scholarly journals Activated thrombin‐activatable fibrinolysis inhibitor (TAFIa) attenuates fibrin‐dependent plasmin generation on thrombin‐activated platelets

2020 ◽  
Vol 18 (9) ◽  
pp. 2364-2376
Author(s):  
Ran Ni ◽  
Miguel A. D. Neves ◽  
Chengliang Wu ◽  
Samantha E. Cerroni ◽  
Matthew J. Flick ◽  
...  
Keyword(s):  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Activated Platelets ◽  
Fibrinolysis Inhibitor

Imaging analyses of coagulation-dependent initiation of fibrinolysis on activated platelets and its modification by thrombin-activatable fibrinolysis inhibitor

2017 ◽  
Vol 117 (04) ◽  
pp. 682-690 ◽  
Author(s):  
Tomasz Brzoska ◽  
Yuko Suzuki ◽  
Hideto Sano ◽  
Seiichirou Suzuki ◽  
Martyna Tomczyk ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Network Formation ◽  
Laser Scanning Microscopy ◽  
Tissue Type ◽  
Confocal Laser ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Activated Platelets ◽  
Fibrin Network ◽  
Fibrinolysis Inhibitor ◽  
Coagulation And Fibrinolysis

SummaryUsing intravital confocal microscopy, we observed previously that the process of platelet phosphatidylserine (PS) exposure, fibrin formation and lysine binding site-dependent plasminogen (plg) accumulation took place only in the centre of thrombi, not at their periphery. These findings prompted us to analyse the spatiotemporal regulatory mechanisms underlying coagulation and fibrinolysis. We analysed the fibrin network formation and the subsequent lysis in an in vitro experiment using diluted platelet-rich plasma supplemented with fluorescently labelled coagulation and fibrinolytic factors, using confocal laser scanning microscopy. The structure of the fibrin network formed by supplemented tissue factor was uneven and denser at the sites of coagulation initiation regions (CIRs) on PS-exposed platelets. When tissue type plasminogen activator (tPA; 7.5 nM) was supplemented, labelled plg (50 nM) as well as tPA accumulated at CIRs, from where fibrinolysis started and gradually expanded to the peripheries. The lysis time at CIRs and their peripheries (50 µm from the CIR) were 27.9 ± 6.6 and 44.4 ± 9.7 minutes (mean ± SD, n=50 from five independent experiments) after the addition of tissue factor, respectively. Recombinant human soluble thrombomodulin (TMα; 2.0 nM) attenuated the CIR-dependent plg accumulation and strongly delayed fibrinolysis at CIRs. A carboxypeptidase inhibitor dose-dependently enhanced the CIR-de- pendent fibrinolysis initiation, and at 20 µM it completely abrogated the TMα-induced delay of fibrinolysis. Our findings are the first to directly present crosstalk between coagulation and fibrinolysis, which takes place on activated platelets’ surface and is further controlled by thrombin-activatable fibrinolysis inhibitor (TAFI).Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals Absence of Thrombin-Activatable Fibrinolysis Inhibitor Protects against Sepsis-Induced Liver Injury in Mice

2005 ◽  
Vol 175 (10) ◽  
pp. 6764-6771 ◽  
Author(s):  
Rosemarijn Renckens ◽  
Joris J. T. H. Roelofs ◽  
Simone A. J. ter Horst ◽  
Cornelis van ′t Veer ◽  
Stefan R. Havik ◽  
...  
Keyword(s):  
Liver Injury ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor

Synthesis and Evaluation of Imidazole Acetic Acid Inhibitors of Activated Thrombin-Activatable Fibrinolysis Inhibitor as Novel Antithrombotics

2003 ◽  
Vol 46 (25) ◽  
pp. 5294-5297 ◽  
Author(s):  
James C. Barrow ◽  
Philippe G. Nantermet ◽  
Shaun R. Stauffer ◽  
Phung L. Ngo ◽  
Melissa A. Steinbeiser ◽  
...  
Keyword(s):  
Acetic Acid ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor

A functional assay for measuring activated thrombin-activatable fibrinolysis inhibitor in plasma

2004 ◽  
Vol 330 (2) ◽  
pp. 332-341 ◽  
Author(s):  
Erin K.T Neill ◽  
Ronald J Stewart ◽  
Mark M Schneider ◽  
Michael E Nesheim
Keyword(s):  
Functional Assay ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor

Effect of Heparin on TAFI-Dependent Inhibition of Fibrinolysis: Relative Importance of TAFIa Generated by Clot-Bound and Fluid Phase Thrombin

2002 ◽  
Vol 88 (08) ◽  
pp. 282-287 ◽  
Author(s):  
Anna Pentimone ◽  
Bianca Binetti ◽  
Marialisa Cramarossa ◽  
Donatella Piro ◽  
Nicola Semeraro ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Blood Clot ◽  
Fluid Phase ◽  
Clot Lysis ◽  
Relative Importance ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Dependent Inhibition ◽  
Fibrinolysis Inhibitor ◽  
Dependent Mechanism

SummaryHeparin has been proposed to enhance thrombolysis by inhibiting thrombin-dependent generation of activated TAFI (thrombin activatable fibrinolysis inhibitor), a carboxypeptidase that inhibits fibrinolysis. We evaluated the effect of heparin in an in vitro thrombolysis model consisting of a radiolabelled blood clot submerged in defibrinated plasma. Fibrinolysis was induced by adding t-PA (250 ng/ml) and calcium to the plasma bath. Control experiments indicated that thrombin generation induced by recalcification caused significant TAFI activation and inhibited clot lysis. Heparin (up to 1 U/ml), added to the plasma bath, failed to enhance clot lysis. Thrombin generation in the fluid phase was totally inhibited by heparin at concentrations > 0.5 U/ml. In contrast, thrombin generation on the clot surface was not inhibited by heparin (1 U/ml). TAFIa generation did occur in heparin-containing samples (1 U/ml) and amounted to about 10% of TAFIa formed in control samples. This low amount of TAFIa did exert antifibrinolytic activity as indicated by the observation that the addition of a specific TAFIa inhibitor (PTI) along with heparin enhanced clot lysis. Hirudin (10 µg/ml), at variance with heparin, inhibited clot-bound thrombin and enhanced clot lysis. These data show that heparin is unable to stimulate fibrinolysis through a TAFI-dependent mechanism, most likely because of its inefficiency in inhibiting thrombin generation on the clot surface. Moreover, they suggest that clot-bound thrombin plays a major role in TAFI-mediated inhibition of fibrinolysis through “localized” TAFIa generation.

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