Importance of platelets in experimental venous thrombosis in the rat.
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.
Herbert
J M
JM
Haemobiology Research Department, Sanofi Recherche, Toulouse, France.
Bernat
A
A
Maffrand
J P
JP
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
D006629:Hirudins; D010975:Platelet Aggregation Inhibitors; D008466:Mechlorethamine; D006493:Heparin; D013925:Thromboplastin; D000077144:Clopidogrel; D013988:Ticlopidine