# Understanding and Enhancing the Therapeutic Efficacy of Factor VIIa for Emergency Hemostasis

> **NIH VA IK2** · DURHAM VA MEDICAL CENTER · 2024 · —

## Abstract

Intracranial hemorrhage (ICH) is the second most common cause of stroke and results in the highest rates
of stroke-related morbidity and mortality. While ICH can be spontaneous, it is also a well-known feature of
severe traumatic brain injury (TBI). Each year 1.7 million Americans sustain a TBI and nearly half of these will
result in long-term disability. In addition, TBI has become the signature wound of recent military operations
and training with 17.3% of veterans meeting criteria for TBI during military service in Iraq and Afghanistan.
 Despite intensive research efforts and advances in critical care, the 30-day mortality rate from ICH has not
changed significantly in the last 30 years. Current management remains largely restricted to optimizing
cerebral perfusion pressure and providing supportive care. While the use of recombinant Factor VIIa (rFVIIa)
as a hemostatic agent significantly reduces hematoma growth for patients with hemorrhagic stroke and TBI,
the mortality benefit remains unclear. This is, in part, due to the significant risk of complications from diffuse
inflammation and microvascular dysfunction that can exacerbate hemorrhage and cause secondary neuronal
injury via mechanisms that are not amenable to surgical or hemostatic intervention. In addition, the use of
rFVIIa is limited by a significant risk of thrombotic complications, particularly at higher doses. Therefore, a
molecule with both hemostatic and anti-inflammatory activities could have distinct advantages over existing
therapies by reducing both the primary and secondary complications of bleeding.
 The efficacy of rFVIIa is dependent on binding to activated platelets; however, previous attempts to improve
this drug have failed, in part, because the mechanism of platelet-rFVIIa binding is not well understood.
Therefore, the overall objective of the proposed studies is to elucidate the mechanisms of platelet-rFVIIa
interaction as a means to design rFVIIa variants with enhanced hemostatic efficacy, reduced thrombotic risk,
and potential anti-inflammatory and cytoprotective properties.
 Studies in the current proposal will focus on how procoagulant platelets store and regulate the surface
expression of a novel protein that contributes to the binding and hemostatic activity of rFVIIa. These studies
will use a combination of confocal microscopy and immunogold staining followed by transmission electron
microscopy to characterize the subcellular localization of this protein and further define its origin, trafficking,
and the potential regulation of its platelet-surface expression. This data will be enhanced by further studies
that will utilize a chemical cross-linking and proteomics approach to identify additional partner(s) that make up
the complex simultaneous interactions required for platelet-rFVIIa binding. Finally, this work will also
determine the therapeutic potential of a novel Protein C-FVIIa chimera designed with the potential for
increased hemostatic efficacy and re...

## Key facts

- **NIH application ID:** 10873010
- **Project number:** 5IK2BX005303-04
- **Recipient organization:** DURHAM VA MEDICAL CENTER
- **Principal Investigator:** AMMON M FAGER
- **Activity code:** IK2 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873010

## Citation

> US National Institutes of Health, RePORTER application 10873010, Understanding and Enhancing the Therapeutic Efficacy of Factor VIIa for Emergency Hemostasis (5IK2BX005303-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10873010. Licensed CC0.

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