Our goal is to understand hemostatic mechanisms; improve diagnosis and treatment of patients with hemostatic defects. The interaction of platelet and blood vessel is being investigated in the porcine model of von Willebrand's disease. The role of Willebrand factor in hemostasis is being investigated at a molecular level by the use of monoclonal antibodies in the animal and in in vitro systems. Factor VIII has been purified and its gene has been cloned. Radiolabeled nucleotide probes will be used to identify the cell responsible for factor VIII synthesis; the epitopes which bind to factor IXa/X, phospholipid, Willebrand factor and protein C will be localized by monoclonal antibodies, chemical cross-linking and with biosynthetic peptides from genetically engineered bacteria. Information about platelet function will be obtained by investigating platelet activation by tannin. Tannin is responsible for byssinosis and results in a decrease in circulating platelet numbers. This study will define the mechanism of tannin induced signal transduction that results in the secretion of platelet granule components. Other studies will be performed in relation to platelet-derived microparticles which appear to result from platelet activation processes. The production and biological role of these microparticles will be studied as well as their occurrence in a number of hematologic diseases. The coagulation system is implicated in the development of infective endocarditis, although initial cellular events that allow the development of the thrombotic lesion on the cardiac valve and subsequent bacterial attachment are largely unknown. The role of the platelet in the establishment of the infective lesion will be studied and preliminary data suggest that the thrombotic lesion in the von Willebrand pig is smaller than in the normal pig. Fundamental to an understanding of the platelet is an understanding of megakaryocytopoiesis and this will be described as the cells progress along the stem cell, megakaryocyte, platelet axis.
Our aim i s to understand the normal mechanism by which this pathway is regulated. Transforming growth factor B, for example, has a remarkable inhibitory effect on committed megakaryocyte progenitors. The project will also involve the isolation of megakaryocyte-colony stimulating activity and the study of patients with megakaryocytic disorders. The investigation of normal and abnormal hemostasis is designed to give greater insight into the control of hemostasis and how symptoms arise and laboratory tests become abnormal when the control is imperfect.
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