Authors: Bhanu Kanth Manne (University of Utah, United States) Frederik Denorme (Molecular Medicine Program, University of Utah, United States), Elizabeth Middleton (University of Utah, United States), Irina Portier (University of Utah, United States) Jesse Rowley (University of Utah, United, States) Chris Stubben (University of Utah, United States) Aaron Petrey (University of Utah, United States) Neal Tolley (University of Utah, United States) Li Guo (University of Utah, United States) Mark Cody (University of Utah, United States) Andrew Weyrich (University of Utah, United States) Christian Yost (Department of Pediatrics, University of Utah, United States) Matthew Rondina (University of Utah Health Sciences Center, United States) Robert Campbell (University of Utah, United States).
There is an urgent need to understand the pathogenesis of coronavirus disease 2019 (COVID-19). In particular, thrombotic complications in
patients with COVID-19 are common and contribute to organ failure and mortality. Patients with severe COVID-19 present with hemostatic
abnormalities that mimic disseminated intravascular coagulopathy associated with sepsis with the major difference being increased risk of
thrombosis rather than bleeding. However, whether SARS-CoV-2 infection alters platelet function to contribute to the pathophysiology of COVID19 remains unknown. In this study, we report altered platelet gene expression and functional responses in patients infected with SARS-CoV-2.
RNA sequencing demonstrated distinct changes in the gene expression profile of circulating platelets of COVID-19 patients. Pathway analysis
revealed differential gene expression changes in pathways associated with protein ubiquitination, antigen presentation and mitochondrial
dysfunction. The receptor for SARS-CoV-2 binding, ACE2, was not detected by mRNA or protein in platelets. Surprisingly, mRNA from the SARSCoV-2 N1 gene was detected in platelets from 2/25 COVID-19 patients, suggesting platelets may take-up SARS-COV-2 mRNA independent of
ACE2. Resting platelets from COVID-19 patients had increased P-selectin expression basally and upon activation. Circulating platelet-neutrophil, –
monocyte, and -T-cell aggregates were all significantly elevated in COVID-19 patients compared to healthy donors. Furthermore, platelets from
COVID-19 patients aggregated faster and showed increased spreading on both fibrinogen and collagen. The increase in platelet activation and
aggregation could partially be attributed to increased MAPK pathway activation and thromboxane generation. These findings demonstrate that
SARS-CoV-2 infection is associated with platelet hyperreactivity which may contribute to COVID-19 pathophysiology.
For More Information: https://medicine.utah.edu/internalmedicine/generalmedicine/files/campbell-covid-platelet-blood-2020.pdf
Authors: Jia Yu, Xuan Yuan, Hang Chen, Shruti Chaturvedi, Evan M. Braunstein, Robert A. Brodsky
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly contagious respiratory virus that can lead to venous/arterial thrombosis, stroke, renal failure, myocardial infarction, thrombocytopenia, and other end-organ damage. Animal models demonstrating end-organ protection in C3-deficient mice and evidence of complement activation in humans have led to the hypothesis that SARS-CoV-2 triggers complement-mediated endothelial damage, but the mechanism is unclear. Here, we demonstrate that the SARS-CoV-2 spike protein (subunit 1 and 2), but not the N protein, directly activates the alternative pathway of complement (APC). Complement-dependent killing using the modified Ham test is blocked by either C5 or factor D inhibition. C3 fragments and C5b-9 are deposited on TF1PIGAnull target cells, and complement factor Bb is increased in the supernatant from spike protein–treated cells. C5 inhibition prevents the accumulation of C5b-9 on cells, but not C3c; however, factor D inhibition prevents both C3c and C5b-9 accumulation. Addition of factor H mitigates the complement attack. In conclusion, SARS-CoV-2 spike proteins convert nonactivator surfaces to activator surfaces by preventing the inactivation of the cell-surface APC convertase. APC activation may explain many of the clinical manifestations (microangiopathy, thrombocytopenia, renal injury, and thrombophilia) of COVID-19 that are also observed in other complement-driven diseases such as atypical hemolytic uremic syndrome and catastrophic antiphospholipid antibody syndrome. C5 inhibition prevents accumulation of C5b-9 in vitro but does not prevent upstream complement activation in response to SARS-CoV-2 spike proteins.
For More Information: https://ashpublications.org/blood/article/136/18/2080/463611/Direct-activation-of-the-alternative-complement
Authors: Monia Marchetti 1
COVID-19 pandemia is a major health emergency causing hundreds of deaths worldwide. The high reported morbidity has been related to hypoxia and inflammation leading to endothelial dysfunction and aberrant coagulation in small and large vessels. This review addresses some of the pathways leading to endothelial derangement, such as complement, HIF-1α, and ABL tyrosine kinases. This review also highlights potential targets for prevention and therapy of COVID-19-related organ damage and discusses the role of marketed drugs, such as eculizumab and imatinib, as suitable candidates for clinical trials.
For More Information: https://pubmed.ncbi.nlm.nih.gov/32583086/