학술논문
ADAMTS13 or Caplacizumab Reduces the Accumulation of Neutrophil Extracellular Traps and Thrombus in Whole Blood of COVID-19 Patients under Flow.
Document Type
Academic Journal
Author
Yada N; Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kanas City, Kansas, United States.; Zhang Q; Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kanas City, Kansas, United States.; Bignotti A; Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kanas City, Kansas, United States.; Ye Z; Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kanas City, Kansas, United States.; Zheng XL; Department of Pathology and Laboratory Medicine, The University of Kansas Medical Center, Kanas City, Kansas, United States.; Institute of Reproductive Medicine and Developmental Sciences, The University of Kansas Medical Center, Kanas City, Kansas, United States.
Source
Publisher: Thieme Country of Publication: Germany NLM ID: 7608063 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2567-689X (Electronic) Linking ISSN: 03406245 NLM ISO Abbreviation: Thromb Haemost Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Neutrophil NETosis and neutrophil extracellular traps (NETs) play a critical role in pathogenesis of coronavirus disease 2019 (COVID-19)-associated thrombosis. However, the extents and reserve of NETosis, and potential of thrombus formation under shear in whole blood of patients with COVID-19 are not fully elucidated. Neither has the role of recombinant ADAMTS13 or caplacizumab on the accumulation of NETs and thrombus in COVID-19 patients' whole blood under shear been investigated.
Methods: Flow cytometry and microfluidic assay, as well as immunoassays, were employed for the study.
Results: We demonstrated that the percentage of H3Cit + MPO+ neutrophils, indicative of NETosis, was dramatically increased in patients with severe but not critical COVID-19 compared with that in asymptomatic or mild disease controls. Upon stimulation with poly [I:C], a double strain DNA mimicking viral infection, or bacterial shigatoxin-2, the percentage of H3Cit + MPO+ neutrophils was not significantly increased in the whole blood of severe and critical COVID-19 patients compared with that of asymptomatic controls, suggesting the reduction in NETosis reserve in these patients. Microfluidic assay demonstrated that the accumulation of NETs and thrombus was significantly enhanced in the whole blood of severe/critical COVID-19 patients compared with that of asymptomatic controls. Like DNase I, recombinant ADAMTS13 or caplacizumab dramatically reduced the NETs accumulation and thrombus formation under arterial shear.
Conclusion: Significantly increased neutrophil NETosis, reduced NETosis reserve, and enhanced thrombus formation under arterial shear may play a crucial role in the pathogenesis of COVID-19-associated coagulopathy. Recombinant ADAMTS13 or caplacizumab may be explored for the treatment of COVID-19-associated thrombosis.
Competing Interests: X.L.Z. is a consultant for Alexion, Sanofi, Takeda, Apollo, GC Biopharma, and Stago. X.L.Z. is also the co-founder of Clotsolution. All other authors have declared no relevant conflict.
(Thieme. All rights reserved.)
Methods: Flow cytometry and microfluidic assay, as well as immunoassays, were employed for the study.
Results: We demonstrated that the percentage of H3Cit + MPO+ neutrophils, indicative of NETosis, was dramatically increased in patients with severe but not critical COVID-19 compared with that in asymptomatic or mild disease controls. Upon stimulation with poly [I:C], a double strain DNA mimicking viral infection, or bacterial shigatoxin-2, the percentage of H3Cit + MPO+ neutrophils was not significantly increased in the whole blood of severe and critical COVID-19 patients compared with that of asymptomatic controls, suggesting the reduction in NETosis reserve in these patients. Microfluidic assay demonstrated that the accumulation of NETs and thrombus was significantly enhanced in the whole blood of severe/critical COVID-19 patients compared with that of asymptomatic controls. Like DNase I, recombinant ADAMTS13 or caplacizumab dramatically reduced the NETs accumulation and thrombus formation under arterial shear.
Conclusion: Significantly increased neutrophil NETosis, reduced NETosis reserve, and enhanced thrombus formation under arterial shear may play a crucial role in the pathogenesis of COVID-19-associated coagulopathy. Recombinant ADAMTS13 or caplacizumab may be explored for the treatment of COVID-19-associated thrombosis.
Competing Interests: X.L.Z. is a consultant for Alexion, Sanofi, Takeda, Apollo, GC Biopharma, and Stago. X.L.Z. is also the co-founder of Clotsolution. All other authors have declared no relevant conflict.
(Thieme. All rights reserved.)