESULTS: VTE risk increased linearly across FVIII tertiles (Ptrend < .001) in models adjusted for age, sex, body mass index, and C-reactive protein. In the combined analysis, participants with FVIII levels in the highest tertile and an MPV of ≥9.5 fL (ie, joint exposure) had an odds ratio for VTE of 2.71 (95% CI, 1.44-5.11) compared with those with FVIII levels in the lowest tertile and an MPV of <8.5 fL (reference). In the joint exposure group, 52% (95% CI, 17%-88%) of VTEs were attributable to the biological interaction between FVIII and MPV. CONCLUSION: Our results suggest that large platelets, as reflected by high MPV, might play a role in the mechanism by which high FVIII level increases the risk of incident VTE.