Decreased prothrombotic effects of pegylated recombinant human megakaryocyte growth and development factor in thrombocytopenic state in a rat thrombosis model

U. Nishiyama, T. Kuwaki, H. Akahori, Takashi Kato, Y. Ikeda, Hiroshi Miyazaki

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract

    Previous in vitro studies demonstrated that thrombopoietin (TPO) acts on platelets to activate a variety of intracellular signaling pathways and to enhance platelet sensitivity to multiple agonists. Little is known, however, about whether TPO exerts prothrombotic effects in vivo. The aim of this study was to examine the effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a pegylated N-terminal domain of human TPO, in a rat model of venous thrombosis. A microthrombus was photochemically induced on the vessel wall of a mesenteric venule, but the vessel was not occluded by it. A single intravenous injection of PEG-rHuMGDF (3 μg kg -1) after the thrombus generation into normal rats enhanced the thrombus size, resulting in transient thrombotic occlusion in the majority of rats. Stimulatory effects on thrombus growth were also observed following administration of glycosylated recombinant human full-length TPO (6 μg kg-1). In rats rendered thrombocytopenic by total body irradiation, however, PEG-rHuMGDF, even at 300 μ kg-1, did not induce a significant increase in thrombus size or thrombotic occlusion. Platelets from thrombocytopenic rats had decreased surface levels of c-Mp1 and decreased sensitivity to PEG-rHuMGDF in an in vitro aggregation response. Thus, decreased prothrombotic effects of PEG-rHuMGDF in thrombocytopenic rats might be the result not only of low platelet counts but also of decreased platelet reactivity to PEG-rHuMGDF. These results indicate that PEG-rHuMGDF has little effect on venous thrombus formation in thrombocytopenic states associated with high endogenous TPO levels.

    Original languageEnglish
    Pages (from-to)355-360
    Number of pages6
    JournalJournal of Thrombosis and Haemostasis
    Volume3
    Issue number2
    DOIs
    Publication statusPublished - 2005 Feb

    Fingerprint

    Thrombopoietin
    Thrombosis
    Blood Platelets
    Venules
    Whole-Body Irradiation
    polyethylene glycol-recombinant human megakaryocyte growth and development factor
    Platelet Count
    Intravenous Injections
    Venous Thrombosis
    Growth

    Keywords

    • Thrombopoietin
    • Thrombosis
    • Thrombus

    ASJC Scopus subject areas

    • Medicine(all)

    Cite this

    Decreased prothrombotic effects of pegylated recombinant human megakaryocyte growth and development factor in thrombocytopenic state in a rat thrombosis model. / Nishiyama, U.; Kuwaki, T.; Akahori, H.; Kato, Takashi; Ikeda, Y.; Miyazaki, Hiroshi.

    In: Journal of Thrombosis and Haemostasis, Vol. 3, No. 2, 02.2005, p. 355-360.

    Research output: Contribution to journalArticle

    @article{1d3882c4c20340e8888f1a0ba6c015ab,
    title = "Decreased prothrombotic effects of pegylated recombinant human megakaryocyte growth and development factor in thrombocytopenic state in a rat thrombosis model",
    abstract = "Previous in vitro studies demonstrated that thrombopoietin (TPO) acts on platelets to activate a variety of intracellular signaling pathways and to enhance platelet sensitivity to multiple agonists. Little is known, however, about whether TPO exerts prothrombotic effects in vivo. The aim of this study was to examine the effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a pegylated N-terminal domain of human TPO, in a rat model of venous thrombosis. A microthrombus was photochemically induced on the vessel wall of a mesenteric venule, but the vessel was not occluded by it. A single intravenous injection of PEG-rHuMGDF (3 μg kg -1) after the thrombus generation into normal rats enhanced the thrombus size, resulting in transient thrombotic occlusion in the majority of rats. Stimulatory effects on thrombus growth were also observed following administration of glycosylated recombinant human full-length TPO (6 μg kg-1). In rats rendered thrombocytopenic by total body irradiation, however, PEG-rHuMGDF, even at 300 μ kg-1, did not induce a significant increase in thrombus size or thrombotic occlusion. Platelets from thrombocytopenic rats had decreased surface levels of c-Mp1 and decreased sensitivity to PEG-rHuMGDF in an in vitro aggregation response. Thus, decreased prothrombotic effects of PEG-rHuMGDF in thrombocytopenic rats might be the result not only of low platelet counts but also of decreased platelet reactivity to PEG-rHuMGDF. These results indicate that PEG-rHuMGDF has little effect on venous thrombus formation in thrombocytopenic states associated with high endogenous TPO levels.",
    keywords = "Thrombopoietin, Thrombosis, Thrombus",
    author = "U. Nishiyama and T. Kuwaki and H. Akahori and Takashi Kato and Y. Ikeda and Hiroshi Miyazaki",
    year = "2005",
    month = "2",
    doi = "10.1111/j.1538-7836.2005.01113.x",
    language = "English",
    volume = "3",
    pages = "355--360",
    journal = "Journal of Thrombosis and Haemostasis",
    issn = "1538-7933",
    publisher = "Wiley-Blackwell",
    number = "2",

