TY - JOUR
T1 - Secretion and antifibrinolytic function of thrombin-activatable fibrinolysis inhibitor from human platelets
AU - Schadinger, S. L.
AU - Lin, J. H.H.
AU - Garand, M.
AU - Boffa, M. B.
PY - 2010/11
Y1 - 2010/11
N2 - 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.
AB - 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.
KW - Carboxypeptidases
KW - Fibrinolysis
KW - Platelets
KW - TAFI
KW - α-granules
UR - http://www.scopus.com/inward/record.url?scp=78149277497&partnerID=8YFLogxK
U2 - 10.1111/j.1538-7836.2010.04024.x
DO - 10.1111/j.1538-7836.2010.04024.x
M3 - Article
C2 - 20723026
AN - SCOPUS:78149277497
SN - 1538-7933
VL - 8
SP - 2523
EP - 2529
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
IS - 11
ER -