{
  "abstract": "Factor VIII Aurora (FVIII-R571S) is the first described naturally occurring enhanced-potency FVIII variant identified in a patient with recurrent thrombosis and early mortality. The patient's plasma exhibited increased procoagulant activity and reduced responsiveness to activated protein C (APC). To define the mechanism, we generated recombinant FVIII-R571S and performed in vitro and in vivo studies. Consistent with the clinical phenotype, FVIII-R571S demonstrated a 6-fold increase in one-stage assay activity, while chromogenic substrate assay activity was comparable to wild-type FVIII (FVIII-WT). This discrepancy was explained by biochemical studies showing that activated FVIII-R571S (FVIIIa-R571S) has 10-20-fold higher affinity for FIXa; notably, the chromogenic assay is insensitive to differences in FVIIIa-FIXa affinity. Additional analyses demonstrated that FVIII-R571S is inactivated by APC and protein S analogous to FVIII-WT, indicating that the variant is not intrinsically APC-resistant. However, the increased affinity of FVIIIa-R571S for FIXa confers FIXa-dependent reduced A2-domain dissociation and APC-mediated inactivation in purified and plasma-based studies. These enhanced biochemical properties translated in vivo to a more potent procoagulant phenotype in hemophilia A mice. In the tail clip assay, FVIII-R571S exhibited a 4-5-fold increase in potency compared to FVIII-WT. In a thrombosis model, FVIII-R571S promoted significantly increased platelet and fibrin accumulation relative to FVIII-WT at equivalent antigen levels. Collectively, these data demonstrate that the prothrombotic phenotype of FVIII-R571S is driven by increased FIXa affinity, which enhances FVIIIa-FIXa complex assembly and function. This same mechanism confers reduced A2 dissociation and functional APC resistance, providing a unifying explanation for the observed gain-of-function phenotype.",
  "abstract_shown": true,
  "affiliations": [
    "Perelman Center for Cellular and Molecular Therapeutics and Hematology, Children’s Hospital of Philadelphia, PA, United States",
    "Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Johnathan J. Morris"
    },
    {
      "affs": [
        0
      ],
      "name": "Robert J. Davidson"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Connor T. Watson"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Lindsey A. George"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/a4kbq2k61918m.bib",
  "cited_by": 0,
  "doi": "10.1182/blood.2026034515",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13725783/",
  "id": "a4kbq2k61918m",
  "issns": [
    "0006-4971",
    "1528-0020"
  ],
  "landing_url": "https://doi.org/10.1182/blood.2026034515",
  "language": "en",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "2720|Hemophilia Treatment and Research"
    ]
  ],
  "openalex": "W7168269355",
  "pdf_url": null,
  "pmcid": "PMC13725783",
  "pmid": "42446089",
  "published": "2026-07-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/a4kbq2k61918m.ris",
  "sources": [
    {
      "first_seen": "2026-11-05T12:22:15Z",
      "native_id": "PMC13725783",
      "source": "pmc",
      "url": "https://doi.org/10.1182/blood.2026034515"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2720|Hemophilia Treatment and Research",
      "subfield": "general"
    }
  ],
  "title": "Factor VIII Aurora: A Naturally Occurring Gain of Function FVIII Variant with Enhanced FIXa Affinity",
  "title_text": "Factor VIII Aurora: A Naturally Occurring Gain of Function FVIII Variant with Enhanced FIXa Affinity",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:21:53Z",
  "url": "https://research.draconitic.com/paper/a4kbq2k61918m",
  "venue": "Blood",
  "versions": []
}