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 ADAMTS13 (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.

Zguro, K., Baldassarri, M., Fava, F., Beligni, G., Daga, S., Leoncini, R., et al. (2022). Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19. VIRUSES, 14(6) [10.3390/v14061185].

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

Zguro, Kristina
Conceptualization
;
Baldassarri, Margherita
Conceptualization
;
Fava, Francesca
Methodology
;
Beligni, Giada
Methodology
;
Daga, Sergio
Methodology
;
Leoncini, Roberto
Formal Analysis
;
Bocchia, Monica
Formal Analysis
;
Renieri, Alessandra
Validation
;
Fallerini Chiara
Conceptualization
;
Francesca Mari
Membro del Collaboration Group
;
Mirella Bruttini
Membro del Collaboration Group
;
Ilaria Meloni
Membro del Collaboration Group
;
Susanna Croci
Membro del Collaboration Group
;
Viola Bianca Serio
Membro del Collaboration Group
;
Debora Maffeo
Membro del Collaboration Group
;
Elena Pasquinelli
Membro del Collaboration Group
;
Giulia Brunelli
Membro del Collaboration Group
;
Caterina Lo Rizzo
Membro del Collaboration Group
;
Anna Maria Pinto
Membro del Collaboration Group
;
Francesca Ariani
Membro del Collaboration Group
;
Francesca Montagnani
Membro del Collaboration Group
;
Mario Tumbarello
Membro del Collaboration Group
;
Elena Bargagli
Membro del Collaboration Group
;
Laura Bergantini
Membro del Collaboration Group
;
Miriana D’Alessandro
Membro del Collaboration Group
;
Paolo Cameli
Membro del Collaboration Group
;
David Bennett
Membro del Collaboration Group
;
Sabino Scolletta
Membro del Collaboration Group
;
Federico Franchi
Conceptualization
;
Maria Antonietta Mazzei
Membro del Collaboration Group
;
Luca Cantarini
Membro del Collaboration Group
;
Bruno Frediani
Membro del Collaboration Group
;
Serafina Valente
Membro del Collaboration Group
;
Marco Mandala
Membro del Collaboration Group
;
Alessia Giorli
Membro del Collaboration Group
;
Lorenzo Salerni
Membro del Collaboration Group
;
Marco Gori
Membro del Collaboration Group
;
2022-01-01

Abstract

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 ADAMTS13 (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.
2022
Zguro, K., Baldassarri, M., Fava, F., Beligni, G., Daga, S., Leoncini, R., et al. (2022). Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19. VIRUSES, 14(6) [10.3390/v14061185].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/1223540