Abstract Number: PB0982
Meeting: ISTH 2021 Congress
Background: High altitude residents and pathologic existence of COPD exist as certain of the oxygen-compromised environments. These surroundings are associated with platelet hyperactivity. Platelets have restricted access to oxygen if they are confined within a core of aggregate. However, to sustain thrombus, they continue to perform some energy-intensive procoagulant activities. So, studying the platelet signaling in relation to mechanistic basis of thrombus stability under hypoxia is critical.
Aims: We aim to:
1. Investigate role of hypoxia-inducible factor-2 alpha (HIF-2a) in hpoxia and
2. Rule out whether hypoxia will induce synthesis of PAI-1 and shedding of extracellular vesicles.
Methods: 1. Platelet preparation and western-blot analysis,
2. Hypoxic stimulation of isolated human platelets,
3. Isolation & analysis of platelet-derived extracellular vesicles,
4. Measurement of intracellular free calcium,
5. Analysis of platelets from COPD and individuals residing at high altitude.
Results: 1. Human platelets express HIF-2a. The exposure to either hypoxic stress of physiological agonists had augmented the expression of HIF-2a in human platelets.
2. Hypoxia and hypoxia-mimetics induced the shedding of extracellular vesicles and synthesis of PAI-1 in human platelets.
3. Hypoxia-mimetics induce shedding of extracellular vesicles and a rise in intracellular free calcium in human platelets.
4. Platelets from patients with COPD have higher expression of HIF-2a and PAI-1 than those from healthy counterparts.
5. Platelets from high-altitude residents have higher expression of HIF-2a and PAI-1 than those from lowlander counterparts.
Conclusions: Hypoxia stress stimulates platelets to synthesize PAI-1 and shed extracellular vesicles. Both of these contribute to prothrombotic phenotype associated with hypoxia. The hypoxia mimetics had laid to stabilization of HIF-2a and accelerates thrombus formation. In agreement of these findings, platelets from COPD and high-altitude-residents exhibited thrombotic attributes with abundant expression of HIF-2a and PAI-1. So, the approach to target hypoxia-signaling can be an effective anti-thrombotic strategy.
To cite this abstract in AMA style:Mallick RL, Chaurasia SN, Dash D, Mallick P. Role of Platelet HIF-2 Alpha to Indorse Thrombogenicity through Synthesis of PAI-1 during Hypoxia [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/role-of-platelet-hif-2-alpha-to-indorse-thrombogenicity-through-synthesis-of-pai-1-during-hypoxia/. Accessed May 20, 2022.
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