Review
Addressing Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT) Following COVID-19 Vaccination: A Mini-Review of Practical Strategies
Po-Wei Chen et al. Acta Cardiol Sin. 2021 Jul.
Free PMC article
Abstract
In response to the COVID-19 pandemic, several vaccines were developed and rolled out at unprecedented speed, and notwithstanding this rapid pace of development, the results from initial clinical trials involving tens of thousands of adult subjects generally indicated that most vaccines were remarkably effective and safe, with no major safety warnings noted. However, with more than 2 billion vaccination doses administered to date, reports of rare adverse events following immunization (AEFI) are beginning to emerge. In late February 2021, atypical thrombotic events following immunization with the adenoviral vector-based ChAdOx1 nCov-19 vaccine were first reported, and similar events have also been observed in recipients of the adenoviral vector-based Ad26.COV2.S vaccine and the mRNA-based BNT162b2 and mRNA-1273 vaccines. These manifestations of atypical thrombosis and thrombocytopenia following COVID-19 vaccine immunization are now collectively referred to as vaccine-induced immune thrombotic thrombocytopenia (VITT). Although the reported incidence remains very low and does not affect the overall benefit of immunization, it is also true that if left untreated, VITT can be debilitating or even fatal. Therefore, this review seeks to provide a comprehensive overview regarding the incidence, pathogenesis, presentation, diagnosis, and treatment of VITT, as well as considerations for special populations, based on the currently available evidence in the literature. It is hoped that this will enhance awareness of this vaccine side effect, so that cases of VITT may be identified and treated in a timely and appropriate manner.
Keywords: Adverse events following immunization; COVID-19; Vaccine; Vaccine side effects; Vaccine-induced immune thrombotic thrombocytopenia; Vaccine-induced prothrombotic immune thrombocytopenia.
Figures

Schematic depicting the mechanism of action of adenoviral vector-based COVID-19 vaccines (with the ChAdOx1 nCov-19 vaccine as an example) and a hypothetical model of how this could induce vaccine-induced immune thrombotic thrombocytopenia. Adenoviruses in the vaccines infect coxsackievirus and adenovirus receptor-positive (CAR+) cells after intramuscular injection, and these CAR+ cells subsequently produce SARS-CoV-2 spike protein, which is taken up by antigen-presenting cells (APC) for stimulation of T cells, resulting in the activation of adaptive immune responses. However, the SARS-CoV-2 spike proteins may also activate platelets, leading to the release of platelet factor 4 (PF4) from platelet α-granules, and ultimately resulting in stimulation of the coagulation system and clinically significant thromboembolic complications. Further research is needed to confirm this hypothetical model. TFH cells, T follicular helper cells.

Proposed algorithm for the management of vaccine-induced immune thrombotic thrombocytopenia. 1Thrombocytopenia is defined as platelet count < 150,000 μL, with typical reported nadirs ranging from 9,000 μL to 107,000 μL. 2Normal plasma levels of D-dimers are < 500 ng/mL, and the application of age-adjusted cut-offs (age × 10 ng/mL when above 50 years) for the exclusion of thrombosis can improve specificity. 3If available, anti-PF4-heparin ELISA testing and functional platelet activation testing are recommended for confirmed VITT cases (definite VITT). 4Further exams for probable VITT include sending serum samples for PF4 antibody assays (HIT ELISA); abdominal ultrasonography/CT imaging for portal or splanchnic vein thrombosis (even in the absence of symptoms); or imaging for CVST, which should be examined closely as initial images may be negative but positive results seen in subsequent testing., APTT, activated partial thromboplastin time; CBC, complete blood count; CT, computer tomography; CVST, cerebral venous sinus thrombosis; ELISA, enzyme-linked immunosorbent assay; HIT, heparin-induced thrombocytopenia; IVIG, intravenous immunoglobulin; NOAC, novel oral anticoagulant; PF4, platelet factor 4; PT, prothrombin time; VITT, vaccine-induced immune thrombotic thrombocytopenia.
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