Downregulation of the Protein C Signaling System Is Associated with COVID-19 Hypercoagulability—A Single-Cell Transcriptomics Analysis

Silva, Bruna Rafaela dos Santos; Jara, Carlos Poblete; Sidarta-Oliveira, Davi; Velloso, Lı́cio A.; Velander, William H.; Araújo, Eliana P.

doi:10.3390/v14122753

Cited by 7 publications

(6 citation statements)

References 79 publications

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“…Several studies focus on COVID-19 patients' increased thromboembolic risk. Protein C could play a mechanistic role in the hypercoagulability syndrome affecting patients with severe COVID-19 [41]. The overwhelming inflammatory response in patients with SARS-CoV-2 infection can lead to a hypercoagulable state [42].…”

Section: Discussionmentioning

confidence: 99%

COVID-19: The Development and Validation of a New Mortality Risk Score

Zinna,

Pipitò,

Colomba

et al. 2024

JCM

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Background: The coronavirus disease 2019 (COVID-19) pandemic has found the whole world unprepared for its correct management. Italy was the first European country to experience the spread of the SARS-CoV-2 virus at the end of February 2020. As a result of hospital overcrowding, the quality of care delivered was not always optimal. A substantial number of patients admitted to non-ICU units could have been treated at home. It would have been extremely useful to have a score that, based on personal and clinical characteristics and simple blood tests, could have predicted with sufficient reliability the probability that a patient had or did not have a disease that could have led to their death. This study aims to develop a scoring system to identify which patients with COVID-19 are at high mortality risk upon hospital admission, to expedite and enhance clinical decision making. Methods: A retrospective analysis was performed to develop a multivariable prognostic prediction model. Results: Derivation and external validation cohorts were obtained from two Italian University Hospital databases, including 388 (10.31% deceased) and 1357 (7.68% deceased) patients with confirmed COVID-19, respectively. A multivariable logistic model was used to select seven variables associated with in-hospital death (age, baseline oxygen saturation, hemoglobin value, white blood cell count, percentage of neutrophils, platelet count, and creatinine value). Calibration and discrimination were satisfactory with a cumulative AUC for prediction mortality of 0.924 (95% CI: 0.893–0.944) in derivation cohorts and 0.808 (95% CI: 0.886–0.828) in external validation cohorts. The risk score obtained was compared with the ISARIC 4C Mortality Score, and with all the other most important scores considered so far, to evaluate the risk of death of patients with COVID-19. It performed better than all the above scores to evaluate the predictability of dying. Its sensitivity, specificity, and AUC were higher than the other COVID-19 scoring systems when the latter were calculated for the 388 patients in our derivation cohort. Conclusions: In conclusion, the CZ-COVID-19 Score may help all physicians by identifying those COVID-19 patients who require more attention to provide better therapeutic regimens or, on the contrary, by identifying those patients for whom hospitalization is not necessary and who could therefore be sent home without overcrowding healthcare facilities. We developed and validated a new risk score based on seven variables for upon-hospital admission of COVID-19 patients. It is very simple to calculate and performs better than all the other similar scores to evaluate the predictability of dying.

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Section: Discussionmentioning

confidence: 99%

COVID-19: The Development and Validation of a New Mortality Risk Score

Zinna,

Pipitò,

Colomba

et al. 2024

JCM

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“…We did not find active viral replication in cell culture (Figure 3A). Nevertheless, as our previous study suggested, protein C could play an important role in hypercoagulability in severe COVID-19 (Silva, Jara et al 2022). We asked whether treatment of ECs with PC before exposure to SARS-CoV-2 infection could result in a protective endothelial effect.…”

Section: Pc Pretreatment Reduces the Expression Of Ccl2 Il6 And Serpi...mentioning

confidence: 95%

“…Datasets were retrieved from Gene Expression Omnibus (GEO) and the European Genome-phenome Archive (EGA) under accession numbers GSE171668 and EGAS00001004344, respectively. The raw data with the .h5 format were processed using the standard toolkit Scanpy 1.7.2 in Python igraph 0.9.6. processing and quality control flow previously described (Silva, Jara et al 2022) and available at https://scanpy-tutorials.readthedocs.io/en/latest/pbmc3k.html. Data were then integrated using Harmony's algorithm, which designs cells in a shared embedding grouped by cell type (Korsunsky, Millard et al 2019).…”

Section: Methodsmentioning

confidence: 99%

Protein C Pretreatment Protects Endothelial Cells from SARS-CoV-2-Induced Activation

