Mw. Mosesson et al., EVALUATION OF THE FACTORS CONTRIBUTING TO FIBRIN-DEPENDENT PLASMINOGEN ACTIVATION, Thrombosis and haemostasis, 79(4), 1998, pp. 796-801
Polymerized fibrin strongly enhances tissue plasminogen activator (tPA
)-mediated plasminogen activation, concomitant with exposure of 'fibri
n-specific' epitopes at 'A alpha 148-160' and 'gamma 312-324'. To inve
stigate which aspects of polymerization are involved in these activiti
es, we explored the fibrin polymerization process by evaluating the ab
ility of factor XIIIa-crosslinked fibrinogen polymers to expose 'fibri
n-specific' epitopes and enhance plasminogen activation. Crosslinked n
ormal fibrinogen, fibrinogen with deficient [des B beta 1-42] or defec
tive [Birmingham (A alpha R16H)] fibrin 'D:E' assembly sites ('E-A'),
or with defective end-to-end self-association sites ('D:D') [Cedar Rap
ids (gamma R275C)], exposed both 'fibrin-specific' epitopes and enhanc
ed tPA-dependent plasminogen activation, whereas non-crosslinked fibri
nogens showed minimal or no such activities. Epitope expression in cro
sslinked fibrinogen was retained in the presence of the fibrin E-A sit
e peptide homolog, gly-pro-arg-pro (GPRP), which inhibits fibrin D:E a
ssociation, except for the A alpha 148-160 epitope in des B beta 1-42
fibrinogen, which was not expressed. Fibrin prepared from crosslinked
normal or abnormal fibrinogen, except for the des B beta 1-42 fibrin e
pitopes, which were reduced or absent, expressed 'fibrin-specific' epi
topes even in the presence of GPRP, which otherwise impairs such expre
ssion in non-cross-linked fibrin. Epitope exposure in fibrin prepared
from non-crosslinked fibrinogen was nearly normal in Cedar Rapids fibr
in (heterozygous D:D defect), but reduced in Birmingham fibrin (hetero
zygous E-A defect), nil in des B beta 1-42 fibrin (E-A deficient), and
absent in all cases in the presence of GPRP. Ln contrast, plasminogen
activation stimulatory activity that had been exposed in crosslinked
normal fibrinogen or in crosslinked des B beta 1-42 or Cedar Rapids fi
brin, was preserved to a large extent in the presence of GPRP, suggest
ing 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-spe
cific' epitope exposure, but that polymerization brought about in fibr
inogen through factor XIIIa crosslinking, or in fibrin through 'D:E' i
nteractions, is necessary for 'fibrin-specific' (more correctly, 'poly
merization-specific') epitope exposure and enhancement of plasminogen
activation.