Uncoupling of platelet granule release and integrin activation suggests GPIIb/IIIa as a therapeutic target in COVID-19

•Blunted GPIIb/IIIa activation is uncoupled from functional α-granule release in patients with COVID-19, differing from bacterial sepsis.•Subthreshold doses of GPIIb/IIIa blockers prevent thrombus formation in COVID-19. [Display omitted] Thromboembolic events are frequent and life-threating complica...

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Published in:Blood advances 2023-06, Vol.7 (11), p.2324-2338
Main Authors: Weiss, Lukas J., Drayss, Maria, Manukjan, Georgi, Zeitlhöfler, Maximilian, Kleiss, Judith, Weigel, Mathis, Herrmann, Johannes, Mott, Kristina, Beck, Sarah, Burkard, Philipp, Lâm, Thiên-Trí, Althaus, Karina, Bakchoul, Tamam, Frantz, Stefan, Meybohm, Patrick, Nieswandt, Bernhard, Weismann, Dirk, Schulze, Harald
Format: Article
Language:English
Subjects:
Cohort Studies
COVID-19
Humans
Platelet Aggregation Inhibitors - therapeutic use
Platelet Glycoprotein GPIIb-IIIa Complex
Regular
Sepsis
Thrombosis - drug therapy
Thrombosis - etiology
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Summary:•Blunted GPIIb/IIIa activation is uncoupled from functional α-granule release in patients with COVID-19, differing from bacterial sepsis.•Subthreshold doses of GPIIb/IIIa blockers prevent thrombus formation in COVID-19. [Display omitted] Thromboembolic events are frequent and life-threating complications of COVID-19 but are also observed in patients with sepsis. Disseminated thrombosis can occur despite anticoagulation, suggesting that platelets play a direct but incompletely understood role. Several studies demonstrated altered platelet function in COVID-19 with some controversial findings, while underlying disease-specific mechanisms remain ill defined. We performed a comprehensive cohort study with 111 patients, comprising 37 with COVID-19, 46 with sepsis, and 28 with infection, compared with control participants. Platelet phenotype and function were assessed under static and flow conditions, revealing unexpected disease-specific differences. From hospital admission onward, platelets in COVID-19 failed to activate the integrin glycoprotein IIb/IIa (GPIIb/IIIa) in response to multiple agonists. Dense granule release was markedly impaired due to virtually missing granules, also demonstrated by whole-mount electron microscopy. By contrast, α-granule marker CD62P exposure was only mildly affected, revealing a subpopulation of PAC-1−/CD62P+ platelets, independently confirmed by automated clustering. This uncoupling of α-granule release was not observed in patients with sepsis, despite a similar disease severity. We found overall unaltered thrombus formation in COVID-19 and sepsis samples under venous shear rates, which was dependent on the presence of tissue factor. Unexpectedly, under arterial shear rates, thrombus formation was virtually abrogated in sepsis, whereas we detected overall normal-sized and stable thrombi in blood from patients with COVID-19. These thrombi were susceptible to subthreshold levels of GPIIb/IIIa blockers, eptifibatide, or tirofiban that had only a minor effect in control participants’ blood. We provide evidence that low-dose GPIIb/IIIa blockade could be a therapeutic approach in COVID-19.
ISSN:2473-9529
2473-9537
DOI:10.1182/bloodadvances.2022008666