Thrombin-thrombomodulin connects coagulation and fibrinolysis: more than an in vitro phenomenon

• Published in: Blood Vol. 110; no. 9; pp. 3168 - 3175
• Main Authors: Binette, Tanya M., Taylor, Fletcher B., Peer, Glenn, Bajzar, Laszlo
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01.11.2007; The Americain Society of Hematology; American Society of Hematology
• Series: Hemostasis, Thrombosis, and Vascular Biology
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Biological and medical sciences; Blood Coagulation - physiology; Carboxypeptidase B2 - antagonists & inhibitors; Carboxypeptidase B2 - blood; Carboxypeptidase B2 - immunology; Carboxypeptidase B2 - metabolism; Escherichia coli Infections - blood; Escherichia coli Infections - pathology; Fibrin Fibrinogen Degradation Products - metabolism; Fibrinogen - metabolism; Fibrinolysis - physiology; Half-Life; Hematologic and hematopoietic diseases; Hemostasis, Thrombosis, and Vascular Biology; Humans; Medical sciences; Microbial Sensitivity Tests; Papio cynocephalus; Sepsis - blood; Sepsis - pathology; Thrombin - physiology; Thrombomodulin - physiology; Peptidases; Blood coagulation; Serine endopeptidases; Hematology; Enzyme; Hydrolases; Thrombin; Thrombomodulin; Fibrinolysis; In vitro
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2007-03-078824

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 (mAbTAFI/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 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.