Silva,

Sidarta-Oliveira,

Bombassaro

et al. 2024

Preprint

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SARS-CoV-2 can induce vascular dysfunction and thrombotic events in patients with severe COVID-19; however, the cellular and molecular mechanisms behind these effects remain largely unknown. In this study, we used a combination of experimental and in silico approaches to explore the mechanisms behind the vascular and thrombotic events in COVID-19. Single-cell RNA-sequencing data from patients with COVID-19 and healthy subjects were obtained from the publicly available Gene Expression Omnibus (GEO) repository. In addition, HUVECs were treated with inactivated protein C before exposure to SARS-CoV-2 infection or a severe COVID-19 serum. An RT-qPCR array containing 84 related genes was used, and the candidate genes obtained were evaluated. Activated protein C levels were measured using an ELISA kit. We identified at the single-cell level the expression of several pro-inflammatory and pro-coagulation genes in endothelial cells from the patients with COVID-19. Furthermore, we demonstrated that exposure to SARS-CoV-2 promoted transcriptional changes in HUVECs that were partly reversed by the activated protein C pretreatment. We also observed that the serum of severe COVID-19 had a significant amount of activated protein C that could protect endothelial cells from serum-induced activation. In conclusion, activated protein C protects endothelial cells from pro-inflammatory and pro-coagulant effects during exposure to the SARS-CoV-2 virus.

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“…aPC can suppress thrombin formation by proteolytical degradation or inactivation of coagulation factor Va (FVa) and FVIIIa and increases fibrinolytic activity by neutralizing PAI-1. However, the thrombin-thrombomodulin-EPCR complex is dysfunctional under COVID-19, affecting the aPC synthesis [ 113 , 114 ]. Also, an enhanced thrombin generation, decreased fibrinolytic activity, and elevated levels of PAI-1 were identified in patients with long-COVID [ 115 ].…”

Section: Disbalanced Endothelial-derived Hemostatic Regulators In Cov...mentioning

confidence: 99%

“…Stimulation of coagulation factors in DM may accentuate the risk of thrombotic events. In this sense, the thrombin-thrombomodulin-EPCR complex has been often observed dysfunctional under both DM and COVID-19, affecting aPC synthesis [ 113 , 114 ]. Therefore, COVID-19 and DM, by sharing or accumulating mechanisms of endothelial activation and dysfunction, may stimulate more severe vascular-driven complications than these entities alone.…”

Section: Diabetes Mellitus a Comorbidity In Covid-19mentioning

confidence: 99%

Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus

Valencia,

Lumpuy-Castillo,

Magalhaes

et al. 2024

Cardiovasc Diabetol

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Early since the onset of the COVID-19 pandemic, the medical and scientific community were aware of extra respiratory actions of SARS-CoV-2 infection. Endothelitis, hypercoagulation, and hypofibrinolysis were identified in COVID-19 patients as subsequent responses of endothelial dysfunction. Activation of the endothelial barrier may increase the severity of the disease and contribute to long-COVID syndrome and post-COVID sequelae. Besides, it may cause alterations in primary, secondary, and tertiary hemostasis. Importantly, these responses have been highly decisive in the evolution of infected patients also diagnosed with diabetes mellitus (DM), who showed previous endothelial dysfunction. In this review, we provide an overview of the potential triggers of endothelial activation related to COVID-19 and COVID-19 under diabetic milieu. Several mechanisms are induced by both the viral particle itself and by the subsequent immune-defensive response (i.e., NF-κB/NLRP3 inflammasome pathway, vasoactive peptides, cytokine storm, NETosis, activation of the complement system). Alterations in coagulation mediators such as factor VIII, fibrin, tissue factor, the von Willebrand factor: ADAMST-13 ratio, and the kallikrein-kinin or plasminogen-plasmin systems have been reported. Moreover, an imbalance of thrombotic and thrombolytic (tPA, PAI-I, fibrinogen) factors favors hypercoagulation and hypofibrinolysis. In the context of DM, these mechanisms can be exacerbated leading to higher loss of hemostasis. However, a series of therapeutic strategies targeting the activated endothelium such as specific antibodies or inhibitors against thrombin, key cytokines, factor X, complement system, the kallikrein-kinin system or NETosis, might represent new opportunities to address this hypercoagulable state present in COVID-19 and DM. Antidiabetics may also ameliorate endothelial dysfunction, inflammation, and platelet aggregation. By improving the microvascular pathology in COVID-19 and post-COVID subjects, the associated comorbidities and the risk of mortality could be reduced.

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Downregulation of the Protein C Signaling System Is Associated with COVID-19 Hypercoagulability—A Single-Cell Transcriptomics Analysis

Cited by 7 publications

References 79 publications

COVID-19: The Development and Validation of a New Mortality Risk Score

COVID-19: The Development and Validation of a New Mortality Risk Score

Protein C Pretreatment Protects Endothelial Cells from SARS-CoV-2-Induced Activation

Mechanisms of endothelial activation, hypercoagulation and thrombosis in COVID-19: a link with diabetes mellitus

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