A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis

Activated protein C (APC) resistance caused by the factor V Leiden mutation is associated with an increased risk of venous thrombosis. We investigated whether a reduced response to APC, not due to the factor V point mutation, is also a risk factor for venous thrombosis. For this analysis, we used th e Leiden Thrombophilia Study (LETS), a case-control study for venous thromb osis including 474 patients with a first deep-vein thrombosis and 474 age- and sex-matched controls. All carriers of the factor V Leiden mutation were excluded. A dose-response relationship was observed between the sensitivit y for APC and the risk of thrombosis: the lower the normalized APC sensitiv ity ratio, the higher the associated risk. The risk for the lowest quartile of normalized APC-SR (<0.92). which included 16.5% of the healthy controls , compared with the highest quartile (normalized APC-SR > 1.05) was greater than fourfold increased (OR = 4.4; 95% confidence interval, 2.9 to 6.6), W e adjusted for VIII:C levels, which appeared to affect our APC resistance t est. The adjusted (age, sex, FVIII:C) odds ratio for the lowest quartile wa s 2.5 (95% confidence interval, 1.5 to 4.2). So, after adjustment for facto r VIII levels, a reduced response to APC remained a risk factor. Our result s show that a reduced sensitivity for APC, not caused by the factor V Leide n mutation, is a risk factor for venous thrombosis. (C) 1999 by The America n Society of Hematology.