EVALUATION OF HEMOSTATIC AND FIBRINOLYTIC ALTERATIONS ASSOCIATED WITHDAILY ADMINISTRATION OF LOW-MOLECULAR-WEIGHT HEPARIN FOR A 12-WEEK PERIOD

The PTCA procedure fails in 30-50% of patients due to late restinosis, meaning that this is a problem of 100,000-150,000 people per year in the USA alone. It has been found that heparin and low-molecular-weight heparin (LMWH) have an inhibitory effect on smooth muscle cell (SMC) proliferation and migration, the major causes of restinosis. However, little is known about the toxicity and side effects of these drugs whe n used for a long period as may be required for prophylaxis of PTCA re stinosis. To investigate possible side effects, non-human primates rec eived daily injections of 1 mg/kg s.c. LMWH (Mono-Embolex(R)) over a 1 2-week period. The hemostatic system was monitored through measurement of ACT-celite, APTT, Heptest,(R) TT(10U/mL), TFPI, Anti-IIa activity, Anti-Xa activity, ACA-Heparin, AT III, factor VIII R:Ag, fibrinogen, and thrombomodulin levels. Elisa tests for t-PA, PAI-1, u-PA, FgDP, TD P, and D-Di levels were used for measurements of fibrinolytic activity . Increased values of ACT, APTT, Heptest,(R) TT, Anti-IIa, Anti-Xa, AC A-Heparin, and TFPI were observed four hours after LMWH injections. AT III, vWFAg, fibrinogen and thrombomodulin showed no change from the p re-study baseline. An accumulation effect was seen in the APTT and Hep test(R) over the 12 weeks. After the first week the blood levels of An ti-IIa activity remained elevated at 20% inhibition rather than 0% 24 hrs after drug administration. This activity slowly decreased after di scontinuation of drug. The Anti-Xa blood level activity remained eleva ted at 40% inhibition 24 hrs after drug administration 2 weeks into th e study, and this activity was detectable even 2 weeks after cessation of drug administration. There was increasing activity of the fibrinol ytic system with LMWH treatment. After two weeks t-PA increased two-fo ld to 6 ng/mL but returned to baseline at six weeks. There was a corre sponding increase of the TDP but not a clear increase in D-DI and FgDP . The increase of u-PA was limited to the first days of LMWH treatment only. The PAI-1 activity increased gradually over the entire study pe riod. No bleeding complications occurred throughout the study. The lon g-term administration of Mono-Embolex(R) as projected for the use in t he prophylaxis of restinosis following PTCA appears to be safe for pat ients.