In vivo models of arterial thrombosis and thrombolysis

Abstract

This year approximately 1.5 million Americans will undergo a myocardial infarction (MI). Of those who make it to the hospital (approximately 1.2 million), only about 20% will receive thrombolytic therapy. Multiple factors contribute to this dismaying figure, but most of them are risk/benefit-related. Moreover, of those receiving lytic therapy, the coronary arteries of as many as one-third may not reopen, and of those that do undergo coronary thrombolysis, an unacceptable fraction will experience reocclusion acutely. Thus, despite significant progress, major challenges for antithrombotic and thrombolytic therapy remain. Promising results with aspirin provide some hope that the figures above can be altered favorably. Efforts are under way in industry and academia to develop drugs to accomplish one or more of the following: lower the incidence of MI, prevent the development of unstable angina or retard its progression to frank MI, increase the inclusion window for lytic therapy, raise the percentage of patients undergoing successful thrombolysis, and maintain coronary patency. During the period that thrombolytic agents have come into vogue important advances have been made in our understanding of platelet function, coagulation, and the endogenous fibrinolytic system. These have spurred the development of novel drugs, such as platelet fibrinogen receptor antagonists, plasminogen activators, and inhibitors of factor IIa (thrombin) and XIIIa. Evaluation of these agents for their antithrombotic or profibrinolytic activity requires relevant animal models of thrombosis. Despite appropriate concerns about their clinical relevance, these models bridge the wide gap between test tube assays of aggregation or coagulation and humans.

Thrombolytic Activity of a Novel Modified Tissue-Type Plasminogen Activator, YM866, in a Canine Model of Coronary Artery Thrombosis

“…The thrombus induced by the insertion of a copper coil in this study was fibrin-rich; such thrombi have generally been recognized as a useful model for the evaluation of the efficacy of thrombolytic agents (18). In acute myo cardial infarction, the success rate of thrombolytic ther apy diminishes with time after onset (19), probably due to progressive cross-linking of the fibrin network (20).…”

Active site-blocked factor IXa prevents intravascular thrombus formation in the coronary vasculature without inhibiting extravascular coagulation in a canine thrombosis model.

“…After discontinuation of the current, complete cessation of blood flow occurred within 70±1 1 min (Fig. 1 top and Table I), due to continuing thrombus formation, eventually leading to an occlusive fibrin/platelet thrombus (10), which on histologic examination resembled thrombi observed in coronary vessels from patients (10,15,16). Ifthe animal received a single intravenous bolus of Factor IXai (300 jg/kg) at the time the current was discontinued, although coronary blood flow initially appeared to decrease, it never ceased and subsequently it returned to levels observed before discontinuing the current (Fig.…”

The Fab Fragment of a Novel Anti-GPVI Monoclonal Antibody, OM4, Reduces In Vivo Thrombosis Without Bleeding Risk in Rats

“…Abciximab, the human/mouse chimeric Fab fragment of 7E3, is not effective in the rat and 7E3 IgG causes thrombocytopenia; thus it is necessary to use the F(abЈ) 2 fragment as an alternative. 26 Folts model 20,21 is probably the most often used in large laboratory animals (rats, rabbits, monkeys, and dogs) because of its close mimicking of clinical thrombus formation. An advantage of this model is that the effectiveness of a drug can be monitored over time; in addition, a comparison of the effectiveness of different drugs is possible in the same animal, if the half-lives are suitably short.…”

“…In addition, we examined the effect of OM4 Fab in a cyclic flow reduction (CFR) model, or Folts-type model. 20,21 Moreover, the effect of OM4 Fab on hemostasis was examined by measuring tail-and nail-bleeding times. We used the F(abЈ) 2 fragment of 7E3, a murine anti-human integrin ␣ IIb ␤ 3 (GPIIb/ IIIa) antibody for comparison.…”