Little evidence of increased thrombotic risk is available in COVID-19 patients. Our purpose was to assess thrombotic risk in severe forms of SARS-CoV-2 infection. All patients referred to 4 intensive care units (ICUs) from two centers of a French tertiary hospital for acute respiratory distress syndrome (ARDS) due to COVID-19 between March 3rd and 31st 2020 were included. Medical history, symptoms, biological data and imaging were prospectively collected. Propensity score matching was performed to analyze the occurrence of thromboembolic events between non-COVID-19 ARDS and COVID-19 ARDS patients. 150 COVID-19 patients were included (122 men, median age 63 [53; 71] years, SAPSII 49 [37; 64] points). Sixty-four clinically relevant thrombotic complications were diagnosed in 150 patients, mainly pulmonary embolisms (16.7%). 28/29 patients (96.6%) receiving continuous renal replacement therapy experienced circuit clotting. Three thrombotic occlusions (in 2 patients) of centrifugal pump occurred in 12 patients (8%) supported by ECMO. Most patients (> 95%) had elevated D-dimer and fibrinogen. No patient developed disseminated intravascular coagulation. Von Willebrand (vWF) activity, vWF antigen and FVIII were considerably increased, and 50/57 tested patients (87.7%) had positive lupus anticoagulant. Comparison with non-COVID-19 ARDS patients (n = 145) confirmed that COVID-19 ARDS patients (n = 77) developed significantly more thrombotic complications, mainly pulmonary embolisms (11.7 vs. 2.1%, p < 0.008). Coagulation parameters significantly differed between the two groups. Despite anticoagulation, a high number of patients with ARDS secondary to COVID-19 developed life-threatening thrombotic complications. Higher anticoagulation targets than in usual critically ill patients should therefore probably be suggested.

/pdf/high-risk-of-thrombosis-in-patients-with-severe-sars-cov-2-33bb5czu95.pdf

High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study.

Skeletal muscle has recently been identified as an endocrine organ. It has, therefore, been suggested that cytokines and other peptides that are produced, expressed, and released by muscle fibers and exert paracrine, autocrine, or endocrine effects should be classified as "myokines." Recent research demonstrates that skeletal muscles can produce and express cytokines belonging to distinctly different families. However, the first identified and most studied myokine is the gp130 receptor cytokine interleukin-6 (IL-6). IL-6 was discovered as a myokine because of the observation that it increases up to 100-fold in the circulation during physical exercise. Identification of IL-6 production by skeletal muscle during physical activity generated renewed interest in the metabolic role of IL-6 because it created a paradox. On one hand, IL-6 is markedly produced and released in the postexercise period when insulin action is enhanced but, on the other hand, IL-6 has been associated with obesity and reduced insulin action. This review focuses on the myokine IL-6, its regulation by exercise, its signaling pathways in skeletal muscle, and its role in metabolism in both health and disease.

/pdf/muscle-as-an-endocrine-organ-focus-on-muscle-derived-3c7h8gsq1u.pdf

Muscle as an endocrine organ: focus on muscle-derived interleukin-6.

The Phosphatidylinositol 3-Kinase-Akt Pathway Limits Lipopolysaccharide Activation of Signaling Pathways and Expression of Inflammatory Mediators in Human Monocytic Cells

The lung pathology seen in patients with coronavirus disease 2019 (COVID-19) shows marked microvascular thrombosis and haemorrhage linked to extensive alveolar and interstitial inflammation that shares features with macrophage activation syndrome (MAS). We have termed the lung-restricted vascular immunopathology associated with COVID-19 as diffuse pulmonary intravascular coagulopathy, which in its early stages is distinct from disseminated intravascular coagulation. Increased circulating D-dimer concentrations (reflecting pulmonary vascular bed thrombosis with fibrinolysis) and elevated cardiac enzyme concentrations (reflecting emergent ventricular stress induced by pulmonary hypertension) in the face of normal fibrinogen and platelet levels are key early features of severe pulmonary intravascular coagulopathy related to COVID-19. Extensive immunothrombosis over a wide pulmonary vascular territory without confirmation of COVID-19 viraemia in early disease best explains the adverse impact of male sex, hypertension, obesity, and diabetes on the prognosis of patients with COVID-19. The immune mechanism underlying diffuse alveolar and pulmonary interstitial inflammation in COVID-19 involves a MAS-like state that triggers extensive immunothrombosis, which might unmask subclinical cardiovascular disease and is distinct from the MAS and disseminated intravascular coagulation that is more familiar to rheumatologists.

Immune mechanisms of pulmonary intravascular coagulopathy in COVID-19 pneumonia

https://open.library.ubc.ca/media/download/pdf/24/1.0069549/1

Lipopolysaccharide signaling in endothelial cells

Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression.

Although oxygen deprivation has long been associated with triggering of the procoagulant pathway and venous thrombosis, blood hypoxemia and stasis by themselves do not lead to fibrin formation. A pathway is outlined through which diminished levels of oxygen activate the transcription factor early growth response-1 (Egr-1) leading to de novo transcription/translation of tissue factor in mononuclear phagocytes and smooth muscle cells, which eventuates in vascular fibrin deposition. The procoagulant response is magnified by concomitant suppression of fibrinolysis by hypoxia-mediated upregulation of plasminogen activator inhibitor-1. These data add a new facet to the biology of thrombosis associated with hypoxemia/stasis and imply that interference with mechanisms causing Egr-1 activation in response to oxygen deprivation might prevent vascular fibrin deposition occurring in ischemia without directly interfering with other pro/anticoagulant pathways.

Hypoxia/Hypoxemia-Induced Activation of the Procoagulant Pathways and the Pathogenesis of Ischemia-Associated Thrombosis

of Hematology, December 1-5, 2000, San Francisco, CA.Presented in abstract form at the 42nd annual meeting of the American Societyexpression by inducing Elk-1 phosphorylation and Egr-1 expression : monocytic cells mediates tissue factor and tumor necrosis factor αLipopolysaccharide activation of the MEK-ERK1/2 pathway in human

Presented in abstract form at the 42nd annual meeting of the American Society expression by inducing Elk-1 phosphorylation and Egr-1 expression : α monocytic cells mediates tissue factor and tumor necrosis factor Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human

Nigel Mackman

Papers

Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human monocytic cells mediates tissue factor and tumor necrosis factor alpha expression by inducing Elk-1 phosphorylation and Egr-1 expression.

Hypoxia/Hypoxemia-Induced Activation of the Procoagulant Pathways and the Pathogenesis of Ischemia-Associated Thrombosis

Presented in abstract form at the 42nd annual meeting of the American Society expression by inducing Elk-1 phosphorylation and Egr-1 expression : α monocytic cells mediates tissue factor and tumor necrosis factor Lipopolysaccharide activation of the MEK-ERK1/2 pathway in human

required for embryonic development and hemostasis in adult mice A balance between tissue factor and tissue factor pathway inhibitor is