دورية أكاديمية
Downregulation of thrombomodulin-thrombin-activated protein C pathway as a mechanism for SARS-CoV-2 induced endotheliopathy and microvascular thrombosis
| العنوان: | Downregulation of thrombomodulin-thrombin-activated protein C pathway as a mechanism for SARS-CoV-2 induced endotheliopathy and microvascular thrombosis |
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| المؤلفون: | S. Agarwal, C.T. Cohen, M. Zobeck, P.M. Jacobi, S.E. Sartain |
| المصدر: | Thrombosis Update, Vol 8, Iss , Pp 100116- (2022) |
| بيانات النشر: | Elsevier |
| سنة النشر: | 2022 |
| المجموعة: | Directory of Open Access Journals: DOAJ Articles |
| مصطلحات موضوعية: | Endothelial injury, Microvascular thrombosis, COVID-19 and thrombosis, Thrombomodulin, Alternate complement pathway activation, Diseases of the circulatory (Cardiovascular) system, RC666-701 |
| الوصف: | There is emerging evidence of microvascular thrombosis and thrombotic microangiopathy (TMA) induced by COVID-19, presumably from endothelial injury. Thrombomodulin (TM) is an endothelial glycoprotein that plays a dual role in maintaining healthy endothelium-as a natural anticoagulant by binding thrombin to activate protein C (APC) and a negative regulator of the alternate complement pathway (AP). TM is shed into the plasma as soluble TM (sTM) during endothelial injury.We hypothesize that SARS-CoV-2 spike proteins cause direct microvascular endothelial injury, leading to TM shedding, decreased activation of PC, and consequently, microvascular thrombosis in COVID-19. We conducted this study twofold: 1) in vivo, we assessed endothelial injury (by measuring sTM) and AP activation by quantifying Ba (cleavage product of AP component Factor B) in a cohort of critically ill COVID-19 pediatric patients and the implications on clinical outcomes; and 2)in vitro, we investigated endothelial injury (TM shedding) by SARS-COV-2 spike proteins and the subsequent functional consequence in activated PC (APC) levels and Ba levels.sTM and Ba in plasma samples from SARS-CoV-2 positive patients admitted to Texas Children's Hospital Pediatric Intensive Care Unit (n = 33) and from healthy controls (n = 38) were measured by ELISA. In vitro, confluent glomerular microvascular endothelial cells (GMVECs) were incubated for 48 h in the presence or absence (control) of purified SARS-CoV-2 spike proteins, S1 and S2. TM from the cell lysates while Ba and APC from the cell supernatants were measured by ELISA. sTM and Ba levels were significantly higher in the COVID-19 pediatric patients compared to healthy controls (p < 0.01 and p < 0.001, respectively). Among the COVID-19 patients, elevated sTM was associated with increased vasopressor use (p = 0.01) and elevated Ba was associated with increased duration of mechanical ventilation (p = 0.04). In vitro, surface bound TM and soluble APC were significantly lower in GMVECs after addition of ... |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| ردمك: | 978-2-666-57272-5 2-666-57272-2 |
| تدمد: | 2666-5727 |
| العلاقة: | http://www.sciencedirect.com/science/article/pii/S2666572722000207Test; https://doaj.org/toc/2666-5727Test; https://doaj.org/article/280c1eb873934c8e860f8c621921b8f1Test |
| DOI: | 10.1016/j.tru.2022.100116 |
| الإتاحة: | https://doi.org/10.1016/j.tru.2022.100116Test https://doaj.org/article/280c1eb873934c8e860f8c621921b8f1Test |
| رقم الانضمام: | edsbas.F018251D |
| قاعدة البيانات: | BASE |
Full Text Finder | ردمك: | 9782666572725 2666572722 |
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| تدمد: | 26665727 |
| DOI: | 10.1016/j.tru.2022.100116 |