Human platelets express endothelial protein C receptor, which can be utilized to enhance localization of factor VIIa activity
Author(s): ,
A. M. Fager
Division of Hematology, Department of Medicine, Duke University School of Medicine, Durham, USA. Pathology and Laboratory Medicine Service, Durham Veterans Affairs Medical Center, Durham, USA
Correspondence: Ammon M. Fager, Division of Hematology, Duke University Medical Center, DUMC Box 3422, Durham, NC 27710, USA|Tel.: +1 919 684 3355|E‐mail:
K. R. Machlus
Division of Hematology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, USA
M. Ezban
Pharmacology, Novo Nordisk A/S, Måløv, Denmark
M. Hoffman
Pathology and Laboratory Medicine Service, Durham Veterans Affairs Medical Center, Durham, USA. Department of Pathology, Duke University School of Medicine, Durham, USA
ISTH Academy. M. Fager A. Sep 4, 2018; 230965
Ammon M. Fager
Ammon  M. Fager
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High‐dose factor VIIa (FVIIa) is routinely used as an effective bypassing agent to treat hemophilia patients with inhibitory antibodies that compromise factor replacement. However, the mechanism by which FVIIa binds activated platelets to promote hemostasis is not fully understood. FVIIa‐DVQ is an analog of FVIIa with enhanced tissue factor (TF)‐independent activity and hemostatic efficacy relative to FVIIa. Our previous studies have shown that FVIIa‐DVQ exhibits greater platelet binding, thereby suggesting that features in addition to lipid composition contribute to platelet–FVIIa interactions.
Endothelial cell protein C receptor (EPCR) also functions as a receptor for FVIIa on endothelial cells. We therefore hypothesized that an interaction with EPCR might play a role in platelet–FVIIa binding.
In the present study, we used flow cytometric analyses to show that platelet binding of both FVIIa and FVIIa‐DVQ is partially inhibited in the presence of excess protein C or an anti‐EPCR antibody. This decreased binding results in a corresponding decrease in the activity of both molecules in FXa and thrombin generation assays. Enhanced binding to EPCR was sufficient to account for the increased platelet binding of FVIIa‐DVQ compared with wild‐type FVIIa. As EPCR protein expression has not previously been shown in platelets, we confirmed the presence of EPCR in platelets using immunofluorescence, flow cytometry, immunoprecipitation, and mass spectrometry.
This work represents the first demonstration that human platelets express EPCR and suggests that modulation of EPCR binding could be utilized to enhance the hemostatic efficacy of rationally designed FVIIa analogs.
coagulation, endothelial protein c receptor, factor VIIa, hemophilia, hemostasis
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