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SARS-CoV-2 spike protein-induced platelet activation: Mechanism for virus and vaccine-induced thrombotic thrombocytopenia

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Covid-19 pandemic stimulated an extremely fast development of effective vaccines. Recent studies found platelet-activating antibodies against platelet factor 4 (PF4) in both clinically ill Covid-19 patients and vaccine-induced thrombotic thrombocytopenia (VITT) patients. Here, we use various tools to identify the binding reaction of the SARS-CoV-2 spike glycoprotein (SP) with PF4 that results in immunogenic platelet-activating PF4/SP complexes. This binding is evidenced by an increase in mass, optical intensity, and stable binding force observed by quartz crystal microbalance, enzyme immune assay, and force spectroscopy, respectively. The SP induced an increase in the size of PF4 and switched the surface zeta potential of the PF4 from positive to negative values as evaluated by dynamic light scattering. The SP-induced platelet aggregation was identified by functional assay and flow cytometry but in a concentration-dependent manner. Our results indicated that the formed PF4/SP complexes can, on one hand, trigger the formation of PF4-antibodies and on the other hand mediate/activate platelets followed by inducing thrombotic events, which is the mechanism for excessive procoagulant activity observed in Covid-19 patients. With vector-based vaccines, we suggest that soluble SP are produced during the transcription process, forming antigenic PF4/SP complexes that result in a high rate of clotting effects in vaccinated individuals with Ad26.COV2.S and ChAdOx1nCoV-19 vaccines. An additional consideration of PF4/SP complexes in the current guidelines for the diagnosis of VITT will improve the treatment in patients. Our results serve a high demand to develop an effective method to treat Covid-19 patients and improve the safety for Covid-19 vaccination.