Measurement of B‐domain‐deleted ReFacto <scp>AF</scp> activity with a product‐specific standard is affected by choice of reagent and patient‐specific factors

Jacquemin, Marc; Vodolazkaia, Alexandra; Toelen, Jaan; Schoeters, Joke; Horenbeeck, Isa Van; Vanlinthout, Ingrid; Debasse, Mirjam; Peerlinck, Kathelijne

doi:10.1111/hae.13123

Cited by 6 publications

(7 citation statements)

References 16 publications

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“…Furthermore, it remains to be determined whether an identical underestimation of FVIII activity with OSAs is observed with all patients and in all circumstances, notably during surgical intervention. By comparison, we recently observed that in samples from patients treated with ReFacto AF R , the ratios between FVIII:C levels measured with a CSA and with an OSA varied from 1 patient to another, despite both assays having been calibrated with the product‐specific calibrator, ReFacto AF laboratory standard . As all samples analyzed during that study were collected during and immediately after a surgical intervention, it cannot be excluded that the ratios between the OSAs and the CSAs were not only dependent on the patients themselves but also on the type of surgical intervention.…”

Section: How Can We Do Better?mentioning

confidence: 97%

“…In this case, the measurement of the product was shown to be highly dependent on the type and concentration of the phospholipids used in the assay . However, the mechanisms may be more complex, as the discordance between the assays also varies from 1 patient to another …”

Section: Mechanisms Responsible For Discrepancies Between Fviii and Fmentioning

confidence: 99%

“…Spiked samples showing the same discordances between assays as plasma samples from treated patients are likely highly representative of the latter . The evaluation of the commutability of spiked samples must also take into account potential variability from patient to patient …”

Section: How Can We Do Better?mentioning

confidence: 99%

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New challenges and best practices for the laboratory monitoring of factor VIII and factor IX replacement

Bossche

Peerlinck

Jacquemin

2018

Int J Lab Hematology

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Several recombinant factor VIII and factor IX concentrates with extended half-life (EHL) have recently been validated by clinical studies. The availability of these novel concentrates is expected to significantly facilitate the treatment of patients with hemophilia A and B. However, the modification applied to these molecules has introduced variations in their activity measurement in routine coagulation assays. Depending on the assays, underestimations of up to 10-fold or overestimations of up to approximately 30-fold in the measurements of the recovery have been reported in some factor concentrates. Such biases in monitoring may lead to major under- or overtreatment, as well as unnecessary searching for inhibitor antibodies. In this review, we discuss the guidelines and recommendations that allow the selection of optimal strategies to monitor patients treated with these novel factor concentrates. Based on the specificities of the assays and on local regulations, different chromogenic substrate assays in addition to one-stage clotting assays may be validated to allow the accurate measurement of all novel products. An efficient communication between the clinical laboratory and the clinicians is essential to ensure that the appropriate assays are carried out in laboratories and that the clinicians correctly evaluate the data. Further laboratory and clinical studies are still required for the optimization of the laboratory assays that can be used in the measurement of novel factor VIII and factor IX concentrates with EHL.

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Section: How Can We Do Better?mentioning

confidence: 97%

Section: Mechanisms Responsible For Discrepancies Between Fviii and Fmentioning

confidence: 99%

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New challenges and best practices for the laboratory monitoring of factor VIII and factor IX replacement

Bossche

Peerlinck

Jacquemin

2018

Int J Lab Hematology

Self Cite

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“…In the only phase 3 trial of gene therapy for hemophilia completed and published to date (of valoctocogene roxaparvovec), the primary endpoint was the change from baseline in median FVIII activity during weeks 49–52, assessed using the CSA [ 62 , 63 ]. We would like to point out that, as successfully experimented with the BDD-FVIII recombinant product, the use of a standard reference factor provided by the company, would assure accuracy and precision in measuring the achieved levels of a transgenic factor in treated patients in a simple one-stage assay [ 107 ].…”

Section: Assessment Of Efficacy Of Fviii Expressionmentioning

confidence: 99%

The Arrival of Gene Therapy for Patients with Hemophilia A

Castaman

Minno

Cristofaro

et al. 2022

IJMS

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Historically, the standard of care for hemophilia A has been intravenous administration of exogenous factor VIII (FVIII), either as prophylaxis or episodically. The development of emicizumab, a humanized bispecific monoclonal antibody mimicking activated FVIII, was a subsequent advance in treatment. However, both exogenous FVIII and emicizumab require repeated and lifelong administration, negatively impacting patient quality of life. A recent breakthrough has been the development of gene therapy. This allows a single intravenous treatment that could result in long-term expression of FVIII, maintenance of steady-state plasma concentrations, and minimization (or possibly elimination) of bleeding episodes for the recipient’s lifetime. Several gene therapies have been assessed in clinical trials, with positive outcomes. Valoctocogene roxaparvovec (an adeno-associated viral 5-based therapy encoding human B domain-deleted FVIII) is expected to be the first approved gene therapy in European countries, including Italy, in 2022. Some novel challenges exist including refining patient selection criteria, managing patient expectations, further elucidation of the durability and variability of transgene expression and long-term safety, and the development of standardized ‘hub and spoke’ centers to optimize and monitor this innovative treatment. Gene therapy represents a paradigm shift, and may become a new reference standard for treating patients with hemophilia A.

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“…Calibration of the one‐stage assay with a product‐specific standard has also been recommended . However, this has not eliminated some patient‐specific factors that can contribute to discrepancy when assaying postinfusion plasma samples …”

Section: Challenges To Be Addressed With Bioengineered Fviii Constructsmentioning

confidence: 99%

Bioengineered molecules for the management of haemophilia: Promise and remaining challenges

Pipe

2018

Haemophilia

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Recombinant DNA technology has led to accelerating introduction of novel therapeutics for the treatment of haemophilia. This technology has driven the development of recombinant clotting factors, extended half-life clotting factors, alternative biologics to promote haemostasis and enabled the launch of the gene therapy era for haemophilia. At the core of this technology is the ability to study the structure and function of the native molecules and to apply rational bioengineering to overcome limitations to the existing therapies. Through the study of haemophilia-causing mutations, site-directed mutagenesis, detailed structural models and a wide repertoire of animal models, new bioengineering strategies are helping overcome some of the remaining limitations and challenges of traditional clotting factor concentrates. Some of these bioengineering strategies are now being partnered with improvements in vectorology leading to the first wave of successful gene therapy approaches. This study will review past and present bioengineered molecules that are advancing care for haemophilia as well as novel approaches that promise to continue to improve care and outcomes for patients with haemophilia.

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Measurement of B‐domain‐deleted ReFacto AF activity with a product‐specific standard is affected by choice of reagent and patient‐specific factors

Cited by 6 publications

References 16 publications

New challenges and best practices for the laboratory monitoring of factor VIII and factor IX replacement

New challenges and best practices for the laboratory monitoring of factor VIII and factor IX replacement

The Arrival of Gene Therapy for Patients with Hemophilia A

Bioengineered molecules for the management of haemophilia: Promise and remaining challenges

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