Cerebral Venous and Sinus Thrombosis with Immunological Pathogenesis: VITT and Pre-VITT

ABSTRACT

In this review, we summarise the current knowledge on vaccine-induced immune thrombotic thrombocytopenia (VITT) and new insights into its underlying pathogenesis. VITT is characterised by severe thromboses occurring 5-20 days after vaccination with an adenoviral vector-based SARS-CoV-2 vaccine (AstraZeneca or Johnson & Johnson). Thromboses typically involve the cerebral sinus and venous system. Routine laboratory analyses show thrombocytopenia and high D-dimer levels. The pathogenesis is based on immunological processes similar to those in heparin-induced thrombocytopenia. Accordingly, VITT is associated with high-titre immunoglobulin G directed against platelet factor 4 (PF4). Interaction with adenoviral vector-based vaccines leads to modifications of PF4 allowing antibody-producing cells to identify PF4. Anti-PF4 antibodies activate platelets through FcgammaIIa receptors. The detection of platelet-activating anti-PF4 antibodies confirms the diagnosis of VITT. Treatment is based on anticoagulation, which inhibits thrombin itself or thrombin formation, and high-dose intravenous immunoglobulin G, which inhibits cell activation via FcgammaIIa receptors. In severe cases, plasma exchange could also be an option. In some patients, a pre-VITT syndrome precedes VITT. Pre-VITT patients typically present with severe headache before thromboses are manifest. The early identification of a pre-VITT syndrome allows for the prevention of thrombotic complications. The specific dynamics of the immune reaction in VITT correspond to a transient, secondary immune response. Current studies address how PF4 binds to different adenoviral proteins and investigate the functional role of other vaccine components. Some of these factors contribute to the induction of a pro-inflammatory danger signal that triggers the first stage of VITT pathogenesis. In the second stage, high-titre anti-PF4 antibodies activate platelets and granulocytes. In a process called NETosis (neutrophil extracellular traps), activated granulocytes release DNA. Anti-PF4 antibodies then bind to complexes of PF4 and DNA. This enhances further cell activation via Fcgamma receptors and consequently also the formation of thrombin. At the end of the article, we comment on how the current knowledge on VITT may influence global vaccination campaigns against SARS-CoV-2 and we address how anti-PF4 antibodies may be involved in recurrent arterial and venous thromboses not associated with VITT and HIT. Copyright © 2022 Georg Thieme Verlag. All rights reserved.