Whole Exome Sequencing in Vaccine-Induced Thrombotic Thrombocytopenia (VITT).

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.

Diffuse prothrombotic syndrome after ChAdOx1 nCoV-19 vaccine administration: a case report.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia is emerging as one of the most relevant side effects of adenoviral-based vaccines against coronavirus disease 2019. Given the novelty of this disease, the medical community is seeking new evidence and clinical experiences on the management of these patients. CASE PRESENTATION: In this article, we describe the case of a 73-year-old Caucasian woman who presented with diffuse prothrombotic syndrome, both in the arterial and venous districts, following the first dose administration of ChAdOx1 CoV-19 vaccine. The main thrombotic sites included the brain, with both a cortical ischemic lesion and thromboses of the left transverse and sigmoid sinuses and the lower limbs, with deep venous thrombosis accompanied by subsegmental pulmonary thromboembolism. The deep venous thrombosis progressively evolved into acute limb ischemia, requiring surgical intervention with thromboendoarterectomy. Anticoagulation was maintained throughout the whole hospitalization period and continued in the outpatient setting using vitamin K antagonists for a recommended period of 6 months. CONCLUSIONS: This case describes the management of vaccine-induced immune thrombotic thrombocytopenia in a complicated clinical scenario, including multisite arterial and venous thromboses. Given the complexity of the patient presentation, this case may implement the comprehension of the mechanisms and clinical features of this disease; it also provides a picture of the challenges related to the management, often requiring a multidisciplinary approach.