| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2000: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1999: ¥2,900,000 (Direct Cost: ¥2,900,000)
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| Research Abstract |
Platelet plug formation at sites of vascular injury is crucial for primary hemostasis, and von Willebrand factor (vWF) plays a key role in this process, particularly under flow conditions of high shear stress. Although GP IIb/IIIa is known to be involved in platelet thrombus growth on the surface following platelet adhesion, the detailed mechanisms of this secondary thrombus growth have not yet been determined. In particular, it remains unclear whether the interaction of vWF with GP Ib, in addition to its essential function in initial platelet adhesion, plays a role in secondary thrombus growth. In the present study, We found that the interaction of soluble vWF with platelet GP Ib, in addition to the essential role of interaction of surface-immobilized vWF with GP Ib in platelet adhesion, is also crucial for secondary thrombus growth on a collagen surface under flow conditions with high shear rate. Next, we evaluated real-time processes of platelet thrombus formation on a collagen surf
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ace in a flow chamber using whole blood from patients with various platelet aggregation disorders : Bernard-Soulier syndrome (BSS), Glanzmann's thrombasthenia (GTA), type 3 von Willebrand disease (vWd), and congenital afibrinogenemia (Af), who lack platelet glycoprotein (GP) Ib-IX complex, GP IIb-IIIa, von Willebrand factor (vWf), and fibrinogen, respectively. As a result, we found distinct molecular mechanisms underlie the pathologic bleeding in these diseases, and point to the distinct roles of two major adhesive proteins, vWf and fibrinogen, in mural thrombus formation under flow conditions : vWf, perhaps mainly through its interaction with GP Ib-IX, acts as an "initiator and promoter", whereas fibrinogen, via its binding to GP IIb-IIIa, acts as a "stabilizer" against heightened shear forces that could lead to peeling off of platelets from the surface. Finally, with respect to the intracellular calcium changes in the platelet adhesive process, we found that the [Ca^<2+>]i elevation is a downstream phenomenon and not a prerequisite for firm platelet adhesion to a vWf-coated surface, while both firm adhesion and cohesion of platelets have been thought to require activation of GP IIb-IIIa. Less
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