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

Erik Tucker, Ulla M. Marzec, Tara C. White, Sawan Hurst, Sandra Rugonyi, Owen McCarty, David Gailani, Andras Gruber, Stephen R. Hanson

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

The protease thrombin is required for normal hemostasis and pathologic throm- bogenesis. Since the mechanism of co- agulation factor XI (FXI)-dependent thrombus growth remains unclear, we investigated the contribution of FXI to thrombus formation in a primate thrombo- sis model. Pretreatment of baboons with a novel anti-human FXI monoclonal anti- body (aXIMab; 2 mg/kg) inhibited plasma FXI by at least 99% for 10 days, and suppressed thrombin-antithrombin (TAT) complex and β-thromboglobulin (βTG) formation measured immediately down- stream from thrombi forming within collagen-coated vascular grafts. FXI inhi- bition 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 with- out affecting template bleeding times. In comparison, pretreatment with aspirin (32 mg/kg) prolonged bleeding times but failed to prevent graft occlusion, support- ing the concept that FXI blockade may of- fer therapeutic advantages over other an- tithrombotic agents in terms of bleeding complications. In whole blood, aXIMab prevented fibrin formation in a collagen- coated flow chamber, independent of fac- tor XII and factor VII. These data suggest that endogenous FXI contributes to arte- rial thrombus propagation through a strik- ing amplification of thrombin generation at the thrombus luminal surface.

Original languageEnglish (US)
Pages (from-to)936-944
Number of pages9
JournalBlood
Volume113
Issue number4
DOIs
StatePublished - Jan 22 2009

Fingerprint

Vascular Graft Occlusion
Factor XI
Grafts
Thrombin
Thrombosis
Transplants
Bleeding Time
Fibrin
Collagen
Factor VII
Fibrinolytic Agents
Papio
Platelets
Human engineering
Hemostasis
Primates
Aspirin
Amplification
Blood Vessels
Blood

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI. / Tucker, Erik; Marzec, Ulla M.; White, Tara C.; Hurst, Sawan; Rugonyi, Sandra; McCarty, Owen; Gailani, David; Gruber, Andras; Hanson, Stephen R.

In: Blood, Vol. 113, No. 4, 22.01.2009, p. 936-944.

Research output: Contribution to journalArticle

Tucker, Erik ; Marzec, Ulla M. ; White, Tara C. ; Hurst, Sawan ; Rugonyi, Sandra ; McCarty, Owen ; Gailani, David ; Gruber, Andras ; Hanson, Stephen R. / Prevention of vascular graft occlusion and thrombus-associated thrombin generation by inhibition of factor XI. In: Blood. 2009 ; Vol. 113, No. 4. pp. 936-944.
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