Impact of a product‐specific reference standard for the measurement of a <scp>PEG</scp>ylated <scp>rFVIII</scp> activity: the Swiss Multicentre Field Study

Bulla, Oana; Poncet, Antoine; Alberio, Lorenzo; Asmis, Lars M.; Gähler, Anita; Graf, Laura; Nagler, Michael; Studt, Jan Dirk; Tsakiris, Dimitrios Α.; Fontana, Pierre

doi:10.1111/hae.13250

Cited by 21 publications

(36 citation statements)

References 11 publications

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“…In a sample spiked with 3 IU/dL, however, the recovery of the same product reached a mean of 213.5% . Interestingly, during this study calibration of the assay with a product‐specific standard improved the recovery in the normal range, but not in the low range . A similar overestimation of low FVIII activity was observed in another multicentre study …”

Section: Introductionsupporting

confidence: 75%

“…Similarly, in a multicentre study, Bulla et al recorded a mean recovery of 127.7% of the expected FVIII activity in a sample spiked with 80 IU/dL PEGylated rFVIII (Adynovate ® ). In a sample spiked with 3 IU/dL, however, the recovery of the same product reached a mean of 213.5% . Interestingly, during this study calibration of the assay with a product‐specific standard improved the recovery in the normal range, but not in the low range .…”

Section: Introductionmentioning

confidence: 62%

“…For example, single chain rFVIII (ScrFVIII, Afstyla ® , CSL Behring, Mechelen, Belgium) or PEGylated rFVIII Bay94‐9027 (Bayer, Diegem, Belgium) are underestimated twofold and 10‐fold, respectively, when measured using one‐stage assays activated with silica . By contrast, PEGylated rFVIII BAX 855 (Adynovate ® , Shire, Brussels, Belgium) and Fc‐fusion rFVIII (rFVIIIFc, Elocta ® , Swedish Orphan Biovitrum, Woluwe Saint‐Lambert, Belgium) can be reliably measured with these reagents . Therefore, assays and their reagents must be carefully selected in relation to the EHL‐rFVIII being measured.…”

Section: Introductionmentioning

confidence: 99%

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Accurate measurement of extended half‐life and unmodified factor VIII low levels with one‐stage FVIII assays is dependent on the matrix of calibration curves

et al. 2018

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Introduction The monitoring of factor VIII (FVIII) replacement therapy relies on the accurate measurement of FVIII activity over a large concentration range. However, unexplained overestimation of low FVIII levels has recently been reported with extended half‐life recombinant FVIIIs. Aim The objective of this study was to confirm previous publications indicating that the reagents used to generate the calibration curves determine the accuracy of the measurement of low FVIII levels. Methods We generated FVIII calibration curves with FVIII‐deficient plasmas or a commercial diluent buffer. We then measured FVIII levels in FVIII‐deficient plasma spiked with plasma FVIII, a full‐length recombinant FVIII (Advate®, Shire, Brussels, Belgium) and two extended half‐life recombinant FVIIIs (Elocta® , Swedish Orphan Biovitrum, Woluwe Saint‐Lambert, Belgium and Afstyla®, CSL Behring, Mechelen, Belgium). FVIII levels were also analyzed in spiked samples prediluted two‐ and fourfold, either in diluent buffer or in FVIII‐deficient plasma to evaluate parallelism. Results Coagulation times of calibration curves generated with diluent buffer were longer than those with FVIII‐deficient plasmas. This resulted in an overestimation of FVIII levels lower than 25 IU/dL in spiked samples and in detection of FVIII activity (≥1 IU/dL) in FVIII‐deficient plasma. Predilution of samples with diluent buffer rather than with FVIII‐deficient plasma also led to discordant results. Conclusion Our data confirm that the generation of calibration curves by dilution in FVIII‐deficient plasma is crucial for the accurate measurement of low FVIII levels. When serial dilutions of samples are analyzed, predilution in FVIII‐deficient plasma is required to respect the parallelism criteria. These methods should be more generally implemented for coagulation instruments.

