Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19

• Published in: Viruses 2022-05, Vol.14 (6), p.1185
• Main Authors: Zguro, Kristina, Baldassarri, Margherita, Fava, Francesca, Beligni, Giada, Daga, Sergio, Leoncini, Roberto, Galasso, Lucrezia, Cirianni, Michele, Rusconi, Stefano, Siano, Matteo, Francisci, Daniela, Schiaroli, Elisabetta, Luchi, Sauro, Morelli, Giovanna, Martinelli, Enrico, Girardis, Massimo, Busani, Stefano, Parisi, Saverio Giuseppe, Panese, Sandro, Piscopo, Carmelo, Capasso, Mario, Tacconi, Danilo, Spertilli Raffaelli, Chiara, Giliberti, Annarita, Gori, Giulia, Katsikis, Peter D, Lorubbio, Maria, Calzoni, Paola, Ognibene, Agostino, Bocchia, Monica, Tozzi, Monica, Bucalossi, Alessandro, Marotta, Giuseppe, Furini, Simone, Gen-Covid Multicenter Study, Renieri, Alessandra, Fallerini, Chiara
• Format: Article
• Language: English
• Subjects: ADAM Proteins - genetics; ADAM Proteins - metabolism; ADAMTS13; ADAMTS13 Protein - genetics; add-on therapy; Adenoviruses; Age; Blood platelets; Blood tests; Congenital diseases; Coronaviruses; COVID-19; COVID-19 - genetics; Disease transmission; Enzymes; Estrogens; Ethnicity; Females; Hereditary diseases; Hospitalization; Humans; Infections; Leukocyte migration; Males; Metalloproteinase; Mutation; P-selectin; Patients; Pediatrics; Plasma; Platelet aggregation; Purpura, Thrombotic Thrombocytopenic - diagnosis; Purpura, Thrombotic Thrombocytopenic - genetics; Rotavirus; SARS-CoV-2 - pathogenicity; Severe acute respiratory syndrome coronavirus 2; Statistical analysis; Thrombocytopenic purpura; thromboembolism; Thrombosis; Thrombospondin; Thrombotic microangiopathy; Thrombotic thrombocytopenic purpura; Ultrasonic imaging; Viruses; von Willebrand Factor - chemistry; von Willebrand Factor - genetics; von Willebrand Factor - metabolism
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v14061185

Thrombosis of small and large vessels is reported as a key player in COVID-19 severity. However, host genetic determinants of this susceptibility are still unclear. Congenital Thrombotic Thrombocytopenic Purpura is a severe autosomal recessive disorder characterized by uncleaved ultra-large vWF and thrombotic microangiopathy, frequently triggered by infections. Carriers are reported to be asymptomatic. Exome analysis of about 3000 SARS-CoV-2 infected subjects of different severities, belonging to the GEN-COVID cohort, revealed the specific role of vWF cleaving enzyme (A disintegrin-like and metalloprotease with thrombospondin type 1 motif, 13). We report here that ultra-rare variants in a heterozygous state lead to a rare form of COVID-19 characterized by hyper-inflammation signs, which segregates in families as an autosomal dominant disorder conditioned by SARS-CoV-2 infection, sex, and age. This has clinical relevance due to the availability of drugs such as Caplacizumab, which inhibits vWF-platelet interaction, and Crizanlizumab, which, by inhibiting P-selectin binding to its ligands, prevents leukocyte recruitment and platelet aggregation at the site of vascular damage.