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Thromb Haemost 2002; 88(02): 282-287
DOI: 10.1055/s-0037-1613199
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Effect of Heparin on TAFI-Dependent Inhibition of Fibrinolysis: Relative Importance of TAFIa Generated by Clot-Bound and Fluid Phase Thrombin

Mario Colucci
1   Department of Biomedical Sciences, Section of General Pathology, University of Bari, Bari, Italy
,
Anna Pentimone
1   Department of Biomedical Sciences, Section of General Pathology, University of Bari, Bari, Italy
,
Bianca M. Binetti
1   Department of Biomedical Sciences, Section of General Pathology, University of Bari, Bari, Italy
,
Marialisa Cramarossa
1   Department of Biomedical Sciences, Section of General Pathology, University of Bari, Bari, Italy
,
Donatella Piro
1   Department of Biomedical Sciences, Section of General Pathology, University of Bari, Bari, Italy
,
Nicola Semeraro
1   Department of Biomedical Sciences, Section of General Pathology, University of Bari, Bari, Italy
› Author Affiliations
Further Information

Publication History

Received 30 January 2002

Accepted after resubmission 13 May 2002

Publication Date:
07 December 2017 (online)

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Summary

Heparin 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.

Keywords

Thrombin - thrombin inhibitors - clot lysis - carboxypeptidase
 

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