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Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination.
N Engl J Med. 2021 06 10; 384(23):2202-2211.NEJM

Abstract

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.

Authors+Show Affiliations

From the Department of Haematology, University College London Hospitals NHS Foundation Trust (M.S., M.L.), National Institute for Health Research University College London Hospitals Biomedical Research Centre (M.S., M.L.), Special Coagulation, Health Services Laboratories (D.S.), Great Ormond Street Institute of Child Health, University College London (D.G.), and National Institute for Health Research Great Ormond Street Biomedical Research Centre (D.G.), London, the Department of Haematology, University Hospital Southampton, Southampton (R.L.), National Health Service Blood and Transplant, Bristol (A.P.), National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool (T.S.), the Department of Haematology, Mid Essex Hospitals, Chelmsford (P.K.), the Department of Haematology, Addenbrookes Hospital, Cambridge (W.T.), and the Department of Haematology, University Hospitals Birmingham, and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (W.L.) - all in the United Kingdom; and the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam (M.L.).From the Department of Haematology, University College London Hospitals NHS Foundation Trust (M.S., M.L.), National Institute for Health Research University College London Hospitals Biomedical Research Centre (M.S., M.L.), Special Coagulation, Health Services Laboratories (D.S.), Great Ormond Street Institute of Child Health, University College London (D.G.), and National Institute for Health Research Great Ormond Street Biomedical Research Centre (D.G.), London, the Department of Haematology, University Hospital Southampton, Southampton (R.L.), National Health Service Blood and Transplant, Bristol (A.P.), National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool (T.S.), the Department of Haematology, Mid Essex Hospitals, Chelmsford (P.K.), the Department of Haematology, Addenbrookes Hospital, Cambridge (W.T.), and the Department of Haematology, University Hospitals Birmingham, and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (W.L.) - all in the United Kingdom; and the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam (M.L.).From the Department of Haematology, University College London Hospitals NHS Foundation Trust (M.S., M.L.), National Institute for Health Research University College London Hospitals Biomedical Research Centre (M.S., M.L.), Special Coagulation, Health Services Laboratories (D.S.), Great Ormond Street Institute of Child Health, University College London (D.G.), and National Institute for Health Research Great Ormond Street Biomedical Research Centre (D.G.), London, the Department of Haematology, University Hospital Southampton, Southampton (R.L.), National Health Service Blood and Transplant, Bristol (A.P.), National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool (T.S.), the Department of Haematology, Mid Essex Hospitals, Chelmsford (P.K.), the Department of Haematology, Addenbrookes Hospital, Cambridge (W.T.), and the Department of Haematology, University Hospitals Birmingham, and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (W.L.) - all in the United Kingdom; and the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam (M.L.).From the Department of Haematology, University College London Hospitals NHS Foundation Trust (M.S., M.L.), National Institute for Health Research University College London Hospitals Biomedical Research Centre (M.S., M.L.), Special Coagulation, Health Services Laboratories (D.S.), Great Ormond Street Institute of Child Health, University College London (D.G.), and National Institute for Health Research Great Ormond Street Biomedical Research Centre (D.G.), London, the Department of Haematology, University Hospital Southampton, Southampton (R.L.), National Health Service Blood and Transplant, Bristol (A.P.), National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool (T.S.), the Department of Haematology, Mid Essex Hospitals, Chelmsford (P.K.), the Department of Haematology, Addenbrookes Hospital, Cambridge (W.T.), and the Department of Haematology, University Hospitals Birmingham, and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (W.L.) - all in the United Kingdom; and the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam (M.L.).From the Department of Haematology, University College London Hospitals NHS Foundation Trust (M.S., M.L.), National Institute for Health Research University College London Hospitals Biomedical Research Centre (M.S., M.L.), Special Coagulation, Health Services Laboratories (D.S.), Great Ormond Street Institute of Child Health, University College London (D.G.), and National Institute for Health Research Great Ormond Street Biomedical Research Centre (D.G.), London, the Department of Haematology, University Hospital Southampton, Southampton (R.L.), National Health Service Blood and Transplant, Bristol (A.P.), National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool (T.S.), the Department of Haematology, Mid Essex Hospitals, Chelmsford (P.K.), the Department of Haematology, Addenbrookes Hospital, Cambridge (W.T.), and the Department of Haematology, University Hospitals Birmingham, and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (W.L.) - all in the United Kingdom; and the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam (M.L.).From the Department of Haematology, University College London Hospitals NHS Foundation Trust (M.S., M.L.), National Institute for Health Research University College London Hospitals Biomedical Research Centre (M.S., M.L.), Special Coagulation, Health Services Laboratories (D.S.), Great Ormond Street Institute of Child Health, University College London (D.G.), and National Institute for Health Research Great Ormond Street Biomedical Research Centre (D.G.), London, the Department of Haematology, University Hospital Southampton, Southampton (R.L.), National Health Service Blood and Transplant, Bristol (A.P.), National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool (T.S.), the Department of Haematology, Mid Essex Hospitals, Chelmsford (P.K.), the Department of Haematology, Addenbrookes Hospital, Cambridge (W.T.), and the Department of Haematology, University Hospitals Birmingham, and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (W.L.) - all in the United Kingdom; and the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam (M.L.).From the Department of Haematology, University College London Hospitals NHS Foundation Trust (M.S., M.L.), National Institute for Health Research University College London Hospitals Biomedical Research Centre (M.S., M.L.), Special Coagulation, Health Services Laboratories (D.S.), Great Ormond Street Institute of Child Health, University College London (D.G.), and National Institute for Health Research Great Ormond Street Biomedical Research Centre (D.G.), London, the Department of Haematology, University Hospital Southampton, Southampton (R.L.), National Health Service Blood and Transplant, Bristol (A.P.), National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool (T.S.), the Department of Haematology, Mid Essex Hospitals, Chelmsford (P.K.), the Department of Haematology, Addenbrookes Hospital, Cambridge (W.T.), and the Department of Haematology, University Hospitals Birmingham, and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (W.L.) - all in the United Kingdom; and the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam (M.L.).From the Department of Haematology, University College London Hospitals NHS Foundation Trust (M.S., M.L.), National Institute for Health Research University College London Hospitals Biomedical Research Centre (M.S., M.L.), Special Coagulation, Health Services Laboratories (D.S.), Great Ormond Street Institute of Child Health, University College London (D.G.), and National Institute for Health Research Great Ormond Street Biomedical Research Centre (D.G.), London, the Department of Haematology, University Hospital Southampton, Southampton (R.L.), National Health Service Blood and Transplant, Bristol (A.P.), National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool (T.S.), the Department of Haematology, Mid Essex Hospitals, Chelmsford (P.K.), the Department of Haematology, Addenbrookes Hospital, Cambridge (W.T.), and the Department of Haematology, University Hospitals Birmingham, and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (W.L.) - all in the United Kingdom; and the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam (M.L.).From the Department of Haematology, University College London Hospitals NHS Foundation Trust (M.S., M.L.), National Institute for Health Research University College London Hospitals Biomedical Research Centre (M.S., M.L.), Special Coagulation, Health Services Laboratories (D.S.), Great Ormond Street Institute of Child Health, University College London (D.G.), and National Institute for Health Research Great Ormond Street Biomedical Research Centre (D.G.), London, the Department of Haematology, University Hospital Southampton, Southampton (R.L.), National Health Service Blood and Transplant, Bristol (A.P.), National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool (T.S.), the Department of Haematology, Mid Essex Hospitals, Chelmsford (P.K.), the Department of Haematology, Addenbrookes Hospital, Cambridge (W.T.), and the Department of Haematology, University Hospitals Birmingham, and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (W.L.) - all in the United Kingdom; and the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam (M.L.).From the Department of Haematology, University College London Hospitals NHS Foundation Trust (M.S., M.L.), National Institute for Health Research University College London Hospitals Biomedical Research Centre (M.S., M.L.), Special Coagulation, Health Services Laboratories (D.S.), Great Ormond Street Institute of Child Health, University College London (D.G.), and National Institute for Health Research Great Ormond Street Biomedical Research Centre (D.G.), London, the Department of Haematology, University Hospital Southampton, Southampton (R.L.), National Health Service Blood and Transplant, Bristol (A.P.), National Institute for Health Research Health Protection Research Unit in Emerging and Zoonotic Infections, University of Liverpool, Liverpool (T.S.), the Department of Haematology, Mid Essex Hospitals, Chelmsford (P.K.), the Department of Haematology, Addenbrookes Hospital, Cambridge (W.T.), and the Department of Haematology, University Hospitals Birmingham, and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham (W.L.) - all in the United Kingdom; and the Department of Vascular Medicine, Amsterdam University Medical Center, Amsterdam (M.L.).

