Prothrombotic immune thrombocytopenia after COVID-19 vaccination

Abstract

We report 5 cases of prothrombotic immune thrombocytopenia after exposure to the ChAdOx1 vaccine (AZD1222, Vaxzevria) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients presented 5 to 11 days after first vaccination. The spectrum of clinical manifestations included cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial cerebral thromboembolism, and thrombotic microangiopathy. All patients had thrombocytopenia and markedly elevated D-dimer. Autoantibodies against platelet factor 4 (PF4) were detected in all patients, although they had never been exposed to heparin. Immunoglobulin from patient sera bound to healthy donor platelets in an AZD1222-dependent manner, suppressed by heparin. Aggregation of healthy donor platelets by patient sera was demonstrated in the presence of buffer or AZD1222 and was also suppressed by heparin. Anticoagulation alone or in combination with eculizumab or intravenous immunoglobulin (IVIG) resolved the pathology in 3 patients. Two patients had thromboembolic events despite anticoagulation at a time when platelets were increasing after IVIG. In summary, an unexpected autoimmune prothrombotic disorder is described after vaccination with AZD1222. It is characterized by thrombocytopenia and anti-PF4 antibodies binding to platelets in AZD1222-dependent manner. Initial clinical experience suggests a risk of unusual and severe thromboembolic events.

Graphical abstract

Figure 1.

Anti-PF4 autoantibodies were detected in all samples by ELISA but not CLIA. (A) ELISA reactivity was inhibited to optical density <0.3 by heparin in all samples (2 U/mL, data not shown). (B) Binding of antibodies from patient sera to healthy donor platelets in the presence of AZD1222 was suppressed by heparin. Fluorescent intensity ratio of AZD1222 (or AZD1222 + heparin 100 U/mL) to buffer is shown. (C) Schistocytes in blood smear high power field in patient 1, indicative of TMA, on day 4. (D) Course of selected laboratory markers over time. X-axes show days of hospital stay. Y-axes on the left are for all panels.