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Section: Introductionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 62%

Section: Introductionmentioning

confidence: 99%

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Accurate measurement of extended half‐life and unmodified factor VIII low levels with one‐stage FVIII assays is dependent on the matrix of calibration curves

et al. 2018

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“…43 A field study has been published in which 35 laboratories in 12 countries returned one-stage clotting FVIII assay data, and 11 centres in eight countries returned chromogenic assay results. 45 In contrast to the study of Turecek, this article reported that FVIII assays in spiked samples containing 30-80 IU/dL overestimated relative to the labelled potency by 28%-32% for one-stage assay and 69%-82% for chromogenic. Results of chromogenic assays and one-stage assays were on average 113% (range 101%-124% for the three samples) and 116% (range 92%-129%) of target based on stated potency, respectively.…”

Section: Adynovimentioning

confidence: 63%

Laboratory measurement of factor replacement therapies in the treatment of congenital haemophilia: A United Kingdom Haemophilia Centre Doctors’ Organisation guideline

et al. 2019

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Laboratory monitoring of factor (F) VIII or FIX replacement therapy for treatment of haemophilia A or B is performed to ensure optimal therapy. A wide variety of commercially available one-stage clotting assays or chromogenic assays of FVIII and FIX is used for this purpose. Discrepancies between results obtained using the different assays have been described in hereditary haemophilia A 1,2 and haemophilia B, 3,4 in the absence of replacement therapy, and after gene therapy for both haemophilia A and B. 5,6 Although discrepancies after infusion of FVIII have been recognized since the advent of recombinant FVIII over 20 years ago, 7,8 this guideline will highlight recent studies of enhanced half-life FVIII and FIX products which demonstrate discrepancies in results both between chromogenic and one-stage clotting assays, and within assay type. There is currently no published consensus or guidance on what magnitude of discrepancy after concentrate infusion is acceptable for clinical use, and this may vary according to the factor level and the clinical AbstractAssay discrepancies can occur with laboratory monitoring of FVIII and FIX replacement therapy, particularly for the extended half-life products. This guideline collates current published data and provides advice on appropriate choice of assays for laboratory measurement of replacement therapy for patients with Haemophilia A and B without inhibitors. It is recommended that each haemophilia centre should ensure that appropriate laboratory assays are available for FVIII and FIX products in local clinical use. Patient samples should be assayed against calibrators traceable to WHO Plasma International Standards. Assay discrepancies are common especially for the extended half-life FVIII and FIX products, and assays of these products may need to be verified with the specific CFC being used. K E Y W O R D Schromogenic assay, extended half-life, factor concentrate, haemophilia, laboratory monitoring

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“…FVIII activity is most commonly measured using the one‐stage aPTT assay. The one‐stage assay is simple but can be associated with significant reagent‐dependent variability due to the wide range of assay reagents (activator type, phospholipid composition), type of deficient plasma, calibrators and instrumentation . It has been reported that PEGylation can interfere with certain APTT reagents, in particular with some silica‐based reagents causing poor precision …”

Section: Introductionmentioning

confidence: 99%

Evaluating the thrombin generation profiles of four different rFVIII products in FVIII‐deficient plasma using FIXa and FXIa activation

et al. 2018

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Impact of a product‐specific reference standard for the measurement of a PEGylated rFVIII activity: the Swiss Multicentre Field Study

Abstract: In this in vitro study, the type of reference standard had a major impact on the measurement of BAX 855 activity. Evaluation was more accurate and precise when using a product-specific reference standard.

Cited by 21 publications

References 11 publications

Accurate measurement of extended half‐life and unmodified factor VIII low levels with one‐stage FVIII assays is dependent on the matrix of calibration curves

Accurate measurement of extended half‐life and unmodified factor VIII low levels with one‐stage FVIII assays is dependent on the matrix of calibration curves

Laboratory measurement of factor replacement therapies in the treatment of congenital haemophilia: A United Kingdom Haemophilia Centre Doctors’ Organisation guideline

Evaluating the thrombin generation profiles of four different rFVIII products in FVIII‐deficient plasma using FIXa and FXIa activation

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