Of macrophages and red blood cells; a complex love story

Macrophages tightly control the production and clearance of red blood cells (RBC). During steady state hematopoiesis, approximately 10(10) RBC are produced per hour within erythroblastic islands in humans. In these erythroblastic islands, resident bone marrow macrophages provide erythroblasts with interactions that are essential for erythroid development. New evidence suggests that not only under homeostasis but also under stress conditions, macrophages play an important role in promoting erythropoiesis. Once RBC have matured, these cells remain in circulation for about 120 days. At the end of their life span, RBC are cleared by macrophages residing in the spleen and the liver. Current theories about the removal of senescent RBC and the essential role of macrophages will be discussed as well as the role of macrophages in facilitating the removal of damaged cellular content from the RBC. In this review we will provide an overview on the role of macrophages in the regulation of RBC production, maintenance and clearance. In addition, we will discuss the interactions between these two cell types during transfer of immune complexes and pathogens from RBC to macrophages

Transfusion practice in the bleeding critically ill:An international online survey-The TRACE-2 survey

Background: Transfusion is very common in the intensive care unit (ICU), but practice is highly variable, as has recently been shown in non-bleeding critically ill patients practices survey. Bleeding patients in ICU require different blood products across a range of specific patient categories. We hypothesize that a large variety in transfusion practice exists in bleeding patients. Study design and methods: An international online survey was performed among physicians working in the ICU. Transfusion practice in massively and non-massively bleeding patients was examined, including transfusion ratios, thresholds, and the presence of transfusion guidelines. Results: Six hundred eleven respondents filled in the survey of which 401 could be analyzed, representing 64 countries. Among the respondents, 52% had a massive transfusion protocol (MTP) available at their ICU. In massively bleeding patients, 46% of the respondents used fixed transfusion component ratios. Of those who used fixed blood ratios, the 1:1:1 ratio (red blood cell [RBC] concentrates: plasma: platelet concentrates) was most commonly used (33%). The presence of an MTP was associated with a more frequent use of fixed ratios (p <.001). For RBC transfusion in the general non-massively bleeding ICU population, a hemoglobin (Hb) threshold of 7.0[7.0–7.3] g/dl was reported. In the general ICU population, a platelet count threshold of 50[26–50] × 109/L was applied. Discussion: Half of the centers had no massive transfusion protocol available. Transfusion practice in massively bleeding critically ill patients is highly variable and driven by the presence of an MTP. In the general non-massively bleeding ICU population restrictive transfusion triggers were chosen

Transfusion practice in the non-bleeding critically ill:an international online survey-the TRACE survey

Background Over the last decade, multiple large randomized controlled trials have studied alternative transfusion strategies in critically ill patients, demonstrating the safety of restrictive transfusion strategies. Due to the lack of international guidelines specific for the intensive care unit (ICU), we hypothesized that a large heterogeneity in transfusion practice in this patient population exists. The aims of this study were to describe the current transfusion practices and identify the knowledge gaps. Methods An online, anonymous, worldwide survey among ICU physicians was performed evaluating red blood cell, platelet and plasma transfusion practices. Furthermore, the presence of a hospital- or ICU-specific transfusion guideline was asked. Only completed surveys were analysed. Results Nine hundred forty-seven respondents filled in the survey of which 725 could be analysed. Hospital transfusion protocol available in their ICU was reported by 53% of the respondents. Only 29% of respondents used an ICU-specific transfusion guideline. The reported haemoglobin (Hb) threshold for the general ICU population was 7 g/dL (7-7). The highest reported variation in transfusion threshold was in patients on extracorporeal membrane oxygenation or with brain injury (8 g/dL (7.0-9.0)). Platelets were transfused at a median count of 20 x 10(9) cells/L IQR (10-25) in asymptomatic patients, but at a higher count prior to invasive procedures (p &lt;0.001). In patients with an international normalized ratio (INR) &gt; 3, 43% and 57% of the respondents would consider plasma transfusion without any upcoming procedures or prior to a planned invasive procedure, respectively. Finally, doctors with base specialty in anaesthesiology transfused critically ill patients more liberally compared to internal medicine physicians. Conclusion Red blood cell transfusion practice for the general ICU population is restrictive, while for different subpopulations, higher Hb thresholds are applied. Furthermore, practice in plasma and platelet transfusion is heterogeneous, and local transfusion guidelines are lacking in the majority of the ICUs.</p

