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

Masato Takikawa1, Kosuke Hagisawa2, Manabu Kinoshita3, Haruka Asahina4, Daizo Saito5 and Shinji Takeoka1
  • 1 Waseda University, Graduate School of Advanced Science and Engineering, Japan
  • 2 National Defense Medical College, Department of Physiology, Japan
  • 3 National Defense Medical College, Department of Immunology and Microbioogy, Japan
  • 4 National Defense Medical College, Department of Traumatology and Critical Care Medicine, Japan
  • 5 National Defense Medical College Research Institute, Division of Traumatology, Japan

Introduction: Hemorrhagic shock and the following coagulopathy are critical conditions in traumatic patients[1]. 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[2]. 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 46×103/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.

References:
[1] J.B. Holcomb et al., "Increased plasma and platelet to red blood cell ratios improves outcome in 466 massively transfused civilian trauma patients,"Annals of Surgery. Vol. 248, Sep. 2008.
[2] Y. Okamura et al., "Development of fibrinogen gamma-chain peptide-coated, adenosine diphosphate-encapsulated liposomes as a synthetic platelet substitute,"Journal of Thrombosis and Haemostasis. Vol. 7, Mar. 2009

Keywords: self-assembly, Drug delivery, clinical application

Conference: 10th World Biomaterials Congress, Montréal, Canada, 17 May - 22 May, 2016.

Presentation Type: General Session Oral

Topic: Biomaterials in thrombosis and hemostasis

Citation: Takikawa M, Hagisawa K, Kinoshita M, Asahina H, Saito D and Takeoka S (2016). Transfusion with synthetic platelet substitutes, H12-(ADP)liposomes, effectively rescues thrombocytopenic rabbits from massive hemorrhage. Front. Bioeng. Biotechnol. Conference Abstract: 10th World Biomaterials Congress. doi: 10.3389/conf.FBIOE.2016.01.00592

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Received: 27 Mar 2016; Published Online: 30 Mar 2016.