title: Importance of platelets in experimental venous thrombosis in the rat.
abstract: Venous thrombosis was induced by ligature of the inferior vena cava in rats whose blood was made hypercoagulable by intravenous (IV) administration of tissue thromboplastin. From a dose-response showing that the administration of increasing doses of tissue thromboplastin resulted in a subsequent progressive increase of thrombus weight, two concentrations of tissue thromboplastin were chosen: a high dose (550 microL/kg, IV) where thrombus formation was optimal and a concentration (7 microL/kg, IV) where tissue thromboplastin-hypercoagulability was intermediate. In both experimental conditions, leukopenia provoked by a myelotoxic drug did not influence the development of venous thrombosis. However, after thrombocytopenia induced by an antiplatelet antiserum, a dramatic decrease in thrombus formation was observed in animals that had been pre-challenged with the lower dose of tissue thromboplastin, whereas decrease in platelet count did not affect venous thrombosis under high thrombogenic challenge. When administered orally 2 hours before thrombosis induction, the ticlopidine analogue clopidogrel showed dose-dependent inhibition of thrombus formation in animals that were pre-challenged with a low dose of tissue thromboplastin (ED50 = 7.9 +/- 1.5 mg/kg, orally) but remained ineffective against high tissue thromboplastin-induced venous thrombosis. We further determined the effect of heparin and hirudin, and showed that both of these drugs exhibited a more potent antithrombotic activity after injection of the lower dose of tissue thromboplastin than after injection of a high dose of tissue thromboplastin. Therefore, using our model of stasis and hypercoagulability, platelet activation played a major role in the development of venous thrombosis when the thrombogenitic stimulus was mild.
authors.affiliation: Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
authors.forename: J M
authors.initials: JM
authors.lastname: Herbert
authors.forename: A
authors.initials: A
authors.lastname: Bernat
authors.forename: J P
authors.initials: JP
authors.lastname: Maffrand
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000502:physiology*; D000077144:Clopidogrel; D004195:Disease Models, Animal; D006493:Heparin / Q000494:pharmacology; D006629:Hirudins / Q000494:pharmacology; D007970:Leukopenia / Q000097:blood; D008297:Male; D008466:Mechlorethamine / Q000494:pharmacology; D010314:Partial Thromboplastin Time; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013921:Thrombocytopenia / Q000097:blood* / Q000150:complications; D013924:Thrombophlebitis / Q000097:blood*; D013925:Thromboplastin / Q000008:administration & dosage; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D006629:Hirudins; D010975:Platelet Aggregation Inhibitors; D008466:Mechlorethamine; D006493:Heparin; D013925:Thromboplastin; D000077144:Clopidogrel; D013988:Ticlopidine