Faculty, Staff and Student Publications
Publication Date
1-1-2025
Journal
Research and Practice in Thrombosis and Haemostasis
Abstract
Management of bleeding in persons with hemophilia and inhibitors involves treatment with bypassing agents, including recombinant activated factor VII (rFVIIa). Two rFVIIa products are commercially approved for use in the United States and the European Union. Eptacog alfa and eptacog beta share the same amino acid sequence but differ in posttranslational modifications. Although rFVIIa has been used to manage bleeding in persons with hemophilia and inhibitors for over 30 years, its mechanisms of action is still being studied. In vitro and in vivo studies have suggested that rFVIIa could promote hemostasis by (1) increasing tissue factor-dependent activation of factor (F)X (FX); (2) directly activating FX on the surface of activated platelets; and (3) downregulating protein C anticoagulant activity through binding to the endothelial protein C receptor (EPCR). Studies of rFVIIa and rFVIIa variants in murine models demonstrate that platelet-dependent activity is sufficient for hemostatic efficacy. Dosing levels required in clinical practice are most consistent with a platelet-dependent mechanism of action. However, in vivo models also suggest that pathways involving EPCR binding contribute to rFVIIa hemostatic activity. Eptacog beta displays increased platelet- and EPCR-dependent endothelial cell binding compared to eptacog alfa. Thus, the relative contribution of these mechanisms to the overall hemostatic efficacy of eptacog alfa and eptacog beta may differ. Further research is required to assess the clinical relevance of these differences. A better understanding of the mechanisms by which rFVIIa promotes hemostasis in patients will provide insights when evaluating clinical outcomes of safety and efficacy for innovative bypassing therapies.
Keywords
blood platelets, endothelial protein C receptor, factor VIIa, hemophilia A, hemophilia B, hemostasis, tissue factor
DOI
10.1016/j.rpth.2024.102670
PMID
39990097
PMCID
PMC11847032
PubMedCentral® Posted Date
12-31-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Hematology Commons, Hemic and Lymphatic Diseases Commons, Internal Medicine Commons, Medical Sciences Commons