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    Oral Communication

    COVID

    Vaccination Against COVID-19 and Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT)

    OC 76.2 - PAD4-mediated NETosis in ChAdOx1 vaccine-induced thrombosis

    Wednesday, June 28, 2023
    10:30 – 10:45 ET
    Room: 524
    Session Available As: On-Demand

      Presenting Author(s)

    • Cristina Nocella, PhD

      Assistant Professor
      Sapienza University of Rome, Department of Clinical Internal, Anesthesiology and Cardiovascular Sciences
      Rome, Lazio, Italy

      • Co-Author(s)

    • RC

      Roberto Carnevale

      Associate Professor
      Sapienza University of Rome, Department of Medical-Surgical Sciences and Biotechnologies
      Rome, Lazio, Italy

    • ML

      Martina Leopizzi

      Research Fellow
      Sapienza University of Rome, Department of Medical-Surgical Sciences and Biotechnologies
      Rome, Lazio, Italy

    • MD

      Marcello Dominici

      Professor
      Santa Maria Hospital, Interventional Cardiology Unit
      Terni, Umbria, Italy

    • Gd

      Giulia d 'Amati

      Professor
      Sapienza University of Rome, Department of Radiological, Oncological and Pathological Sciences
      Rome, Lazio, Italy

    • SB

      Simona Bartimoccia

      Research Fellow
      Sapienza University of Rome,Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences
      Rome, Lazio, Italy

    • Vittoria Cammisotto, PhD

      Researcher
      Sapienza University of Rome,Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences
      Rome, Lazio, Italy

    • AD

      Alessandra D'Amico

      Research Fellow
      University of Rome "Foro Italico", Department of Movement, Human and Health Sciences
      Rome, Lazio, Italy

    • VC

      Valentina Castellani

      PhD student
      Sapienza University of Rome, Department of General Surgery and Surgical Speciality Paride Stefanini
      Rome, Lazio, Italy

    • FB

      Francesco Baratta

      Medical director
      Sapienza University of Rome,Department of Clinical Internal, Anaesthesiological and Cardiovascular Sciences
      Rome, Lazio, Italy

    • AB

      Alessia Bertelli

      PhD student
      University of Florence, Atherothrombotic Disease Unit, Department of Experimental and Clinical Medicine
      Firenze, Toscana, Italy

    • AA

      Alessio Arrivi

      Professor
      Santa Maria Hospital, Interventional Cardiology Unit
      Terni, Umbria, Italy

    • DT

      Danilo Toni

      Professor
      Sapienza University of Rome, Emergency Department, Stroke Unit
      Rome, Lazio, Italy

    • MD

      Manuela De Michele

      Neurologist
      Sapienza University of Rome, Department of Human Neurosciences
      Rome, Lazio, Italy

    • Pasquale Pignatelli, PhD

      Professor
      Dept. of Clinical, Internistic, Anesthesiologic and Cardiovascular Sciences, Sapienza University
      Roma, Lazio, Italy

    • RM

      Rossella Marcucci

      Professor
      Dept. of Experimental and Clinical Medicine, University of Florence
      Firenze, Toscana, Italy

    • Francesco Violi, Professor of internal medicine, Sapienza University, Rome

      MD
      Department of Clinical, InternalMedicine, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
      Rome, Lazio, Italy

    Background: Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare syndrome associated with the Vaxevria (Astra Zeneca) vaccine and in a few cases after Ad26.COV2 against severe acute respiratory syndrome coronavirus 2. Like heparin-induced thrombocytopenia (HIT), this condition has been associated with the development of anti-platelet factor 4 antibodies, leading to neutrophil-platelet aggregate formation and neutrophil extracellular traps (NETs) release. However, the precise molecular mechanism accounting for VITT has not been fully understood.

    Aims: To assess if in VITT patients thrombogenesis occurs via platelet-leucocyte interaction.

    Methods: We included 10 patients with VITT after ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccine administration, 10 ischemic patients, and 10 control subjects. We analyzed NETs release and coagulation by measuring in plasma and cerebral thrombi citrullination of histone H3 (CitH3), and tissue factor (TF), respectively. Furthermore, we investigated in vitro if plasma post-ChAdOx nCoV-19 vaccination enhanced PAD4 and NETs release.

    Results: We observed higher blood levels of NETs, soluble TF, and thrombin generation in VITT compared to ischemic stroke patients and healthy subjects. Platelet-leucocyte mixture with VITT plasma resulted in higher NETs formation, soluble TF and thrombin generation, and platelet-dependent thrombus growth under laminar flow compared with IS plasma; these effects were blunted by PAD4 and cathepsin G inhibitors, anti-FcγRIIa and heparin high doses. Immunohistochemistry analysis showed a more marked expression of PAD4 along with more diffuse leucocyte infiltration and NETs formation as well as TF and cathepsin expression in VITT thrombus compared to thrombi from non-VITT patients.

    Conclusion(s): VITT patients display enhanced thrombogenesis by platelet/leucocyte interaction via PAD4-mediated NETs formation and clotting activation.

    Learning Objectives:

    • Upon completion, participant will be able to describe a mechanism accounting for Vaccine-induced immune thrombotic thrombocytopenia (VITT)
    • Upon completion, participant will be able to explore the mechanism of NETosis in VITT
    • Upon completion, participant will be able to increase their knowledge about tools to develop novel antithrombotic treatments in VITT or other immuno-mediated thromboses