ENDOGENOUS REGULATION OF NEUTROPHIL EXTRACELLULAR TRAPS IN ACUTE ISCHAEMIC STROKE DUE TO VACCINE-INDUCED IMMUNE THROMBOTIC THROMBOCYTOPENIA

ABSTRACT

Background and aims: Vaccination is one of the most important countermeasures in the ongoing COVID19-pandemic. Pharmacovigilance concerns, however, emerged after very rare, but potentially disastrous thrombotic complications following vaccination with ChAdOx1. The underlying pathology was described as platelet factor 4 antibody mediated vaccine-induced immune thrombotic thrombocytopenia (VITT). Mechanisms of immunothrombosis including the regulation of neutrophil extracellular traps (NETs) might be of crucial importance in VITT. Methods: In this study, we had the exceptional opportunity to investigate blood and thrombus samples of a patient who suffered severe ischaemic stroke due to VITT undergoing successful mechanical thrombectomy (MT) in comparison to 13 control stroke patients with similar clinical characteristics without VITT. Cerebral thrombi were stained for complement factors, NETs-markers, DNase and LL-37 and were histologically assessed. In blood samples before MT and 7 days later, cell-free DNA, myeloperoxidase-histone complexes, myeloperoxidase activity, DNase activity, LL-37 and inflammatory cytokines were determined. Results: We identified NETs-markers in thrombi of all patients. The thrombus of the VITT-patient, however, exclusively revealed complement factors and high amounts of NETs-degrading DNase and LL-37, which protects NETs from degradation. In accordance, ex vivo and in vitro studies also implied a disturbed regulation of NETs in VITT-samples. Moreover, we found markedly pronounced temporal changes of specific circulating cytokines in the VITT-case. Conclusions: The results of this study suggest a disturbed endogenous regulation of NETs in VITT involving a pro-inflammatory response and fulminant clinical course. Further studies are warranted to confirm our results and to provide deeper insights into the causative mechanisms.