Abstract Number: PB1742
Meeting: ISTH 2020 Congress
Background: Thrombus exists as meshwork of polymerized fibrin clot. It holds the aggregated platelets which remain cut-off from supplies of O2 and nutrients. As we understand in this aspect, access to O2 drops from periphery of a mass of thrombus to its inner core. It, therefore, exposes these cells to differential hypoxic stress. In spite of it, platelets perform several energy-intensive tasks such as protein synthesis, retraction of fibrin clot and extracellular vesicle release.
Aims: As little is known about signalling dynamics in platelets exposed to hypoxia, we aim to explore:
- Nature of hypoxia signalling in human platelets,
- Mechanistic basis of platelet responses to hypoxia and
- Possibility for evolution towards pro-thrombotic phenotype
- Isolation of platelets from fresh human blood by differential centrifugation
- Separation of platelet proteins by SDS-PAGE followed by Western Analysis
- Extraction of total RNA from platelets and reverse-transcription to cDNA followed by qRT-PCR
- Hypoxic stimulation of platelets in automatically controlled hypoxia chamber
- Isolation and analysis of platelet-derived extracellular vesicles (EV) using a Nanoparticle Tracking Analyzer
- Human platelets express HIF-2α. Here, we observed that circulating platelets express HIF-2α and its expression is increased in hypoxia.
- Either hypoxic stress or physiological agonists such as thrombin & collagen augmented expression of HIF-2α.
- Hypoxia had increased the shedding of EVs and synthesis of PAI-1 in human platelets-indicative to inducing the prothrombotic phenotype
Conclusions: Our study elucidates adaptive signalling of human platelets in response to challenges from hypoxic environments & agonist stimulation that closely resemble to environment within thrombus. Under these situations, platelets synthesize HIF-2α and thrombogenic polypeptide PAI-1 as well as EV release which correlate towards prothrombotic state.
As hypoxic adaptation in platelets contribute to prothrombotic phenotype, the strategies to target platelet hypoxia signalling could be an effective, new generation anti-thrombotic strategy.
To cite this abstract in AMA style:Mallick RL, Chaurasia SN, Dash D. Role of HIF-2α in Promoting Thrombogenicity through PAI-1 Synthesis & EV-Releae during Adaptive Signalling in Human Platelets [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/role-of-hif-2%ce%b1-in-promoting-thrombogenicity-through-pai-1-synthesis-ev-releae-during-adaptive-signalling-in-human-platelets/. Accessed March 4, 2024.
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