The case definition excludes patients with recent heparin exposure to avoid confusion with heparin-induced thrombocytopenia. to the Paul-Ehrlich Institute, of whom 52 patients fulfilled the BC case definition; 37 (71%) women, 15 (29%) men, median age 460 years (interquartile range 310-603 years). Cerebral venous sinus thrombosis was confirmed in 37 (71%), (additional) multiple thromboses in 19 (37%) patients. Twelve patients died. Non-survivors showed lower platelet counts compared to survivors (median nadir 15,000/L vs 49,000/L; p<00001). Combined anti-PF4/heparin IgG ELISA and PF4-dependent platelet activation testing Rabbit polyclonal to FN1 yielded sensitivity of 96% (95% confidence interval Pifithrin-alpha 87-100%) and specificity of 77% (50-93%) for TTS. Four patients with thrombocytopenia but without thrombosis presented with severe headache or cerebral bleeding, explaining the lower specificity. == Interpretation == VITT has high mortality and can present with isolated thrombocytopenia, severe headache, and bleeding. Demonstration of platelet activating anti-PF4 IgG has high sensitivity for TTS and captures a wider spectrum of clinically relevant VITT than the current BC case definition. == Funding == Deutsche Forschungsgemeinschaft: 374031971-TRR240; Domagk-Programm Universittsmedizin Greifswald Keywords:Vaccine, thrombosis, thrombocytopenia, Sars-CoV-2, TTS, VITT == Research in context. == == Evidence before this study == Vaccine-induced immune thrombotic thrombocytopenia (VITT) was recognized from March 2021 after vaccination with the adenoviral vector-based vaccines ChAdOx1 nCoV-19, and Ad26nCoV.2S. Strongly reacting anti-platelet factor 4 (PF4) IgG antibodies, which activate platelets in presence of PF4 are found in VITT patients. Apart from VITT, the Thrombosis and Thrombocytopenia Syndrome (TTS) has been defined by the Brighton Collaboration for secondary data analysis following vaccination. We identified all cases with TTS reported in Germany to the federal agency Paul-Ehrlich Institute and provide an analysis of clinical and laboratory features of patients with TTS and confirmed positive PF4-antibody ELISA and functional tests. == Added value of this study == Our nation-wide analysis represents one of the largest cohorts of laboratory confirmed VITT patients. It consolidates that VITT is associated with a high mortality especially at low platelet counts <30,000/L. It adds the information that a subgroup of patients with VITT presents with isolated thrombocytopenia, severe headache, and bleeding but no thrombosis. == Implications of all the available Pifithrin-alpha evidence == The Brighton Collaboration criteria of TTS do not cover all patients with VITT. Combined anti-PF4 IgG ELISA and PF4-enhanced functional testing results in high sensitivity and specificity for TTS and captures a wider spectrum of VITT compared to the Brighton Collaboration case definition. Alt-text: Unlabelled box == Introduction == Pandemic coronavirus disease 2019 (Covid-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Vaccination against SARS-CoV-2 is key to control this pandemic. Since end Pifithrin-alpha of February 2021, venous thromboses at unusual sites including cerebral venous sinus thrombosis (CVST) and/or splanchnic vein thrombosis in combination with moderate to severe thrombocytopenia were observed in individuals approximately 5 to 30 days after vaccination with ChAdOx1 nCoV-19 COVID-19 Vaccine (Astra-Zeneca)1,2,3and with the Covid-19 Vaccine Janssen (Ad26.COV2.S).4,5We and others identified immunoglobulin G class platelet-activating antibodies directed against the platelet chemokine, platelet factor 4 (PF4; CXCL4), as the underlying cause.1,2,3 This adverse reaction to SARS CoV-2 vaccines has been named vaccine-induced immune thrombotic thrombocytopenia (VITT)2,3as clinical definition for this syndrome, while US and European Union regulatory and public health authorities as well as the Brighton collaboration (BC) introduced the term - thrombosis with Pifithrin-alpha thrombocytopenia syndrome - (TTS).6The BC developed an interim case definition of TTS for use in epidemiological studies based on clinical criteria: i) presence of thrombocytopenia defined as a platelet count below 150,000 per L, and ii) new thrombosis. Depending on the methods to confirm thrombosis, three levels (1-3) of evidence are used. The case definition excludes patients with recent heparin exposure to avoid confusion with heparin-induced thrombocytopenia. Importantly, the combination of thrombocytopenia and thrombosis can occur in a variety of other clinical situations apart.