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 inhibition is an important antithrombotic strategy. However, the place of vitamin K antagonists among the different therapeutic strategies for preventing arterial thrombus formation is still debated. We studied the antithrombotic efficacy of the vitamin K antagonist fluindione in a human ex vivo model of arterial thrombosis and determined whether aspirin enhances fluindione efficacy. Ten healthy male volunteers were randomly assigned to receive fluindione, alone or in combination with aspirin (325 mg/d). Fluindione was given at increasing doses to give a stable international normalized ratio (INR) between 1.5 and 2.0 and between 2.1 and 3.0. We induced arterial thrombus formation ex vivo by exposing collagen- or tissue factor (TF)-coated coverslips 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 formation 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 combination with aspirin inhibited TF-induced thrombus formation in a comparable manner. Collagen-induced thrombus formation was not reduced in subjects treated by fluindione. It was reduced by 50% to 60% in those treated with fluindione plus aspirin, regardless of the level of anticoagulation (P<0.05). Thus, the effectiveness of fluindione for preventing arterial thrombosis is dependent on the nature of the thrombogenic trigger. Fluindione is very effective in preventing TF- but not collagen-triggered thrombus formation. Aspirin enhances the antithrombotic effectiveness of fluindione, because combined treatment interrupts both TF- and collagen-induced thrombus formation.
Bossavy
J P
JP
Laboratoire de Recherche sur l'Hémostase et la Thrombose, Pavillon Lefèbvre, CHU Purpan, Toulouse France.
Sakariassen
K S
KS
Thalamas
C
C
Boneu
B
B
Cadroy
Y
Y
D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000627:therapeutic use; D001241:Aspirin / Q000627:therapeutic use; D003094:Collagen; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D010630:Phenindione / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013925:Thromboplastin; D013927:Thrombosis / Q000139:chemically induced / Q000517:prevention & control*; D014812:Vitamin K / Q000037:antagonists & inhibitors*
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D014812:Vitamin K; D010630:Phenindione; D003094:Collagen; D013925:Thromboplastin; C017673:fluindione; D001241:Aspirin