Understanding thrombosis with thrombocytopenia syndrome after COVID-19 vaccination

An overview of the clinical and diagnostic features of VITT in the UK was presented. VITT has been described as a cause of TTS, but not as a synonym. As cases were collected from daily clinical meetings during the vaccination campaign, a pattern emerged consisting of five equally weighted clinical characteristics, and using these, the probability that the case is VITT could be classified as definite, probable, possible and unlikely.18. The initial female overrepresentation of TTS cases appeared to reflect the demographics during the initial launch of the adenovirus vector vaccine in the UK. Of note, administration of second doses of COVID-19 vaccine in 40 UK patients who had definite (26), probable (2), and possible (12) VITT after a first dose of Vaxzevria did not lead to recurrent VITT.19even in the few subjects (north= 5) who had received a second dose of Vaxzevria.

This was corroborated by work done in an independent research group in Germany. The latter demonstrated that anti-PF4 antibodies in TTS vaccinates are transienttwenty. Detection of anti-PF4 antibodies is a crucial marker for VITT but available assays have different sensitivitiestwenty-one, and ELISA-based approaches can be combined with specific functional assays. It has been previously shown that VITT-associated anti-PF4 antibodies do not cross-react with the spike protein, indicating that VITT is specifically induced after vaccination with adenovirus vectors.22. In vivo human evidence that the anti-PF4 response in VITT is not related to spike protein or SARS-CoV2 came from data collected in a cohort of 11 patients with a history of VITT and subsequent COVID-19. In these patients, no significant increase in anti-PF4 antibody levels was observed after recovery from COVID-19.23.

Since VITT occurs as early as 5 days after vaccine administration, the anti-PF4 B cell response does not align with notions of the conventional immune response following primary antigen challenge and appears to be a secondary immune response. Recently, the molecular signature of clonotypic anti-PF4 antibodies was identified in five patients, defined as a single IgG heavy (H) chain species paired with a single lambda light (L) chain species, and all L chains were encoded by the identical IGLV3-21*02 gene subfamily24. These results may reveal a shared pathway of antibody production in VITT patients and could point to a possible genetic predisposition underlying the syndrome.

According to a working hypothesis, the complexes formed by PF4 and adenovirus vector vaccines together with a strong immune activation induced by vaccination could lead to the formation of pathogenic anti-PF4 autoantibodies that trigger platelet activation and the subsequent prothrombotic cascade.25. Adenovirus vaccine components that bind to PF4 can induce conformational changes in PF4 and create potential neoantigens, responsible for activation of marginal zone B cells. This latter immunobiological process still requires further investigation. However, data generated with super-resolution microscopy show that the vaccine components form complexes with PF4 to which anti-PF4 antibodies obtained from VITT patients bind in vitro. Participants reflected on the fact that anti-PF4 antibodies can be found in ~5% of the population.26.27, but these common antibodies do not activate platelets and are likely to have little or no clinical relevance. In very rare cases, pathogenic anti-PF4 platelet activating antibodies can also occur independently of vaccination against COVID-19 and heparin-induced thrombocytopenia (HIT) syndrome, such as occurred after viral infections or knee replacement surgery .28. HIT is an adverse reaction to the drug heparin.

An overview of clinical cases of vaccine-associated TTS following Vaxzevria in Australia was provided. These cases in Australia are classified according to the International Network of Special Immunization Services approach to characterizing the risk factors and mechanisms underlying adverse events of special interest after vaccination.29. Of relevance, cases of mortality after the second dose of Vaxzevria in Australia appeared to be associated with a shorter dosing interval than current national recommendations. In addition, participants discussed ongoing research plans to study genetic risk factors and characterization of autoantibody-producing B-cell clones in VITT using multi-omics.

Interestingly, the data generated by mass spectrometry showed that anti-PF4 antibodies obtained from VITT patients are monoclonal or oligoclonal, in contrast to anti-PF4 antibodies in conventional HIT, which are always polyclonal.30. It was commented that in addition to the monoclonal versus polyclonal humoral response dichotomous distinction between VITT and HIT, it will be crucial to understand the exact binding epitopes to PF4 shared or not between the two antibody responses. Recent data suggest that antibody binding to uncomplexed PF4 appears to be the key feature that differentiates VITT from cases of HIT and spontaneous HIT.31however, the degree of specificity of this assay needs to be evaluated in larger studies. VITT antibodies only occasionally activate platelets in the presence of heparin as in the serotonin release assay, but consistently activate PF4-treated platelets, in line with previous findings. Therefore, it is important to use only PF4-treated platelets in functional testing for VITT.

Attendees discussed the relative merits of centralized versus decentralized laboratories for functional testing to reliably detect TTS and VITT cases worldwide. Furthermore, although VITT is associated with a high optical density (OD) of anti-PF4 antibodies in PF4-polyanion ELISAs (HIT ELISAs), exceptions exist, and many HIT antibodies also have high ODs in this assay. In addition, a small percentage of healthy individuals test positive on this ELISA (typically with low OD). Due to the short time period for the detection of anti-PF4 antibodies in the serum (sometimes as early as 5 days after immunization), the most likely immunological explanation is that TTS vaccinates harbored pre-existing anti-PF4 B cell clones that were activated after vaccination. vaccination. The concept of monoclonality versus polyclonality antibody, as well as the type and signature of the B cell population involved in the immune response, will require further study.

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