Transfusion with synthetic platelet substitutes, H12-(ADP)liposomes, effectively rescues thrombocytopenic rabbits from massive hemorrhage

摘要

Introduction: Hemorrhagic shock and the following coagulopathy are critical conditions in traumatic patients. Resuscitative transfusion composed of plasma, red blood cells (RBCs) and platelets (PLTs) ratios of 1:1:1 was reported to be effective in rescuing such fatally injured patients. Although PLT transfusion is desirable to treat the coagulopathy, it is restricted in particular prehospital resuscitation due to its short shelf life. In order to address this crucial issue, we have developed H12-(ADP)liposomes as a liposome-type PLTs substitute. H12-(ADP)liposomes are conjugated with dodecapeptides (H12, HHLGGAKQAGDV). which is a carboxy terminal sequence of fibrinogen gamma-chain, on liposomes' surface, and encapsulated with adenosine 5'-phosphate (ADP), which enhances PLT aggregation. We investigated a hemostatic effect of H12-(ADP)liposomes on the massive hemorrhage in thrombocytopenic rabbits. Materials and Methods: Sixteen male NZW rabbits weighed 2.4 kg were used. Thrombocytopenia (PLT count; approximately 46×10~3/μL) was induced in the rabbits by repeated blood withdrawal and isovolemic transfusion of autologous washed RBCs. Thereafter, a liver injury was made followed by balloon compression for 5 min. During balloon compression, H12-(ADP)liposomes/PPP (Platelet-Poor Plasma) (n=6), PRP (Platelet-Rich Plasma) (n=6), PPP (n=4) was transfused to the rabbits. After the removal of compression, bleeding volume from the injured site was measured for the initial 10 min. Bleeding time was also monitored in the subsequent 120 min. After achieving hemostasis, transfusion of RBCs from other rabbits ([Hb] = 17.1 g/dL) was performed to recover from the severe hypotension and hypohemoglobinemia. Thereafter, their survivals were observed for 48 hours. Results: Rabbits in the H12-(ADP)liposomes/PPP transfusion group stopped bleeding at 47 min after liver injury (PRP group stopped at 37 min), and their bleeding volume for 10 min after liver injury was 18.9 g (PRP group; 19.4 g). None of the rabbits in PPP group was able to achieve hemostasis and thereby survived beyond 3 hours. RBCs transfusion after achieving hemostasis raised MAP from 53 to 59 mmHg in H12-(ADP)liposomes/PPP and PRP groups. Survival rates of H12-(ADP)liposomes/PPP and PRP groups were 83%. Discussions: Transfusion with H12-(ADP)liposomes/PPP as well as PRP effectively reduced bleeding time and volume in rabbits comparing to the transfusion with PPP. There were no significant differences in bleeding time/volume between these two groups. Conclusion: Thus, H12-(ADP)liposomes may have a potent hemostatic effect and thereby improve the survival rate that is equivalent to PRP.