Platelet thrombus formation occurs when platelets become activated, secrete vasoactive and proaggregatory substances and aggregate. These platelet responses develop under flow conditions that modulate specific molecular interactions between platelet surface receptors and extracellular ligands. Previous studies demonstrate that pathological arterial wall shear stresses cause plasma von Willebrand factor (Vwf) to bind to the platelet glycoprotein (GP) Ib/IX/V and GPIIb-IIIa complexes, and that this binding leads to platelet activation associated with secretion and aggregation. The purpose of this proposal is to determine precisely the mechanisms by which large and unusually large Vwf multimers bind to platelets under shear, influence the threshold of shear-induced platelet-Vwf interaction, and signal the functional responses that lead to platelet thrombus formation. Elucidation of these mechanisms will involve studies on platelets from normal subjects, as well as on platelets from patients with thrombotic thrombocytopenic purpura (TTP) and other disorders. Systemic microvascular platelet aggregation, producing organ ischemia and thrombocytopenia, is the essential pathophysiologic event in patients with TTP. The precise explanation for excessive platelet activation and aggregation in vivo in this paradigm of arterial thrombosis is presently unknown. There is indirect evidence that Vwf multimers, especially unusually large Vwf forms, may be release from stimulated or injured endothelial cells in TTP. It is not known, however, if plasma Vwf multimers subsequently attach to platelets and induce aggregation in high shear stress regions of the microcirculation in TTP patients. The investigators will determine by direct flow cytometric analysis: whether or not Vwf binds to the platelets of TTP patients in vivo; and, if so, whether or not Vwf attachment to platelets occurs concurrently with the intravascular platelet activation, aggregation and thrombocytopenia that characterize TTP episodes in patients who have chronic relapsing, single episode and other types of TTP. They also will determine if the initiation, progression and recovery from incipient or severe TTP episodes correlates with: platelet-bound Vwf, platelet activation, platelet aggregation; and with the response of these platelet parameters in vitro shear stress.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL018584-20
Application #
2027983
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
1976-06-01
Project End
2000-12-31
Budget Start
1997-01-01
Budget End
1997-12-31
Support Year
20
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Rice University
Department
Type
Schools of Engineering
DUNS #
050299031
City
Houston
State
TX
Country
United States
Zip Code
77005
Christodoulides, N; Feng, S; Resendiz, J C et al. (2001) Glycoprotein Ib/IX/V binding to the membrane skeleton maintains shear-induced platelet aggregation. Thromb Res 102:133-42
Turner, N A; Moake, J L; McIntire, L V (2001) Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow. Blood 98:3340-5
Tsai, H M; Rice, L; Sarode, R et al. (2000) Antibody inhibitors to von Willebrand factor metalloproteinase and increased binding of von Willebrand factor to platelets in ticlopidine-associated thrombotic thrombocytopenic purpura. Ann Intern Med 132:794-9
Merten, M; Chow, T; Hellums, J D et al. (2000) A new role for P-selectin in shear-induced platelet aggregation. Circulation 102:2045-50
Chow, T W; Hellums, J D; Thiagarajan, P (2000) Thrombin receptor activating peptide (SFLLRN) potentiates shear-induced platelet microvesiculation. J Lab Clin Med 135:66-72
Chapman, G B; Durante, W; Hellums, J D et al. (2000) Physiological cyclic stretch causes cell cycle arrest in cultured vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 278:H748-54
Bennett, C L; Connors, J M; Carwile, J M et al. (2000) Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 342:1773-7
Baker, K R; Moake, J L (2000) Thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. Curr Opin Pediatr 12:23-8
Feng, S; Christodoulides, N; Kroll, M H (1999) The glycoprotein Ib/IX complex regulates cell proliferation. Blood 93:4256-63
Moake, J L; Chow, T W (1998) Increased von Willebrand factor (vWf) binding to platelets associated with impaired vWf breakdown in thrombotic thrombocytopenic purpura. J Clin Apher 13:126-32

Showing the most recent 10 out of 33 publications