A non-occlusive model of arterial thrombus formation in the rat and its modification by inhibitors of platelet function, or thrombin activity.
A technically simple model of arterial thrombosis in the rat, induced by a crush injury to the dorsal aorta is described. The mechanical injury to the artery caused deep medial injury and the formation of a platelet-rich thrombus with associated fibrin formation which was assessed both radiometrically and morphometrically. No significant inclusion of erythrocytes was noted in the thrombus. Administration of the platelet inhibitors aspirin, BM 13505 (a thromboxane receptor antagonist) or CGS 12970 (a thromboxane synthase inhibitor) reduced the extent of platelet deposition on the injured vessel, but no decrease in fibrin(ogen) was observed. In contrast, infusion of prostacyclin resulted in reductions in both these components of the thrombus. In studies involving inhibition of thrombin activity, the direct thrombin inhibitor CGP 39393 (recombinant desulphatohirudin) inhibited both the platelet and fibrin(ogen) deposition. The indirect thrombin inhibitors were less effective; unfractionated heparin and low-molecular-weight heparin inhibited both platelet and fibrin(ogen) deposition but only at doses which rendered the blood uncoagulable, as evaluated by the activated partial thromboplastin time. Dermatan sulphate only inhibited platelet deposition. The results suggest that thrombin plays a key role in the initiation of thrombus formation in this experimental model. The agonist prostaglandins (PGG2, PGH2, and TXA2) would appear to have a supporting role in the platelet deposition onto the thrombotic surface but do not have a role to play with respect to fibrin(ogen) deposition.
Butler
K D
KD
Thrombosis Research Unit, Ciba-Geigy Pharmaceuticals, Horsham, West Sussex, UK.
Ambler
J
J
Dolan
S
S
Giddings
J
J
Talbot
M D
MD
Wallis
R B
RB
D000818:Animals; D001011:Aorta / Q000293:injuries; D001241:Aspirin / Q000494:pharmacology; D004195:Disease Models, Animal; D007124:Immunoenzyme Techniques; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D008297:Male; D010314:Partial Thromboplastin Time; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011874:Radiometry; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy*
D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D013917:Thrombin; D001241:Aspirin