Damage-associated cellular markers in the clinical and pathogenic pro file of vaccine-induced immune thrombotic thrombocytopenia

Background: Adenoviral vector -based COVID-19 vaccine -induced immune thrombotic thrombocytopenia (VITT) is rare but carries signi ficant risks of mortality and long-term morbidity. The underlying pathophysiology of severe disease is still not fully understood. The objectives were to explore the pathophysiological pro file and examine for clinically informative biomarkers in patients with severe VITT. Methods: Twenty-two hospitalized patients with VITT, 9 pre- and 21 post-ChAdOx1 vaccine controls, were recruited across England, United Kingdom. Admission blood samples were analyzed for cytokine pro files, cell death markers (lactate dehydrogenase and circulating histones), neutrophil extracellular traps, and coagulation parameters. Tissue specimens from deceased patients were analyzed. Results: There were strong immune responses characterized by signi ficant elevations in proin flammatory cytokines and T helper 1 and 2 cell activation in patients with VITT. Markers of systemic endothelial activation and coagulation activation in both circulation and organ sections were also signi ficantly elevated. About 70% ( n = 15/22) of patients met the International Society for Thrombosis and Haemostasis criteria for disseminated intravascular coagulation despite negligible changes in the prothrombin time. The increased neutrophil extracellular trap formation, in conjunction with marked lymphopenia, elevated lactate dehydrogenase, and circulating histone levels, indicates systemic immune cell injury or death. Both lymphopenia and circulating histone levels independently predicted 28 -day mortality in patients with VITT. Conclusion: The coupling of systemic cell damage and death with strong immunein flammatory and coagulant responses are pathophysiologically dominant and clinically relevant in severe VITT.