Pub Type(s)

Journal Article

Language

eng

PubMed ID

33861525

Citation

Scully, Marie, et al. "Pathologic Antibodies to Platelet Factor 4 After ChAdOx1 nCoV-19 Vaccination." The New England Journal of Medicine, vol. 384, no. 23, 2021, pp. 2202-2211.
Scully M, Singh D, Lown R, et al. Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021;384(23):2202-2211.
Scully, M., Singh, D., Lown, R., Poles, A., Solomon, T., Levi, M., Goldblatt, D., Kotoucek, P., Thomas, W., & Lester, W. (2021). Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. The New England Journal of Medicine, 384(23), 2202-2211. https://doi.org/10.1056/NEJMoa2105385
Scully M, et al. Pathologic Antibodies to Platelet Factor 4 After ChAdOx1 nCoV-19 Vaccination. N Engl J Med. 2021 06 10;384(23):2202-2211. PubMed PMID: 33861525.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pathologic Antibodies to Platelet Factor 4 after ChAdOx1 nCoV-19 Vaccination. AU - Scully,Marie, AU - Singh,Deepak, AU - Lown,Robert, AU - Poles,Anthony, AU - Solomon,Tom, AU - Levi,Marcel, AU - Goldblatt,David, AU - Kotoucek,Pavel, AU - Thomas,William, AU - Lester,William, Y1 - 2021/04/16/ PY - 2021/4/17/pubmed PY - 2021/6/17/medline PY - 2021/4/16/entrez SP - 2202 EP - 2211 JF - The New England journal of medicine JO - N Engl J Med VL - 384 IS - 23 N2 - 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. SN - 1533-4406 UR - https://www.unboundmedicine.com/medline/citation/33861525/full_citation L2 - https://www.nejm.org/doi/10.1056/NEJMoa2105385?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -