SARS-CoV-2 ORF7a activates the endothelium to release von Willebrand factor that promotes thrombosis
Background: Patients with severe and critical COVID-19 frequently exhibit thromboembolic complications, a significant cause of mortality and morbidity. Increased plasma levels of von Willebrand factor (VWF) following SARS-CoV-2 infection have been extensively reported, which links to thrombosis and...
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Elsevier
2025-05-01
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| Series: | Research and Practice in Thrombosis and Haemostasis |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2475037925002717 |
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| author | Quan Zhang Xiaohu Huang Hangnoh Lee Jin-Gu Lee Szumam Liu Shiwani Limbu Malay K. Basu Joyce van de Leemput Felice D’Agnillo Zhe Han X. Long Zheng |
| author_facet | Quan Zhang Xiaohu Huang Hangnoh Lee Jin-Gu Lee Szumam Liu Shiwani Limbu Malay K. Basu Joyce van de Leemput Felice D’Agnillo Zhe Han X. Long Zheng |
| author_sort | Quan Zhang |
| collection | DOAJ |
| description | Background: Patients with severe and critical COVID-19 frequently exhibit thromboembolic complications, a significant cause of mortality and morbidity. Increased plasma levels of von Willebrand factor (VWF) following SARS-CoV-2 infection have been extensively reported, which links to thrombosis and increased mortality. However, the mechanism underlying SARS-CoV-2–associated thrombotic complications is not fully understood. Objectives: To determine the mechanism of SARS-CoV-2–associated thrombosis. Methods: Drosophila genetic screening and molecular, cellular, and biochemical approaches were used. Results: Genetic screening identified a SARS-CoV-2 accessory protein, Orf7a, as a crucial factor promoting agglutination of hemolymph, the circulatory fluid of flies, which is functionally comparable to the blood and lymph of vertebrates. Further studies using cultured murine splenic vascular endothelial cells and human umbilical cord endothelial cells demonstrated that overexpression of ORF7a in these cells significantly activated and stimulated the release of VWF, leading to an increased rate and final coverage of Adamts-13-/- murine platelets on activated endothelial surfaces under arterial shear. Moreover, a soluble recombinant ORF7a could also activate human endothelial cells and trigger the release of VWF from Weibel–Palade bodies. Conclusion: We demonstrate for the first time that SARS-CoV-2 ORF7a may be one of the pathogenic factors contributing to COVID-19–associated thrombosis by activating the vascular endothelium to release ultralarge VWF, which promotes platelet adhesion and agglutination, and thrombus formation. Thus, a strategy specifically targeting VWF-platelet interaction, such as recombinant a disintegrin and metalloprotease with thrombospondin type 1 repeats, 13 (ADAMTS-13) and/or caplacizumab, may be efficacious in reducing COVID-19–associated thrombosis and mortality. |
| format | Article |
| id | doaj-art-25512a7cc53b4e4e843fd3dc248f70f9 |
| institution | DOAJ |
| issn | 2475-0379 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Research and Practice in Thrombosis and Haemostasis |
| spelling | doaj-art-25512a7cc53b4e4e843fd3dc248f70f92025-08-20T03:04:58ZengElsevierResearch and Practice in Thrombosis and Haemostasis2475-03792025-05-019410294710.1016/j.rpth.2025.102947SARS-CoV-2 ORF7a activates the endothelium to release von Willebrand factor that promotes thrombosisQuan Zhang0Xiaohu Huang1Hangnoh Lee2Jin-Gu Lee3Szumam Liu4Shiwani Limbu5Malay K. Basu6Joyce van de Leemput7Felice D’Agnillo8Zhe Han9X. Long Zheng10Departments of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA; Department of Pulmonary and Critical Care Medicine, The Second Xiangya Hospital, Central South University, Changsha, ChinaDepartment of Medicine, Center for Precision Disease Modeling, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USADepartment of Medicine, Center for Precision Disease Modeling, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USADepartment of Medicine, Center for Precision Disease Modeling, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USADepartments of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USADepartments