The prothrombin gene mutation G20210A is a common risk factor for thrombosis and has been reported to cause APC resistance. However, the inhibition of thrombin formation by APC not only limits fibrin formation but also stimulates fibrinolysis by reducing TAR activation. We evaluated the influence of prothrombin 620210A mutation on the anticoagulant and fibrinolytic activities of APC (1 mu g/ml). Thirty-two heterozygous carriers and 32 non carriers were studied. APC anticoagulant activity was assessed by aPTT prolongation whereas APC fibrinolytic activity was determined by a microplate clot lysis assay. APC-induced aPTT prolongation was markedly less pronounced in carriers than in non carriers. On the contrary, fibrinolysis time was shortened by APC to a comparable extent in both groups. Accordingly, prothrombin levels were strongly correlated with APC-induced aPTT prolongation but not with APC-induced shortening of lysis time. The addition of purified prothrombin to normal plasma (final concentration 150%) caused APC resistance in the clotting assay over the whole range of tested APC concentrations (0.125-1.5 mu g/ml). In the fibrinolytic assay, instead, prothrombin supplementation made the sample resistant to low but not to high concentrations of APC (&rt; 0.5 mu g/ml). Thrombin and TAF1a determination in the presence of 1 mu g/ml APC revealed that hyperprothrombinemia, although capable of enhancing thrombin generation, was unable to induce detectable TAF1a formation. It is suggested that APC resistance caused by hyperprothrombinaemia does not translate in impaired fibrinolysis, at least in the presence of high APC levels, because the increase in thrombin formation is insufficient to activate the amount of TAR required to inhibit plasminogen conversion. These data might help to better understand the relationship between thrombin formation and fibrinolysis down-regulation.
|Titolo:||Hyperprothrombinaemia-induced APC resistance : differential influence on fibrin formation and fibrinolysis|
|Autori interni:||TRIPODI, ARMANDO|
|Parole Chiave:||protein C ; prothrombin G20210A ; TAFI ; thrombin generation ; thrombosis|
|Settore Scientifico Disciplinare:||Settore MED/15 - Malattie del Sangue|
|Data di pubblicazione:||2006|
|Digital Object Identifier (DOI):||10.1160/TH05-10-0684|
|Appare nelle tipologie:||01 - Articolo su periodico|