Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI.

Abstract

The protease thrombin is required for normal hemostasis and pathologic thrombogenesis. Since the mechanism of coagulation factor XI (FXI)-dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombosis model. Pretreatment of baboons with a novel anti-human FXI monoclonal antibody (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and beta-thromboglobulin (betaTG) formation measured immediately downstream from thrombi forming within collagen-coated vascular grafts. FXI inhibition with aXIMab limited platelet and fibrin deposition in 4-mm diameter grafts without an apparent increase in D-dimer release from thrombi, and prevented the occlusion of 2-mm diameter grafts without affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, supporting the concept that FXI blockade may offer therapeutic advantages over other antithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagen-coated flow chamber, independent of factor XII and factor VII. These data suggest that endogenous FXI contributes to arterial thrombus propagation through a striking amplification of thrombin generation at the thrombus luminal surface.

• Authors: Erik I Tucker, Ulla M Marzec, Tara C White, Sawan Hurst, Sandra Rugonyi, Owen J T McCarty, David Gailani, András Gruber, Stephen R Hanson
• Journal: Blood (Blood) Vol. 113 Issue 4 Pg. 936-44 (Jan 22 2009) ISSN: 1528-0020 [Electronic] United States
• PMID: 18945968 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Factor XII
• Fibrin
• Collagen
• Factor XI
• Thrombin

Topics

• Animals
• Antibodies, Monoclonal (immunology)
• Bleeding Time
• Blood Platelets (drug effects, metabolism)
• Collagen (pharmacology)
• Factor XI (antagonists & inhibitors, immunology, metabolism)
• Factor XII (metabolism)
• Fibrin (metabolism)
• Humans
• Male
• Papio
• Platelet Activation (immunology)
• Thrombin (metabolism)
• Thrombosis (immunology, metabolism, prevention & control)