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Nathan Connell: Can a Thrombophilic Factor VIII Variant Inform Future Hemophilia A Therapies?

Nathan Connell/LinkedIn

Nov 11, 2026, 09:32

Nathan Connell: Can a Thrombophilic Factor VIII Variant Inform Future Hemophilia A Therapies?

Nathan Connell, Clinical Chief of Hematology at Brigham and Women’s Faulkner Hospital, shared a post on LinkedIn about a recent article by Johnathan Morris et al. published in Blood, adding:

“Can a naturally occurring thrombophilic variant of factor VIII help inform the next generation of hemophilia A therapies?

Fascinating new work from Johnathan Morris, Lindsey George, and colleagues in Blood characterizes FVIII Aurora (R571S), a naturally occurring gain-of-function FVIII variant with important implications for thrombosis, hemostasis, and potentially hemophilia A gene therapy.

The mechanism is particularly interesting. FVIII Aurora exhibits a 10- to 20-fold increase in affinity for activated factor IX (FIXa), enhancing intrinsic tenase complex formation. This interaction also protects FVIIIa from A2-domain dissociation and activated protein C (APC)-mediated inactivation. Importantly, the variant is not intrinsically resistant to APC; this protection depends on its enhanced interaction with FIXa.

The functional consequences are striking:

Approximately sixfold greater FVIII activity by one-stage assay, despite essentially normal chromogenic activity.
Four- to fivefold greater hemostatic potency in hemophilia A mice.
Significantly increased platelet and fibrin accumulation in a venous thrombosis model, even at physiologic FVIII antigen concentrations.

In their accompanying commentary, Andrew Song and Jorge Di Paola raise an intriguing translational possibility: Could FVIII Aurora play a role in hemophilia A gene therapy, analogous to FIX Padua (R338L) in hemophilia B?

The use of a high-specific-activity FIX variant has been an important advance in hemophilia B gene therapy. A similarly enhanced FVIII construct could theoretically provide meaningful hemostatic correction at lower levels of transgene expression, potentially addressing some of the challenges associated with FVIII expression and durability.

But there is an important distinction. FVIII Aurora was discovered through a severe thrombotic phenotype. Enhanced FVIII potency, particularly when coupled with reduced physiologic downregulation, may substantially narrow the therapeutic window. Careful evaluation of expression levels, thrombin generation, thrombosis risk, and long-term safety would be essential before clinical translation.

The marked discrepancy between one-stage and chromogenic FVIII assays is also a reminder that our laboratory measurements do not always capture the same aspects of coagulation biology, with implications for both thrombophilia evaluation and monitoring future therapies.

This is an excellent example of how understanding the molecular basis of thrombosis can generate new opportunities for treating bleeding disorders. The challenge will be translating enhanced coagulation efficiency into safer, more durable hemostasis, without increasing thrombotic risk.

Original study: Morris et al., Blood (2026)

Accompanying commentary: Song and Di Paola, Blood (2026)”

Title: Factor VIII Aurora: a naturally occurring gain-of-function FVIII variant with enhanced FIXa affinity

Authors: Johnathan Morris, Robert Davidson, Connor Watson, Lindsey George

Nathan Connell: Can a Thrombophilic Factor VIII Variant Inform Future Hemophilia A Therapies?