Formation of fibrin monomers in experimental disseminated intravascular coagulation and its inhibition by recombinant hirudin.
An experimental disseminated intravascular coagulation (DIC) was induced in female CD rats by the intravenous administration of living bacteria (9.5 x 10(7) cfu Klebsiella pneumoniae), sublethal (5 mg/kg) or lethal (50 mg/kg) lipopolysaccharide (LPS), or tissue factor (1.5 micrograms/kg i.v. bolus or 0.4 micrograms/kg x hr i.v. infusion). We used a new fibrin monomer (FM) assay to follow the course of DIC. FM were detected by their 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 levels of FM were observed with all DIC-inducing agents (plasma levels were up to 90 micrograms/ml). The kinetics of FM formation were similar to the course of thrombin-antithrombin III (TAT) levels (maximal plasma levels 70 ng/ml); however, in the bacterial infection group, both parameters rose after a lag phase of about 1 hr. A 4 hr infusion of the highly specific thrombin inhibitor recombinant (rec.) hirudin (0.125 mg/kg x hr) resulted in a decrease of FM levels from 89.2 +/- 14.4 micrograms/ml in the LPS group (n = 10) to 27.4 +/- 11.2 micrograms/ml in the rec. hirudin group (n = 10; P < 0.001). The respective values for TAT levels were 73.1 +/- 19.7 micrograms/ml in the LPS group and 52.7 +/- 15.7 ng/ml in the rec. hirudin group (P < 0.001). Other coagulation parameters, such as platelets, fibrinogen, and fibrin(ogen) degradation products, were ameliorated accordingly.(ABSTRACT TRUNCATED AT 250 WORDS)
Dickneite
G
G
Research Laboratories of Behringwerke AG, Marburg, Germany.
Czech
J
J
Keuper
H
H
D000818:Animals; D000990:Antithrombin III / Q000378:metabolism; D004211:Disseminated Intravascular Coagulation / Q000097:blood* / Q000139:chemically induced / Q000401:mortality; D005260:Female; D005337:Fibrin / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D006629:Hirudins / Q000494:pharmacology*; D008070:Lipopolysaccharides; D010447:Peptide Hydrolases / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011994:Recombinant Proteins; D016019:Survival Analysis; D013997:Time Factors
D006629:Hirudins; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; C046193:antithrombin III-protease complex; D000990:Antithrombin III; D005337:Fibrin; D010447:Peptide Hydrolases