PROTAMINE NEUTRALIZATION OF INTRAVENOUS AND SUBCUTANEOUS LOW-MOLECULAR-WEIGHT HEPARIN (TINZAPARIN, LOGIPARIN(TM)) - AN EXPERIMENTAL INVESTIGATION IN HEALTHY-VOLUNTEERS

The aim of the present study was to investigate whether tinzaparin sod ium (a low-molecular-weight heparin (LMWH)) was fully and permanently neutralized in vivo in man by protamine sulphate (PS) after intravenou s (i.v.) or subcutaneous (s.c.) injection. Fifty healthy adults equall y divided in five age- and sex-matched groups were included. The group s received 50 IU unfractionated heparin (UH)/kg body weight (b.w.) i.v ., 50 anti-factor Xa (anti-Xa) IU tinzaparin/kg b.w. i.v., 75 anti-Xa IU tinzaparin/kg b.w. s.c., 175 anti-Xa IU tinzaparin/kg b.w. s.c., or 1 ml of saline s.c. PS was given as a 10 min infusion in a dose of 1 mg/100 IU of heparin in the four first groups while 0.5 mg PS/kg b.w. was given in the placebo group. In the i.v. groups PS was administered 45 min after the heparin injection, and in the s.c. groups 180 min po st-heparin injection. In the UH group PS fully and permanently neutral ized all three activities. In the i.v. tinzaparin group PS reversed 80 % of the anti-Xa activity, while the anti-IIa and aPTT activities were fully reversed. A slight, but statistically significant, increase in anti-Xa and anti-IIa activities were seen following i.v. tinzaparin. I n the s.c. groups 60-65% of the observed peak anti-Xa activity was neu tralized, anti-IIa was almost completely reversed, and aPTT returned n early to baseline values. A gradual return of the anti-Xa activity (65 -75%), anti-IIa activity (55%) and aPTT activity (35-45%) was seen in the s.c. groups 3 h after reversal compared with the observed peak val ues. A continuous absorption of tinzaparin from the s.c. depot is pres umably the cause of the returned activity. PS caused an 8-27% transien t drop in the platelet count in all groups. This study confirms that t he anti-Xa activity following i.v. and s.c. administration of tinzapar in (a LMWH) is only partially neutralizable by protamine. This is not due to insufficient dosages of the antidote, as an excess of protamine could be demonstrated ex vivo immediately after the protamine infusio n. The present results suggest that protamine neutralization of tinzap arin given s.c. should be obtained with intermittent injections or con tinuous infusion.