Neutralizing capacity of inhibitors on <scp>FVIII</scp> is lower for natural <scp>FVIII</scp>/<scp>VWF</scp> complex than for isolated <scp>FVIII</scp>:<i> in vitro</i> comparative study in eleven different therapeutic <scp>FVIII</scp> concentrates

Bravo, M I; Ortiz, Ana M.; Costa, Montserrat; Grancha, Salvador; Jorquera, Juan I.

doi:10.1111/hae.12975

Cited by 2 publications

(9 citation statements)

References 10 publications

(13 reference statements)

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“…Data from our studies in the in vivo model indicated that pdFVIII/VWF is more efficient in restoring circulating FVIII levels in the FVIII null E16 KO mouse model preinfused with inhibitors. This information confirms the results of previous in vitro studies 11–15,25 . Moreover, our results in the in vivo model are compatible with those previously reported in similar mouse models of HA using different FVIII concentrates or mixes of the isolated proteins (FVIII+VWF) prepared in the lab 15,27 .…”

Section: Discussionsupporting

confidence: 93%

“…Previous studies performed in vitro on different FVIII-containing products have shown that the rFVIII concentrates invariably contained a fraction of factor FVIII related antigen (FVIII:Ag) molecules (approximately 20%) which was unable to associate with VWF. 28,29 Results of the present clinically oriented ex vivo study confirmed a high level of correspondence with those of previous in vitro studies 14,30 (refer to Supporting information for indirect comparisons). Overall, these ex vivo and in vivo studies are in agreement with the concept that the natural FVIII/VWF complex conferred stronger protection to FVIII against inhibitors.…”

Section: Discussionsupporting

confidence: 87%

“…This product contains an approximate 1:1 ratio between FVIII:C and VWF:RCo activities. Inhibitor reactivity of products with ratio ≥ 1 is similar to that obtained with normal plasma 14 . The FVIII concentrates produced by recombinant technologies (third and fourth generation) were: Advate ® rFVIII, CHO, full chain; Refacto ® BDD‐rFVIII, CHO, moroctocog alfa, B domain deleted; Nuwiq ® BDD‐hrFVIII, HEK, simoctocog alfa, B domain deleted, and Elocta ® BDD‐hrFVIII‐Fc, HEK, Fc fusion protein efmoroctocog alfa, B domain deleted (refer to Table 1, for details on commercial names and abbreviations see Schiavoni et al 19 ).…”

Section: Methodssupporting

confidence: 66%

“…Despite evidence for the presence of VWF in pdFVIII protecting from the development of inhibitors in HA patients, 7,8 there is no consensus in the literature that these concentrates are less immunogenic than FVIII without VWF 9,24 . In contrast, numerous experimental studies have demonstrated that VWF‐containing pdFVIII concentrates provide better protection against inhibitor neutralization than rFVIII products 11,12,14,15,25 . It has been proposed that VWF may act as a shield and chaperone, protecting FVIII from the neutralizing effects of inhibitors 8 .…”

Section: Discussionmentioning

confidence: 99%

“…Concerning antigenicity, early experimental evidence indicated a differential reactivity to inhibitors when several commercial FVIII preparations were challenged in studies in vitro 11,12 . Protection against the inactivating actions of inhibitors seemed to be superior with concentrates containing native pdFVIII/VWF complexes than with preparations that contained complexes produced by combining the isolated proteins in a laboratory 13–15 . Mechanisms of the inactivation of FVIII in in vitro studies or in vivo animal models and their translational impact in the clinical practice have not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Plasma‐derived FVIII/VWF complex shows higher protection against inhibitors than isolated FVIII after infusion in haemophilic patients: A translational study

et al. 2022

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Introduction Presence of von Willebrand factor (VWF) in FVIII concentrates offers protection against neutralizing inhibitors in haemophilia A (HA). Whether this protection is more evident in plasma‐derived (pd) FVIII/VWF or recombinant (r) FVIII concentrates remains controversial. Aim We investigated the protection exerted by VWF against FVIII inhibitors in an in vivo mouse model of HA exposed to pdFVIII/VWF or to various rFVIII concentrates. Methods Haemophilia A mice received the different FVIII concentrates after administration of vehicle or an inhibitory IgG purified from a commercial pool of HA plasma with inhibitors and FVIII:C recoveries were measured. Furthermore, using a novel clinically oriented ex vivo approach, Bethesda inhibitory activities (BU) of a commercial pool of HA plasma with inhibitors were assessed using normal plasma, or plasma from severe HA patients, without inhibitors, after treatment with the same concentrates. Results in vivo studies showed that pdFVIII/VWF offers markedly higher protection against inhibitors when compared with any of the FVIII products without VWF. More importantly, in the ex vivo studies, plasma from patients treated with pdFVIII/VWF showed higher protection against inhibitors (P values ranging .05‐.001) in comparison with that observed in plasma from patients who received FVIII products without VWF, regardless of the type of product evaluated. Conclusion Data indicate that FVIII+VWF complexes assembled in the circulation after rFVIII infusion are not equivalent to the naturally formed complex in pdFVIII/VWF. Therefore, rFVIII infused into HA patients with inhibitors would be less protected by VWF than the FVIII in pdFVIII/VWF concentrates.

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Section: Discussionsupporting

confidence: 93%