Treatment of congenital coagulopathies, from biologic to biotechnological drugs: The relevance of gene editing (CRISPR/Cas)

De Pablo-Moreno, Juan A.; Miguel-Batuecas, Andrea; Rodríguez-Merchán, E. Carlos; Liras, Antonio

doi:10.1016/j.thromres.2023.10.001

Cited by 2 publications

(1 citation statement)

References 144 publications

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“…In vitro studies indicate that VGA039 increases thrombin generation in a concentration dependent manner in congenital VWD and in FVII‐, FVIII‐, FIX‐, FXI‐, and FXIII‐deficient plasmas, but not in FX‐ or FV‐deficient plasmas, tested in the presence of APC. Drug repurposing 15 and gene editing strategies, mainly those based on CRISPR/Cas technology, have been also investigated as treatment for RBDs 16 . Some interesting novel therapeutic under exploration include SerpinPC, which was designed to inhibit the anticoagulant function of APC, but it has not been yet investigated in RBDs, 17 and several anti‐TFPI agents, Concizumab (currently approved for treating haemophilia B patients with inhibitors in some regions of the world), and Marstacimab that is undergoing testing in clinical trial 18,19 .…”

Section: Discussionmentioning

confidence: 99%

Rare bleeding disorders: Advances in management

Casini,

Al‐Samkari,

Hayward

et al. 2024

Haemophilia

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Inherited factor coagulation deficiencies and vascular bleeding disorders, associated with bleeding of various severity, are often classified as rare bleeding disorders (RBDs). These include inherited fibrinogen disorders, inherited platelet function disorders (IPFD) and hereditary haemorrhagic telangiectasia (HHT). In the last decades, there have been large increases in knowledge on the epidemiology, genetics, physiopathology, clinical features, and diagnosis of RBDs, but improvements in management have been more limited and remain challenging. The treatment mainstay of RBDs is based only on replacement of a few available coagulation factor concentrates or cryoprecipitates. There is growing interest in therapeutic agents that enhance coagulation or inhibiting anticoagulant pathways in RBDs. In severe IPFD, the optimal platelet transfusion strategy is not yet established. Moreover, data is scarce on the effectiveness and safety of desmopressin and/or antifibrinolytic drugs often used for milder IPFD treatment. The best fibrinogen replacement strategy (prophylaxis vs. on demand) in afibrinogenemia is still debated. Similarly, the optimal trough fibrinogen target level for treatment of acute bleeding, and the role of fibrinogen replacement during pregnancy in mild hypofibrinogenemia and dysfibrinogenemia, have not been properly evaluated. The therapeutic arsenal in HHT includes antifibrinolytics and a series of antiangiogenic agents whose potential efficacy has been tested in small studies or are under investigation for treatment of bleeding. However, there is need to address several issues, including the optimal dosing strategies, the potential emergent toxicity of longer‐term use, and the impact of systemic antiangiogenic treatment on visceral arteriovenous malformations.

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Section: Discussionmentioning

confidence: 99%

Rare bleeding disorders: Advances in management

Casini,

Al‐Samkari,

Hayward

et al. 2024

Haemophilia

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Clinical, Laboratory Aspects and Management of Factor X Deficiency

Menegatti,

Peyvandi

2024

Semin Thromb Hemost

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Coagulation factor X (FX), originally named Stuart–Prower factor, plays a pivotal role in the coagulation cascade, activating thrombin to promote platelet plug formation and prevent excess blood loss. Genetic variants in F10 may lead to FX deficiency and to impaired coagulation. FX variants are phenotypically classified as being type I, with the concomitant reduction of FX coagulant activity and FX antigen levels or type II, corresponding to a reduction in activity with normal antigen plasma levels. Patients affected with FX deficiency tend to be one of the most seriously affected among those with rare bleeding disorders. They show a variable bleeding tendency strongly associated with FX coagulant activity levels in plasma and may present, in the severe form of the deficiency, life-threatening symptoms such as gastrointestinal and umbilical stump bleeding and intracranial hemorrhages or central nervous system bleeding. Treatment of FX deficiency was originally based on the replacement of the missing factor using fresh frozen plasma, cryoprecipitate and prothrombin complex concentrates; however, a plasma-derived concentrate, shown to be safe and effective in clinical trials, is now available. In addition, novel nonreplacement therapy such as small interference RNA, gene therapy, drug repurposing, and gene editing may also represent novel therapeutic approaches for FX deficiency, but further, much focused studies are needed before considering this emerging therapy in such patients.

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Treatment of congenital coagulopathies, from biologic to biotechnological drugs: The relevance of gene editing (CRISPR/Cas)

Cited by 2 publications

References 144 publications

Rare bleeding disorders: Advances in management

Rare bleeding disorders: Advances in management

Clinical, Laboratory Aspects and Management of Factor X Deficiency

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