Abstract Number: PB1001
Meeting: ISTH 2022 Congress
Background: Despite advances in critical care, the treatment of intracranial hemorrhage (ICH) is primarily restricted to supportive measures. This is largely due to diffuse thrombin-mediated inflammation and microvascular dysfunction that leads to neurotoxicity via mechanisms not amenable to surgical or hemostatic intervention. At pharmacologic doses, recombinant Factor VIIa (rFVIIa) binds to activated platelets and activates Factor X in a tissue factor (TF)-independent manner. rFVIIa also binds endothelial protein C receptor (EPCR) to initiate signaling that promotes cytoprotective and anti-inflammatory effects via cleavage of protease-activated receptor (PAR)-1. However, the efficacy of rFVIIa in ICH is limited by a significant risk of TF-dependent thrombosis. We have designed a novel FVIIa chimera (PC-FVIIa) to retain the hemostatic and anti-inflammatory properties of rFVIIa while minimizing its ability to promote TF-dependent thrombosis.
Aims: The purpose of this study was to characterize the in vitro activity of PC-FVIIa.
Methods: Antithrombin active-site titrations determined the proteolytic activity of PC-FVIIa. The hemostatic activity of PC-FVIIa was evaluating using standard FXa and thrombin generation assays. A cell-surface ELISA evaluated the ability of PC-FVIIa to cleave endothelial PAR-1. The ability of PC-FVIIa to protect against thrombin-induced endothelial barrier disruption was determined in a well-described transwell assay.
Results: PC-FVIIa retains the proteolytic activity of rFVIIa. PC-FVIIa had no measureable TF binding, but exhibited increased TF-independent hemostatic activity compared to rFVIIa on phospholipids and activated platelets (Figure1). PC-FVIIa cleaved PAR-1 more efficiently than rFVIIa or Activated Protein C (APC) and provided better protection against endothelial barrier disruption (Figure2).
Conclusion(s): PC-FVIIa has the potential for increased hemostatic and anti-inflammatory activity compared to rFVIIa while decreasing the risk for thrombotic complications and providing distinct advantages over existing therapies for emergency hemostasis.
This work was supported by the US Department of Veteran’s Affairs, Office of Research and Development. Additional support included an investigator-initiated grant from Otello Medical, Inc.
To cite this abstract in AMA style:Fager A, Hoffman M, Monroe D. A Novel Human Factor VIIa Chimera with Increased Tissue Factor-Independent Hemostatic and Anti-Inflammatory Activities [abstract]. https://abstracts.isth.org/abstract/a-novel-human-factor-viia-chimera-with-increased-tissue-factor-independent-hemostatic-and-anti-inflammatory-activities/. Accessed March 4, 2024.
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