Treatment with fibrinogen γ-chain peptide-coated, adenosine 5′-diphosphate-encapsulated liposomes as an infusible hemostatic agent against active liver bleeding in rabbits with acute thrombocytopenia

Kohsuke Hagisawa, Kahoko Nishikawa, Rempei Yanagawa, Manabu Kinoshita, Mami Doi, Hidenori Suzuki, Keiichi Iwaya, Daizoh Saitoh, Shuhji Seki, Shinji Takeoka, Makoto Handa, Yasuhiro Nishida

    Research output: Contribution to journalArticle

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    Abstract

    Background: We evaluated the hemostatic efficacy of H12-(adenosine 5′-diphosphate [ADP])-liposomes in the setting of active liver bleeding in rabbits with dilutional thrombocytopenia after massive transfusion. Study Design and Methods: Acute thrombocytopenia (platelet [PLT] count < 50 × 109/L) was induced in rabbits by repeated blood withdrawal and isovolemic transfusion of autologous washed red blood cells. Liver hemorrhage was initiated by a penetrating liver injury. Subsequently, the animals received tamponade treatment for the liver hemorrhage for 5 minutes and were intravenously administered H12-(ADP)-liposomes with PLT-poor plasma (PPP), PLT-rich plasma (PRP), PPP alone, H12-(phosphate-buffered saline [PBS])-liposome/PPP, or H12-(ADP)-liposomes/PPP plus fibrinogen concentrate during the tamponade. Results: Administration of H12-(ADP)-liposomes/PPP rescued 60% of the rabbits from the liver hemorrhage; PRP administration rescued 50%. In contrast, rabbits receiving PPP or H12-(PBS)-liposome/PPP achieved only 10 or 17% survival, respectively, for the first 24 hours. H12-(ADP)-liposomes/PPP as well as PRP consistently reduced bleeding volumes and shortened clotting times (CTs) in comparison to PPP administration. Specifically, bleeding volumes in the initial 5 minutes averaged 11 mL (H12-(ADP)-liposomes/PPP) and 17 mL (PRP) versus 30 mL (PPP; p < 0.05); CTs averaged 270 and 306 seconds versus 401 seconds (p < 0.05). H12-(ADP)-liposomes were observed at the bleeding site with thrombus formation, suggesting an induction of thrombi. Neither macro- nor microthrombi were detected in the lung, kidney, spleen, or liver in rabbits treated with H12-(ADP)-liposomes. Supplementation of fibrinogen to H12-(ADP)-liposomes/PPP did not significantly improve rabbit survival. Conclusions: H12-(ADP)-liposomes might be a safe and effective therapeutic tool during damage control surgery for trauma patients with acute thrombocytopenia and massive bleeding.

    Original languageEnglish
    Pages (from-to)314-325
    Number of pages12
    JournalTransfusion
    Volume55
    Issue number2
    DOIs
    Publication statusPublished - 2015 Feb 1

    Fingerprint

    Hemostatics
    Liposomes
    Thrombocytopenia
    Adenosine Diphosphate
    Fibrinogen
    Hemorrhage
    Rabbits
    Peptides
    Liver
    Therapeutics
    Thrombosis
    Phosphates
    Platelet-Rich Plasma
    Wounds and Injuries
    Platelet Count

    ASJC Scopus subject areas

    • Hematology
    • Immunology
    • Immunology and Allergy

    Cite this

    Treatment with fibrinogen γ-chain peptide-coated, adenosine 5′-diphosphate-encapsulated liposomes as an infusible hemostatic agent against active liver bleeding in rabbits with acute thrombocytopenia. / Hagisawa, Kohsuke; Nishikawa, Kahoko; Yanagawa, Rempei; Kinoshita, Manabu; Doi, Mami; Suzuki, Hidenori; Iwaya, Keiichi; Saitoh, Daizoh; Seki, Shuhji; Takeoka, Shinji; Handa, Makoto; Nishida, Yasuhiro.

    In: Transfusion, Vol. 55, No. 2, 01.02.2015, p. 314-325.

