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PLATELET-NEUTROPHIL AGGREGATE FORMATION INDUCES NLRP3 INFLAMMASOME ACTIVATION IN VACCINE-INDUCED THROMBOTIC THROMBOCYTOPENIA
Inflammasome
Platelet activation
Platelet-neutrophil aggregate
Vaccineinduced thrombotic thrombocytopenia
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Abstract
Background: Although rare, vaccine-induced thrombotic thrombocytopenia (VITT) following adenoviral vector COVID-19 vaccination is a concerning and often severe adverse effect of vaccination. The generation of high antiplatelet factor 4 antibody titers promotes the formation of immune complexes capable of activating platelets and neutrophils through FcγRIIa. Objectives: Given that platelet-leukocyte aggregate formation and inflammasome activation are common features of thromboinflammatory diseases, we aimed to evaluate if these are also features of VITT. Methods: Samples from a cohort of 57 postvaccination thrombosis patients and 28 age- and sex-matched unvaccinated individuals were used for ex vivo investigation of platelet-leukocyte aggregate formation and inflammasome activation. Results: Patients with clinical features of VITT presented elevated levels of activated caspase-1, interleukin-18, and interleukin-1β in the plasma. We also found that soluble factors in the plasma of VITT patients induce the formation of platelet-neutrophil aggregates but not platelet-monocyte or platelet T-cell aggregates, which are associated with increased caspase-1 activation in neutrophils ex vivo. Platelet-neutrophil aggregate formation was prevented through blockage of FcγRIIa with the neutralizing antibody IV.3 and through blockage of P-selectin or integrin αɪɪbβ₃, also inhibiting caspase-1 activation. Additionally, MCC950, an NLRP3 inflammasome inhibitor, blocked caspase-1 activation. Conclusion: Taken together, these data show that VITT plasma induces platelet-neutrophil aggregate formation in a FcγRIIa-dependent manner and that platelet-neutrophil interactions may contribute to thromboinflammation in VITT patients by supporting NLRP3 inflammasome activation. These data shed light on novel immunopathological events associated with inflammation and thrombosis in VITT patients.
Keywords
ImmunothrombosisInflammasome
Platelet activation
Platelet-neutrophil aggregate
Vaccineinduced thrombotic thrombocytopenia
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