By Antonella Macerollo
For July 2021, we have selected: Greinacher A. et al, Thrombotic Thrombocytopenia after ChAdOx1 nCov-19 Vaccination. N Engl J Med. 2021 Jun 3;384(22):2092-2101. doi: 10.1056/NEJMoa2104840.
The spread of the Covid-19 pandemic has led to the development of four vaccines to fight this severe infection, and their subsequent approval by European Medicines Agency.
Two vaccines are messenger RNA–based [BNT162b2 (Pfizer–BioNTech) and mRNA-1273 (Moderna)] encoding the spike protein antigen of SARS-CoV-2, encapsulated in lipid nanoparticles. One vaccine is a recombinant chimpanzee adenoviral vector [ChAdOx1 nCov-19 (AstraZeneca)] encoding the spike glycoprotein of SARS-CoV-2. One vaccine is a recombinant adenovirus type 26 vector [Ad26.COV2.S (Johnson & Johnson/Janssen)] encoding the SARS-CoV-2 spike glycoprotein.
Beginning in late February 2021, several cases of unusual thrombotic events in combination with thrombocytopenia were observed in patients after vaccination with ChAdOx1 nCov-19, with a lack of knowledge on the pathogenesis of this unusual clotting disorder.
Our authors of the month investigated the clinical and laboratory features of 11 patients (9 females; median age=36 years) in Germany and Austria, in whom thrombosis or thrombocytopenia had developed after vaccination with ChAdOx1 nCov-19.
A standard enzyme-linked immunosorbent assay was used to detect platelet factor 4 (PF4)–heparin antibodies, whereas a modified (PF4-enhanced) platelet-activation test was used to detect platelet-activating antibodies under various reaction conditions.
Our authors also tested 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.
Greinacher A. et al found that the patients presented with one or more thrombotic events 5-16 days after vaccination (9 cerebral venous thrombosis, 3 splanchnic-vein thrombosis, 3 pulmonary embolism, 4 other thromboses, 1 fatal intracranial haemorrhage). Notably, 6 patients died. Disseminated intravascular coagulation was found in five patients. None of the patients had received heparin before symptom onset.
All 28 positive patients for antibodies against PF4–heparin, were also 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 ml). Additional studies with PF4 or PF4–heparin affinity purified antibodies in two patients confirmed PF4-dependent platelet activation.
Our paper of the month has clarified an important vaccine-related query, which has been under discussion worldwide over the last six months. This study has confirmed that 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. Therefore, management should include a high-dose of intravenous immune globulin to inhibit Fcγ receptor–mediated platelet activation. Moreover, anticoagulant options should include non-heparin anticoagulants used for the management of heparin-induced thrombocytopenia, unless a functional test has excluded heparin-dependent enhancement of platelet activation.