Squamous gastric ulceration complicated by gastric stenosis in a foal

A 2-month-old Warmblood colt presented with recurrent colic and regurgitation. Gastroscopy, performed on several occasions, and barium-contrast radiography revealed severe squamous gastric ulceration and stenosis at the level of the margo plicatus. Treatment with omeprazole reduced the extent and severity of the gastric ulcers but did not affect the stenosis. The foal was euthanised because of a poor prognosis, and post-mortem examination confirmed the clinical diagnosis. Severe squamous gastric ulceration, granulation tissue formation and cicatrisation of deep gastric lesions were considered to have caused the stenosis. Gastroduodenal outflow obstruction is a recognised disorder in foals, but stenosis at the level of the margo plicatus has not been reported in foals or adult horses. To the authors' knowledge, this is the first case of severe squamous gastric ulceration, complicated by stenosis at the level of the margo plicatus, in a foal. Although rare, gastric stenosis should be considered in foals suffering recurrent colic and regurgitatio

Development of a model for anemia of inflammation that is relevant to critical care

Background: Anemia of inflammation (AI) is common in critically ill patients. Although this syndrome negatively impacts the outcome of critical illness, understanding of its pathophysiology is limited. Also, new therapies that increase iron availability for erythropoiesis during AI are upcoming. A model of AI induced by bacterial infections that are relevant for the critically ill is currently not available. This paper describes the development of an animal model for AI that is relevant for critical care research. Results: In experiments with rats, the rats were inoculated either repeatedly or with a slow release of Streptococcus pneumoniae or Pseudomonas aeruginosa. Rats became ill, but their hemoglobin levels remained stable. The use of a higher dose of bacteria resulted in a lethal model. Then, we turned to a model with longer disease duration, using pigs that were supported by mechanical ventilation after inoculation with P. aeruginosa. The pigs became septic 12 to 24 h after inoculation, with a statistically significant decrease in mean arterial pressure and base excess, while heart rate tended to increase. Pigs needed resuscitation and vasopressor therapy to maintain a mean arterial pressure > 60 mmHg. After 72 h, the pigs developed anemia (baseline 9.9 g/dl vs. 72 h, 7.6 g/dl, p = 0.01), characterized by statistically significant decreased iron levels, decreased transferrin saturation, and increased ferritin. Hepcidin levels tended to increase and transferrin levels tended to decrease. Conclusions: Using pathogens commonly involved in pulmonary sepsis, AI could not be induced in rats. Conversely, in pigs, P. aeruginosa induced pulmonary sepsis with concomitant AI. This AI model can be applied to study the pathophysiology of AI in the critically ill and to investigate the effectivity and toxicity of new therapies that aim to increase iron availability. Keywords: Anemia of inflammation; Animal model; ICU; Infection; Iron

Sodium stibogluconate and CD47-SIRPa blockade overcome resistance of anti-CD20–opsonized B cells to neutrophil killing

Anti-CD20 antibodies such as rituximab are broadly used to treat B-cell malignancies. These antibodies can induce various effector functions, including immune cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Neutrophils can induce ADCC toward solid cancer cells by trogoptosis, a cytotoxic mechanism known to be dependent on trogocytosis. However, neutrophils seem to be incapable of killing rituximab-opsonized B-cell lymphoma cells. Nevertheless, neutrophils do trogocytose rituximab-opsonized B-cell lymphoma cells, but this only reduces CD20 surface expression and is thought to render tumor cells therapeutically resistant to further rituximab-dependent destruction. Here, we demonstrate that resistance of B-cell lymphoma cells toward neutrophil killing can be overcome by a combination of CD47-SIRPa checkpoint blockade and sodium stibogluconate (SSG), an anti-leishmaniasis drug and documented inhibitor of the tyrosine phosphatase SHP-1. SSG enhanced neutrophil-mediated ADCC of solid tumor cells but enabled trogoptotic killing of B-cell lymphoma cells by turning trogocytosis from a mechanism that contributes to resistance into a cytotoxic anti-cancer mechanism. Tumor cell killing in the presence of SSG required both antibody opsonization of the target cells and disruption of CD47-SIRPa interactions. These results provide a more detailed understanding of the role of neutrophil trogocytosis in antibody-mediated destruction of B cells and clues on how to further optimize antibody therapy of B-cell malignancies

