Molecular Diagnostic Method for Detection of Platelet Activation- Prognostic Significance for Sepsis and Venous Thromboembolism
Platelets are specialized blood cells that function in the formation of blood clots, and these cells act as the key cellular effectors of thrombosis. This work demonstrates that Cdc2-like kinase 1 (Clk1) mediated pre-mRNA splicing is an early control point in platelet activation, and is required for generation of TF protein, an essential cofactor for activation of coagulation and clot formation. Early studies indicate that the presence and amount of spliced mRNA in platelets has prognostic significance for conditions involving disordered coagulation
In particular, pre-mRNA splicing is markedly increased in patients with sepsis, a clinical condition in which disordered coagulation is a central feature. The incidence of pre-mRNA splicing in platelets is increased in septic patients and that the degree of splicing correlates with abnormal coagulation indices, and predicts the severity of sepsis as well as mortality. In addition, the incidence of mortality more than doubled in patients whose platelets expressed spliced TF mRNA compared to those who did not
Determination of the degree of mRNA splicing in platelets may also be significant for predicting the risk of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, particularly in elderly patients. While little is known about factors that predispose patients to VTE, results from early studies show circulating platelets from elderly subjects have increased mRNA splicing and high TF activity. Identification of such individuals may be important in assessing their risk for developing VTE.
Detection of spliced mRNA provides a novel molecular diagnostic method for detection of platelet aggregation and disordered coagulation. In addition to its prognostic relevance for sepsis and VTE, splicing in platelets is likely to prove an important biomarker for other disorders in which coagulation is altered. Monitoring the presence and amount of spliced platelet mRNA also provides a method for tracking response to anticoagulant or antithrombotic treatments.
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.
Andrew Weyrich, Hansjorg Schwertz, Guy Zimmerman, Neal Tolley
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