Upon activation, platelets from the primary hemostatic plug at sites of vascular injury. In addition, activated platelets provide an efficient pro- coagulant surface for the subsequent activation of the coagulation cascade. The transbilayer movement of anionic phospholipids from the inner to the outer leaflet of the platelet membrane is a major determinant of pro-coagulant activity. This is accompanied by the release of procoagulant membrane particles called microvesicles. Individuals with impaired generation of platelet procoagulant activity have a life-long bleeding diathesis (Scott syndrome) Our studies show that shear stress, such as that which occurs at a site of atherosclerotic narrowing of arteries, is a potent stimulus for the development of platelet procoagulant activity and microvesiculation. Moreover, thrombin accentuates the shear stress- induced anionic phospholipid exposure and microvesiculation. The microvesicles adhere to matrix components, provide a binding site for platelet adhesion, and localize to the site of vascular injury in vivo. Microvesicles bind beta2-glycoprotein I, an anionic phospholipid-binding plasma protein, which promotes its clearance by macrophages. The presence of autoantibodies to beta2-glycoprotein I, as well as inherited mutations in beta2-glycoprotein I (which impair its philosophical- binding) are associated with increased incidence of thrombosis. In this proposal, we will investigate the role of shear stress-induced platelet procoagulant activity on thrombus formation.
The specific aims of this proposal are: (1) To define the signal transduction pathways leading to shear stress-induced platelet pro-coagulant activity. We will test the hypothesis that signal transduction that signal transduction through ITAM-containing proteins and Syk leads to anionic phospholipid exposure and microvesiculation. (2) To assess, under shear stress, the development of platelet pro-coagulant activity and its role in the stability of thrombus. The hypothesis to be tested: Platelets develop procoagulant activity following adhesion on von Willebrand factor and/or a collagen surface and this activity on adherent platelets plays a significant role in thrombus stability. (3) To define the role of beta2-glycoprotein I in the clearance of platelet-derived microvesicles from the circulation. The hypothesis to be tested: beta2-glycoprotein I binds to anionic phospholipid on the surface of platelet-derived microvesicles and mediates their clearance by macrophages. The corollary of this is that deficiency of beta2-glycoprotein I function will lead to a hypercoagulable state.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
1P50HL065967-01
Application #
6473671
Study Section
Special Emphasis Panel (ZHL1)
Project Start
2001-06-06
Project End
2006-01-31
Budget Start
Budget End
Support Year
1
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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Chen, Junmei; Reheman, Adili; Gushiken, Francisca C et al. (2011) N-acetylcysteine reduces the size and activity of von Willebrand factor in human plasma and mice. J Clin Invest 121:593-603
Chen, Junmei; Fu, Xiaoyun; Wang, Yi et al. (2010) Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13. Blood 115:706-12
Munday, A D; Gaus, K; López, J A (2010) The platelet glycoprotein Ib-IX-V complex anchors lipid rafts to the membrane skeleton: implications for activation-dependent cytoskeletal translocation of signaling molecules. J Thromb Haemost 8:163-72
Nambi, Vijay; Kimball, Kay T; Bray, Paul F et al. (2009) Differences in responses of platelets to fluid shear stress in patients with peripheral artery disease (PAD) and coronary artery disease (CAD). Platelets 20:199-205
Shah, Mona D; Bergeron, Angela L; Dong, Jing-Fei et al. (2008) Flow cytometric measurement of microparticles: pitfalls and protocol modifications. Platelets 19:365-72
Yago, Tadayuki; Lou, Jizhong; Wu, Tao et al. (2008) Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF. J Clin Invest 118:3195-207
Moake, Joel L (2007) Journey in reverse: TTP from bedside to blood bank to bench. J Clin Apher 22:37-49
Auton, Matthew; Cruz, Miguel A; Moake, Joel (2007) Conformational stability and domain unfolding of the Von Willebrand factor A domains. J Mol Biol 366:986-1000
Nguyen, Trung C; Liu, Anne; Liu, Li et al. (2007) Acquired ADAMTS-13 deficiency in pediatric patients with severe sepsis. Haematologica 92:121-4

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