EFFECTS OF LOW-MOLECULAR-WEIGHT HEPARINS ON FIBRIN POLYMERIZATION ANDCLOT SENSITIVITY TO T-PA-INDUCED LYSIS

We have previously demonstrated that therapeutic concentrations of unf ractionated heparin (UFH) impair fibrin polymerization leading to the formation of clots which are more sensitive to lysis induced by tissue plasminogen activator (t-PA). The aim of this study was to compare th e effect of UFH with that of three different low molecular weight hepa rins (LMWHs) on clot sensitivity to t-PA-induced lysis. Labelled fibri n clots, prepared from plasma containing UFH, Fraxiparine(R), Revipari ne(R), Enoxaparine(R) or saline, were incubated in phosphate buffer co ntaining t-PA (0.1 and 0.5 mug/ml) and plasminogen (20 mug/ml). The ex tent of clot lysis was quantified by counting the residual radioactivi ty of the clots and by measuring D-dimer levels released into the medi um. Fibrin polymerization and clot structure were evaluated by means o f a turbidimetric assay and by electron microscopic scanning. Pre-incu bation of plasma with 0.5 or 1.0 U/ml UFH resulted in a marked dose-de pendent acceleration of lysis induced by 0.1 or 0.5 mug/ml t-PA. In co ntrast, lysis rates induced by 0.5 mug/ml t-PA were not modified by pr e-incubation of plasma with LMWHs. When exposed to 0.1 mug/ml t-PA clo ts formed from plasma containing 0.5-2 IU/ml of Fraxiparine, Reviparin e and Enoxaparine showed only a minor increase in lysis rates compared to control dots. There was not a clear dose-response curve with LMWHs . Furthermore, lysis rates obtained with UFH-treated clots were always significantly higher than those seen with LMWHs-treated clots. We fou nd that UFH, in contrast to LMWHs, induced marked changes of fibrin as sembly and clot structure, resulting in the formation of clots with th icker fibres and larger pores. The relatively poor effects of LMWHs on clot structure and clot sensitivity to t-PA-induced lysis may contrib ute to their lower haemorrhagic potential.