Journal
BLOOD
Volume 110, Issue 9, Pages 3168-3175Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2007-03-078824
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Funding
- NHLBI NIH HHS [R01 HL078658, 1R01 HL 078658-01] Funding Source: Medline
- NIGMS NIH HHS [R01 GM 37704-16, R01 GM037704] Funding Source: Medline
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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 Escherichia coli-induced sepsis, where multiple potential activators of TAFI are elaborated, was used to study TAFI activation. A monoclonal antibody (mAbTAFV TM#16) specifically inhibiting thrombin-thrombomodulin-dependent activation of TAFI was used to assess the contribution of thrombin-thrombomodulin in TAFI activation in vivo. Coinfusion of mAbTAFVTM#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#l6; 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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