COVID-19 Vaccine-Related Thrombosis: A Systematic Review and Exploratory Analysis

Front Immunol. 2021 Nov 29:12:729251. doi: 10.3389/fimmu.2021.729251. eCollection 2021.


Introduction: The World Health Organization declared the coronavirus disease 2019 (COVID-19) pandemic on March 11, 2020. Two vaccine types were developed using two different technologies: viral vectors and mRNA. Thrombosis is one of the most severe and atypical adverse effects of vaccines. This study aimed to analyze published cases of thrombosis after COVID-19 vaccinations to identify patients' features, potential pathophysiological mechanisms, timing of appearance of the adverse events, and other critical issues.

Materials and methods: We performed a systematic electronic search of scientific articles regarding COVID-19 vaccine-related thrombosis and its complications on the PubMed (MEDLINE) database and through manual searches. We selected 10 out of 50 articles from February 1 to May 5, 2021 and performed a descriptive analysis of the adverse events caused by the mRNA-based Pfizer and Moderna vaccines and the adenovirus-based AstraZeneca vaccine.

Results: In the articles on the Pfizer and Moderna vaccines, the sample consisted of three male patients with age heterogeneity. The time from vaccination to admission was ≤3 days in all cases; all patients presented signs of petechiae/purpura at admission, with a low platelet count. In the studies on the AstraZeneca vaccine, the sample consisted of 58 individuals with a high age heterogeneity and a high female prevalence. Symptoms appeared around the ninth day, and headache was the most common symptom. The platelet count was below the lower limit of the normal range. All patients except one were positive for PF4 antibodies. The cerebral venous sinus was the most affected site. Death was the most prevalent outcome in all studies, except for one study in which most of the patients remained alive.

Discussion: Vaccine-induced thrombotic thrombocytopenia (VITT) is an unknown nosological phenomenon secondary to inoculation with the COVID-19 vaccine. Several hypotheses have been formulated regarding its physiopathological mechanism. Recent studies have assumed a mechanism that is assimilable to heparin-induced thrombocytopenia, with protagonist antibodies against the PF4-polyanion complex. Viral DNA has a negative charge and can bind to PF4, causing VITT. New experimental studies have assumed that thrombosis is related to a soluble adenoviral protein spike variant, originating from splicing events, which cause important endothelial inflammatory events, and binding to endothelial cells expressing ACE2.

Conclusion: Further studies are needed to better identify VITT's pathophysiological mechanisms and genetic, demographic, or clinical predisposition of high-risk patients, to investigate the correlation of VITT with the different vaccine types, and to test the significance of the findings.

Keywords: COVID-19 vaccine; PF4 antibodies; vaccine adverse effects; vaccine complications; vaccine-related thrombosis.

Publication types

  • Systematic Review

MeSH terms

  • 2019-nCoV Vaccine mRNA-1273 / adverse effects
  • 2019-nCoV Vaccine mRNA-1273 / immunology*
  • Antigen-Antibody Complex / metabolism
  • BNT162 Vaccine / adverse effects
  • BNT162 Vaccine / immunology*
  • COVID-19 / complications
  • COVID-19 / epidemiology
  • COVID-19 / immunology*
  • Cerebral Veins / metabolism
  • Cerebral Veins / pathology
  • ChAdOx1 nCoV-19 / adverse effects
  • ChAdOx1 nCoV-19 / immunology*
  • Female
  • Headache
  • Humans
  • Mass Vaccination
  • Platelet Factor 4 / immunology
  • SARS-CoV-2 / physiology*
  • Sex Factors
  • Survival Analysis
  • Thrombosis / epidemiology*
  • Thrombosis / etiology
  • Thrombosis / mortality


  • Antigen-Antibody Complex
  • PF4 protein, human
  • Platelet Factor 4
  • ChAdOx1 nCoV-19
  • 2019-nCoV Vaccine mRNA-1273
  • BNT162 Vaccine