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Human platelets express endothelial protein C receptor, which can be utilized to enhance localization of factor VIIa activity.

Publication ,  Journal Article
Fager, AM; Machlus, KR; Ezban, M; Hoffman, M
Published in: J Thromb Haemost
September 2018

UNLABELLED: Essentials Factor VIIa binds activated platelets to promote hemostasis in hemophilia patients with inhibitors. The interactions and sites responsible for platelet-FVIIa binding are not fully understood. Endothelial cell protein C receptor (EPCR) is expressed on activated human platelets. EPCR binding enhances the efficacy of a FVIIa variant and could impact design of new therapeutics. SUMMARY: Background 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. Objectives 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. Methods/results 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. Conclusions 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.

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Published In

J Thromb Haemost

DOI

EISSN

1538-7836

Publication Date

September 2018

Volume

16

Issue

9

Start / End Page

1817 / 1829

Location

England

Related Subject Headings

  • Protein C
  • Protein Binding
  • Platelet Activation
  • Peptides
  • Lectins, C-Type
  • Humans
  • Hemostasis
  • Factor Xa
  • Factor VIIa
  • Endothelial Protein C Receptor
 

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Fager, A. M., Machlus, K. R., Ezban, M., & Hoffman, M. (2018). Human platelets express endothelial protein C receptor, which can be utilized to enhance localization of factor VIIa activity. J Thromb Haemost, 16(9), 1817–1829. https://doi.org/10.1111/jth.14165
Fager, A. M., K. R. Machlus, M. Ezban, and M. Hoffman. “Human platelets express endothelial protein C receptor, which can be utilized to enhance localization of factor VIIa activity.J Thromb Haemost 16, no. 9 (September 2018): 1817–29. https://doi.org/10.1111/jth.14165.
Fager AM, Machlus KR, Ezban M, Hoffman M. Human platelets express endothelial protein C receptor, which can be utilized to enhance localization of factor VIIa activity. J Thromb Haemost. 2018 Sep;16(9):1817–29.
Fager, A. M., et al. “Human platelets express endothelial protein C receptor, which can be utilized to enhance localization of factor VIIa activity.J Thromb Haemost, vol. 16, no. 9, Sept. 2018, pp. 1817–29. Pubmed, doi:10.1111/jth.14165.
Fager AM, Machlus KR, Ezban M, Hoffman M. Human platelets express endothelial protein C receptor, which can be utilized to enhance localization of factor VIIa activity. J Thromb Haemost. 2018 Sep;16(9):1817–1829.
Journal cover image

Published In

J Thromb Haemost

DOI

EISSN

1538-7836

Publication Date

September 2018

Volume

16

Issue

9

Start / End Page

1817 / 1829

Location

England

Related Subject Headings

  • Protein C
  • Protein Binding
  • Platelet Activation
  • Peptides
  • Lectins, C-Type
  • Humans
  • Hemostasis
  • Factor Xa
  • Factor VIIa
  • Endothelial Protein C Receptor