https://www.zora.uzh.ch/id/eprint/71621/4/Schaer_et_al_Hemolysis_and_free_hemoglobin_revisited.pdf

Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins

BACKGROUND Alcoholic hepatitis is a clinical syndrome characterized by jaundice and liver impairment that occurs in patients with a history of heavy and prolonged alcohol use. The short-term mortality among patients with severe disease exceeds 30%. Prednisolone and pentoxifylline are both recommended for the treatment of severe alcoholic hepatitis, but uncertainty about their benefit persists. METHODS We conducted a multicenter, double-blind, randomized trial with a 2-by-2 factorial design to evaluate the effect of treatment with prednisolone or pentoxifylline. The primary end point was mortality at 28 days. Secondary end points included death or liver transplantation at 90 days and at 1 year. Patients with a clinical diagnosis of alcoholic hepatitis and severe disease were randomly assigned to one of four groups: a group that received a pentoxifylline-matched placebo and a prednisolone-matched placebo, a group that received prednisolone and a pentoxifylline-matched placebo, a group that received pentoxifylline and a prednisolone-matched placebo, or a group that received both prednisolone and pentoxifylline. RESULTS A total of 1103 patients underwent randomization, and data from 1053 were available for the primary end-point analysis. Mortality at 28 days was 17% (45 of 269 patients) in the placebo–placebo group, 14% (38 of 266 patients) in the prednisolone–placebo group, 19% (50 of 258 patients) in the pentoxifylline–placebo group, and 13% (35 of 260 patients) in the prednisolone–pentoxifylline group. The odds ratio for 28-day mortality with pentoxifylline was 1.07 (95% confidence interval [CI], 0.77 to 1.49; P = 0.69), and that with prednisolone was 0.72 (95% CI, 0.52 to 1.01; P = 0.06). At 90 days and at 1 year, there were no significant between-group differences. Serious infections occurred in 13% of the patients treated with prednisolone versus 7% of those who did not receive prednisolone (P = 0.002). CONCLUSIONS Pentoxifylline did not improve survival in patients with alcoholic hepatitis. Prednisolone was associated with a reduction in 28-day mortality that did not reach significance and with no improvement in outcomes at 90 days or 1 year. (Funded by the National Institute for Health Research Health Technology Assessment program; STOPAH EudraCT number, 2009-013897-42, and Current Controlled Trials number, ISRCTN88782125.)

/pdf/prednisolone-or-pentoxifylline-for-alcoholic-hepatitis-3snh7doyme.pdf

Prednisolone or Pentoxifylline for Alcoholic Hepatitis

Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation

https://www.hal.inserm.fr/inserm-00696264/document

Red blood cell alloimmunization in sickle cell disease: pathophysiology, risk factors, and transfusion management

Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal. In various pathophysiological conditions, however, erythrocyte life span is compromised severely, which threatens the organism with anemia and iron toxicity. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 (LY6C1, also known as Ly-6C) ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1 (FPN1, encoded by SLC40A1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1(+)Tim-4(neg) macrophages are transient, reside alongside embryonically derived T cell immunoglobulin and mucin domain containing 4 (Timd4, also known as Tim-4)(high) Kupffer cells (KCs), and depend on the growth factor Csf1 and the transcription factor Nrf2 (encoded by Nfe2l2). The spleen, likewise, recruits iron-loaded Ly-6C(high) monocytes, but these do not differentiate into iron-recycling macrophages, owing to the suppressive action of Csf2. The accumulation of a transient macrophage population in the liver also occurs in mouse models of hemolytic anemia, anemia of inflammation, and sickle cell disease. Inhibition of monocyte recruitment to the liver during stressed erythrocyte delivery leads to kidney and liver damage. These observations identify the liver as the primary organ that supports rapid erythrocyte removal and iron recycling, and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity.

On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver

Classical anaphylaxis is the most severe, and potentially fatal, type of allergic reaction, manifested by hypotension, bronchoconstriction, and vascular permeability. Similarly, a hemolytic transfusion reaction (HTR) is the most feared consequence of blood transfusion. Evidence for the existence of an alternative, IgG-mediated pathway of anaphylaxis may be relevant for explaining the pathophysiology of IgG-mediated-HTRs. The purpose of this review is to summarize the evidence for this alternative pathway of anaphylaxis and to present the hypothesis that an IgG-mediated HTR is one example of this type of anaphylaxis.

Hypothesis: Hemolytic Transfusion Reactions Represent an Alternative Type of Anaphylaxis

Review Article Hypothesis: Hemolytic Transfusion Reactions Represent an Alternative Type of Anaphylaxis

reactions Cytokine storm in a mouse model of IgG-mediated hemolytic transfusion

Cytokine storm in a mouse model of IgG-mediated hemolytic transfusion reactions

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