Current and Future Options of Haemophilia A Treatments

Miesbach, Wolfgang; Eladly, Fagr

doi:10.1080/14712598.2021.1908993

Cited by 9 publications

(6 citation statements)

References 50 publications

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“…First-line treatment for FVIII deficiency consists in factor replacement therapy using plasma-derived or recombinant concentrates [ 297 , 298 , 299 , 300 ]. This treatment prevents bleeding episodes as well as the joint deterioration resulting from accumulation of blood in the synovial space, which may cause irreversible cartilage damage.…”

Section: Homeostasis-modifying Treatments In Coagulationmentioning

confidence: 99%

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

Pablo-Moreno

Serrano

Revuelta

et al. 2022

IJMS

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The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.

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Section: Homeostasis-modifying Treatments In Coagulationmentioning

confidence: 99%

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

Pablo-Moreno

Serrano

Revuelta

et al. 2022

IJMS

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“…Among others, these comprise FVIII/FIX gene therapy, factor concentrates with further improved properties and/or the possibility for subcutaneous application as well as strategies for rebalancing pro-and anticoagulant mechanisms. [102][103][104][105] As also true for the currently established therapies, also these novel treatment regimens do and will prompt questions about the general need for treatment monitoring but also about their impact on assay results as well as the applicability of established test systems for patient sample analysis. 11,106 Currently, five (three HA and two HB) gene therapy approaches are within phase 3 clinical trials, making a licensed product possible within the near future.…”

Section: Outlook To Future Treatment Optionsmentioning

confidence: 99%

An Update on Laboratory Diagnostics in Haemophilia A and B

et al. 2022

Self Cite

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Haemophilia A (HA) and B (HB) are X-linked hereditary bleeding disorders caused by lack of activity of coagulation factors VIII (FVIII) or IX (FIX), respectively. Besides conventional products, modern replacement therapies include FVIII or FIX concentrates with an extended half-life (EHL-FVIII/FIX). Two main strategies for measuring plasma FVIII or FIX activity are applied: the one-stage clotting assay (OSCA) and the chromogenic substrate assay (CSA), both calibrated against plasma (FVIII/FIX) standards. Due to the structural modifications of EHL-FVIII/FIX, reagent-dependent assay discrepancies have been described when measuring the activity of these molecules. Assay discrepancies have also been observed in FVIII/FIX gene therapy approaches. On the other hand, nonfactor replacement by the bispecific antibody emicizumab, a FVIIIa-mimicking molecule, artificially shortens activated partial thromboplastin time–based clotting times, making standard OSCAs inapplicable for analysis of samples from patients treated with this drug. In this review, we aim to give an overview on both, the currently applied and future therapies in HA and HB with or without inhibitors and corresponding test systems suitable for accompanying diagnostics.

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“…22 An aptamer derived from recom bi nant human TFPI (BAX499, Takeda) was also devel oped and found to effi ciently inhibit TFPI in vitro and in vivo, with dosedepen dent increases in throm bin gen er a tion and decreased bleed ing in ani mal mod els and in earlyphase human tri als. 15,25 Development is on hold due to bleed ing in sub jects. 15…”

Section: Protease Nexin-1inhibitormentioning

confidence: 99%

Factor-mimetic and rebalancing therapies in hemophilia A and B: the end of factor concentrates?

Ellsworth

2021

Hematology

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Hemophilia A (HA) and B are inherited bleeding disorders caused by a deficiency of factor VIII or factor IX, respectively. The current standard of care is the administration of recombinant or purified factor. However, this treatment strategy still results in a high economic and personal burden to patients, which is further exacerbated by the development of inhibitors—alloantibodies to factor. The treatment landscape is changing, with nonfactor therapeutics playing an increasing role in what we consider to be the standard of care. Emicizumab, a bispecific antibody that mimics the function of factor VIIIa, is the first such nonfactor therapy to gain US Food and Drug Administration approval and is rapidly changing the paradigm for HA treatment. Other therapies on the horizon seek to target anticoagulant proteins in the coagulation cascade, thus “rebalancing” a hemorrhagic tendency by introducing a thrombotic tendency. This intricate hemostatic balancing act promises great things for patients in need of more treatment options, but are these other therapies going to replace factor therapy? In light of the many challenges facing these therapies, should they be viewed as a replacement of our current standard of care? This review discusses the background, rationale, and potential of nonfactor therapies as well as the anticipated pitfalls and limitations. This is done in the context of a review of our current understanding of the many aspects of the coagulation system.

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Current and Future Options of Haemophilia A Treatments

Cited by 9 publications

References 50 publications

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

An Update on Laboratory Diagnostics in Haemophilia A and B

Factor-mimetic and rebalancing therapies in hemophilia A and B: the end of factor concentrates?

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