ArticleBlood2026
One-stage assay factor VIII activity reflects AAV-derived factor VIII-enhanced thrombin activation and predicts phenotype.
Article in Blood, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
abstractHemophilia A (HA) phenotype is predicted by factor VIII (FVIII) activity. Most HA adeno-associated virus (AAV) trials incorporate the B-domain-deleted FVIII-SQ variant, and 1-stage assay (OSA) FVIII activity exceeds chromogenic substrate assay (CSA) values by 1.5-fold to twofold. This contrasts with recombinant FVIII-SQ (rFVIII-SQ), suggests altered biochemical properties, and highlights the need to determine which assay reflects hemostatic function. In gene therapy-treated mice and SPK-8011 trial participants, AAV-derived FVIII-SQ (AAV-FVIII-SQ) activation and function within the intrinsic tenase enzyme complex was compared with rFVIII-SQ. In both species, AAV-FVIII-SQ demonstrated normal cofactor function and A2-domain stability. In mice, the assay discrepancy persisted without von Willebrand factor (VWF), indicating it is not driven by altered VWF interactions. Both species demonstrated enhanced thrombin-mediated activation of AAV-FVIII-SQ, detectable by OSA but not CSA. Negative binomial regression analysis of 23 SPK-8011 participants, representing 99 cumulative patient-years, trended toward better prediction of annualized bleeding rate with OSA than CSA. In vivo evaluation of AAV-FVIII-SQ in mice demonstrated that OSA activity better correlated with hemostatic function and corresponded to rFVIII-SQ function. These findings support that OSA FVIII activity reflects AAV-FVIII-SQ function within the intrinsic tenase complex, captures enhanced activation not detected by CSA, and best predicts clinical outcome.
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