Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination

N Engl J Med. 2021 Jun 10;384(23):2202-2211. doi: 10.1056/NEJMoa2105385. Epub 2021 Apr 16.


Background: The mainstay of control of the coronavirus disease 2019 (Covid-19) pandemic is vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a year, several vaccines have been developed and millions of doses delivered. Reporting of adverse events is a critical postmarketing activity.

Methods: We report findings in 23 patients who presented with thrombosis and thrombocytopenia 6 to 24 days after receiving the first dose of the ChAdOx1 nCoV-19 vaccine (AstraZeneca). On the basis of their clinical and laboratory features, we identify a novel underlying mechanism and address the therapeutic implications.

Results: In the absence of previous prothrombotic medical conditions, 22 patients presented with acute thrombocytopenia and thrombosis, primarily cerebral venous thrombosis, and 1 patient presented with isolated thrombocytopenia and a hemorrhagic phenotype. All the patients had low or normal fibrinogen levels and elevated d-dimer levels at presentation. No evidence of thrombophilia or causative precipitants was identified. Testing for antibodies to platelet factor 4 (PF4) was positive in 22 patients (with 1 equivocal result) and negative in 1 patient. On the basis of the pathophysiological features observed in these patients, we recommend that treatment with platelet transfusions be avoided because of the risk of progression in thrombotic symptoms and that the administration of a nonheparin anticoagulant agent and intravenous immune globulin be considered for the first occurrence of these symptoms.

Conclusions: Vaccination against SARS-CoV-2 remains critical for control of the Covid-19 pandemic. A pathogenic PF4-dependent syndrome, unrelated to the use of heparin therapy, can occur after the administration of the ChAdOx1 nCoV-19 vaccine. Rapid identification of this rare syndrome is important because of the therapeutic implications.

MeSH terms

  • Adult
  • Aged
  • Algorithms
  • Antibodies, Viral / blood
  • Anticoagulants / adverse effects
  • Autoantibodies / blood*
  • COVID-19 / prevention & control
  • COVID-19 Vaccines / adverse effects
  • COVID-19 Vaccines / immunology*
  • ChAdOx1 nCoV-19
  • Female
  • Flow Cytometry
  • Heparin / adverse effects
  • Humans
  • Male
  • Middle Aged
  • Platelet Factor 4 / immunology*
  • Thrombocytopenia / etiology
  • Thrombocytopenia / immunology*
  • Thrombosis / etiology
  • Thrombosis / immunology*


  • Antibodies, Viral
  • Anticoagulants
  • Autoantibodies
  • COVID-19 Vaccines
  • PF4V1 protein, human
  • Platelet Factor 4
  • Heparin
  • ChAdOx1 nCoV-19