The Journal of Experimental Medicine
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Published online 23 October 2006 doi:10.1084/jem.20061302
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 11, 2433-2440
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BRIEF DEFINITIVE REPORT

 Signal-dependent splicing of tissue factor pre-mRNA modulates the thrombogenecity of human platelets

Hansjörg Schwertz3,5, Neal D. Tolley3, Jason M. Foulks3, Melvin M. Denis3, Ben W. Risenmay3, Michael Buerke5, Rachel E. Tilley4, Matthew T. Rondina1, Estelle M. Harris1,3, Larry W. Kraiss2,3, Nigel Mackman4, Guy A. Zimmerman1,3, and Andrew S. Weyrich1,3

1 Department of Internal Medicine, 2 Department of Surgery, and 3 The Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112
4 Department of Immunology and Department of Cell Biology, The Scripps Research Institute, La Jolla, CA 92037
5 Department of Internal Medicine III, Martin-Luther-University-Halle-Wittenberg, 06097 Halle/Saale, Germany

CORRESPONDENCE Andrew S. Weyrich: Andy.weyrich{at}hmbg.utah.edu

Tissue factor (TF) is an essential cofactor for the activation of blood coagulation in vivo. We now report that quiescent human platelets express TF pre-mRNA and, in response to activation, splice this intronic-rich message into mature mRNA. Splicing of TF pre-mRNA is associated with increased TF protein expression, procoagulant activity, and accelerated formation of clots. Pre-mRNA splicing is controlled by Cdc2-like kinase (Clk)1, and interruption of Clk1 signaling prevents TF from accumulating in activated platelets. Elevated intravascular TF has been reported in a variety of prothrombotic diseases, but there is debate as to whether anucleate platelets—the key cellular effector of thrombosis—express TF. Our studies demonstrate that human platelets use Clk1-dependent splicing pathways to generate TF protein in response to cellular activation. We propose that platelet-derived TF contributes to the propagation and stabilization of a thrombus.

Dr. Denis died on 11 December 2004.


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