Corpus overview


MeSH Disease

Human Phenotype


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    Thrombotic microvascular injury is not mediated by thrombotic microangiopathy MESHD despite systemic complement activation in Covid-19 patients

    Authors: Adrien De Voeght; Doriane Calmes; Floran Beck; Jean-Baptiste Sylvestre; Philippe Delvenne; Pierre Peters; Gaelle Vertenoeil; Frederic Baron; Nathalie Layios; Jean-Luc Canivet

    doi:10.1101/2020.06.18.20115873 Date: 2020-06-22 Source: medRxiv

    Hypoxemia HP and coagulopathy are common in severe symptomatic patients of coronavirus disease MESHD 2019 (COVID-19). Histological evidence shows implication of complement activation and lung injury MESHD. We research sign of complement activation and presence of thrombotic microangiopathy MESHD in 8 severe patients. Six of them presented moderate elevation of final pathway of complement / sC5b-9 (median value : 350 ng/mL [IQR : 300,5-514,95 ng/mL]). Two patients have been autopsied and presence of thrombotic microvascular injury have been found. Interestingly, none the 8 patients had signs of mechanical hemolytic anemia MESHD hemolytic anemia HP (median value of hemoglobin : 10,5 gr/dL[IQR : 8,1-1,9], median value of haptoglobuline 4,49 [IQR 3,55-4,66], none of the patients has schistocyte) and thrombocytopenia MESHD thrombocytopenia HP (median value: 348000/mL [IQR : 266 000-401 000). Finally, all 8 patients had elevated d-dimer (median value : 2226 microgr/l [IQR : 1493- 2362]) and soluble fibrin monomer complex (median value : 8.5 mg/mL, IQR[ <6-10.6]). In summary, this study show moderate activation of complement and coagulation with presence of thrombotic microvascular injury in patients with severe COVID-19 without evidence of systemic thrombotic microangiopathy MESHD.

    Complement and tissue factor-enriched neutrophil extracellular traps are key drivers in COVID-19 immunothrombosis

    Authors: Panagiotis Skendros; Alexandros Mitsios; Akrivi Chrysanthopoulou; Dimitrios C Mastellos; Simeon Metallidis; Petros Rafailidis; Maria Ntinopoulou; Eleni Sertaridou; Victoria Tsironidou; Christina Tsigalou; Maria Tektonidou; Theocharis Konstantinidis; Charalampos Papagoras; Ioannis Mitroulis; Georgios Germanidis; John D Lambris; Konstantinos Ritis

    doi:10.1101/2020.06.15.20131029 Date: 2020-06-16 Source: medRxiv

    Emerging data indicate that complement and neutrophils are involved in the maladaptive host immune response that fuels hyper- inflammation MESHD and thrombotic microangiopathy MESHD increasing the mortality rate in coronavirus disease MESHD 2019 (COVID-19). Here, we investigated the interaction between complement and the platelet/neutrophil extracellular traps (NETs)/thrombin axis, using COVID-19 clinical samples, cell-based inhibition studies and NETs/human aortic endothelial cell (HAEC) co-cultures. Increased plasma SERO levels of NETs, TF activity and sC5b-9 were detected in patients. Neutrophils yielded high tissue factor (TF) expression and released NETs carrying functionally active TF. Confirming our ex vivo findings, treatment of control neutrophils with COVID-19 platelet-rich plasma SERO generated TF-bearing NETs that induced thrombotic activity of HAEC. Thrombin or NETosis inhibition or C5aR1 blockade attenuated platelet-mediated NET-driven thrombogenicity. Serum SERO isolated from COVID-19 patients induces complement activation in vitro, which is consistent with high complement activity in clinical samples. Complement inhibition at the level of C3 with compstatin Cp40 disrupted TF expression in neutrophils. In conclusion, we provide a mechanistic basis that reveals the pivotal role of complement and NETs in COVID-19 immmunothrombosis. This study supports emerging strategies against SARS-CoV-2 infection MESHD that exploit complement therapeutics or NETosis inhibition.

    Respiratory Failure HP in Covid19 is associated with increased monocyte expression of complement receptor 3

    Authors: Rajeev Gupta; Vanya A Gant; Bryan Williams; Tariq Enver

    doi:10.1101/2020.05.31.20118638 Date: 2020-06-02 Source: medRxiv

    A key question in COVID-19 infection MESHD is why some previously healthy patients develop severe pulmonary failure and some ultimately die. Initial pulmonary failure does not exhibit classical features of ARDS; hypercoagulability HP is a common laboratory feature, and pulmonary thrombotic microangiopathy MESHD has been reported post mortem1,2,3. Biomarkers cannot robustly identify such patients pre-emptively and no specific interventions exist to mitigate clinical deterioration MESHD. Mononuclear phagocytic cells are key immune cells and bind fibrinogen through the CD11b/CD18 dimer CR3, whose activated form can initiate microthrombus formation. Accordingly, we profiled circulating monocyte CD11b/CD18 cell surface density from COVID-19 infected adults TRANS who were (i) symptomatic but breathless, (ii) requiring ventilatory support, and (iii) recovering following ICU care for hypoxia MESHD.

