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Histidine-rich glycoprotein binds GPIIb/IIIa and attenuates platelet aggregation

1McMaster University, Hamilton, ON, Canada | Thrombosis and Atherosclerosis Research Institute (TaARI), Hamilton, ON, Canada, Hamilton, Ontario, Canada, 2Department of Laboratory Medicine and Pathobiology, University of Toronto | Keenan Research Center for Biomedical Science, St. Michael’s Hospital, Toronto, ON, Canada | Canadian Blood Services Centre for Innovation, Toronto, ON, Canada, Toronto, Ontario, Canada, 3McMaster University, Hamilton, ON, Canada | Thrombosis and Atherosclerosis Research Institute (TaARI), Hamilton, ON, Canada, Kitchener, Ontario, Canada, 4St. Michael's Hospital, Keenan Research Centre, Toronto, Ontario, Canada

Abstract Number: OC 41.3

Meeting: ISTH 2022 Congress

Theme: Platelets and Megakaryocytes » Platelet Function and Interactions

Background: Histidine-rich glycoprotein (HRG) circulates in plasma at a concentration of 1-3 µM and is released from activated platelets. HRG downregulates the contact system by inhibiting (F) XIIa. In murine models, HRG attenuates FeCl3- and polyphosphate-induced thrombosis and colocalizes with platelets and fibrin in thrombi. Therefore, we hypothesized that HRG binds to platelets and modulates their function.

Aims: Determine whether HRG binds to platelets and if so, identify the mechanism and consequences of this interaction.

Methods: The binding of HRG to glycoprotein (GP) Ibα, thrombin-binding GPIbα peptide, and active GPIIb/IIIa was examined using surface plasmon resonance (SPR), ELISA, and receptor-coated silica beads. HRG binding to washed human and murine platelets was assessed by flow cytometry. The effect of HRG on platelet aggregation in whole blood and platelet-rich plasma was examined using multiple electrode and light transmission aggregometry, respectively.

Results: Using SPR, HRG binds to immobilized GPIbα and thrombin-binding GPIbα peptide with Kd values of 1.0 nM and 0.2 nM, respectively. Using an ELISA, HRG binds immobilized GPIIb/IIIa with a Kd value of 247 nM. HRG binds to GPIIb/IIIa-coated beads with a 4-fold higher affinity than to GPIbα-coated beads. HRG binding increases 3-fold when resting platelets are activated with thrombin. HRG does not bind to resting platelets from GPIbα-deficient mice or activated platelets from Beta3-integrin-deficient mice, suggesting that binding to resting and activated platelets is mediated by GPIbα and GPIIb/IIIa, respectively. HRG competes with fibrinogen for binding to GPIIb/IIIa on thrombin-activated human or mouse platelets and inhibits aggregation in mouse whole blood or human platelet-rich plasma. Finally, whole blood platelet aggregation is enhanced in HRG-deficient mice compared with wild-type mice.

Conclusion(s): HRG binds to GPIbα on resting platelets and GPIIb/IIIa on activated platelets where it competes with fibrinogen, thereby attenuating platelet aggregation. Therefore, HRG may modulate platelet aggregation as well as coagulation.

To cite this abstract in AMA style:

Malik R, Neves M, Zhou J, Hussain R, Fredenburgh J, Ni H, Weitz J. Histidine-rich glycoprotein binds GPIIb/IIIa and attenuates platelet aggregation [abstract]. https://abstracts.isth.org/abstract/histidine-rich-glycoprotein-binds-gpiib-iiia-and-attenuates-platelet-aggregation/. Accessed October 1, 2023.

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