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Blood, Vol. 93 No. 4 (February 15), 1999:
pp. 1271-1276
A Reduced Sensitivity for Activated Protein C in the Absence of
Factor V Leiden Increases the Risk of Venous Thrombosis
Marieke C.H. de Visser,
Frits R. Rosendaal, and
Rogier M. Bertina
From the Hemostasis and Thrombosis Research Center, Department of
Hematology, and the Department of Clinical Epidemiology, Leiden
University Medical Center, Leiden, The Netherlands.
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 the Leiden Thrombophilia Study (LETS), a case-control
study for venous thrombosis 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 sensitivity for APC and the risk
of thrombosis: the lower the normalized APC sensitivity 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). We adjusted for VIII:C levels, which
appeared to affect our APC resistance test. The adjusted (age, sex,
FVIII:C) odds ratio for the lowest quartile was 2.5 (95% confidence
interval, 1.5 to 4.2). So, after adjustment for factor VIII levels, a
reduced response to APC remained a risk factor. Our results show that a
reduced sensitivity for APC, not caused by the factor V Leiden
mutation, is a risk factor for venous thrombosis.
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