    Research output: Contribution to journalArticle

    Hagisawa, Kohsuke ; Nishikawa, Kahoko ; Yanagawa, Rempei ; Kinoshita, Manabu ; Doi, Mami ; Suzuki, Hidenori ; Iwaya, Keiichi ; Saitoh, Daizoh ; Seki, Shuhji ; Takeoka, Shinji ; Handa, Makoto ; Nishida, Yasuhiro. / Treatment with fibrinogen γ-chain peptide-coated, adenosine 5′-diphosphate-encapsulated liposomes as an infusible hemostatic agent against active liver bleeding in rabbits with acute thrombocytopenia. In: Transfusion. 2015 ; Vol. 55, No. 2. pp. 314-325.
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    abstract = "Background: We evaluated the hemostatic efficacy of H12-(adenosine 5′-diphosphate [ADP])-liposomes in the setting of active liver bleeding in rabbits with dilutional thrombocytopenia after massive transfusion. Study Design and Methods: Acute thrombocytopenia (platelet [PLT] count < 50 × 109/L) was induced in rabbits by repeated blood withdrawal and isovolemic transfusion of autologous washed red blood cells. Liver hemorrhage was initiated by a penetrating liver injury. Subsequently, the animals received tamponade treatment for the liver hemorrhage for 5 minutes and were intravenously administered H12-(ADP)-liposomes with PLT-poor plasma (PPP), PLT-rich plasma (PRP), PPP alone, H12-(phosphate-buffered saline [PBS])-liposome/PPP, or H12-(ADP)-liposomes/PPP plus fibrinogen concentrate during the tamponade. Results: Administration of H12-(ADP)-liposomes/PPP rescued 60{\%} of the rabbits from the liver hemorrhage; PRP administration rescued 50{\%}. In contrast, rabbits receiving PPP or H12-(PBS)-liposome/PPP achieved only 10 or 17{\%} survival, respectively, for the first 24 hours. H12-(ADP)-liposomes/PPP as well as PRP consistently reduced bleeding volumes and shortened clotting times (CTs) in comparison to PPP administration. Specifically, bleeding volumes in the initial 5 minutes averaged 11 mL (H12-(ADP)-liposomes/PPP) and 17 mL (PRP) versus 30 mL (PPP; p < 0.05); CTs averaged 270 and 306 seconds versus 401 seconds (p < 0.05). H12-(ADP)-liposomes were observed at the bleeding site with thrombus formation, suggesting an induction of thrombi. Neither macro- nor microthrombi were detected in the lung, kidney, spleen, or liver in rabbits treated with H12-(ADP)-liposomes. Supplementation of fibrinogen to H12-(ADP)-liposomes/PPP did not significantly improve rabbit survival. Conclusions: H12-(ADP)-liposomes might be a safe and effective therapeutic tool during damage control surgery for trauma patients with acute thrombocytopenia and massive bleeding.",
    author = "Kohsuke Hagisawa and Kahoko Nishikawa and Rempei Yanagawa and Manabu Kinoshita and Mami Doi and Hidenori Suzuki and Keiichi Iwaya and Daizoh Saitoh and Shuhji Seki and Shinji Takeoka and Makoto Handa and Yasuhiro Nishida",
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    T1 - Treatment with fibrinogen γ-chain peptide-coated, adenosine 5′-diphosphate-encapsulated liposomes as an infusible hemostatic agent against active liver bleeding in rabbits with acute thrombocytopenia

