Oral contraceptives and venous thrombosis: different sensitivities to activated protein C in women using second- and third-generation oral contraceptives

Authors

  • J. Rosing,

    1. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht; Department of Haematology, University Hospital, Maastricht University, Maastricht; and General Practitioners Offices at Vaals and Valkenburg, The Netherlands
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  • G. Tans,

    1. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht; Department of Haematology, University Hospital, Maastricht University, Maastricht; and General Practitioners Offices at Vaals and Valkenburg, The Netherlands
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  • G. A. F. Nicolaes,

    1. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht; Department of Haematology, University Hospital, Maastricht University, Maastricht; and General Practitioners Offices at Vaals and Valkenburg, The Netherlands
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  • M. C. L. G. D. Thomassen,

    1. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht; Department of Haematology, University Hospital, Maastricht University, Maastricht; and General Practitioners Offices at Vaals and Valkenburg, The Netherlands
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  • R. Van Oerle,

    1. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht; Department of Haematology, University Hospital, Maastricht University, Maastricht; and General Practitioners Offices at Vaals and Valkenburg, The Netherlands
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  • P. M. E. N. Van DerPloeg,

    1. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht; Department of Haematology, University Hospital, Maastricht University, Maastricht; and General Practitioners Offices at Vaals and Valkenburg, The Netherlands
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  • P. Heijnen,

    1. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht; Department of Haematology, University Hospital, Maastricht University, Maastricht; and General Practitioners Offices at Vaals and Valkenburg, The Netherlands
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  • K. Hamulyak,

    1. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht; Department of Haematology, University Hospital, Maastricht University, Maastricht; and General Practitioners Offices at Vaals and Valkenburg, The Netherlands
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  • H. C. Hemker

    1. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht; Department of Haematology, University Hospital, Maastricht University, Maastricht; and General Practitioners Offices at Vaals and Valkenburg, The Netherlands
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Dr J. Rosing Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.

Abstract

Epidemiological studies have shown that women who use third-generation oral contraceptives (OC) containing desogestrel, gestodene or norgestimate have a higher risk of venous thrombosis than women who use second-generation OC containing levonorgestrel. It is also known that a mutation in factor V (factor VLeiden), which results in resistance to activated protein C (APC) and which is the most common cause of hereditary thrombophilia, potentiates the prothrombotic effect of OC.

Effects of APC on thrombin generation in the plasma of women using OC were compared to the response to APC in non-OC users and in individuals that were hetero-zygous or homozygous for factor VLeiden. The response towards APC was evaluated on basis of the ratio (APC-sr) of the time integrals of thrombin formation determined in the presence and absence of APC.

Compared with women not using OC, women who used OC exhibited a significantly decreased sensitivity to APC (P < 0.001), independent of the kind of OC used. Women who used third-generation monophasic OC were significantly less sensitive to APC than women using second-generation OC (P < 0.001) and had APC-sr that did not significantly differ from heterozygous female carriers of factor VLeiden who did not use OC. Women who were heterozygous for factor VLeiden and used OC had APC-sr in the range of homozygous carriers of factor VLeiden. Two women who started OC therapy had significantly elevated APC-sr within 3 d.

Acquired APC resistance may explain the epidemiol-ogical observation of increased risk for venous thrombosis in OC users, especially in women using third-generation OC.

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