M.P.G. (E)-Ferulic acid against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in silico prediction tools and 3D modeling. The SARS-CoV-2 spike protein and PF4 share at least 1 comparable epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 patients with VITT cross-reacted with SARS-CoV-2 spike protein. Sera from 222 polymerase chain reactionCconfirmed patients with COVID-19 from 5 European centers were tested by PF4-heparin enzyme-linked immunosorbent assays and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in sera from 19 (8.6%) of 222 patients with COVID-19. However, only 4 showed weak to moderate platelet activation in the presence of PF4, and none of those patients developed thrombotic complications. Among 10 (4.5%) of 222 patients who had COVID-19 with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, (E)-Ferulic acid indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in patients with COVID-19 in this study were not associated with thrombotic complications. Introduction Coronavirus disease 2019 (COVID-19) is usually caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded RNA virus encoding 16 nonstructural proteins (1-16), 8 accessory proteins (ORF3a, 6, 7a, 7b, 8, 9b, 9c, and 10), and 4 structural proteins known as S (spike), E (envelope), M (membrane), and N (nucleocapsid) proteins.1 The spike glycoprotein is responsible for recognition of host cell membrane receptors ACE2 and TMPRSS2 and for mediating fusion with the host cell membrane.2 The European Medical Agency has approved 4 vaccines3 for prevention of symptomatic COVID-19. Two of the vaccines are messenger RNA (mRNA)Cbased vaccines encoding the spike protein antigen of SARS-CoV-2 encapsulated in lipid nanoparticles, Comirnaty (BioNTech/Pfizer) and COVID-19 mRNA-1273 vaccine (Moderna). A third vaccine is usually a recombinant chimpanzee adenoviral vector (ChAdOx1-S) encoding the spike glycoprotein of SARS-CoV-2, ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria; AstraZeneca). The fourth is usually a recombinant adenovirus type 26 vector (Ad26.COV2.S) encoding the SARS-CoV-2 spike glycoprotein, the Janssen COVID-19 Vaccine. In Germany since March 2021, about 100 patients4 with venous thromboses at unusual CDC42BPA sites (cerebral venous sinus thrombosis and splanchnic vein thrombosis) in combination with moderate to severe thrombocytopenia were observed (E)-Ferulic acid in individuals 5 to 30 days after vaccination with the ChAdOx1 nCoV-19 COVID-19 vaccine.5-7 Comparable complications have also been reported after vaccination with the Ad26.COV2.S Janssen COVID-19 vaccine,8,9 known as?vaccine-induced immune thrombotic thrombocytopenia (VITT).10 We have identified immunoglobulin G (IgG) class platelet-activating antibodies directed against the cationic platelet chemokine platelet factor 4 (PF4; CXCL4), as the underlying cause of VITT.5 Thromboembolic complications are a major disease burden in (E)-Ferulic acid hospitalized patients with COVID-19, even in patients without severe respiratory disease. Sometimes thrombosis in patients with COVID-19 also occurs at unusual locations such as in cerebral veins.11-13 However, the overall presentations of the patients with COVID-19 or VITT are quite different. VITT patients often show laboratory signs of disseminated intravascular coagulation with severe thrombocytopenia and were otherwise well before the abrupt onset of thrombosis. In contrast, patients with COVID-19 show disseminated intravascular coagulation typically only with severe disease or as a complication of extracorporeal circulatory support.14 A further similarity between patients with COVID-19 or VITT is IgG-mediated platelet activation via platelet FcIIa receptors..