Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination

N Engl J Med. 2021 Jun 3;384(22):2092-2101. doi: 10.1056/NEJMoa2104840. Epub 2021 Apr 9.

Abstract

Background: Several cases of unusual thrombotic events and thrombocytopenia have developed after vaccination with the recombinant adenoviral vector encoding the spike protein antigen of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (ChAdOx1 nCov-19, AstraZeneca). More data were needed on the pathogenesis of this unusual clotting disorder.

Methods: We assessed the clinical and laboratory features of 11 patients in Germany and Austria in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19. We used a standard enzyme-linked immunosorbent assay to detect platelet factor 4 (PF4)-heparin antibodies and a modified (PF4-enhanced) platelet-activation test to detect platelet-activating antibodies under various reaction conditions. Included in this testing were samples from patients who had blood samples referred for investigation of vaccine-associated thrombotic events, with 28 testing positive on a screening PF4-heparin immunoassay.

Results: Of the 11 original patients, 9 were women, with a median age of 36 years (range, 22 to 49). Beginning 5 to 16 days after vaccination, the patients presented with one or more thrombotic events, with the exception of 1 patient, who presented with fatal intracranial hemorrhage. Of the patients with one or more thrombotic events, 9 had cerebral venous thrombosis, 3 had splanchnic-vein thrombosis, 3 had pulmonary embolism, and 4 had other thromboses; of these patients, 6 died. Five patients had disseminated intravascular coagulation. None of the patients had received heparin before symptom onset. All 28 patients who tested positive for antibodies against PF4-heparin tested positive on the platelet-activation assay in the presence of PF4 independent of heparin. Platelet activation was inhibited by high levels of heparin, Fc receptor-blocking monoclonal antibody, and immune globulin (10 mg per milliliter). Additional studies with PF4 or PF4-heparin affinity purified antibodies in 2 patients confirmed PF4-dependent platelet activation.

Conclusions: Vaccination with ChAdOx1 nCov-19 can result in the rare development of immune thrombotic thrombocytopenia mediated by platelet-activating antibodies against PF4, which clinically mimics autoimmune heparin-induced thrombocytopenia. (Funded by the German Research Foundation.).

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Autoantibodies / blood*
  • Autoimmune Diseases / etiology
  • Blood Chemical Analysis
  • COVID-19 Vaccines / adverse effects*
  • ChAdOx1 nCoV-19
  • Disseminated Intravascular Coagulation / etiology
  • Enzyme-Linked Immunosorbent Assay
  • Fatal Outcome
  • Female
  • Humans
  • Intracranial Hemorrhages / etiology
  • Male
  • Middle Aged
  • Platelet Activation
  • Platelet Factor 4 / immunology*
  • Thrombocytopenia / etiology*
  • Thrombocytopenia / immunology
  • Thrombosis / etiology*
  • Thrombosis / immunology
  • Young Adult

Substances

  • Autoantibodies
  • COVID-19 Vaccines
  • Platelet Factor 4
  • ChAdOx1 nCoV-19