A segment of Staphylococcus aureus clumping factor A with fibrinogen-binding activity (ClfA221-550) inhibits platelet-plug formation in mice.

Abstract

We previously reported that the fibrinogen-binding segment (residues 221-550) of Staphylococcus aureus clumping factor A (ClfA), which binds to fibrinogen gamma chain C-terminus, exerted inhibitory effects on platelet aggregation and fibrin clot formation in vitro. Here, we further demonstrated the effectiveness of using ClfA221-550 to inhibit platelet-rich thrombus formation in vivo. Platelet-rich thrombi were formed in the mesenteric venules of fluorescein-loaded mice by filtered light illumination. It grew rapidly and ultimately resulted in the cessation of blood flow due to vessel occlusion. Given by intravenous bolus injection, ClfA221-550 delayed occlusive thrombi formation in a dose-dependent manner: 2-, 3- and 4.5-fold prolongations of vessel occlusion time were attained with 0.69, 6.9 and 34.5 mg/kg of ClfA221-550, respectively. Reduced fibrin clot formation at the late phase with plasmas, which were prepared from ClfA221-550-treated mice, was also dose-dependent. The suppression of fibrin formation ex vivo coincided with the delay of occlusive thrombus formation in vivo, suggesting that the antithrombotic effect of ClfA221-550 may result from the blockade of fibrinogen gamma chain C-terminal functions, in mediating platelet aggregation and fibrin clot formation. Administration of ClfA221-550 also lengthened the tail bleeding of mice; however, significant effect was achieved only with a higher dosage, namely 34.5 mg/kg. These results together showed that blockade of fibrinogen gamma chain C-terminus with ClfA221-550 preferentially affected platelet-rich thrombus formation rather than normal haemostasis, thus providing a rationale for selecting fibrinogen gamma chain C-terminus as a new target for thrombotic intervention.

• Authors: Chao-Zong Liu, Tur-Fu Huang, Po-Jun Tsai, Pei-Jane Tsai, Ling-Ya Chang, Mei-Chi Chang
• Journal: Thrombosis research (Thromb Res) Vol. 121 Issue 2 Pg. 183-91 ( 2007) ISSN: 0049-3848 [Print] United States
• PMID: 17467042 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ClfA protein, Staphylococcus aureus
• Coagulants
• Coagulase
• Fibrinogen

Topics

• Animals
• Blood Platelets (drug effects, physiology)
• Coagulants (pharmacology)
• Coagulase (pharmacology)
• Dose-Response Relationship, Drug
• Fibrinogen (drug effects, metabolism)
• Male
• Mice
• Mice, Inbred ICR
• Platelet Aggregation (drug effects, physiology)
• Protein Binding
• Staphylococcus aureus (physiology)
• Thrombosis (metabolism)