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Updated: Jun 5, 2026

A Uniform Shear Assay for Human Platelet and Cell Surface Receptors via Cone-plate Viscometry
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Histidine-rich glycoprotein modulates platelet adhesion and aggregation by binding to GPIbα and GPIIb/IIIa

Rida Malik1,2, Ji Zhou1,2, Miguel A D Neves3,4

  • 1Thrombosis and Atherosclerosis Research Institute and Hamilton Health Sciences, Hamilton, ON, Canada.

Blood
|June 4, 2026
PubMed

Insights

Histidine-rich glycoprotein (HRG) regulates platelet function by binding to key receptors, inhibiting adhesion and aggregation. Lower HRG levels in sepsis and COVID-19 patients correlate with hyperreactive platelets.

Area of Science:

  • Hematology
  • Biochemistry
  • Molecular Biology

Background:

  • Histidine-rich glycoprotein (HRG) is a plasma protein known to modulate the contact system.
  • HRG's role in platelet biology, despite its presence on platelet surfaces, was previously unclear.
  • Understanding HRG's interaction with platelet receptors is crucial for elucidating its function in hemostasis and thrombosis.

Purpose of the Study:

  • To investigate the direct engagement of HRG with platelet receptors.
  • To determine HRG's effect on platelet adhesion, aggregation, and thrombus formation.
  • To explore the clinical relevance of HRG levels in inflammatory conditions.

Main Methods:

  • Utilized human and murine platelets for in vitro experiments.
  • Employed binding assays to assess HRG interaction with glycoprotein (GP)Ibα and GPIIb/IIIa.
  • Performed flow-based assays and microperfusion chambers to evaluate platelet function under shear stress.
  • Analyzed plasma HRG levels in patients with sepsis and COVID-19.

Main Results:

  • HRG binds to GPIbα on resting and activated platelets and to GPIIb/IIIa on activated platelets.
  • HRG competitively inhibits von Willebrand factor (VWF) and fibrinogen binding to their respective platelet receptors.
  • HRG attenuates platelet agglutination, aggregation, VWF-mediated platelet string formation, and thrombus growth under high shear.
  • Reduced plasma HRG levels in sepsis and COVID-19 patients were associated with a hyperreactive platelet phenotype in vitro.

Conclusions:

  • HRG directly modulates platelet adhesion and aggregation by interacting with GPIbα and GPIIb/IIIa.
  • HRG acts as an endogenous inhibitor of platelet activation, competing with VWF and fibrinogen.
  • HRG deficiency contributes to platelet hyperreactivity, suggesting a role in thrombotic complications of sepsis and COVID-19.

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