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Principal Investigator: Dr. Tracy Stokol
Contact Information: E-mail: ts23@cornell.edu - Phone: 607-253-3255
Sponsor: Winn Feline Foundation
Grant Number: N/A
Title: Tissue Factor: Initiator of Thrombosis and Potential Therapeutic Target in Cats with Cardiac Disease?
Annual Direct Cost: $19,751
Project Period: 01/01/07-12/31/07
DESCRIPTION (provided by applicant): Cats with cardiac dysfunction frequently develop thromboembolic disease. In particular, aortic thromboembolism (ATE) causes severe pain and high mortality, with up to one third of cases succumbing to this devastating syndrome. Survivors are typically treated with anti-platelet drugs (clopidogrel, aspirin) or anticoagulants (heparin, warfarin), in the hopes of ameliorating the thrombotic tendency. Empiric therapy, however, has not proven to reduce the recurrence of ATE. New drugs are urgently needed to target the events that initiate thrombosis.
Tissue factor (TF) is the physiologic stimulus for coagulation. TF-bearing cells (e.g. fibroblasts, smooth muscle cells) at sites of endothelial injury support coagulation cascade activation and local generation of high concentrations of thrombin. In patbologic states, TF expression is upregulated on circulating monocytes. This aberrant TF expression promotes systemic thrombin generation and intravascular thrombosis.
Our preliminary data indicates that thrombin mediates the hypercoagulability of feline cardiac disease. We hypothesize that induced TF expression on circulating monocytes stimulates thrombin generation, thereby promoting the thromboembolic events associated with cardiac syndromes. If this hypothesis proves correct, then inhibition of TF represents a novel approach for treating ATE. Tissue factor pathway inhibitor (TFPI) is the primary inhibitor of TF and recombinant human TFPI shows promise in anticoagulant treatment trials. In order to define the role of TF in feline hypercoagulability, we aim to: 1)Measure TF activity of feline monocytes; and 2) Test the ex vivo TF-inhibitory activity of recombinant feline TFPI. Our long-term goal is to develop feline recombinant TFPI for thromboprophylaxis of feline ATE.
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