A novel STING variant triggers endothelial toxicity and SAVI disease.

Gain-of-function mutations in STING cause STING-associated vasculopathy with onset in infancy (SAVI) characterized by early-onset systemic inflammation, skin vasculopathy, and interstitial lung disease. Here, we report and characterize a novel STING variant (F269S) identified in a SAVI patient. Single-cell transcriptomics of patient bone marrow revealed spontaneous activation of interferon (IFN) and inflammatory pathways across cell types and a striking prevalence of circulating naïve T cells was observed. Inducible STING F269S expression conferred enhanced signaling through ligand-independent translocation of the protein to the Golgi, protecting cells from viral infections but preventing their efficient immune priming. Additionally, endothelial cell activation was promoted and further exacerbated by cytokine secretion by SAVI immune cells, resulting in inflammation and endothelial damage. Our findings identify STING F269S mutation as a novel pathogenic variant causing SAVI, highlight the importance of the crosstalk between endothelial and immune cells in the context of lung disease, and contribute to a better understanding of how aberrant STING activation can cause pathology.

Management of Microvascular Bleeding after On-Pump Cardiac Surgery in a Patient with Perioperative Diagnosis of Impairment of Platelet Responses to Adenosine Diphosphate: A Case Report and a Literature Review.

BACKGROUND: Impairment of platelet responses to adenosine diphosphate (ADP) is typified by mild to severe bleeding diathesis, easy bruising, excessive mucosal and post-operative bleeding. Patients lack full platelet activation and aggregation in response to ADP. Following research of the literature in Scopus, PubMed/MEDLINE, ScienceDirect, and the Cochrane Library, we report only 18 patients described to date with impaired platelet response to ADP, none of whom in the high bleeding-risk surgical setting or exploring potential therapeutic options. Data regarding population, putative genetic mutations, modes of inheritance, functional defects, and related clinical manifestations were retrieved from case series and case reports. CASE PRESENTATION: A 40-year-old woman was scheduled for on-pump cardiac surgery. Her past medical history included episodes of spontaneous mucocutaneous hemorrhages of the mild entity since childhood. Multiple electrode aggregometry (MEA, Multiplate® Roche Diagnostics, Rotkreuz, Switzerland) was used to evaluate platelet response to thrombin-activated peptide-6 (TRAP), arachidonic acid (ASPI), and ADP. An inadequate platelet aggregation induced using a high concentration of ADP with normal TRAP and ASPI tests was detected preoperatively. Therefore, intravenous desmopressin (DVVAP) 0.3 µg/kg body weight was administered to manage microvascular bleeding developed after weaning from cardiopulmonary bypass (CPB). CONCLUSIONS: Proper management of impaired platelet response to ADP requires a systematic assessment. The Multiplate analyzer is a valuable tool to promptly detect the disorder when a high clinical suspect is present and obtain insights during high bleeding-risk surgical procedures. DVVAP can be beneficial as first-line therapy in bleeding patients to improve platelet function.