BACKGROUND: The thrombin-activatable fibrinolysis inhibitor (TAFI) is a zymogen first characterized in human plasma that is activated through proteolytic cleavage by thrombin, thrombin in complex with thrombomodulin, or plasmin. Active TAFI attenuates fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin, thereby inhibiting a potent positive feedback loop in the fibrinolytic cascade. The existence of a separate pool of TAFI within platelets has been described. OBJECTIVES AND METHODS: We aimed to confirm the presence of TAFI in the medium of washed, thrombin-stimulated platelets and to evaluate the characteristics of platelet TAFI by western blot analysis and with a quantitative assay for activated TAFI. We also assessed the ability of platelet TAFI to inhibit fibrinolysis in vitro, using a platelet-rich thrombus lysis assay. RESULTS: Our data are consistent with the presence of TAFI in the α-granules of resting platelets. In contrast to previous reports, platelet TAFI is very similar in electrophoretic mobility to plasma-derived TAFI. We also show, for the first time, that platelet-derived TAFI is capable of attenuating platelet-rich thrombus lysis in vitro independently of plasma TAFI. Moreover, we demonstrate additive effects on thrombolysis of platelet-derived TAFI and TAFI present in plasma. CONCLUSIONS: Taken together, these observations indicate that the secretion of platelet-derived TAFI can augment the concentrations of TAFI already present in plasma to enhance attenuation of the fibrinolytic cascade. This could be significant in regions of vascular damage or pathologic thrombosis, where activated platelets are known to accumulate.
BACKGROUND: The thrombin-activatable fibrinolysis inhibitor (TAFI) is a zymogen first characterized in human plasma that is activated through proteolytic cleavage by thrombin, thrombin in complex with thrombomodulin, or plasmin. Active TAFI attenuates fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin, thereby inhibiting a potent positive feedback loop in the fibrinolytic cascade. The existence of a separate pool of TAFI within platelets has been described. OBJECTIVES AND METHODS: We aimed to confirm the presence of TAFI in the medium of washed, thrombin-stimulated platelets and to evaluate the characteristics of platelet TAFI by western blot analysis and with a quantitative assay for activated TAFI. We also assessed the ability of platelet TAFI to inhibit fibrinolysis in vitro, using a platelet-rich thrombus lysis assay. RESULTS: Our data are consistent with the presence of TAFI in the α-granules of resting platelets. In contrast to previous reports, platelet TAFI is very similar in electrophoretic mobility to plasma-derived TAFI. We also show, for the first time, that platelet-derived TAFI is capable of attenuating platelet-rich thrombus lysis in vitro independently of plasma TAFI. Moreover, we demonstrate additive effects on thrombolysis of platelet-derived TAFI and TAFI present in plasma. CONCLUSIONS: Taken together, these observations indicate that the secretion of platelet-derived TAFI can augment the concentrations of TAFI already present in plasma to enhance attenuation of the fibrinolytic cascade. This could be significant in regions of vascular damage or pathologic thrombosis, where activated platelets are known to accumulate.
Authors: Yoshimasa Imoto; Atsushi Kato; Tetsuji Takabayashi; Whitney Stevens; James E Norton; Lydia A Suh; Roderick G Carter; Ava R Weibman; Kathryn E Hulse; Kathleen E Harris; Anju T Peters; Leslie C Grammer; Bruce K Tan; Kevin Welch; Stephanie Shintani-Smith; David B Conley; Robert C Kern; Shigeharu Fujieda; Robert P Schleimer Journal: J Allergy Clin Immunol Date: 2019-09-25 Impact factor: 10.793
Authors: Claire S Whyte; Gael B Morrow; Nagyung Baik; Nuala A Booth; Mohammed M Jalal; Robert J Parmer; Lindsey A Miles; Nicola J Mutch Journal: Blood Date: 2021-01-14 Impact factor: 22.113