Recombinant factor VIIa: new insights into the mechanism of action through product innovation
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 s...
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Elsevier
2025-01-01
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| Series: | Research and Practice in Thrombosis and Haemostasis |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2475037924003650 |
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| author | Miguel A. Escobar Maureane Hoffman Giancarlo Castaman Cedric Hermans Johnny Mahlangu Johannes Oldenburg Charles L. Percy Mark T. Reding Amy D. Shapiro Steven W. Pipe |
| author_facet | Miguel A. Escobar Maureane Hoffman Giancarlo Castaman Cedric Hermans Johnny Mahlangu Johannes Oldenburg Charles L. Percy Mark T. Reding Amy D. Shapiro Steven W. Pipe |
| author_sort | Miguel A. Escobar |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0ac2bdcebab44f5a978697bc80b22ccd |
| institution | Kabale University |
| issn | 2475-0379 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Research and Practice in Thrombosis and Haemostasis |
| spelling | doaj-art-0ac2bdcebab44f5a978697bc80b22ccd2025-02-05T04:32:29ZengElsevierResearch and Practice in Thrombosis and Haemostasis2475-03792025-01-0191102670Recombinant factor VIIa: new insights into the mechanism of action through product innovationMiguel A. Escobar0Maureane Hoffman1Giancarlo Castaman2Cedric Hermans3Johnny Mahlangu4Johannes Oldenburg5Charles L. Percy6Mark T. Reding7Amy D. Shapiro8Steven W. Pipe9Gulf States Hemophilia and Thrombophilia Center, Houston, Texas, USA; Department of Internal Medicine, University of Texas Health Science Center and McGovern Medical School, Houston, Texas, USA; Correspondence Miguel Escobar, University of Texas Health Science Center, 6655 Travis Street, Suite 400, 77030 Houston, TX, USA.Department of Veterans Affairs Medical Center, Pathology and Laboratory Medicine Service, Durham, North Carolina, USA; Department of Pathology, Duke University School of Medicine, Durham, North Carolina, USADepartment of Oncology, Centre for Bleeding Disorders and Coagulation, Careggi University Hospital, Firenze, ItalyDivision of Hematology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), Brussels, BelgiumDepartment of Molecular Medicine and Haematology, Hemophilia Comprehensive Care Center, University of the Witwatersrand and National Health Laboratory Service, Johannesburg, South AfricaDepartment of Experimental Hematology and Transfusion Medicine, Institute of Experimental Hematology and Transfusion Medicine, University Hospital Bonn, Medical Faculty, University of Bonn, Bonn, GermanyDepartment of Clinical Haematology, West Midlands Adult Comprehensive Care Haemophilia & Thrombosis Centre, Queen Elizabeth Hospital, Birmingham, UKDepartment of Medicine, Center for Bleeding and Clotting Disorders, University of Minnesota Medical Center, Minneapolis, Minnesota, USAIndiana Hemophilia and Thrombosis Center, Indianapolis, Indiana, USADepartments of Pediatrics and Pathology, University of Michigan, Ann Arbor, Michigan, USAManagement 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.http://www.sciencedirect.com/science/article/pii/S2475037924003650blood plateletsendothelial protein C receptorfactor VIIahemophilia Ahemophilia Bhemostasis |
| spellingShingle | Miguel A. Escobar Maureane Hoffman Giancarlo Castaman Cedric Hermans Johnny Mahlangu Johannes Oldenburg Charles L. Percy Mark T. Reding Amy D. Shapiro Steven W. Pipe Recombinant factor VIIa: new insights into the mechanism of action through product innovation Research and Practice in Thrombosis and Haemostasis blood platelets endothelial protein C receptor factor VIIa hemophilia A hemophilia B hemostasis |
| title | Recombinant factor VIIa: new insights into the mechanism of action through product innovation |
| title_full | Recombinant factor VIIa: new insights into the mechanism of action through product innovation |
| title_fullStr | Recombinant factor VIIa: new insights into the mechanism of action through product innovation |
| title_full_unstemmed | Recombinant factor VIIa: new insights into the mechanism of action through product innovation |
| title_short | Recombinant factor VIIa: new insights into the mechanism of action through product innovation |
| title_sort | recombinant factor viia new insights into the mechanism of action through product innovation |
| topic | blood platelets endothelial protein C receptor factor VIIa hemophilia A hemophilia B hemostasis |
| url | http://www.sciencedirect.com/science/article/pii/S2475037924003650 |
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