EFFECTS OF LOW-MOLECULAR-WEIGHT DERMATAN SULFATE ON COAGULATION, FIBRINOLYSIS AND TISSUE FACTOR PATHWAY INHIBITOR IN HEALTHY-VOLUNTEERS

Low-molecular-weight (LMW)-dermatan sulfate (Desmin) with the mean mol ecular weight of 5600 Da has been obtained by limited depolymerization of natural dermatan sulfate. The pharmacokinetic and pharmacodynamic data of 100 and 200 mg were analyzed after intravenous injection and o f 50, 100 and 200 mg after subcutaneous injection on tissue factor pat hway inhibitor (TFPI) antigen and activity, heparin cofactor (HC) II a ctivity, Heptest(TM) coagulation value, chromogenic S-2222 anti-factor Xa (aXa) assay, activated partial thromboplastin time (AMTT), thrombi n clotting time (TCT), plasminogen, tissue plasminogen activator activ ity (t-PA) and plasminogen activator inhibitor (PAI). After i.v. injec tion of 100 mg and 200 mg Desmin TFPI antigen and activity increased 2 .2- and 2.7-fold, and returned to normal values within 60 and 90 min, respectively. Using the HC II assay the elimination half-lives (T1/2 e l) increased from 1.9 h to 3.3 h with increasing doses of LMW-dermatan sulfate. T1/2 el were 4.3 and 6.9 h with the Heptest assay and 3.3 an d 5.1 h with the aXa method, respectively. AMT, TCT and the fibrinolyt ic parameters were not modified by either dose of i.v. LMW-dermatan su lfate. After s.c. administration of 100 mg or 200 mg LMW-dermatan sulf ate no increase of TFPI antigen or activity was detected. T1/2 el was 5.6 h using HC II method, 11.1 h using Heptest and 7.8 h with the aXa activity. The total clearance was about ten-fold higher when determine d by the HC II method compared with Heptest and aXa method The volume of distribution (VD) increased with increasing doses of s.c. LMW-derma tan sulfate and was highest with the HC II method. Intravenous adminis tration of 100 mg protamine chloride 15 min after i.v. dosing of 100 m g LMW-dermatan sulfate did not modify TFPI, coagulation or fibrinolyti c parameters. Further analysis of the complex mechanism of action has to include studies which should explain the low release of TFPI in rel ation to the antithrombotic effects of LMW-dermatan sulfate.