Experimental thrombosis on a collagen coated arterioarterial shunt in rats: a pharmacological model to study antithrombotic agents inhibiting thrombin formation and platelet deposition.
A rat thrombosis model was developed to assess the efficacity of antithrombotic drugs. It had the following characteristics: controlled hemodynamic and rheological conditions corresponding to arterial flow, a collagen coated surface as a relevant thrombogenic stimulus, a method of measurement allowing dynamic monitoring of thrombus formation and the possibility to assess the thrombus structure. A shunt composed of polyethylene and silicone catheters, including in the middle of the shunt a collagen coated glass capillary, was inserted between the two primitive carotids of the rat. The duration of patency of the shunt was recorded using a thermic probe fixed on its central part. In this model, the patency of the shunt was 539 +/- 55 s. Platelet and fibrinogen-fibrin accumulation in successive one centimeter segments along the shunt were measured using 111In labeled platelets and 125I labeled fibrinogen. Platelet accumulation occurred on the collagen coated surface and at the junctions between the different components of the shunt, where flow was disturbed. The effects of four antithrombotic agents were measured: aspirin, clopidogrel, heparin and r-hirudin. Clopidogrel, heparin and hirudin significantly prolonged patency duration of the shunt, whereas aspirin was inactive. Aspirin did not reduce platelet or fibrinogen-fibrin accumulation on the collagen coated surface. Platelet accumulation on the collagen surface was significantly lower in the clopidogrel group (50 mg/kg) than in the group treated with heparin (500 U/kg), demonstrating the direct antiplatelet effect of clopidogrel. Hirudin at doses giving similar values of APTT as heparin (500 U/kg) prolonged the occlusion time to over 2 h while the heparin occlusion time was only 20 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Freund
M
M
INSERM U.311, Biologie et Pharmacologie des Interactions du Sang avec les Vaisseaux et les Biomatériaux, Centre Régional de Transfusion Sanguine, Strasbourg, France.
Mantz
F
F
Nicolini
P
P
Gachet
C
C
Mulvihill
J
J
Meyer
L
L
Beretz
A
A
Cazenave
J P
JP
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology / Q000627:therapeutic use*; D001159:Arterio-Arterial Fistula; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use; D002341:Carotid Artery Thrombosis / Q000188:drug therapy / Q000517:prevention & control*; D000077144:Clopidogrel; D003094:Collagen; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005337:Fibrin / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005898:Glass; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use; D024764:Hirudin Therapy; D006629:Hirudins / Q000494:pharmacology; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011095:Polyethylenes; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012039:Regional Blood Flow; D012828:Silicones; D013917:Thrombin / Q000096:biosynthesis*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006629:Hirudins; D010975:Platelet Aggregation Inhibitors; D011095:Polyethylenes; D011994:Recombinant Proteins; D012828:Silicones; D005337:Fibrin; D005340:Fibrinogen; D006493:Heparin; D003094:Collagen; D000077144:Clopidogrel; D013917:Thrombin; D013988:Ticlopidine; D001241:Aspirin