Summary. Background: High body mass index (BMI) is associated with an increased risk of venous thrombosis (VT). Clotting factor VIII levels are increased in obese subjects, possibly because of a chronic inflammatory state, which increases activated protein C (APC) resistance. The APC resistance in FV Leiden carriers could be aggravated and further worsened by high FVIII levels in blood group non-O carriers. We hypothesized that an association exists between BMI and APC resistance, and that this is amplified by the presence of FV Leiden and/or blood group non-O.
Methods: We used the Leiden Thrombophilia Study (LETS) to determine whether an association exists between BMI and APC resistance, and whether the combination of high BMI and APC resistance increases the risk of VT. In a pooled analysis of LETS and a Norwegian case-cohort study (TROL), we verified whether FV Leiden modified the risk of the occurrence of VT with increasing BMI, and whether this risk was further increased by blood group non-O.
Results: APC resistance increased linearly with increasing BMI, partly because of a concurrent rise in FVIII. A BMI in the median or upper tertile was associated with a 1.9-fold (95% confidence interval [CI] 1.0–2.5) and 2.2-fold (95% CI 1.4–3.4) increased risk as compared with the lowest tertile. Both relative risks decreased slightly after FVIII and APC resistance adjustments. The effect of BMI on VT risk was enhanced two-fold to 10-fold in FV Leiden or blood group non-O carriers.
Conclusions: The increased risk of VT in individuals with high BMI is partly mediated by FVIII-related APC resistance. This risk is more pronounced when other causes of increased APC resistance are also present.