Summary

Elevated plasma prothrombin levels, due to the prothrombin20210 G/A mutation or to acquired causes, are a risk factor forvenous thrombosis,partly because of prothrombin-mediated inhibitionof the protein C anticoagulant pathway and consequentactivated protein C (APC) resistance.We determined the effectof plasma prothrombin concentration on the APC resistancephenotype and evaluated the role of protein S levels as a modulatingvariable.The effect of prothrombin and protein S levels onAPC resistance was investigated in reconstituted plasma systemsand in a population of healthy individuals using both theaPTT-based and the thrombin generation-based APC resistancetests. In reconstituted plasma, APC resistance increased at increasingprothrombin concentration in both assays. EnhancedAPC resistance was caused by the effect of prothrombin on the clotting time in the absence of APC in the aPTT-based test, andon thrombin formation in the presence of APC in the thrombingeneration-based test. In plasma from healthy individuals prothrombinlevels were highly correlated to protein S levels. Sinceprothrombin and protein S had opposite effects on the APC resistancephenotype, the prothrombin/protein S ratio was abetter predictor of APC resistance than the levels of either proteinalone. Prothrombin titrations in plasmas containing differentamounts of protein S confirmed that protein S levels modulatethe ability of prothrombin to induce APC resistance.Thesefindings suggest that carriers of the prothrombin 20210 G/Amutation, who have a high prothrombin/protein S ratio, may experiencea higher thrombosis risk than non-carriers with comparableprothrombin levels.