The severe spontaneous bleeding phenotype in a novel hemophilia A rat model is rescued by platelet FVIII expression

Shi, Qizhen; Mattson, Jeremy G; Fahs, Scot A.; Geurts, Aron M.; Weiler, Hartmut; Montgomery, Robert R.

doi:10.1182/bloodadvances.2019000944

Cited by 13 publications

(8 citation statements)

References 42 publications

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“…However, when FVIII was expressed and stored in platelets in FVIII null mice (with levels corresponding to 1.2–22.7%), CFT and α‐angle were completely normalized in whole blood, although CT was not fully restored compared to WT mice. These results are consistent with our previous platelet‐specific gene therapy reports in hemophilia A rats with platelet‐FVIII expression 29 . Our results indicate that once platelets are activated, the clot development could be normalized and with corrected viscoelastic properties of the blood clot if FVIII is stored in platelets.…”

Section: Discussionsupporting

confidence: 93%

Thromboelastometry assessment of hemostatic properties in various murine models with coagulopathy and the effect of factor VIII therapeutics

Schroeder

Kuether

Fang

et al. 2021

Journal of Thrombosis and Haemostasis

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Background Rotational thromboelastometry (ROTEM) has been commonly used to assess the viscoelastic properties of the blood clotting process in the clinic for patients with a hemostatic or prothrombotic disorder. Objective To evaluate the capability of ROTEM in assessing hemostatic properties in whole blood from various mouse models with genetic bleeding or clotting disease and the effect of factor VIII (FVIII) therapeutics in FVIIInull mice. Methods Mice with a genetic deficiency in either a coagulation factor or a platelet glycoprotein were used in this study. The properties of platelet‐ or plasma‐FVIII were also assessed. Citrated blood from mice was recalcified and used for ROTEM analysis. Results We found that blood collected from the vena cava could generate reliable results from ROTEM analysis, but not blood collected from the tail vein, retro‐orbital plexus, or submandibular vein. Age and sex did not significantly affect the hemostatic properties determined by ROTEM analysis. Clotting time (CT) and clot formation time (CFT) were significantly prolonged in FVIIInull (5‐ and 9‐fold, respectively) and FIXnull (4‐ and 5.7‐fold, respectively) mice compared to wild‐type (WT)‐C57BL/6J mice. Platelet glycoprotein (GP)IIIanull mice had significantly prolonged CFT (8.4‐fold) compared to WT‐C57BL/6J mice. CT and CFT in factor V (FV) Leiden mice were significantly shortened with an increased α‐angle compared to WT‐C57BL/6J mice. Using ROTEM analysis, we showed that FVIII expressed in platelets or infused into whole blood restored hemostasis of FVIIInull mice in a dose‐dependent manner. Conclusion ROTEM is a reliable and sensitive assay for assessing therapeutics on hemostatic properties in mouse models with a bleeding or clotting disorder.

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Section: Discussionsupporting

confidence: 93%

Thromboelastometry assessment of hemostatic properties in various murine models with coagulopathy and the effect of factor VIII therapeutics

Schroeder

Kuether

Fang

et al. 2021

Journal of Thrombosis and Haemostasis

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“…When evaluated for their safety profile, the FVIII‐expressing platelets did not show increased risk of thrombosis, even at supratherapeutic concentrations of FVIII 84 . The efficacy of FVIII‐expressing platelets has also been demonstrated in several other studies, 85–88 including the production of FVIII‐expressing human platelets in a hemophilia A murine model 89 and sustained phenotypic correction in a canine model 90 . This success led to a Phase I clinical trial for treating hemophilia A via bone marrow transplant, which was recently approved 91 .…”

Section: Modifying the Bone Marrow In Vivo For Production Of Modified Plateletsmentioning

confidence: 96%

Emerging gene therapies for enhancing the hemostatic potential of platelets

2021

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Platelet transfusions are an integral component of balanced hemostatic resuscitation protocols used to manage severe hemorrhage following trauma. Enhancing the hemostatic potential of platelets could lead to further increases in the efficacy of transfusions, particularly for non‐compressible torso hemorrhage or severe hemorrhage with coagulopathy, by decreasing blood loss and improving overall patient outcomes. Advances in gene therapies, including RNA therapies, are leading to new strategies to enhance platelets for better control of hemorrhage. This review will highlight three approaches for creating modified platelets using gene therapies: (i) direct transfection of transfusable platelets ex vivo, (ii) in vitro production of engineered platelets from platelet‐precursor cells, and (iii) modifying the bone marrow for in vivo production of modified platelets. In summary, modifying platelets to enhance their hemostatic potential is an exciting new frontier in transfusion medicine, but more preclinical development as well as studies testing the safety and efficacy of these agents are needed.

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“…For hemophilia A, FvIII KO rats have no detectable FVIII activity, and their activated thromboplastin time and clotting time are significantly prolonged. Episodes of spontaneous bleeding requiring treatments were observed in 70% of the FvIII KO rats (Nielsen et al, 2014;Shi et al, 2020). In the rat genome, it is interesting to note that the F8 gene is situated on chromosome 18, rather than the X chromosome as in humans, mice, dogs, and sheep (Lozier and Nichols, 2013).…”

Section: Immune and Hematological Systemsmentioning

confidence: 99%

Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models

et al. 2021

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The rat has been extensively used as a small animal model. Many genetically engineered rat models have emerged in the last two decades, and the advent of gene-specific nucleases has accelerated their generation in recent years. This review covers the techniques and advances used to generate genetically engineered rat lines and their application to the development of rat models more broadly, such as conditional knockouts and reporter gene strains. In addition, genome-editing techniques that remain to be explored in the rat are discussed. The review also focuses more particularly on two areas in which extensive work has been done: human genetic diseases and immune system analysis. Models are thoroughly described in these two areas and highlight the competitive advantages of rat models over available corresponding mouse versions. The objective of this review is to provide a comprehensive description of the advantages and potential of rat models for addressing specific scientific questions and to characterize the best genome-engineering tools for developing new projects.

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The severe spontaneous bleeding phenotype in a novel hemophilia A rat model is rescued by platelet FVIII expression

Abstract: Key Points A novel HA rat model caused by an inversion exhibits a severe spontaneous bleeding phenotype. The severe spontaneous bleeding phenotype in HA rats is rescued by platelet-targeted FVIII expression.

Cited by 13 publications

References 42 publications

Thromboelastometry assessment of hemostatic properties in various murine models with coagulopathy and the effect of factor VIII therapeutics

Thromboelastometry assessment of hemostatic properties in various murine models with coagulopathy and the effect of factor VIII therapeutics

Emerging gene therapies for enhancing the hemostatic potential of platelets

Advances in Genome Editing and Application to the Generation of Genetically Modified Rat Models

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