• Chao-Zong Liu, Mei-Hsu Shih, and Pei-Jane Tsai.
• Department of Pharmacology, College of Medicine, Tzu Chi University, Hualien City, Hualien, Taiwan. czliu33@mail.tcu.edu.tw
• Thromb Haemostasis. 2005 Aug 1; 94 (2): 286-94.

AbstractClumping factor A (ClfA) is a surface protein of Staphylococcus aureus bacteria known for its ability to bind the C-terminus of plasma fibrinogen gamma chain, which participates in mediating fibrinogen-platelet interaction and fibrin cross-linking, resulting in thrombus formation. With an aim to develop agents that block fibrinogen gamma chain C-terminus, the fibrinogen-binding segment of ClfA locating at residues 221-550 was produced by recombinant technology and tested for its ability to inhibit platelet functions and fibrin clot formation. Recombinant ClfA(221-550) bound fibrinogen and blocked fibrinogen-platelet interaction, resulting in the inhibition of both ADP- and collagen-induced platelet aggregations. ClfA(221-550) also affected fibrin clot formation, in which factor XIIIa-mediated cross-linking of fibrinogen gamma chains was abrogated by ClfA(221-550) leaving the release of fibrinopeptides A and B from fibrinogen by thrombin unaltered, indicating that ClfA(221-550) interfered with fibrin clot formation without affecting thrombin's catalytic activity. Platelet-mediated clot retraction depends on both platelet-fibrinogen interaction and fibrin clot formation, which makes platelet thrombus less susceptible to fibrinolysis. At the concentration that reduced platelet aggregation by 40%, ClfA(221-550) prevented platelet-mediated clot retraction, whereas the glycoprotein IIb/IIIa antagonist tirofiban needed a higher concentration in inhibiting clot retraction than inhibiting platelet aggregation. By virtue of the multiple effects of ClfA(221-550) on platelet aggregation, fibrin clot formation and platelet-mediated clot retraction, the binding of ClfA(221-550) to fibrinogen merits further investigation for its potential as a new antithrombotic agent.

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