    AU - Hagisawa, Kohsuke

    AU - Nishikawa, Kahoko

    AU - Yanagawa, Rempei

    AU - Kinoshita, Manabu

    AU - Doi, Mami

    AU - Suzuki, Hidenori

    AU - Iwaya, Keiichi

    AU - Saitoh, Daizoh

    AU - Seki, Shuhji

    AU - Takeoka, Shinji

    AU - Handa, Makoto

    AU - Nishida, Yasuhiro

    PY - 2015/2/1

    Y1 - 2015/2/1

    N2 - Background: We evaluated the hemostatic efficacy of H12-(adenosine 5′-diphosphate [ADP])-liposomes in the setting of active liver bleeding in rabbits with dilutional thrombocytopenia after massive transfusion. Study Design and Methods: Acute thrombocytopenia (platelet [PLT] count < 50 × 109/L) was induced in rabbits by repeated blood withdrawal and isovolemic transfusion of autologous washed red blood cells. Liver hemorrhage was initiated by a penetrating liver injury. Subsequently, the animals received tamponade treatment for the liver hemorrhage for 5 minutes and were intravenously administered H12-(ADP)-liposomes with PLT-poor plasma (PPP), PLT-rich plasma (PRP), PPP alone, H12-(phosphate-buffered saline [PBS])-liposome/PPP, or H12-(ADP)-liposomes/PPP plus fibrinogen concentrate during the tamponade. Results: Administration of H12-(ADP)-liposomes/PPP rescued 60% of the rabbits from the liver hemorrhage; PRP administration rescued 50%. In contrast, rabbits receiving PPP or H12-(PBS)-liposome/PPP achieved only 10 or 17% survival, respectively, for the first 24 hours. H12-(ADP)-liposomes/PPP as well as PRP consistently reduced bleeding volumes and shortened clotting times (CTs) in comparison to PPP administration. Specifically, bleeding volumes in the initial 5 minutes averaged 11 mL (H12-(ADP)-liposomes/PPP) and 17 mL (PRP) versus 30 mL (PPP; p < 0.05); CTs averaged 270 and 306 seconds versus 401 seconds (p < 0.05). H12-(ADP)-liposomes were observed at the bleeding site with thrombus formation, suggesting an induction of thrombi. Neither macro- nor microthrombi were detected in the lung, kidney, spleen, or liver in rabbits treated with H12-(ADP)-liposomes. Supplementation of fibrinogen to H12-(ADP)-liposomes/PPP did not significantly improve rabbit survival. Conclusions: H12-(ADP)-liposomes might be a safe and effective therapeutic tool during damage control surgery for trauma patients with acute thrombocytopenia and massive bleeding.

    AB - Background: We evaluated the hemostatic efficacy of H12-(adenosine 5′-diphosphate [ADP])-liposomes in the setting of active liver bleeding in rabbits with dilutional thrombocytopenia after massive transfusion. Study Design and Methods: Acute thrombocytopenia (platelet [PLT] count < 50 × 109/L) was induced in rabbits by repeated blood withdrawal and isovolemic transfusion of autologous washed red blood cells. Liver hemorrhage was initiated by a penetrating liver injury. Subsequently, the animals received tamponade treatment for the liver hemorrhage for 5 minutes and were intravenously administered H12-(ADP)-liposomes with PLT-poor plasma (PPP), PLT-rich plasma (PRP), PPP alone, H12-(phosphate-buffered saline [PBS])-liposome/PPP, or H12-(ADP)-liposomes/PPP plus fibrinogen concentrate during the tamponade. Results: Administration of H12-(ADP)-liposomes/PPP rescued 60% of the rabbits from the liver hemorrhage; PRP administration rescued 50%. In contrast, rabbits receiving PPP or H12-(PBS)-liposome/PPP achieved only 10 or 17% survival, respectively, for the first 24 hours. H12-(ADP)-liposomes/PPP as well as PRP consistently reduced bleeding volumes and shortened clotting times (CTs) in comparison to PPP administration. Specifically, bleeding volumes in the initial 5 minutes averaged 11 mL (H12-(ADP)-liposomes/PPP) and 17 mL (PRP) versus 30 mL (PPP; p < 0.05); CTs averaged 270 and 306 seconds versus 401 seconds (p < 0.05). H12-(ADP)-liposomes were observed at the bleeding site with thrombus formation, suggesting an induction of thrombi. Neither macro- nor microthrombi were detected in the lung, kidney, spleen, or liver in rabbits treated with H12-(ADP)-liposomes. Supplementation of fibrinogen to H12-(ADP)-liposomes/PPP did not significantly improve rabbit survival. Conclusions: H12-(ADP)-liposomes might be a safe and effective therapeutic tool during damage control surgery for trauma patients with acute thrombocytopenia and massive bleeding.

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