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Thromb Haemost 2008; 100(05): 837-846
DOI: 10.1160/TH08-03-0145
Platelets and Blood Cells
Schattauer GmbH

γA/γ’ fibrinogen inhibits thrombin-induced platelet aggregation

Rehana S. Lovely
1   Department of Biomedical Sciences, Missouri State University, Springfield, Missouri, USA
,
Chantelle M. Rein
2   Department of Pathology
,
Tara C. White
3   Division of Biomedical Engineering, Department of Science and Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA
,
Sari A. Jouihan
2   Department of Pathology
,
Lynn K. Boshkov
2   Department of Pathology
,
Antony C. Bakke
2   Department of Pathology
,
Owen J. McCarty
3   Division of Biomedical Engineering, Department of Science and Engineering, School of Medicine, Oregon Health & Science University, Portland, Oregon, USA
,
David H. Farrell
2   Department of Pathology
› Author AffiliationsFinancial support: This study was supported by grants from the National Heart, Lung, and Blood Institute, National Institutes of Health (grant F32 HL71463) (R.S.L.) (grants R41HL074535, K02HL04215, and R21 HL75006) (D.H.F.), the Office of Naval Research (grant N000140610411) (D.H.F.), and the American Heart Association (grant 0256337Z) (D.H.F.) (grant 0665512Z) (O.J.M.) (grant 0865486G) (R.S.L.).
Further Information

Publication History

Received 07 March 2008

Accepted after major revision 13 August 2008

Publication Date:
22 November 2017 (online)

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Summary

The minor γA/γ’ fibrinogen isoform contains a high affinity binding site for thrombin exosite II that is lacking in the major γA/γA fibrinogen isoform. We therefore investigated the biological consequences of the γ’ chain binding to thrombin. Thrombin-induced platelet aggregation was inhibited by γA/γ’ fibrinogen.Carboxyl terminal peptide fragment γ’410–427 from the γ’ chain was also inhibitory, with an IC50 of ∼200 µM in whole plasma. Deletion of the peptide from either the amino or carboxyl end significantly decreased inhibition. In contrast to thrombin-induced platelet aggregation, aggregation induced by epinephrine, ADP, arachidonic acid, or SFLLRN peptide showed little inhibition by the γ’ peptide. The inhibition of thrombin-induced platelet aggregation was not due to direct inhibition of the thrombin active site, since cleavage of a small peptidyl substrate was 91% of normal even in the presence of 1 mM γ’410–427.The γ’410–427 peptide blocked platelet adhesion to immobilized thrombin under both static and flow conditions,blocked soluble thrombin binding to platelet GPIbα, and inhibited PAR1 cleavage by thrombin. These results suggest that the γ’ chain of fibrinogen inhibits thrombin-induced platelet aggregation by binding to thrombin exosite II. Thrombin that is bound to the γ’ chain is thereby prevented from activating platelets, while retaining its amidolytic activity.

Keywords

Antiplatelet agents - antithrombin - fibrinogen/fibrin - protease activated receptors (PAR) - thrombin
 

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