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Article

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

by
Kristina Zguro
1,†,
Margherita Baldassarri
1,2,†,
Francesca Fava
1,2,3,
Giada Beligni
1,2,
Sergio Daga
1,2,
Roberto Leoncini
4,
Lucrezia Galasso
4,
Michele Cirianni
4,
Stefano Rusconi
5,6,
Matteo Siano
6,
Daniela Francisci
7,
Elisabetta Schiaroli
7,
Sauro Luchi
8,
Giovanna Morelli
8,
Enrico Martinelli
9,
Massimo Girardis
10,
Stefano Busani
10,
Saverio Giuseppe Parisi
11,
Sandro Panese
12,
Carmelo Piscopo
13,
Mario Capasso
14,15,
Danilo Tacconi
16,
Chiara Spertilli Raffaelli
16,
Annarita Giliberti
17,
Giulia Gori
17,
Peter D. Katsikis
18,
Maria Lorubbio
19,
Paola Calzoni
4,
Agostino Ognibene
19,
Monica Bocchia
20,
Monica Tozzi
21,
Alessandro Bucalossi
21,
Giuseppe Marotta
21,
Simone Furini
1,
GEN-COVID Multicenter Study
‡,
Alessandra Renieri
1,2,3,* and
Chiara Fallerini
1,2add Show full author list remove Hide full author list
1
Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy
2
Medical Genetics, University of Siena, 53100 Siena, Italy
3
Genetica Medica, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
4
Laboratorio Patologia Clinica, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy
5
Infectious Diseases Unit, ASST Ovest Milanese, 20025 Legnano, Italy
6
Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, 20157 Milan, Italy
7
Infectious Diseases Clinic, “Santa Maria della Misericordia” Hospital, University of Perugia, 06124 Perugia, Italy
8
Infectious Disease Unit, Hospital of Lucca, 55100 Lucca, Italy
9
Department of Respiratory Diseases, Azienda Ospedaliera di Cremona, 26100 Cremona, Italy
10
Department of Anesthesia and Intensive Care, University of Modena and Reggio Emilia, 41124 Modena, Italy
11
Department of Molecular Medicine, University of Padova, 35121 Padova, Italy
12
Clinical Infectious Diseases, Mestre Hospital, 30171 Venezia, Italy
13
Medical Genetics and Laboratory Genetics Unit, “Antonio Cardarelli” hospital, 80131 Naples, Italy
14
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80138 Naples, Italy
15
CEINGE Biotecnologie Avanzate, 80145 Naples, Italy
16
Department of Specialized and Internal Medicine, Infectious Diseases Unit, San Donato Hospital Arezzo, 52100 Arezzo, Italy
17
Medical Genetics Unit, Meyer Children’s University Hospital, 50134 Florence, Italy
18
Department of Immunology, Erasmus Medical Center, 3015 GD Rotterdam, The Netherlands
19
UOC Laboratorio Analisi Chimico Cliniche, 52100 Arezzo, Italy
20
Hematology Unit, Department of Medical Science, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy
21
Stem Cell Transplant and Cellular Therapy Unit, University Hospital of Siena, 53100 Siena, Italy
 
add Show full affiliation list
 
remove Hide full affiliation list
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
GEN-COVID Multicenter Study members and their affiliations are listed in supplementary materials.
Viruses 2022, 14(6), 1185; https://doi.org/10.3390/v14061185
Submission received: 21 March 2022 / Revised: 25 May 2022 / Accepted: 25 May 2022 / Published: 29 May 2022
(This article belongs to the Special Issue COVID-19 and Thrombosis)
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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.
Keywords: COVID-19; ADAMTS13; thromboembolism; add-on therapy COVID-19; ADAMTS13; thromboembolism; add-on therapy
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MDPI and ACS Style

Zguro, K.; Baldassarri, M.; Fava, F.; Beligni, G.; Daga, S.; Leoncini, R.; Galasso, L.; Cirianni, M.; Rusconi, S.; Siano, M.; et al. Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19. Viruses 2022, 14, 1185. https://doi.org/10.3390/v14061185

AMA Style

Zguro K, Baldassarri M, Fava F, Beligni G, Daga S, Leoncini R, Galasso L, Cirianni M, Rusconi S, Siano M, et al. Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19. Viruses. 2022; 14(6):1185. https://doi.org/10.3390/v14061185

Chicago/Turabian Style

Zguro, Kristina, Margherita Baldassarri, Francesca Fava, Giada Beligni, Sergio Daga, Roberto Leoncini, Lucrezia Galasso, Michele Cirianni, Stefano Rusconi, Matteo Siano, and et al. 2022. "Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19" Viruses 14, no. 6: 1185. https://doi.org/10.3390/v14061185

APA Style

Zguro, K., Baldassarri, M., Fava, F., Beligni, G., Daga, S., Leoncini, R., Galasso, L., Cirianni, M., Rusconi, S., Siano, M., Francisci, D., Schiaroli, E., Luchi, S., Morelli, G., Martinelli, E., Girardis, M., Busani, S., Parisi, S. G., Panese, S., ... Fallerini, C. (2022). Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19. Viruses, 14(6), 1185. https://doi.org/10.3390/v14061185

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