We completed a number of studies presenting evidence that fibrinogen and fibrin play a major role in the formation of hemostatic plug and tissue repair. We described binding of polymerizing fibrin monomers to platelets and to fibroblasts which results in cell aggregation and clot retraction. We demonstrated that fibrinogen does not bind to intact platelets and that stimulation of platelets either with ADP or their treatment with proteolytic enzymes exposes two classes of fibrinogen receptors. We propose that binding of fibrinogen to high affinity receptors results in platelet aggregation by a mechanism in which adjacent platelets are linked by calcium-fibrinogen bridges. The objectives of our project are: 1) further development and characterization of polyclonal and monoclonal antibodies which interact with fibrinogen receptors on platelet surface and block platelet aggregation; 2) purification of fibrinogen receptors from platelet membranes; 3) characterization of the interaction between fibrinogen and its platelet receptors at the cellular level and in the purified system; 4) comparison of the interaction between platelet fibrinogen and plasma fibrinogen with the platelet receptors; 5) identification of the regions of fibrinogen molecule with interacts with the fibrinogen receptor; 6) identification of the fibrin binding sites on platelet surface and their relationship to fibrinogen receptor; 7) study of the significance of fibrinogen receptor in platelet dependent fibrin clot retraction; 8) attempt to identify fibrinogen/fibrin binding sites on human skin fibroblasts and endothelial cells. Our study could contribute to the understanding of the basic mechanisms involved in hemostasis, thrombosis and tissue repair and their abnormalities in diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL015226-13
Application #
3334889
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1977-12-01
Project End
1988-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
13
Fiscal Year
1985
Total Cost
Indirect Cost
Name
Temple University
Department
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Wierzbicka, I; Kowalska, M A; Lasz, E C et al. (1997) Interaction of beta 3 integrin-derived peptides 214-218 and 217-231 with alpha IIb beta 3 complex and with fibrinogen A alpha-chain. Thromb Res 85:115-26
McLane, M A; Kowalska, M A; Silver, L et al. (1994) Interaction of disintegrins with the alpha IIb beta 3 receptor on resting and activated human platelets. Biochem J 301 ( Pt 2):429-36
Kowalska, M A; Juliano, D; Trybulec, M et al. (1994) Zinc ions potentiate adenosine diphosphate-induced platelet aggregation by activation of protein kinase C. J Lab Clin Med 123:102-9
Trybulec, M; Kowalska, M A; McLane, M A et al. (1993) Exposure of platelet fibrinogen receptors by zinc ions: role of protein kinase C. Proc Soc Exp Biol Med 203:108-16
Beviglia, L; Poggi, A; Rossi, C et al. (1993) Mouse antithrombotic assay. Inhibition of platelet thromboembolism by disintegrins. Thromb Res 71:301-15
Lasz, E C; McLane, M A; Trybulec, M et al. (1993) Beta 3 integrin derived peptide 217-230 inhibits fibrinogen binding and platelet aggregation: significance of RGD sequences and fibrinogen A alpha-chain. Biochem Biophys Res Commun 190:118-24
Cook, J J; Trybulec, M; Lasz, E C et al. (1992) Binding of glycoprotein IIIa-derived peptide 217-231 to fibrinogen and von Willebrand factors and its inhibition by platelet glycoprotein IIb/IIIa complex. Biochim Biophys Acta 1119:312-21
Shigeta, O; Gluszko, P; Downing, S W et al. (1992) Protection of platelets during long-term extracorporeal membrane oxygenation in sheep with a single dose of a disintegrin. Circulation 86:II398-404
Fishman, S J; Wylonis, L J; Glickman, J D et al. (1991) Cyclosporin A augments human platelet sensitivity to aggregating agents by increasing fibrinogen receptor availability. J Surg Res 51:93-8
Calvete, J J; Schafer, W; Soszka, T et al. (1991) Identification of the disulfide bond pattern in albolabrin, an RGD-containing peptide from the venom of Trimeresurus albolabris: significance for the expression of platelet aggregation inhibitory activity. Biochemistry 30:5225-9

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