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Thromb Haemost 1998; 79(04): 796-801
DOI: 10.1055/s-0037-1615067
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Schattauer GmbH

Evaluation of the Factors Contributing to Fibrin–dependent Plasminogen Activation

Michael W. Mosesson
1   From the Sinai Samaritan Medical Center, University of Wisconsin Medical School-Milwaukee Clinical Campus, Milwaukee, USA
,
Kevin R. Siebenlist
1   From the Sinai Samaritan Medical Center, University of Wisconsin Medical School-Milwaukee Clinical Campus, Milwaukee, USA
,
Marijke Voskuilen
2   From the Gaubius Laboratory TNO–PG, Leiden, The Netherlands
,
Willem Nieuwenhuizen
2   From the Gaubius Laboratory TNO–PG, Leiden, The Netherlands
› Author AffiliationsThe results of this study were published in abstract form and presented in part at the XIII International Congress on Fibrinolysis and Thrombolysis, Barcelona, Spain, June 24-28, 1996, and at the XIV International Fibrinogen Workshop, Canberra, Australia, August 21-23, 1996 [Fibrinolysis (1996) 10: Suppl. 4, 13]
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Publication History

Received 27 August 1997

Accepted after revision 03 December 1997

Publication Date:
07 December 2017 (online)

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Summary

Polymerized fibrin strongly enhances tissue plasminogen activator (tPA)-mediated plasminogen activation, concomitant with exposure of ‘fibrin-specific’ epitopes at ‘Aα148-160’ and ‘γ312-324’. To investigate which aspects of polymerization are involved in these activities, we explored the fibrin polymerization process by evaluating the ability of factor XIIIa-crosslinked fibrinogen polymers to expose ‘fibrin-specific’ epitopes and enhance plasminogen activation. Crosslinked normal fibrinogen, fibrinogen with deficient [des Bβ1-42] or defective [Birmingham (AαR16H)] fibrin ‘D:E’ assembly sites (‘EA’), or with defective end-to-end self-association sites (‘D:D’) [Cedar Rapids (γR275C)], exposed both ‘fibrin-specific’ epitopes and enhanced tPA-dependent plasminogen activation, whereas non-crosslinked fibrinogens showed minimal or no such activities. Epitope expression in cross-linked fibrinogen was retained in the presence of the fibrin EA site peptide homolog, gly-pro-arg-pro (GPRP), which inhibits fibrin D:E association, except for the Aα148-160 epitope in des Bβ1-42 fibrinogen, which was not expressed. Fibrin prepared from crosslinked normal or abnormal fibrinogen, except for the des Bβ1-42 fibrin epitopes, which were reduced or absent, expressed ‘fibrin-specific’ epitopes even in the presence of GPRP, which otherwise impairs such expression in noncrosslinked fibrin. Epitope exposure in fibrin prepared from non-cross-linked fibrinogen was nearly normal in Cedar Rapids fibrin (heterozygous D:D defect), but reduced in Birmingham fibrin (heterozygous EA defect), nil in des Bβ1-42 fibrin (EA deficient), and absent in all cases in the presence of GPRP. In contrast, plasminogen activation stimula-tory activity that had been exposed in crosslinked normal fibrinogen or in crosslinked des Bβ1-42 or Cedar Rapids fibrin, was preserved to a large extent in the presence of GPRP, suggesting that once enhanced stimulatory activity and epitopes are exposed, they are not completely reversible. The findings indicate that end-to-end intermolecular associations (D:D) are not critical for ‘fibrin-specific’ epitope exposure, but that polymerization brought about in fibrinogen through factor XIIIa crosslinking, or in fibrin through ‘D:E’ interactions, is necessary for ‘fibrin-specific’ (more correctly, ‘polymerization-specific’) epitope exposure and enhancement of plasminogen activation.

 

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