Reduced Response to Activated Protein C Is Associated with Increased Risk for Cerebrovascular Disease

Background: Resistance to activated protein C (APC), which results from various factors, including a mutation in the gene for coagulant factor V, has been associated with increased risk for venous thrombosis. However, its relation to arterial disease is still not well defined. Objective: To investigate the association of both response to APC and the factor V Leiden mutation with arterial disease. Design: Population-based case-control study. Setting: A district of Rotterdam, the Netherlands. Participants: 115 patients with a history of myocardial infarction; 112 patients with a history of stroke, transient ischemic attack, or both; and 222 age-matched controls without arterial disease chosen from among 7983 persons in the Rotterdam Study cohort. Patients using anticoagulant drugs were excluded. Measurements: Response to APC was determined in double-centrifuged platelet-poor plasma. Patients were genotyped for the Arg 506 to GIn mutation in the gene for coagulant factor V. Results: The prevalence of cerebrovascular disease increased gradually and corresponded to a decreasing response to APC (odds ratio per 1-unit decrease of response to APC, 1.43 [95% Cl, 1.12 to 1.81], adjusted for age and sex). Adjustment for the factor V mutation did not change the findings. We found no association between response to APC and myocardial infarction or between factor V mutation and cerebrovascular disease or myocardial infarction. Conclusions: Low response to APC is associated with an increased risk for cerebrovascular disease but not with an increased risk for myocardial infarction, independent of the factor V Leiden mutation. The association between the factor V Leiden mutation and cerebrovascular disease or myocardial infarction remains to be determined.