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

Johanna G. van der Bom, MD; Michiel L. Bots, MD, PhD; Frits Haverkate, PhD; P. Eline Slagboom, PhD; Piet Meijer, BSc; Paulus T.V.M. de Jong, MD, PhD; Albert Hofman, MD, PhD; Diederick E. Grobbee, MD, PhD; and Cornelis Kluft, PhD
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From the Erasmus University Medical School, Rotterdam, the Netherlands; TNO Gaubius Institute for Cardiovascular Research, Leiden, the Netherlands; and the Netherlands Ophthalmic Research Institute, Amsterdam, the Netherlands. Acknowledgments: The authors thank the participants in the Rotterdam Study; P.J. Koudstaal, MD, PhD (University Hospital, Rotterdam), for his contribution in establishing the diagnosis of transient ischemic attacks; and all field workers and laboratory technicians in the Ommoord Research Centre and Bas Heijmans from the Gaubius Laboratory for their enthusiasm and skillful contributions to data collection. Grant Support: The Rotterdam Study is supported in part by the NESTOR program for geriatric research (Ministry of Health and Ministry of Education), the Netherlands Heart Foundation, the Netherlands Organisation for Scientific Research, the Rotterdam Medical Research Foundation, and the Municipality of Rotterdam. Dr. van der Bom is supported by grant 92.398 from the Netherlands Heart Foundation. Requests for Reprints: Diederick E. Grobbee, MD, PhD, Department of Epidemiology and Biostatistics, Erasmus University Medical School, PO Box 1738, 3000 DR Rotterdam, the Netherlands. Current Author Addresses: Drs. van der Bom, Bots, Hofman, and Grobbee: Department of Epidemiology and Biostatistics, Erasmus University Medical School, PO Box 1738, 3000 DR Rotterdam, the Netherlands.

Copyright ©2004 by the American College of Physicians

Ann Intern Med. 1996;125(4):265-269. doi:10.7326/0003-4819-125-4-199608150-00002
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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 Gln 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% CI, 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.





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