    }

    TY - JOUR

    T1 - Decreased prothrombotic effects of pegylated recombinant human megakaryocyte growth and development factor in thrombocytopenic state in a rat thrombosis model

    AU - Nishiyama, U.

    AU - Kuwaki, T.

    AU - Akahori, H.

    AU - Kato, Takashi

    AU - Ikeda, Y.

    AU - Miyazaki, Hiroshi

    PY - 2005/2

    Y1 - 2005/2

    N2 - Previous in vitro studies demonstrated that thrombopoietin (TPO) acts on platelets to activate a variety of intracellular signaling pathways and to enhance platelet sensitivity to multiple agonists. Little is known, however, about whether TPO exerts prothrombotic effects in vivo. The aim of this study was to examine the effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a pegylated N-terminal domain of human TPO, in a rat model of venous thrombosis. A microthrombus was photochemically induced on the vessel wall of a mesenteric venule, but the vessel was not occluded by it. A single intravenous injection of PEG-rHuMGDF (3 μg kg -1) after the thrombus generation into normal rats enhanced the thrombus size, resulting in transient thrombotic occlusion in the majority of rats. Stimulatory effects on thrombus growth were also observed following administration of glycosylated recombinant human full-length TPO (6 μg kg-1). In rats rendered thrombocytopenic by total body irradiation, however, PEG-rHuMGDF, even at 300 μ kg-1, did not induce a significant increase in thrombus size or thrombotic occlusion. Platelets from thrombocytopenic rats had decreased surface levels of c-Mp1 and decreased sensitivity to PEG-rHuMGDF in an in vitro aggregation response. Thus, decreased prothrombotic effects of PEG-rHuMGDF in thrombocytopenic rats might be the result not only of low platelet counts but also of decreased platelet reactivity to PEG-rHuMGDF. These results indicate that PEG-rHuMGDF has little effect on venous thrombus formation in thrombocytopenic states associated with high endogenous TPO levels.

    AB - Previous in vitro studies demonstrated that thrombopoietin (TPO) acts on platelets to activate a variety of intracellular signaling pathways and to enhance platelet sensitivity to multiple agonists. Little is known, however, about whether TPO exerts prothrombotic effects in vivo. The aim of this study was to examine the effects of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF), a pegylated N-terminal domain of human TPO, in a rat model of venous thrombosis. A microthrombus was photochemically induced on the vessel wall of a mesenteric venule, but the vessel was not occluded by it. A single intravenous injection of PEG-rHuMGDF (3 μg kg -1) after the thrombus generation into normal rats enhanced the thrombus size, resulting in transient thrombotic occlusion in the majority of rats. Stimulatory effects on thrombus growth were also observed following administration of glycosylated recombinant human full-length TPO (6 μg kg-1). In rats rendered thrombocytopenic by total body irradiation, however, PEG-rHuMGDF, even at 300 μ kg-1, did not induce a significant increase in thrombus size or thrombotic occlusion. Platelets from thrombocytopenic rats had decreased surface levels of c-Mp1 and decreased sensitivity to PEG-rHuMGDF in an in vitro aggregation response. Thus, decreased prothrombotic effects of PEG-rHuMGDF in thrombocytopenic rats might be the result not only of low platelet counts but also of decreased platelet reactivity to PEG-rHuMGDF. These results indicate that PEG-rHuMGDF has little effect on venous thrombus formation in thrombocytopenic states associated with high endogenous TPO levels.

    KW - Thrombopoietin

    KW - Thrombosis

    KW - Thrombus

    UR - http://www.scopus.com/inward/record.url?scp=20844454392&partnerID=8YFLogxK

    UR - http://www.scopus.com/inward/citedby.url?scp=20844454392&partnerID=8YFLogxK

    U2 - 10.1111/j.1538-7836.2005.01113.x

    DO - 10.1111/j.1538-7836.2005.01113.x

    M3 - Article

    C2 - 15670044

    AN - SCOPUS:20844454392

    VL - 3

    SP - 355

    EP - 360

    JO - Journal of Thrombosis and Haemostasis

    JF - Journal of Thrombosis and Haemostasis

    SN - 1538-7933

    IS - 2

    ER -