FORMATION OF FIBRIN MONOMERS IN EXPERIMENTAL DISSEMINATED INTRAVASCULAR COAGULATION AND ITS INHIBITION BY RECOMBINANT HIRUDIN

An experimental disseminated intravascular coagulation (DIC) was induc ed in female CD rats by the intravenous administration of living bacte ria (9.5 x 10(7) cfu Klebsiella pneumoniae), sublethal (5 mg/kg) or le thal (50 mg/kg) lipopolysaccharide (LPS), or tissue factor (1.5 mu g/k g i.v. bolus or 0.4 mu g/kg x hr i.v. infusion). We used a new fibrin monomer (FM) assay to follow the course of DIC. FM were detected by th eir ability to stimulate the tissue-type (t-PA) plasminogen activator dependent conversion of plasminogen to plasmin by a chromogenic assay. Miniplasminogen was used instead of plasminogen to avoid interference of the assay by alpha(2)-antiplasmin. As a marker of DIC, elevated le vels of FM were observed with all DIC-inducing agents (plasma levels w ere up to 90 mu g/ml). The kinetics of FM formation were similar to th e course of thrombin-antithrombin III (TAT) levels (maximal plasma lev els 70 ng/ml); however, in the bacterial infection group, both paramet ers rose after a lag phase of about 1 hr. A 4 hr infusion of the highl y specific thrombin inhibitor recombinant (rec.) hirudin (0.125 mg/kg x hr) resulted in a decrease of FM levels from 89.2 +/- 14.4 mu g/ml i n the LPS group (n = 10) to 27.4 +/- 11.2 mu g/ml in the rec. hirudin group (n = 10; P < 0.001). The respective values for TAT levels were 7 3.1 +/- 19.7 mu g/ml in the LPS group and 52.7 +/- 15.7 ng/ml in the r ec. hirudin group (P < 0.001). Other coagulation parameters, such as p latelets, fibrinogen, and fibrin(ogen) degradation products, were amel iorated accordingly. In a mortality study (n = 10 rats/group) 100% of the rats in the untreated control group died after 50 mg/kg LPS, where as in the rec. hirudin group a significant reduction of the mortality to 40% was observed (P < 0.01). (C) 1994 Wiley-Liss, Inc.