Tissue factor expression in monocyte subsets during human immunothrombosis, endotoxemia and sepsis.

INTRODUCTION: Tissue factor expression on monocytes is implicated in the pathophysiology of sepsis-induced coagulopathy. How tissue factor is expressed by monocyte subsets (classical, intermediate and non-classical) is unknown. METHODS: Monocytic tissue factor surface expression was investigated during three conditions. Primary human monocytes and microvascular endothelial cell co-cultures were used for in vitro studies. Volunteers received a bolus of lipopolysaccharide (2 ng/kg) to induce endotoxemia. Patients with sepsis, or controls with critical illness unrelated to sepsis, were recruited from four intensive care units. RESULTS: Contact with endothelium and stimulation with lipopolysaccharide reduced the proportion of intermediate monocytes. Lipopolysaccharide increased tissue factor surface expression on classical and non-classical monocytes. Endotoxemia induced profound, transient monocytopenia, along with activation of coagulation pathways. In the remaining circulating monocytes, tissue factor was up-regulated in intermediate monocytes, though approximately 60 % of individuals (responders) up-regulated tissue factor across all monocyte subsets. In critically ill patients, tissue factor expression on intermediate and non-classical monocytes was significantly higher in patients with established sepsis than among non-septic patients. Upon recovery of sepsis, expression of tissue factor increased significantly in classical monocytes. CONCLUSION: Tissue factor expression in monocyte subsets varies significantly during health, endotoxemia and sepsis.

Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation.

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS.

Practical treatment guidance for cancer-associated thrombosis - Managing the challenging patient: A consensus statement.

Cancer-associated thrombosis (CAT) is a leading cause of death amongst people with cancer. Treatment decisions have become increasingly complex with the introduction of direct oral anticoagulants and existing guidelines are limited to evidence from patients meeting stringent trial-entry criteria. To assist decision making for healthcare professionals managing CAT in challenging 'real-world' situations, an expert working group of clinicians from oncology, haematology and pharmacology convened over a series of virtual meetings between September 2020 and January 2021 to catalogue the most challenging clinical problems and define consensus recommendations. Clinical problems were divided amongst the group members according to their areas of expertise, with each reviewing the literature and writing their recommendations. Using a web-based file-sharing platform, each contribution was reviewed until consensus was reached. Each clinical problem is discussed; these include managing gastrointestinal impairment, renal impairment, liver impairment, increased risk of bleeding, extremes of body weight, drug interactions, anticoagulation beyond the initial six months and managing recurrent thrombosis. A user-friendly, practical, colour-coded algorithm was produced to help guide clinical decision-making in CAT. Red highlights decision steps where shared decision making, such as with the multi-disciplinary team, is recommended. Amber steps reflect uncertainty of existing evidence. Multiple amber steps per patient warrant increased caution. Making anticoagulation decisions in people with cancer is challenging; it is important that healthcare providers can discuss where there is a lack of evidence and ensure that patient preference is given priority. This algorithm and consensus recommendations are a useful tool to guide these complex discussions.

Decision-Making with D-Dimer in the Diagnosis of Pulmonary Embolism.

The measurement of D-dimer can provide useful information to aid in the diagnosis of patients with suspected venous thromboembolism. D-dimer measurement in conjunction with adequate estimation of pretest probability can facilitate the safe discharge of patients with suspected pulmonary embolism and limit unnecessary investigation or anticoagulation. We review clinical decision-making strategies in the diagnosis of pulmonary embolism and propose means to minimize diagnostic error that might arise from knowledge of the D-dimer result prior to clinical assessment.