Massive hemolysis and erythrophagocytosis in severe sepsis

Meinders, Arend-Jan; Dijkstra, Ineke M.

doi:10.1182/blood-2014-04-565663

Cited by 9 publications

(10 citation statements)

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“…The contribution of RBC metabolites to the variance of the serum metabolome is particularly relevant because there is growing evidence that in vivo hemolysis contributes to the pathogenesis and severity of sepsis (6, 13, 27). Hemolysis can be a consequence of sepsis that perpetuates inflammation and it has been recently shown that free Hgb is associated with mortality in patients with sepsis (6).…”

Section: Discussionmentioning

confidence: 99%

“…To determine whether the changes found in this controlled setting were likely relevant to clinical sepsis research, we measured free Hgb levels in serum from both control and sepsis patients with a representative visible range of hemolysis. In vivo hemolysis can occur under a number of conditions (6, 13-15), though can commonly occur in sepsis and is increasingly recognized as contributing to the pathology of the condition, forming some of the motivation for this investigation. We do acknowledge, however, that in our study, the free Hgb levels in serum collected from sepsis patients were not different from those of healthy controls.…”

Section: Discussionmentioning

confidence: 99%

“…In sepsis, RBC have gained recognition because they modulate the microcirculation, the RBC membrane participates in the regulation of blood rheology, and RBC width distribution is associated with survivorship (11, 12). In addition, pathogen (6, 13) and complement-induced (14) hemolysis as well as sepsis- induced RBC fragility, enhances the likelihood of in vivo hemolysis. The influence of RBC in sepsis is furthered by the recommendation that patients with septic shock receive RBC transfusion (15), which can lead to hemolysis.…”

Section: Introductionmentioning

confidence: 99%

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Whole Blood Reveals More Metabolic Detail of the Human Metabolome than Serum as Measured by 1H-NMR Spectroscopy

Stringer¹,

Younger²,

McHugh³

et al. 2015

Shock

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Serum is a common sample of convenience for metabolomics studies. Its processing time can be lengthy and may result in the loss of metabolites including those of red blood cells (RBC). Unlike serum, whole blood (WB) is quickly processed, minimizing the influence of variable hemolysis while including RBC metabolites. To determine differences between serum and WB metabolomes, both sample types, collected from healthy volunteers, were assayed by 1H-NMR spectroscopy. A total of 34 and 50 aqueous metabolites were quantified from serum and WB, respectively. Free hemoglobin (Hgb) levels in serum were measured and the correlation between Hgb and metabolite concentrations was determined. All metabolites detected in serum were at higher concentrations in WB with the exception of acetoacetate and propylene glycol. The 18 unique metabolites of WB included adenosine, AMP, ADP and ATP, which are associated with RBC metabolism. The use of serum results in the underrepresentation of a number of metabolic pathways including branched chain amino acid degradation and glycolysis and gluconeogenesis. The range of free Hgb in serum was 0.03-0.01 g/dL and 8 metabolites were associated (p ≤ 0.05) with free Hgb. The range of free Hgb in serum samples from 18 sepsis patients was 0.02-0.46 g/dL. WB and serum have unique aqueous metabolite profiles but the use of serum may introduce potential pathway bias. Use of WB for metabolomics may be particularly important for studies in diseases like sepsis in which RBC metabolism is altered and mechanical and sepsis-induced hemolysis contributes to variance in the metabolome.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Whole Blood Reveals More Metabolic Detail of the Human Metabolome than Serum as Measured by 1H-NMR Spectroscopy

Stringer¹,

Younger²,

McHugh³

et al. 2015

Shock

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“…Using genetic approaches allowing for Dll1/4 inactivation in specific compartments and complementary biochemical strategies, our group demonstrated that both host and donor hematopoietic APCs were dispensable sources of Notch ligands to drive GVHD. 104,105 Indeed, transplant recipients lacking Dll1/4 within the hematopoietic system were not protected from GVHD and remained susceptible to systemic Dll1/4 blockade, while nonhematopoietic elements 106,107 emerged as key sources of Dll1/4. Moreover, Dll1/4 inactivation in fibroblastic reticular cells replicated all the benefits of pan-T cell and systemic Notch blockade.…”

Section: Notch Signaling In Alloimmunitymentioning

confidence: 99%

“…Moreover, Dll1/4 inactivation in fibroblastic reticular cells replicated all the benefits of pan-T cell and systemic Notch blockade. 105 Thus, the cellular source of Dll1/4 in GVHD may overlap with recently identified fibroblastic niches in secondary lymphoid organs that provide critical differentiation inputs to marginal zone B cells, subsets of Notch-dependent DCs and follicular helper T cells. 108 …”

Section: Notch Signaling In Alloimmunitymentioning

confidence: 99%

Notch Signaling and Alloreactivity

Radojčić

Maillard

2016

Transplantation

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Solid organ and allogeneic hematopoietic cell transplantation have become standard therapeutic interventions that save patient lives and improve quality of life. Our enhanced understanding of transplantation immunobiology has refined clinical management and improved outcomes. However, organ rejection and graft-versus-host disease remain major obstacles to the broader successful application of these therapeutic procedures. Notch signaling regulates multiple aspects of adaptive and innate immunity. Preclinical studies identified Notch signaling as a promising target in autoimmune diseases, as well as after allogeneic hematopoietic cell and solid organ transplantation. Notch was found to be a central regulator of alloreactivity across clinically relevant models of transplantation. Notch inhibition in T cells prevented graft-versus-host disease and organ rejection, establishing organ tolerance by skewing CD4+ T helper polarization away from a proinflammatory response towards suppressive regulatory T cells. Notch ligand blockade also dampened alloantibody deposition and prevented chronic rejection through humoral mechanisms. Toxicities of systemic Notch blockade were observed with γ-secretase inhibitors in preclinical and early clinical trials across different indications, but they did not arise upon preclinical targeting of Delta-like Notch ligands, a strategy sufficient to confer full benefits of Notch ablation in T cell alloimmunity. As multiple clinical grade reagents have been developed to target individual Notch ligands and receptors, the benefits of Notch blockade in transplantation are calling for translation of preclinical findings into human transplantation medicine.

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