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Towards Understanding ChAdOx1 nCov-19 Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT)

1Universitätsmedizin Greifswald, Institut für Immunologie und Transfusionsmedizin, Greifswald, Germany, 23. Interfaculty Institute of Genetics and Functional Genomics, Department Functional Genomics, University Medicine Greifswald, Greifswald, Germany, 313. Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany, 4Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, 515. Department of Pathology and Molecular Medicine, and Department of Medicine, McMaster University, Hamilton, Canada

Abstract Number: LB 02.2

Meeting: ISTH 2021 Congress

Theme: COVID and Coagulation » COVID and Coagulation, Basic Science

Background: SARS-CoV-2 vaccine ChAdOx1 nCov-19 rarely causes vaccine-induced immune thrombotic thrombocytopenia (VITT) that—like autoimmune heparin-induced thrombocytopenia—is mediated by platelet-activating anti-platelet factor 4 (PF4) antibodies.

Aims: To understand how the SARS-CoV-2 vaccine ChAdOx1 nCov-19 can induce anti-PF4 antibodies and how these antibodies induce thrombosis

Methods: We investigated vaccine, PF4, and VITT patient-derived anti-PF4 antibody interactions using 3D-super-resolution microscopy, dynamic light scattering, and transmission electron microscopy. Vaccine composition was analyzed by mass spectrometry. Experimental vascular leakage models assessed early post-vaccine reactions. We evaluated VITT antibody-mediated platelet activation and formation of procoagulant DNA-containing neutrophil extracellular traps (NETs), including within VITT patient cerebral venous thrombi.

Results: Biophysical analyses showed HEK cell line proteins and free virus proteins in the vaccine, formation of complexes between PF4 and vaccine constituents (including viral proteins) that were recognized by VITT antibodies. In a murine model, EDTA (vaccine constituent) increased microvascular leakage with dissemination of virus- and cell culture-derived human proteins. Free viral proteins and preexisting antibodies in normal human sera reacting with vaccine-containing constituents, likely contribute to commonly observed acute ChAdOx1 nCov-19 post-vaccination inflammatory reactions. PF4-binding polyanions (polyphosphates, DNA) enhanced PF4-dependent platelet activation by VITT antibodies. In the presence of platelets, PF4 enhanced VITT antibody-driven NETs formation; further evidence for NETosis included elevated NETs biomarkers and low DNase activity in VITT sera, and NETs/neutrophil-rich cerebral vein thrombi extracted from VITT patients.

Conclusions: ChAdOx1 nCoV-19 vaccine constituents form antigenic complexes with PF4, and EDTA increases microvascular permeability, enhancing risk of early post-vaccination acute inflammatory reactions; PF4/polyanion antigen formation in a proinflammatory milieu offers an explanation for anti-PF4 antibody production. Resulting high-titer anti-PF4 antibodies activate platelets and induce neutrophil activation with NETosis, further fueling the VITT prothrombotic response.

To cite this abstract in AMA style:

Greinacher A, Selleng K, Wesche J, Handtke S, Palankar R, Völker U, Thiele T, Siegerist F, Endlich N, Rangaswamy C, K Mailer R, Englert H, Frye M, Warkentin T, Renne T. Towards Understanding ChAdOx1 nCov-19 Vaccine-induced Immune Thrombotic Thrombocytopenia (VITT) [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/towards-understanding-chadox1-ncov-19-vaccine-induced-immune-thrombotic-thrombocytopenia-vitt/. Accessed August 16, 2022.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/towards-understanding-chadox1-ncov-19-vaccine-induced-immune-thrombotic-thrombocytopenia-vitt/