    Pathophysiology of SARS-CoV-2: targeting of endothelial cells renders a complex disease MESHD with thrombotic microangiopathy MESHD and aberrant immune response. The Mount Sinai COVID-19 autopsy experience

    Authors: Clare Bryce; Zachary Grimes; Elisabet Pujadas; Sadhna Ahuja; Mary Beth Beasley; Randy Albrecht; Tahyna Hernandez; Aryeh Stock; Zhen Zhao; Mohamed Al Rasheed; Joyce Chen; Li Li; Diane Wang; Adriana Corben; Kenneth Haines; William Westra; Melissa Umphlett; Ronald E Gordon; Jason Reidy; Bruce Petersen; Fadi Salem; MariaIsabel Fiel; Siraj M El Jamal; Nadejda M Tsankova; Jane Houldsworth; Zarmeen Mussa; Wen-Chun Liu; Brandon Veremis; Emilia Sordillo; Melissa Gitman; Michael Nowak; Rachel Brody; Noam Harpaz; Miriam Merad; Sacha Gnjatic; Ryan Donnelly; Patricia Seigler; Calvin Keys; Jennifer Cameron; Isaiah Moultrie; Kae-Lynn Washington; Jacquelyn Treatman; Robert Sebra; Jeffrey Jhang; Adolfo Firpo; John Lednicky; Alberto Paniz-Mondolfi; Carlos Cordon-Cardo; Mary Fowkes

    doi:10.1101/2020.05.18.20099960 Date: 2020-05-22 Source: medRxiv

    BACKGROUND Severe Acute Respiratory Syndrome MESHD Coronavirus-2 (SARS-CoV-2) and its associated clinical syndrome MESHD COVID-19 are causing overwhelming morbidity and mortality around the globe, disproportionately affecting New York City. A comprehensive, integrative autopsy series that advances the mechanistic discussion surrounding this disease MESHD process is still lacking. METHODS Autopsies were performed at the Mount Sinai Hospital on 67 COVID-19 positive patients and data from the clinical records were obtained from the Mount Sinai Data Warehouse. The experimental design included a comprehensive microscopic examination carried out by a team of expert pathologists, along with transmission TRANS electron microscopy, immunohistochemistry, RNA in situ hybridization, as well as immunology and serology assays. RESULTS Laboratory results of our COVID-19 cohort show elevated inflammatory markers, abnormal coagulation values, and elevated cytokines IL-6, IL-8 and TNF. Autopsies revealed large pulmonary emboli in four cases. We report microthrombi in multiple organ systems including the brain, as well as conspicuous hemophagocytosis HP and a secondary hemophagocytic lymphohistiocytosis MESHD-like syndrome MESHD in many of our patients. We provide electron microscopic, immunofluorescent and immunohistochemical evidence of the presence of the virus and the ACE2 receptor in our samples. CONCLUSIONS We report a comprehensive autopsy series of 67 COVID-19 positive patients revealing that this disease MESHD, so far conceptualized as a primarily respiratory viral illness, also causes endothelial dysfunction, a hypercoagulable state, and an imbalance of both the innate and adaptive immune responses. Novel findings reported here include an endothelial phenotype of ACE2 in selected organs, which correlates with clotting abnormalities and thrombotic microangiopathy MESHD, addressing the prominent coagulopathy and neuropsychiatric symptoms. Another original observation is that of macrophage activation syndrome MESHD, with hemophagocytosis HP and a hemophagocytic lymphohistiocytosis MESHD-like disorder, underlying the microangiopathy and excessive cytokine release. We discuss the involvement of critical regulatory pathways.


    Authors: Giulia Previtali; Michela Seghezzi; Valentina Moioli; Aurelio Sonzogni; Roberto Marozzi; Lorenzo Cerutti; Rudi Ravasio; Andrea Gianatti; Giovanni Guerra; Maria Grazia Alessio

    doi:10.1101/2020.04.30.20086397 Date: 2020-05-06 Source: medRxiv

    Background The most severely COVID-19 patients need intensive care and show increased risk of thromboembolic events. Although some patients meet the diagnostic criteria for the Disseminated Intravascular Coagulation MESHD Disseminated Intravascular Coagulation HP, the pathogenesis of the diffuse thrombotic status remains unclear. The aim of the present study is to evaluate the presence of antiphospholipid antibodies SERO (aPL) in sera of deceased patients with autoptic proven thrombotic microangiopathy MESHD to evaluate if some patients may have developed Catastrophic Antiphospholipid Syndrome MESHD (CAPS). Methods Thirty-five patients were enrolled. The available medical history, comorbidities, therapies, laboratory and autopsy findings were collected post-mortem from clinical records. IgA, IgG and IgM anti cardiolipin (ACA) and anti {beta}2 glycoprotein 1 ({beta}2GP1) antibodies, IgG and IgM SERO anti phosphatidylserine/prothrombin (PS/PT) antibodies were tested SERO for all the patients. Results 3/35 (8.6%) patients were slightly positive for aPL: one for ACA IgG and two for ACA IgM but values were low (< 3X the cut off). No patients tested positive for ACA IgA neither for {beta}2GP1 isotypes. 3/35 (8.6%) patients were positive for PS/PT, one for IgG and two for IgM, but values were less than 2X the cut off. No patients showed simultaneous positivity for ACA and PS/ PT. Conclusions It is difficult to categorize the vascular events into a conventional disease MESHD: we did not find significant association with anti-phospholipid antibodies SERO. It is most likely that several factors contribute to trigger the hypercoagulability HP status and the thromboembolism MESHD thromboembolism HP but, on the basis our results, CAPS is probably not involved into the pathogenesis of these phenomena.

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MeSH Disease
Human Phenotype

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