Combination therapy using fibrinogen γ-chain peptide-coated, ADP-encapsulated liposomes and hemoglobin vesicles for trauma-induced massive hemorrhage in thrombocytopenic rabbits.

Abstract

We previously developed substitutes for red blood cells (RBCs) and platelets (PLTs) for transfusion. These substitutes included hemoglobin vesicles (HbVs) and fibrinogen γ-chain (dodecapeptide HHLGGAKQAGDV, H12)-coated, adenosine diphosphate (ADP)-encapsulated liposomes [H12-(ADP)-liposomes]. Here, we examined the efficacy of combination therapy using these substitutes instead of RBC and PLT transfusion in a rabbit model with trauma-induced massive hemorrhage with coagulopathy. Thrombocytopenia (PLT count approximately 40,000/μL) was induced in rabbits by repeated blood withdrawal and isovolemic transfusion with autologous RBCs. Thereafter, lethal hemorrhage was induced in rabbits by noncompressible penetrating liver injury. Subsequently, H12-(ADP)-liposomes with platelet-poor plasma (PPP), platelet-rich plasma (PRP), or PPP alone were administered to stop bleeding. Once achieving hemostasis, HbVs, allogenic RBCs, or 5% albumin were transfused into rabbits to rescue them from fatal anemia following massive hemorrhage. Administration of H12-(ADP)-liposomes/PPP as well as PRP (but not PPP) effectively stopped liver bleeding (100% hemostasis). The subsequent administration with HbVs as well as RBCs after hemostasis markedly rescued rabbits from fatal anemia (75% and 70% survivals for 24 hr, respectively). In contrast, 5% albumin administration rescued none of the rabbits. Combination therapy with H12-(ADP)-liposomes and HbVs may be effective for damage control resuscitation of trauma-induced massive hemorrhage.