Effects of cross-linking on clearance of circulating alpha-fibrin monomer and its complexes

Preceding studies showed that fibrin-monomer of the type lacking only fibrinopeptide A (alpha-fibrin) cleared from the circulation more rapidly than a tighter aggregating form of monomer that lacks both fibrinopeptides A and B (alpha beta-fibrin). The rapid clearance of alpha-fibrin may be related to the high dissociability of the soluble complexes that it forms with fibrinogen in blood. In this study, we use cross-linking by factor XIIIa to suppress dissociation of fibrin complexes and examine the effect of the cross-linking on the circulatory half-life of the fibrin. Incubation of alpha-fibrin-monomer/fibrinogen solutions with factor XIIIa before injection in rabbits increased the circulatory half-life of the fibrin (range, 2 to 16 hours) in proportion to the percentage conversion of monomer to cross-linked dimers and small oligomers. Electrophoretic analyses of plasma samples confirmed that, compared with non-cross-linked monomer, cross-linked dimers and small oligomers were long lived and, further, were not degraded. The inhibition of clearance through cross-linking occurs only under conditions that produce partial cross-linking of the fibrin. An opposite effect occurs when cross-linking is allowed to approach completion, as a result of polymerization of the fibrin into large fibers that disappear almost immediately after injection. Cross-linking elicited in vivo with injected factor XIIIa has an inhibitory effect on clearance of injected monomer similar to the effect produced by partial cross-linking in vitro. It is proposed that the prolonged survival of cross-linked dimers and small oligomers in the circulation provides a partial explanation for the frequent prevalence of cross-linked rather than non-cross-linked complexes in blood of human subjects with vascular disease.