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Published on: January 16, 2019
Carriers of ADAMTS13 Rare Variants Are at High Risk of Life-Threatening COVID-19
Kristina Zguro1, Margherita Baldassarri1,2, Francesca Fava1,2,3
1Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy.
Insights
Ultra-rare genetic variants in ADAMTS13 increase COVID-19 severity by impairing blood clot regulation. These variants, in heterozygous carriers, can lead to a distinct, infection-triggered COVID-19 presentation.
Area of Science:
- Genetics
- Hematology
- Infectious Diseases
Background:
- Thrombosis is a major factor in COVID-19 severity, but genetic predispositions are not fully understood.
- Congenital Thrombotic Thrombocytopenic Purpura involves uncleaved von Willebrand Factor (vWF) and is infection-triggered.
- ADAMTS13 is the enzyme responsible for cleaving vWF.
Purpose of the Study:
- To investigate the host genetic factors influencing COVID-19 severity, particularly thrombosis.
- To identify specific genetic variants associated with increased susceptibility to severe COVID-19.
Main Methods:
- Exome sequencing of approximately 3000 SARS-CoV-2 infected individuals from the GEN-COVID cohort.
- Analysis of genetic variants in the ADAMTS13 gene.
- Segregation analysis within families to understand inheritance patterns.
Main Results:
- Ultra-rare heterozygous variants in ADAMTS13 were identified.
- These variants are associated with a rare form of COVID-19 characterized by hyper-inflammation.
- The condition segregates as an autosomal dominant disorder influenced by infection, sex, and age.
Conclusions:
- Heterozygous, ultra-rare ADAMTS13 variants represent a novel genetic determinant of severe COVID-19.
- This finding highlights the role of vWF regulation in COVID-19 pathogenesis.
- Available therapies targeting vWF-platelet interactions or P-selectin offer potential treatment avenues.
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.
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