Journal
NATURE
Volume 596, Issue 7873, Pages 565-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41586-021-03744-4
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Funding
- Canadian Institutes of Health Research [CIHR 452655]
- Public Health Agency of Canada
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Alanine-scanning mutagenesis is used to identify the PF4 epitope that is recognized by anti-PF4 antibodies in patients with vaccine-induced immune thrombotic thrombocytopaenia, revealing that the epitope corresponds to the heparin-binding site on PF4. VITT anti-PF4 antibodies show stronger binding response compared to HIT anti-PF4 antibodies, potentially contributing to platelet activation and thrombosis by mimicking the effect of heparin binding on PF4. The findings suggest a potential mechanism for VITT development related to immune complexes formation and platelet activation via Fc gamma receptor IIa.
Vaccine-induced immune thrombotic thrombocytopaenia (VITT) is a rare adverse effect of COVID-19 adenoviral vector vaccines(1-3). VITT resembles heparin-induced thrombocytopaenia (HIT) in that it is associated with platelet-activating antibodies against platelet factor 4 (PF4)(4); however, patients with VITT develop thrombocytopaenia and thrombosis without exposure to heparin. Here we sought to determine the binding site on PF4 of antibodies from patients with VITT. Using alanine-scanning mutagenesis(5), we found that the binding of anti-PF4 antibodies from patients with VITT (n = 5) was restricted to eight surface amino acids on PF4, all of which were located within the heparin-binding site, and that the binding was inhibited by heparin. By contrast, antibodies from patients with HIT (n = 10) bound to amino acids that corresponded to two different sites on PF4. Biolayer interferometry experiments also revealed that VITT anti-PF4 antibodies had a stronger binding response to PF4 and PF4-heparin complexes than did HIT anti-PF4 antibodies, albeit with similar dissociation rates. Our data indicate that VITT antibodies can mimic the effect of heparin by binding to a similar site on PF4; this allows PF4 tetramers to cluster and form immune complexes, which in turn causes Fc gamma receptor IIa (Fc gamma RIIa; also known as CD32a)-dependent platelet activation. These results provide an explanation for VITT-antibody-induced platelet activation that could contribute to thrombosis. Alanine-scanning mutagenesis is used to identify the PF4 epitope that is recognized by anti-PF4 antibodies in patients with vaccine-induced immune thrombotic thrombocytopaenia, revealing that the epitope corresponds to the heparin-binding site on PF4.
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