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  • 1
    Online Resource
    Online Resource
    To Clot or Not to Clot: Deepening Our Understanding of Alterations in the Hemostatic System
    SAGE Publications ; 2022
    In:  Toxicologic Pathology Vol. 50, No. 7 ( 2022-10), p. 890-894
    Details
    In: Toxicologic Pathology, SAGE Publications, Vol. 50, No. 7 ( 2022-10), p. 890-894
    Abstract: The session on the hemostatic system focused on new developments in coagulation and platelet biology as well as how therapeutic agents may affect hemostasis. The classic cascade model of coagulation was compared with the more recent models of cell-based and vascular-based coagulation, which may provide better insight on how the coagulation cascade works in vivo. A review of platelet biology highlighted that, as platelets age, desialylated platelets form and are recognized by Ashwell-Morell receptor (AMR), leading to hepatic uptake and subsequent increase in thrombopoietin (TPO) production. Administration of therapeutics that induce thrombocytopenia was also discussed, including Mylotarg, which is an antibody-drug conjugate that was shown to decrease human megakaryocyte development but had no effect on platelet aggregation. An acetyl co-A carboxylase inhibitor was shown to cause thrombocytopenia by inhibiting de novo lipogenesis, which is critical for the formation of the megakaryocyte demarcation membrane system responsible for platelet production. It was also illustrated how preclinical translation models have been very helpful in the development of adeno-associated virus (AAV) hemophilia B gene therapy and what old and new preclinical tools we have that can predict the risk of a prothrombotic state in people.
    Type of Medium: Online Resource
    ISSN: 0192-6233 , 1533-1601
    URL: Article
    DOI: 10.1177/01926233221125172
    Language: English
    Publisher: SAGE Publications
    Publication Date: 2022
    detail.hit.zdb_id: 2056753-4
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  • 2
    Online Resource
    Online Resource
    Evaluation of biomarkers for monitoring thrombogenic potential of FXaI16L
    Ovid Technologies (Wolters Kluwer Health) ; 2020
    In:  Blood Coagulation & Fibrinolysis Vol. 31, No. 1 ( 2020-01), p. 16-28
    Details
    In: Blood Coagulation & Fibrinolysis, Ovid Technologies (Wolters Kluwer Health), Vol. 31, No. 1 ( 2020-01), p. 16-28
    Abstract: A zymogen-like activated factor X variant (FXa I16L ) is being developed for treating acute bleeding conditions. Activated factor V is an essential cofactor to FXa I16L for activating prothrombin to thrombin. Thrombi/emboli formation was observed microscopically in FXa I16L toxicity studies in animals. The objective of this research was to evaluate candidate biomarkers for FXa I16L -induced thrombi/emboli formation to inform safety monitoring and dose-escalation decisions in FXa I16L clinical trials. Effects of intravenous FXa I16L administration on platelets, fibrinogen, activated partial thromboplastin time (aPTT), prothrombin time (PT), d -dimer, tissue factor pathway inhibitor, thrombin : antithrombin complex, antithrombin, and factor V, and protein C (PC) activities were evaluated in mice, rats, and monkeys. Mice had endogenous factor V activity 10× that of monkeys and were overly sensitive to FXa I16L -induced thrombi/emboli formation. In monkeys, decreases in fibrinogen and prolongation in aPTT and PT emerged as potential biomarkers for impending FXa I16L -induced thrombi/emboli formation, based on association of changes with microscopically observable thrombi/emboli (0–97 thrombi/emboli per monkey). PC decreases, measured by a clot-based assay, were also observed. A similar reduction in PC activity, when measured by clot-based assay, was observed in a phase 1 clinical trial. However, an in-vitro experiment with human plasma spiked with increasing concentrations of FXa I16L indicated dose-dependent FXa I16L -induced interference with clot-based assays and no depletion of PC or S by FXa I16L in non-clot-based assays. Nonclinical biomarker studies identified fibrinogen, aPTT and PT as potential biomarkers for monitoring the clinical safety of FXa I16L . Results of clot-based assays with FXa I16L treatment should be interpreted with caution.
    Type of Medium: Online Resource
    ISSN: 0957-5235 , 1473-5733
    URL: Article
    DOI: 10.1097/MBC.0000000000000866
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2020
    detail.hit.zdb_id: 2035229-3
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  • 3
    Online Resource
    Online Resource
    In vivo overexpression of frataxin causes toxicity mediated by iron-sulfur cluster deficiency
    Elsevier BV ; 2022
    In:  Molecular Therapy - Methods & Clinical Development Vol. 24 ( 2022-03), p. 367-378
    Details
    In: Molecular Therapy - Methods & Clinical Development, Elsevier BV, Vol. 24 ( 2022-03), p. 367-378
    Type of Medium: Online Resource
    ISSN: 2329-0501
    URL: Article
    DOI: 10.1016/j.omtm.2022.02.002
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 2863173-0
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