Antithrombotic efficacy of the vitamin K antagonist fluindione in a human ex vivo model of arterial thrombosis - Effect of anticoagulation level and combination therapy with aspirin

Thrombin is a main mediator of arterial thrombus formation, and its inhibit ion is an important antithrombotic strategy. However, the place of vitamin K antagonists among the different therapeutic strategies for preventing art erial thrombus formation is still debated. We studied the antithrombotic ef ficacy of the vitamin K antagonist fluindione in a human ex vivo model of a rterial thrombosis and determined whether aspirin enhances fluindione effic acy. Ten healthy male volunteers were randomly assigned to receive fluindio ne, alone or in combination with aspirin (325 mg/d). Fluindione was given a t increasing doses to give a stable international normalized ratio (INR) be tween 1.5 and 2.0 and between 2.1 and 3.0, We induced arterial thrombus for mation ex vivo by exposing collagen- or tissue factor (TF)-coated coverslip s in a parallel-plate perfusion chamber to native blood for 3 minutes at an arterial wall shear rate of 2600 s(-1) Platelet and fibrin deposition were measured by immunoenzymatic methods. Fluindione inhibited thrombus formati on on TF-coated coverslips in a dose-dependent manner by 50% and 80% at INR 1.5 to 2.0 and INR 2.1 to 3.0, respectively (P<0.05), Fluindione in combin ation with aspirin inhibited TF-induced thrombus formation in a comparable manner. Collagen-induced thrombus formation was not reduced in subjects tre ated by fluindione. It was reduced by 50% to 50% in those treated with flui ndione plus aspirin, regardless of the level of anticoagulation (P<0.05). T hus, the effectiveness of fluindione for preventing arterial thrombosis is dependent on the nature of the thrombogenic trigger. Fluindione is very eff ective in preventing TF- but not collagen-triggered thrombus formation. Asp irin enhances the antithrombotic effectiveness of fluindione, because combi ned treatment interrupts both TF- and collagen-induced thrombus formation.