Therapeutic Target and Screening Method for Inhibitors of Platelet Activation and Coagulation
Platelets are specialized blood cells that function in the formation of blood clots, and these cells act as the key cellular effectors of thrombosis. Tissue Factor (TF) is an essential cofactor for the activation of coagulation and clot formation. This work demonstrates that platelets express TF, and that Cdc2-like kinase 1 (Clk1) mediated pre-mRNA splicing is an early control point in platelet activation. Clk1-dependent splicing is required for generation of TF protein and triggering platelet activation. Inhibition of Clk1 blocks this response, inhibiting both platelet activation and clot formation, indicating the potential for modulation of Clk1 activity for intervention in disorders resulting in abnormal platelet aggregation and abnormal coagulation.
An elevated level of intravascular TF has been reported in a variety of pro-thrombotic diseases. The identification of a central role for Clk1 in clot formation establishes this enzyme as a potential target for developing therapeutics that block platelet activation at an early stage. These medications could help many people at risk for stroke, heart attack, sepsis, and other life-threatening disorders and diseases associated with abnormal coagulation.
Stage of Development
A provisional patent application has been filed with the USPTO. This technology is available for sponsored research and/or licensing under either exclusive or non-exclusive terms.
*Schwertz et al. (2006) Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenecity of human platelets. J Exp Med. 203(11):2433-40.
Guy Zimmerman, Hansjorg Schwertz, Neal Tolley, Andrew Weyrich
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