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Blood, 1 November 2007, Vol. 110, No. 9, pp. 3168-3175.
Prepublished online as a Blood First Edition Paper on July 20, 2007; DOI 10.1182/blood-2007-03-078824.
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Submitted March 9, 2007
Accepted July 2, 2007
Thrombin-thrombomodulin connects coagulation and fibrinolysis: more than an in vitro phenomenon
Tanya M Binette, Fletcher B. Taylor Jr., Glenn Peer, and Laszlo Bajzar*
Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United States
* Corresponding author; email: lbajzar{at}ualberta.ca.
Thrombin activatable fibrinolysis inhibitor (TAFI), when activated, forms a basic carboxypeptidase that can inhibit fibrinolysis. Potential physiologic activators include both thrombin and plasmin. In vitro, thrombomodulin and glycosaminoglycans increase the catalytic efficiency of TAFI activation by thrombin and plasmin, respectively. The most relevant (patho)physiologic activator of TAFI has not been disclosed. Our purpose was to identify the physiologic activator of TAFI in vivo. Activation of protein C (a thrombin-thrombomodulin dependent reaction), prothrombin, and plasminogen occurs during sepsis. Thus, a baboon model of E. coli-induced sepsis, where multiple potential activators of TAFI are elaborated, was used to study TAFI activation. A monoclonal antibody (mAbTAFI/TM#16) specifically inhibiting thrombin-thrombomodulin-dependent activation of TAFI was utilized to assess the contribution of thrombin-thrombomodulin in TAFI activation in vivo. Co-infusion of mAbTAFI/TM#16 with a lethal dose of E. coli prevented the complete consumption of TAFI observed without mAbTAFI/TM#16. The rate of fibrin degradation products formation is enhanced in septic baboons treated with the mAbTAFI/TM#16; therefore TAFI activation appears to play a key role in the extent of fibrin(ogen) consumption during E. coli challenge, and thrombin-thrombomodulin, in a baboon model of E. coli induced sepsis, appears to be the predominant activator of TAFI.
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