Atypical PF4-dependent thrombosis and thrombocytopenia in some after COVID-19 vaccination

Introduction and methods

Vaccination is key to control the COVID-19 pandemic and high coverage has been achieved in some countries [1,2]. More than half of the 9 million people in Israel have received a second dose of vaccines and more than 25 million people in the United Kingdom have received at least one dose. Adverse events after administration of the ChAdOx1 nCoV-19 vaccine (AstraZeneca) have recently been reported. These involve thrombosis, particularly cerebral venous thrombosis, and thrombocytopenia that have resulted in death in a few cases [3,4]. Although a causal association has not been established yet, the U.K. Medicines and Healthcare Products Regulatory Agency (MHRA) and the European Medicines Agency (EMA) have acknowledged that vaccines against SARS-CoV-2 may be associated with a rare but serious adverse event related to thrombosis and thrombocytopenia [5,6].

This study presents the findings in 23 patients with thrombosis, primarily cerebral venous thrombosis, and/or thrombocytopenia 6 to 24 days after administration of the first dose of the ChAdOx1 nCoV-19 vaccine.

This study describes 22 patients with suspected vaccine-induced thrombosis and thrombocytopenia (VITT) and 1 patient with isolated thrombocytopenia and a hemorrhagic phenotype. The 3 index patients with progressive thrombosis and thrombocytopenia showed clinical features that resemble those observed in patients with heparin-induced thrombocytopenia. Patients were therefore serologically tested for the presence of antibodies directed against platelet factor 4 (PF4) by ELISA assay. The ELISA testing was performed on sera samples obtained before administration of a heparin-based therapy. In several cases (n=7), ELISA results were confirmed by a functional HIT assay at a reference laboratory. Median age of the patients was 46 years (range 21-77). No evidence of thrombophilia or causative precipitant was detected, except for 1 patients with a history of deep venous thrombosis (DVT) and 1 patient who was on the combined oral contraceptive pill.

Main results

• Of the 22 patients with suspected thrombosis 13 had clinical features consistent with cerebral venous thrombosis, 4 had pulmonary embolism, 1 had DVT and bilateral adrenal hemorrhage, 2 had ischemic stroke affecting the middle cerebral artery territory, and 2 had portal vein thrombosis.

• Patients who received platelet transfusions or heparin-based therapy at presentation had additional thrombosis events associated with progression.

• 7 Out of 23 patients died.

• 10 Patients with samples available for testing were negative for antibodies against nucleocapsid protein ruling out recent exposure to SARS CoV-2.

• These 10 patients had similar antibody levels directed against the spike protein and receptor binding domain (RBD) of SARS-CoV-2 compared to recipients who received 1 dose of the ChAdOx1 nCoV-19 vaccine.

• 13 Patients had fibrinogen levels below 1.5 g/L.

• Patients in this cohort had higher D-dimer levels than expected in patients with acute venous thromboembolism (median 31,301 FEU, range: 5,000-80,000 FEU).

• ELISA test demonstrated that 21 out of 23 patients were positive for antibodies against PF4. 1 Patient had a signal (0.156 OD) below the positive threshold of the test (≤0.238 OD) and another one tested negative, but the serum sample was obtained after the patient had received several platelet transfusions.

• Functional HIT assay was positive in 5 out of 7 patients and confirmed the presence of platelet activation similar to that observed in patients with HIT.

Conclusion

References

Find this article online at N Engl J Med