of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USADepartments of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USADepartment of Medicine, Center for Precision Disease Modeling, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USALaboratory of Biochemistry and Vascular Biology, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USADepartment of Medicine, Center for Precision Disease Modeling, University of Maryland School of Medicine, Baltimore, Maryland, USA; Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, USA; Correspondence Zhe Han, Department of Medicine, Center for Precision Disease Modeling, University of Maryland School of Medicine, 670 W Baltimore Street, 4052, HSFIII, Baltimore, MD 21201, USA.Departments of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA; Institute of Reproductive and Developmental Sciences, University of Kansas Medical Center, Kansas City, Kansas, USA; X. Long Zheng, Departments of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66216, USA.Background: Patients with severe and critical COVID-19 frequently exhibit thromboembolic complications, a significant cause of mortality and morbidity. Increased plasma levels of von Willebrand factor (VWF) following SARS-CoV-2 infection have been extensively reported, which links to thrombosis and increased mortality. However, the mechanism underlying SARS-CoV-2–associated thrombotic complications is not fully understood. Objectives: To determine the mechanism of SARS-CoV-2–associated thrombosis. Methods: Drosophila genetic screening and molecular, cellular, and biochemical approaches were used. Results: Genetic screening identified a SARS-CoV-2 accessory protein, Orf7a, as a crucial factor promoting agglutination of hemolymph, the circulatory fluid of flies, which is functionally comparable to the blood and lymph of vertebrates. Further studies using cultured murine splenic vascular endothelial cells and human umbilical cord endothelial cells demonstrated that overexpression of ORF7a in these cells significantly activated and stimulated the release of VWF, leading to an increased rate and final coverage of Adamts-13-/- murine platelets on activated endothelial surfaces under arterial shear. Moreover, a soluble recombinant ORF7a could also activate human endothelial cells and trigger the release of VWF from Weibel–Palade bodies. Conclusion: We demonstrate for the first time that SARS-CoV-2 ORF7a may be one of the pathogenic factors contributing to COVID-19–associated thrombosis by activating the vascular endothelium to release ultralarge VWF, which promotes platelet adhesion and agglutination, and thrombus formation. Thus, a strategy specifically targeting VWF-platelet interaction, such as recombinant a disintegrin and metalloprotease with thrombospondin type 1 repeats, 13 (ADAMTS-13) and/or caplacizumab, may be efficacious in reducing COVID-19–associated thrombosis and mortality.http://www.sciencedirect.com/science/article/pii/S2475037925002717ADAMTS-13coagulationendotheliumHmlOrf7aSARS-CoV-2 |
| spellingShingle | Quan Zhang Xiaohu Huang Hangnoh Lee Jin-Gu Lee Szumam Liu Shiwani Limbu Malay K. Basu Joyce van de Leemput Felice D’Agnillo Zhe Han X. Long Zheng SARS-CoV-2 ORF7a activates the endothelium to release von Willebrand factor that promotes thrombosis Research and Practice in Thrombosis and Haemostasis ADAMTS-13 coagulation endothelium Hml Orf7a SARS-CoV-2 |
| title | SARS-CoV-2 ORF7a activates the endothelium to release von Willebrand factor that promotes thrombosis |
| title_full | SARS-CoV-2 ORF7a activates the endothelium to release von Willebrand factor that promotes thrombosis |
| title_fullStr | SARS-CoV-2 ORF7a activates the endothelium to release von Willebrand factor that promotes thrombosis |
| title_full_unstemmed | SARS-CoV-2 ORF7a activates the endothelium to release von Willebrand factor that promotes thrombosis |
| title_short | SARS-CoV-2 ORF7a activates the endothelium to release von Willebrand factor that promotes thrombosis |
| title_sort | sars cov 2 orf7a activates the endothelium to release von willebrand factor that promotes thrombosis |
| topic | ADAMTS-13 coagulation endothelium Hml Orf7a SARS-CoV-2 |
| url | http://www.sciencedirect.com/science/article/pii/S2475037925002717 |
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