Comparison of the effect of coagulation and platelet function impairments on various mouse bleeding models.
Haemostatic impairments are studied in vivo using one of several murine bleeding models. However it is not known whether these models are equally appropriate for assessing coagulation or platelet function defects. It was our study objective to assess the performance of arterial, venous and combined arterial and venous murine bleeding models towards impaired coagulation or platelet function. Unfractionated heparin (UFH) or αIIbβ3inhibitory antibody (Leo.H4) were administered to mice, and their effects on bleeding in saphenous vein, artery, and tail tip transection models were quantified and correlated with their effects on plasma clotting and ADP-induced platelet aggregation, respectively. All models exhibited similar sensitivity with UFH (EC50 dose = 0.19, 0.13 and 0.07 U/g, respectively) (95% CI = 0.14 - 0.27, 0.08 - 0.20, and 0.03 - 0.16 U/g, respectively). Maximal inhibition of ex vivo plasma clotting could be achieved with UFH doses as low as 0.03 U/g. In contrast, the saphenous vein bleeding model was less sensitive to αIIbβ3 inhibition (EC50 = 6.9 μg/ml) than tail transection or saphenous artery bleeding models (EC50 = 0.12 and 0.37 μg/ml, respectively) (95% CI = 2.4 - 20, 0.05 - 0.33, and 0.06 - 2.2 μg/ml, respectively). The EC50 of Leo.H4 for ADP-induced platelet aggregation in vitro (8.0 μg/ml) was at least 20-fold higher than that of the tail and arterial, but not the venous bleeding model. In conclusion, venous, arterial and tail bleeding models are similarly affected by impaired coagulation, while platelet function defects have a greater influence in models incorporating arterial injury.
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Dr. Peter L. Gross, Thrombosis and Atherosclerosis Research Institute, 237 Barton St East, Hamilton, Ontario, L8L 2X2 Canada, E-mail: peter.gross@taari.ca.
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D000244:Adenosine Diphosphate; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000925:Anticoagulants / Q000494:pharmacology; D001158:Arteries / Q000601:surgery; D001777:Blood Coagulation / Q000187:drug effects; D001780:Blood Coagulation Tests; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006470:Hemorrhage / Q000097:blood* / Q000188:drug therapy / Q000209:etiology; D006493:Heparin / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010979:Platelet Function Tests; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D012501:Saphenous Vein / Q000601:surgery; D013623:Tail / Q000098:blood supply*
D000906:Antibodies; D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D000244:Adenosine Diphosphate; D006493:Heparin
Haemorrhage; experimental animal models; heparin; platelet aggregation inhibitors