Biomarkers for the Discrimination of Acute Kawasaki Disease From Infections in Childhood

Funding Information: We would like to thank all the patients and their relatives as well as the treatment teams for their participation in this study. We also thank Dr. Mischa Keizer for his help in developing the MRP8/14 ELISA. We would like to thank the EUCLIDS Consortium, PERFORM Consortium, and the Genetic Determinants of Kawasaki Disease Study group (UK). Funding. This work was partially supported by the European Seventh Framework Program for Research and Technological Development (FP7) under EUCLIDS grant agreement no. 279185; from the European Union's Horizon 2020 research and innovation program under grant agreement no. 668303; by STINAFO and anonymous donor; and by Sanquin Blood Supply Product and Process Development Cellular Products Fund (PPOC 1957). Publisher Copyright: © Copyright © 2020 Zandstra, van de Geer, Tanck, van Stijn-Bringas Dimitriades, Aarts, Dietz, van Bruggen, Schweintzger, Zenz, Emonts, Zavadska, Pokorn, Usuf, Moll, Schlapbach, Carrol, Paulus, Tsolia, Fink, Yeung, Shimizu, Tremoulet, Galassini, Wright, Martinón-Torres, Herberg, Burns, Levin, Kuijpers, EUCLIDS Consortium, PERFORM Consortium and UK Kawasaki Disease Genetics Study Network. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Kawasaki disease (KD) is a vasculitis of early childhood mimicking several infectious diseases. Differentiation between KD and infectious diseases is essential as KD's most important complication—the development of coronary artery aneurysms (CAA)—can be largely avoided by timely treatment with intravenous immunoglobulins (IVIG). Currently, KD diagnosis is only based on clinical criteria. The aim of this study was to evaluate whether routine C-reactive protein (CRP) and additional inflammatory parameters myeloid-related protein 8/14 (MRP8/14 or S100A8/9) and human neutrophil-derived elastase (HNE) could distinguish KD from infectious diseases. Methods and Results: The cross-sectional study included KD patients and children with proven infections as well as febrile controls. Patients were recruited between July 2006 and December 2018 in Europe and USA. MRP8/14, CRP, and HNE were assessed for their discriminatory ability by multiple logistic regression analysis with backward selection and receiver operator characteristic (ROC) curves. In the discovery cohort, the combination of MRP8/14+CRP discriminated KD patients (n = 48) from patients with infection (n = 105), with area under the ROC curve (AUC) of 0.88. The HNE values did not improve discrimination. The first validation cohort confirmed the predictive value of MRP8/14+CRP to discriminate acute KD patients (n = 26) from those with infections (n = 150), with an AUC of 0.78. The second validation cohort of acute KD patients (n = 25) and febrile controls (n = 50) showed an AUC of 0.72, which improved to 0.84 when HNE was included. Conclusion: When used in combination, the plasma markers MRP8/14, CRP, and HNE may assist in the discrimination of KD from both proven and suspected infection.publishersversionPeer reviewe

Prevention of Non-immune Mediated Transfusion-related Acute Lung Injury; from Blood Bank to Patient

Transfusion-related acute lung injury (TRALI) is a severe form of pulmonary insufficiency induced by transfusion. TRALI is the leading cause of transfusion-related death, and is caused by the infusion of either anti-leukocyte antibodies in plasma containing blood products or neutrophil priming substances that accumulate during storage of cellular blood products. Among these neutrophil priming substances are bioactive lipids, such as lyso-phosphatidylcholines (lysoPCs) and arachidonic acid, soluble CD40L (sCD40L) and possibly other, as yet unidentified substances. The accumulation of these substances during cellular blood product storage and their role in the induction of "non-immune mediated" TRALI pathogenesis are highly relevant for the current debate of the use of longer vs. shorter stored blood products. In this review, the accumulation of these different substances during storage, as well as their mode of action in inducing TRALI are discussed. In addition, different improvements in current blood banking procedures to prevent TRALI due to these non-immune mediators will be propose