Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches

Meeks, Shannon L.; Batsuli, Glaivy

doi:10.1182/asheducation-2016.1.657

Cited by 76 publications

(73 citation statements)

References 48 publications

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“…Collectively, studies of ITI therapy have provided valuable information about prognostic factors for a successful outcome (Table ), although risk stratification is indicative only as ITI therapy can also be effective in patients with poor risk features.…”

Section: History and Experience Of Immune Tolerance Inductionmentioning

confidence: 99%

Immune tolerance induction: What have we learned over time?

et al. 2018

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Development of inhibitory antibodies to infused factor VIII (FVIII) concentrates continues to be the most serious complication of haemophilia A management. Induction of immune tolerance by administering high doses of FVIII concentrate (antigen) and prothrombin complex concentrates to control bleeding was originated in the 1970s in Bonn, Germany, by Dr Hans-Hermann Brackmann, and became known as the Bonn protocol. ITI transformed the life of the index patient, who was 19 years of age when he began treatment, and dramatically improved the medical landscape for all patients with haemophilia and inhibitors. Over the past 40 years, variations to the Bonn protocol have been proposed. All protocols are effective although some are better suited than others for use in certain situations. The specific molecular defect in FVIII and the human leucocyte antigen (HLA) type of an individual with haemophilia are major codependent determinants to inhibitor development. Given the range of potential molecular defects and the staggering number of potential HLA types, it is likely that treatment arms of randomized studies in haemophilia represent highly diverse populations, which reduces the power of a study to demonstrate differences between treatments. Although available clinical guidelines and consensus recommendations for ITI therapy are not always in complete agreement, collectively the guidelines provide a reasonable level of guidance for administering ITI therapy under different clinical scenarios. Several studies of ITI therapy are ongoing with the aim of clarifying unresolved issues in haemophilia management including the role of von Willebrand factor in inhibitor eradication.

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Section: History and Experience Of Immune Tolerance Inductionmentioning

confidence: 99%

Immune tolerance induction: What have we learned over time?

et al. 2018

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“…Bypassing agents (BPAs), including activated prothrombin complex concentrate (aPCC) and recombinant activated factor VII (rfVIIa), have been used in patients with inhibitors during ITI for bleeding prevention and treatment . However, the hemostatic efficacy of BPAs in patients with inhibitors has not matched that of fVIII replacement in patients without inhibitors .…”

Section: Introductionmentioning

confidence: 99%

Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis

et al. 2019

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Haemophilia A is a rare congenital bleeding disorder caused by a deficiency of blood coagulation protein factor VIII (fVIII). Prophylactic fVIII infusions are the standard of care for the prevention of bleeds and their sequela. 1 However, 30% of individuals with severe deficiency will develop neutralizing antibodies, called inhibitors, against fVIII. 2 Most patients who develop inhibitors, particularly individuals with high titre inhibitors (titres ≥ 5 Bethesda units (BU) per mL), require immune tolerance induction (ITI) consisting of frequent and often high dose fVIII to induce peripheral tolerance. ITI is the standard of care for eradicating inhibitors with reported success Abstract Introduction: The formation of neutralizing antifactor VIII (fVIII) antibodies, called inhibitors, is the most common complication in modern haemophilia A care. Novel non-factor replacement therapies, such as emicizumab, have sought to address the limitations of bypassing agents for bleeding management in patients with inhibitors.However, immune tolerance induction (ITI) remains the primary method for eradicating inhibitors and restoring the hemostatic response to fVIII. Aim:The aim of this study was to review a case series of paediatric patients with haemophilia A and inhibitors who have received ITI for inhibitor eradication concomitantly with emicizumab prophylaxis for bleeding prevention.Methods: Single institution retrospective chart review of paediatric patients with severe haemophilia A receiving ITI and emicizumab.Results: Seven patients were included in this cohort. Six patients used three different recombinant fVIII products at 100 IU/kg three times per week, and one patient used a plasma-derived fVIII product at an initial dose of 50 IU/kg three times per week.

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“…28 Specifically, subjects were screened for haemostatic response and these ex vivo data were used to individualize clinical dosing regimens; haemostasis was achieved with a single rFVIIa/FVIII administration in 90% of bleeding events. 37 Regardless of the rationale behind any specific dosing regimen, there now exists a clear emphasis on individualizing patient care, with the goals of bleed prevention, rapid haemostasis, patient convenience and predictable efficacy impacting product(s), dose and timing. 35 Published guidelines support the administration of bypassing agent prophylaxis for inhibitor patients who experience frequent bleeds, including those on immune tolerance induction therapy.…”

Section: Combination Therapymentioning

confidence: 99%

The evolution of factor VIIa in the treatment of bleeding in haemophilia with inhibitors

Meeks

Leissinger

2019

Haemophilia

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The use of activated factor VII (FVIIa) for the treatment of bleeding events in haemophilia patients with inhibitors was first reported over 30 years ago. Since then clinical trials, registries, case series, real‐world experience and an understanding of its mechanism of action have transformed what was originally a scientific curiosity into one of the major treatments for inhibitor patients, with innovative therapeutic regimens, dose optimization and individualized care now widely practiced. Given current understanding and use, it might be easy to forget the years of clinical research that led up to this point; in this review, we lay out changes based on broad eras of rFVIIa use. These eras cover the original uncertainty associated with dosing, efficacy and safety; the transformation of care ushered in with its widespread use; and the optimization and individualization of patient care and the importance of specialized support provided by haemophilia treatment centres. Today with the introduction of novel prophylactic agents such as emicizumab, we once again find ourselves dealing with the uncertainties of how best to utilize rFVIIa and newer investigational variants such as marzeptacog alfa and eptacog beta; we hope that the experiences of the past three decades will serve as a guide for this new era of care.

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Hemophilia and inhibitors: current treatment options and potential new therapeutic approaches

Cited by 76 publications

References 48 publications

Immune tolerance induction: What have we learned over time?

Immune tolerance induction: What have we learned over time?

Immune tolerance induction in paediatric patients with haemophilia A and inhibitors receiving emicizumab prophylaxis

The evolution of factor VIIa in the treatment of bleeding in haemophilia with inhibitors

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