Crosslinking of fihrinogen by factor XIHa exposes fibrin-specific epitopes and induces enhanced plasminogen activation by t-PA

'Fibrin-specific'epitopes 'Aαl48-160' and 'γ312-324' are exposed when fibrinogen (Fbg) is converted to fibrin (Fb). Particularly, polymerized Fb enhances the t-PA-mediated plasminogen activation. Fb polymerization involves 'D:E' assembly, end-to-end self-association ('D:D') and interactions between γ-chain crosslinking sites (γXL.:γXL). It is not known which of these is (are) involved in epitope exposure and/or rate enhancement. We studied epitope exposure and rate enhancement by EIA and a spectrophotometric assay, respectively, by using non-crosslinked and crosslinked Fbg and Fb both in the presence and absence of GPRP. Noncrosslinked Fbg with and without GPRP, and non-crosslinked Fb in the presence of GPRP (disrupting D:E) were inactive in both assays. Noncrosslinked Fb, without GPRP present was active in both assays. Surprisingly, crosslinked Fbg exposed the fibrin-specific epitopes and enhanced plasminogen activation. These properties were preserved when the crosslinked Fbg was converted to Fh, even in the presence of GPRP. These findings indicate that Fb polymerization brought about through 'D:E' interactions or Fbg polymerization brought about through γ chain crosslinking is sufficient for 'fibrin-specific' epitope exposure and for inducing enhanced plasminogen activation. The fact that these properties are preserved in crosslinked Fbg and in the corresponding crosslinked Fb in the presence of GPRP suggests that prior epitope exposure or enhanced stimulatory activity in crosslinked Fbg and Fb are not reversed once they have become exposed. These conclusions were supported by experiments on Fbg's with defects in one or more of the above polymerisation constituents.