Pathogenesis of Clots Following COVID-19 Vaccine Suggests Choice of Treatments

Finding pathologic antibodies to platelet factor 4 (PF4) in patients presenting with thrombosis with thrombocytopenia after receiving the ChAd0x1 nCoV-19 vaccine (AstraZeneca) for SARS-CoV-2 led investigators to recommend treatments that include a non-heparin anticoagulant, and to provide an algorithm that also emphasizes avoiding platelet transfusion.

Marie Scully, MD, Department of Haematology, University College London Hospitals NHS Foundation Trust, London, UK, and colleagues investigated the thrombotic events in 22 patients that occurred 6 to 24 days after receiving the vaccination. These were primarily cerebral venous thrombosis, but also included arterial thrombosis as well as more common types of venous thromboembolism, including pulmonary.

"We identified a novel underlying mechanism associated with the presentation. On the basis of the clinical features and subsequent laboratory findings, we propose an altered therapeutic approach," Scully and colleagues announced.

In an accompanying editorial, Douglas Cines, MD, Department of Pathology and Laboratory Medicine and Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, and James Bussel, MD, Department of Pediatrics, Weill Cornell Medicine, New York, New York, concurred that the findings suggested the course of treatment.

"Although the condition in several patients apparently improved when they were given low-molecular-weight heparin, it seems prudent to choose from among the non-heparin antithrombotic agents that are used to treat heparin-induced thrombocytopenia while the risk of bleeding is being mitigated," they indicated.

"We expect that the high mortality rate associated with VITT (vaccine-induced immune thrombotic thrombocytopenia) will decrease with earlier recognition and improved intervention," Cines and Bussel added.

Scully and colleagues explain that their decision to test for antibodies to PF4 was based on the presentation of progressive thrombosis and thrombocytopenia that is similar to patients with the rare heparin induced thrombocytopenia (HIT), which is also confirmed by the presence of anti-PF4 antibodies.The test for anti-PF4 antibodies was performed by means of enzyme-linked immunosorbent assays (ELISAs), and confirmed, in some cases, by means of a functional HIT assay.

To rule out the possible link of thrombosis to the SARS-CoV-2 virus, rather than to the vaccine, all patients were tested for, and found to have a negative SARS-CoV-2 PCR test at presentation.The 10 patients with samples available for testing were also found negative for SARS-CoV-2 antibodies.In each of the 10, levels of antibodies to the spike protein and the receptor binding domain (RBD) of the virus were within range expected from a dose of the vaccine.The investigators noted, however, that all patients had D-dimer levels that were much higher than would be expected in patients with acute venous thromboembolism.

Scully and colleagues warn against platelet transfusions in patients with this presentation, as these might provide a substrate for further antibody-mediated platelet activation and coagulopathy.Instead, their treatment algorithm includes consideration of glucocorticoids, and administration of intravenous immunoglobulin (IVIg) and non-heparin anticoagulant.

"Although evidence does not yet suggest that the use of heparin will exacerbate this condition, pending further data, we would recommend considering anticoagulation with the use of a non-heparin anticoagulant, such as argatroban, danaparoid, fondaparinux, or direct oral anticoagulants," Scully and colleagues advised.