Platelet activating histone/anti-histone immune complexes are associated with a new entity of thrombosis and thrombocytopenia syndrome

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Introduction: Thrombosis and Thrombocytopenia syndromes (TTS) describe immune mediated thrombotic adverse reactions following vaccination against Covid-19. Vaccine-induced immune thrombotic thrombocytopenia (VITT) is the most prominent entity of TTS, induced by adenovirus vector-based vaccines. VITT is mediated by anti-platelet factor 4 (PF4) IgG-antibodies, activating platelets via Fc-gamma IIa receptors (FcgRIIa). However, other entities of antibody mediated TTS exist apart from VITT. We investigated patients with TTS after mRNA-based Covid-19 vaccination whose sera tested negative for anti-PF4 antibodies. Method: Clinical features of TTS patients whose sera were sent to the Greifswald laboratory were analyzed with the treating physicians and from laboratory forms. Sera were tested for platelet activating anti-PF4 IgG antibodies by ELISA and a functional assay; and for antiplatelet antibodies by the monoclonal antibody-specific immobilization of platelet antigens (MAIPA) assay. Anti-PF4-IgG negative sera were further analyzed for their ability to induce procoagulant platelet formation in platelets from healthy donors by measuring phosphatidylserine (PS) exposure using flow cytometry. Sera containing GPIIb/IIIa autoantibodies were further incubated with platelets from a patient with Glanzmann Thrombasthenia. Polyethylene glycol (PEG) complex precipitation and LC-MS/MS was applied to enrich and identify the antigen in immune complexes. Ex vivo generated histone/anti-histone IgG complexes were incubated with washed platelets to test procoagulant platelet activation. Anti-histone antibodies were analyzed by ELISA in TTS patients and in healthy recipients of mRNA-based Covid-19 vaccines. Results: Eighteen patients with anti-PF4 negative TTS were identified with a median symptom onset of 7 (1-61) days after vaccination. Patients showed thrombocytopenia (59,000/µl, 0-127,000/µl); petechiae (n=7), venous thromboembolism (n=11), arterial thrombosis (n=6), disseminated intravascular coagulopathy (n=1), and combined arterial and venous thromboses (n=1). Twelve sera induced FcgRIIa dependent and caspase independent procoagulant platelet activation indicated by PS-exposure and CD62P expression. Histones precipitated with IgG fractions of TTS sera and 8/12 sera contained platelet activating anti-histone antibodies. Ex vivo generated histone/anti-histone IgG complexes strongly activated platelets via FcgRIIa, whereas anti-histone-IgG alone did not. Platelet autoantibodies were detected in 7/12 patient sera, but sera with GPIIb/IIIa autoantibodies also activated platelets from a Glanzmann patient making it unlikely that these autoantibodies cause platelet activation. Anti-histone antibodies were identified in 8/18 (anti-PF4 antibody negative) TTS patients (44%), compared to 2/114 in asymptomatic recipients (1.8%; p<0.0001) of mRNA-based Covid-19 vaccines. Conclusion: Platelet activating histone/anti-histone IgG complexes likely explain some forms of TTS after mRNA-based Covid-19 vaccination. Publication History Article published online: 13 February 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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