Promising coagulation factor VIII bypassing strategies for patients with haemophilia A

Duan, Xunwei; Tang, Mingqing; Zhang, Junping; Yu, Hao; Xu, Rui‐hua

doi:10.1097/mbc.0000000000000098

Cited by 2 publications

(1 citation statement)

References 102 publications

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“…A major challenge remaining in the care of hemophilia A is the development of recalcitrant anti‐FVIII inhibitors in affected individuals . Current agents that bypass these inhibitors are expensive and have short half‐lives .…”

Section: Introductionmentioning

confidence: 99%

Apoptotic effects of platelet factor VIII on megakaryopoiesis: implications for a modified human FVIII for platelet‐based gene therapy

Greene

Lyde

Bailey

et al. 2014

Journal of Thrombosis and Haemostasis

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Summary. Background: Ectopically expressed B-domainless factor VIII in megakaryocytes is stored in a-granules, is effective in a number of murine hemostatic models, and is protected from circulating inhibitors. However, this platelet (p) FVIII has different temporal-spatial availability from plasma FVIII, with limited efficacy in other murine hemostatic models. Objectives and methods: We sought to improve pFVIII hemostatic efficacy by expressing canine (c) FVIII, which has higher stability and activity than human (h) FVIII in FVIII null mice. Results and conclusions: We found that pcFVIII was more effective than phFVIII at restoring hemostasis, but peak pcFVIII antigen levels were lower and were associated with greater megakaryocyte apoptosis than phFVIII. These new insights suggest that pFVIII gene therapy strategies should focus on enhancing activity rather than levels. We previously showed that modification of the PACE/furin cleavage site in hFVIII resulted in secretion of hFVIII primarily as a single-chain molecule with increased biological activity. In megakaryocytes, this variant was expressed at the same level as phFVIII with a lentiviral bone marrow transplant approach to reconstitute FVIII null mice, but was more effective, resulting in nearnormal hemostasis in the cremaster laser injury model. These studies may have implications for pFVIII gene therapy in hemophilia A.

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Section: Introductionmentioning

confidence: 99%

Apoptotic effects of platelet factor VIII on megakaryopoiesis: implications for a modified human FVIII for platelet‐based gene therapy

Greene

Lyde

Bailey

et al. 2014

Journal of Thrombosis and Haemostasis

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Managing Relevant Clinical Conditions of Hemophilia A/B Patients

Morfini,

Agnelli Giacchiello,

Baldacci

et al. 2023

Hematology Reports

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The Medical Directors of nine Italian Hemophilia Centers reviewed and discussed the key issues concerning the replacement therapy of hemophilia patients during a one-day consensus conference held in Rome one year ago. Particular attention was paid to the replacement therapy needed for surgery using continuous infusion (CI) versus bolus injection (BI) of standard and extended half-life Factor VIII (FVIII) concentrates in severe hemophilia A patients. Among the side effects, the risk of development of neutralizing antibodies (inhibitors) and thromboembolic complications was addressed. The specific needs of mild hemophilia A patients were described, as well as the usage of bypassing agents to treat patients with high-responding inhibitors. Young hemophilia A patients may take significant advantages from primary prophylaxis three times or twice weekly, even with standard half-life (SHL) rFVIII concentrates. Patients affected by severe hemophilia B probably have a less severe clinical phenotype than severe hemophilia A patients, and in about 30% of cases may undergo weekly prophylaxis with an rFIX SHL concentrate. The prevalence of missense mutations in 55% of severe hemophilia B patients allows the synthesis of a partially changed FIX molecule that can play some hemostatic role at the level of endothelial cells or the subendothelial matrix. The flow back of infused rFIX from the extravascular to the plasma compartment allows a very long half-life of about 30 h in some hemophilia B patients. Once weekly, prophylaxis can assure a superior quality of life in a large severe or moderate hemophilia B population. According to the Italian registry of surgery, hemophilia B patients undergo joint replacement by arthroplasty less frequently than hemophilia A patients. Finally, the relationships between FVIII/IX genotypes and the pharmacokinetics of clotting factor concentrates have been investigated.

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Promising coagulation factor VIII bypassing strategies for patients with haemophilia A

Cited by 2 publications

References 102 publications

Apoptotic effects of platelet factor VIII on megakaryopoiesis: implications for a modified human FVIII for platelet‐based gene therapy

Apoptotic effects of platelet factor VIII on megakaryopoiesis: implications for a modified human FVIII for platelet‐based gene therapy

Managing Relevant Clinical Conditions of Hemophilia A/B Patients

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