Altering Anti-Thrombosis Discovery Models to Examine Pro-Thrombotic Activity from a Safety Perspective
Thrombosis, the process through which blood forms a clot, is a two-way street. It protects us from major bleeding following even minor injuries, yet is responsible for over ten million deaths globally every year via heart attacks and strokes.
Over the years we’ve conducted many preclinical thrombosis studies examining the effects of established and potential ANTI-thrombotic agents. Increasingly, a number of clients have asked for the development of slightly altered models to screen compounds for any PRO-thrombotic activity.
This new data set marks our evolution of anti-thrombosis discovery investigations into pro-thrombotic safety models, focusing on our ability to create a pro-thrombotic window. Clearly, pro-thrombotic activity is an undesirable property for drugs outside the cardiovascular arena.
Although our large animal anti-thrombotic models (including the electrolytic injury paradigms) are well characterized in a traditional efficacy mode, it is challenging from a resource perspective to scale those preparations to screen multiple compounds rapidly. As such we’ve been modifying our rodent models of arterial thrombosis – namely, the FeCl3 mouse – for a prothrombotic screening setting.
Briefly, we dose mice with either vehicle or active test article for the specified period prior to administration of reduced levels of FeCl3 to the external surface of the carotid artery. In most mice, the reduced levels of FeCl3 will cause instability in arterial blood flow – but not be associated with significant occlusion (formation of thrombus). Test article pro-thrombotic activity may be quantitated as reductions in arterial blood flow along with increasing incidence of occlusion.
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