Determinants of the APTT- and ETP-based APC sensitivity tests

Authors

  • M. C. H. DE VISSER,

    1. Department of Hematology, Hemostasis and Thrombosis Research Center, Leiden University Medical Center, Leiden, the Netherlands
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  • A. VAN HYLCKAMA VLIEG,

    1. Department of Hematology, Hemostasis and Thrombosis Research Center, Leiden University Medical Center, Leiden, the Netherlands
    2. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
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  • G. TANS,

    1. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
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  • J. ROSING,

    1. Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, the Netherlands
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  • A. E. A. DAHM,

    1. Hematological Research Laboratory, Department of Hematology, Ullevål University Hospital, Oslo, Norway
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  • P. M. SANDSET,

    1. Hematological Research Laboratory, Department of Hematology, Ullevål University Hospital, Oslo, Norway
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  • F. R. ROSENDAAL,

    1. Department of Hematology, Hemostasis and Thrombosis Research Center, Leiden University Medical Center, Leiden, the Netherlands
    2. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
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  • R. M. BERTINA

    1. Department of Hematology, Hemostasis and Thrombosis Research Center, Leiden University Medical Center, Leiden, the Netherlands
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M. C. H. de Visser, Department of Hematology, Hemostasis and Thrombosis Research Center, Leiden University Medical Center, C2-R, PO Box 9600, 2300 RC Leiden, the Netherlands.
Tel.: +31 71 5262267; fax: +31 71 5266755; e-mail: M.C.H.de_Visser@lumc.nl

Abstract

Summary. Background: A reduced sensitivity for activated protein C (APC) is associated with an increased risk of venous thrombosis even in the absence of the factor (F)V Leiden mutation. This risk has been demonstrated with two APC sensitivity tests, which quantify the effects of APC on the activated partial thromboplastin time (APTT) and the endogenous thrombin potential (ETP), respectively. Objectives: We examined determinants of both APC sensitivity tests in the control group of the Leiden Thrombophilia Study (LETS). Methods: Multiple linear regression analysis was performed with normalized APC-SRAPTT or APC-SRETP as dependent variable and putative determinants [levels of FII, FV, FVII, FVIII, FIX, FX, FXI, FXII, FXIII A subunit, FXIII B subunit, protein S total, protein S free, protein C, tissue factor pathway inhibitor (TFPI) total, TFPI free, antithrombin and fibrinogen] as independent variables. Results and conclusions: The major determinant of the APTT-based test was FVIII level, followed by FII level. The ETP-based test was influenced most by free protein S and free TFPI levels. In both tests FXa formation plays a major role, as the effect of FVIII and TFPI on the tests seems to be executed via FXa. The ETP-based test was also strongly influenced by oral contraceptive use, even when we adjusted for all the clotting factors listed above. This means that the effect of oral contraceptives on the ETP-based test is not fully explained by the changes of coagulation factor levels investigated in this study, and that the molecular basis of acquired APC resistance during use of oral contraceptives remains to be established.

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