Thrombus Formation Initiation and Propagation

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DESCRIPTION (provided by applicant): The objectives of this proposal are to determine the role of platelet collagen receptors and of factor XI in thrombus formation in vivo. While the role of these components of the hemostatic system have been well studied in vitro and mutations in some of the participating proteins in humans hint at in vivo roles, the opportunity now exists, using a unique real time intravital microscopy technique, to delineate their importance in vivo. The time course and kinetics of laser induced thrombus formation in the arterioles of mice glycoprotein VI null mice, mice with low levels of glycoprotein VI and mice lacking the integrin alpha2 beta1 will be examined to determine the role of these collagen receptors in thrombus formation in this model. The activation state of the platelets accumulating in thrombi in the three mouse genotypes will be examined to probe the role of the two different collagen receptors in platelet signaling in response to collagen. Both mice lacking glycoprotein VI and mice lacking the alpha2 integrin chain appear to be protected in mouse models of thrombosis but in contrast to the bleeding phenotype present in deficiency of glycoprotein Ib, another initiator of platelet adhesion at sites of injury, mice lacking glycoprotein VI or the alpha2 integrin chain do not bleed. Thus these proteins may be useful targets for anti-thrombotic agents warranting a better understanding of their role in thrombus formation in vivo. A current model for blood coagulation is that the initiation occurs through exposure of tissue factor at sites of vascular injury resulting in the generation of small quantities of factor Xa and thrombin. The amount of thrombin generated through this pathway is limited by the inhibition of the factor Vlla-tissue factor complex by TFPI, in the presence of factor Xa. The initial thrombin among other functions formed activates factor XI which then maintains the thrombin flux through activation of factor IX. The time course and kinetics of laser induced thrombus formation in factor XI null mice will be examined to obtain a better understanding of the role of factor XI in vivo. The elucidation of the molecular architecture of blood coagulation complexes remains one of the major unresolved problems in the understanding of this process. To complement our in vivo studies of the role of factor XI in thrombus formation the structure of the complex formed between the factor XI apple domain(s)and the factor IX Gla domain will be determined.