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The potential of pre-activated platelets to contribute to thrombus formation

1Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands; Institute for Cardiovascular and Metabolic Research, School of Biological sciences, University of Reading, Reading, UK, MAASTRICHT, Limburg, Netherlands, 2Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands; Institute for Molecular Cardiovascular Research, University Hospital Aachen, RWTH Aachen University, Aachen, Germany, Maastricht, Limburg, Netherlands, 3Institute for Cardiovascular and Metabolic Research, School of Biological sciences, University of Reading, Reading, UK, Reading, England, United Kingdom, 4Departments of Biochemistry and Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands;, Maastricht, Limburg, Netherlands, 5Department of Biochemistry, CARIM, Maastricht University, Maastricht, the Netherlands; Synapse Research Institute Maastricht, The Netherlands, Maastricht, Limburg, Netherlands, 6Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands; Thrombosis Expertise Center, Heart+ Vascular Center, Maastricht University Medical Center, Maastricht, The Netherlands, Maastricht, Limburg, Netherlands

Abstract Number: PB0853

Meeting: ISTH 2022 Congress

Theme: Platelets and Megakaryocytes » Platelet Function and Interactions

Background: Platelet activation results in a conformational change of integrin αIIbβ3, which regulates the adhesiveness of platelets to fibrinogen and VWF and is necessary for thrombus formation. Prior integrin activation can be reversed. We hypothesize that platelet activation with different agonists results in diverse integrin (in)activating effects over time, thereby affecting the participation of pre-activated platelets in thrombus formation.

Aims: To study short-and long-term platelet responses upon GPVI and PAR stimulation and to investigate whether pre-activated platelets contribute to thrombus formation.

Methods: Short-and long-term effects of GPVI and PAR stimulation were evaluated via flow cytometry (PAC-1 and fibrinogen binding) and plate-based aggregation. Pre-activated washed platelets were added to washed red blood cells and fibrinogen and were perfused over collagen type I or fibrinogen surfaces, to assess the role of pre-activated platelets in thrombus formation.

Results: After 30 minutes of PAR stimulation, with thrombin or TRAP6, platelets showed 30-50% less PAC-1 (p < 0.01) and fibrinogen binding (p < 0.05) than after 10 minutes. The ability of platelets to aggregate also decreased after 30 minutes of PAR stimulation compared to immediately after agonist addition (p < 0.05). Contrarily, neither PAC-1 and fibrinogen binding nor aggregation were diminished after 30 minutes of GPVI stimulation with CRP-XL. Compared to unstimulated platelets, short- or long-term pre-activation of platelets (0 or 30 minutes, respectively) with CRP-XL resulted in the formation of larger heterogeneous thrombi on collagen and fibrinogen surfaces. Large heterogeneous thrombi were also formed when platelets were pre-activated short-term with TRAP6. However, after longer incubation with TRAP6, the formed homogeneous thrombi on collagen and fibrinogen resembled those of control, unstimulated platelets.

Conclusion(s): The long-term integrin αIIbβ3 activation by prior platelet triggering with GPVI agonists is accompanied by a more prolonged response and enhanced thrombus formation in comparison to PAR triggering. When integrin αIIbβ3 reverses, platelets retain their normal aggregation pattern under flow.

To cite this abstract in AMA style:

De Simone I, Baaten C, Gibbins J, ten Cate H, Heemskerk J, Jones C, van der meijden P. The potential of pre-activated platelets to contribute to thrombus formation [abstract]. https://abstracts.isth.org/abstract/the-potential-of-pre-activated-platelets-to-contribute-to-thrombus-formation/. Accessed October 1, 2023.

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