Abstract
Background: In February 2021, a few cases of unusual, severe thrombotic events associated with thrombocytopenia reported after vaccination with ChAdOx1 nCoV‐19 (Vaxzevria) or with Johnson & Johnson’s Janssen vaccine raise concern about safety. The vaccine‐induced thrombotic thrombocytopenia (VITT) has been related to the presence of platelet‐activating antibodies directed against platelet Factor 4.Objectives: We investigated VITT subject genetic background by a high‐throughput whole exome sequencing (WES) approach in order to investigate VITT genetic predisposition.Methods: Six consecutive patients (females of Caucasian origin with a mean age of 64 years) were referred to the Atherothrombotic Diseases Center (Department of Experimental and Clinical Medicine, Azienda Ospedaliero‐Universitaria Careggi, Florence) with a diagnosis of definite VITT underwent WES analysis. WES analysis was performed on the Illumina NextSeq500 platform.Results:WES analysis revealed a total of 140,563 genetic variants. Due to VITT’s rare occurrence, we focused attention on rare variants. The global analysis of all high‐quality rare variants did not reveal a significant enrichment of mutated genes in biological/functional pathways common to patients analyzed. Afterwards, we focused on rare variants in genes associated with blood coagulation and fibrinolysis, platelet activation and aggregation, integrin‐mediated signaling pathway, and inflammation with particular attention to those involved in vascular damage, as well as autoimmune thrombocytopenia. According to ACMG criteria, 47/194 (24.2%) rare variants were classified as uncertain significance variants (VUS), whereas the remaining were likely benign/benign.Conclusion: WES analysis identifies rare variants possibly favoring the prothrombotic state triggered by the exposure to the vaccine. Functional studies and/or extensions to a larger number of patients might allow a more comprehensive definition of these molecular pathways.
Funder
Università degli Studi di Firenze