Fibrinogen plays an essential role in platelet aggregation. Following platelet activation, fibrinogen binds to a calcium- dependent complex of platelet membrane glycoproteins (Gp) IIb and IIIa. It has been proposed that fibrinogen, with a dimeric structure and two-fold symmetry, may act as a bridge between two Gp IIb-IIIa complex in adjacent platelets. At least two well- defined sequences in fibrinogen, the gamma-400-411 in the N- terminal part of gamma chain and the Arg-Gly-Asp sequences in the A alpha chain (A alpha 95-97 and/or A alpha 574-576) are shown to interact with platelet Gp IIb-IIIa. We have recently shown that the synthetic peptide B beta 15-42 derived from amino terminal end of B beta chain, inhibits ADP and thrombin-induced platelet aggregation in a dose-dependent manner. Furthermore, in binding studies this peptide inhibits 125I-fibrinogen binding to activated platelets. This peptide is generated in vivo by the combined actions of thrombin and plasmin on fibrin(ogen) and has been detected in peripheral blood.
The aims of this proposal are to further define the minimal aminoacid sequence required for this effect, to determine whether the effect of this peptide is mediated through its interaction with Gp IIb-IIIa or with fibrinogen, and to determine the effect of this peptide on the interaction of other adhesive glycoproteins to Gp IIb-IIIa. In addition, fibrinogen lacking B beta 15-42 will be prepared by cleavage with Protease III from Crotalus atrox venom and the effect of this fibrinogen on platelet aggregation will be determined. These studies will elucidate the importance of aminoterminal end of B beta chain in platelet-fibrinogen interactions.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040860-03
Application #
3358132
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1988-07-01
Project End
1992-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
3
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Washington
Department
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Thiagarajan, P; Le, A; Benedict, C R (1999) Beta(2)-glycoprotein I promotes the binding of anionic phospholipid vesicles by macrophages. Arterioscler Thromb Vasc Biol 19:2807-11
Arnett, F C; Thiagarajan, P; Ahn, C et al. (1999) Associations of anti-beta2-glycoprotein I autoantibodies with HLA class II alleles in three ethnic groups. Arthritis Rheum 42:268-74
Day, H M; Thiagarajan, P; Ahn, C et al. (1998) Autoantibodies to beta2-glycoprotein I in systemic lupus erythematosus and primary antiphospholipid antibody syndrome: clinical correlations in comparison with other antiphospholipid antibody tests. J Rheumatol 25:667-74
Thiagarajan, P; Shapiro, S S (1998) Lupus anticoagulants and antiphospholipid antibodies. Hematol Oncol Clin North Am 12:1167-92, v
Pereira, B; Benedict, C R; Le, A et al. (1998) Cardiolipin binding a light chain from lupus-prone mice. Biochemistry 37:1430-7
Thiagarajan, P; Le, A; Shapiro, S S (1997) Characterization of beta2-glycoprotein I-dependent and -independent ""antiphospholipid"" antibodies from lupus-prone NZW/BXSB F1 hybrid male mice. Am J Hematol 56:86-92
Thiagarajan, P; Benedict, C R (1997) Inhibition of arterial thrombosis by recombinant annexin V in a rabbit carotid artery injury model. Circulation 96:2339-47
Thiagarajan, P; Rippon, A J; Farrell, D H (1996) Alternative adhesion sites in human fibrinogen for vascular endothelial cells. Biochemistry 35:4169-75
Thiagarajan, P; Le, A; Snuggs, M B et al. (1996) The role of carboxy-terminal glycosaminoglycan-binding domain of vitronectin in cytoskeletal organization and migration of endothelial cells. Cell Adhes Commun 4:317-25
Zaidi, T N; McIntire, L V; Farrell, D H et al. (1996) Adhesion of platelets to surface-bound fibrinogen under flow. Blood 88:2967-72

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