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Concept: Hemolysis

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Primaquine is a key drug for malaria elimination. In addition to being the only drug active against the dormant relapsing forms of Plasmodium vivax, primaquine is the sole effective treatment of infectious P. falciparum gametocytes, and may interrupt transmission and help contain the spread of artemisinin resistance. However, primaquine can trigger haemolysis in patients with a deficiency in glucose-6-phosphate dehydrogenase (G6PDd). Poor information is available about the distribution of individuals at risk of primaquine-induced haemolysis. We present a continuous evidence-based prevalence map of G6PDd and estimates of affected populations, together with a national index of relative haemolytic risk.

Concepts: Malaria, Plasmodium falciparum, Plasmodium, Plasmodium vivax, Hemolytic anemia, Hemolysis, Glucose-6-phosphate dehydrogenase deficiency, Primaquine

151

We sought to evaluate the feasibility and efficacy of hybrid transapical closure of paravalvar mitral leaks using a new Occlutech PLD occluder in patients with heart failure and/or haemolytic anaemia.

Concepts: Hemoglobin, Red blood cell, Anemia, Hemolytic anemia, Hemolysis, Hematology

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Mutations in hemoglobin can cause a wide range of phenotypic outcomes, including anemia due to protein instability and red cell lysis. Uncovering the biochemical basis for these phenotypes can provide new insights into hemoglobin structure and function as well as identify new therapeutic opportunities. We report here a new hemoglobin α chain variant in a female patient with mild anemia, whose father also carries the trait and is from the Turkish city of Kirklareli. Both the patient and her father had a His58(E7)→Leu mutation in α1. Surprisingly, the patient’s father is not anemic, but he is a smoker with high levels of HbCO (~16%). In order to understand these phenotypes, we examined recombinant human Hb (rHb) Kirklareli containing the α H58L replacement. Mutant α subunits containing Leu58(E7) autooxidize ~8 times and lose hemin ~200 times more rapidly than native α subunits, causing the oxygenated form of rHb Kirklareli to denature very rapidly under physiological conditions. The crystal structure of rHb Kirklareli shows that the α H58L replacement creates a completely apolar active site, which prevents electrostatic stabilization of bound O2, promotes autooxidation, and enhances hemin dissociation by inhibiting water coordination to the Fe(III) atom. At the same time, the mutant α subunit has an ~80,000 fold higher affinity for CO than O2, causing it to rapidly take up and retain carbon monoxide, which prevents denaturation both in vitro and in vivo and explains the phenotypic differences between the father, who is a smoker, and his daughter.

Concepts: Hemoglobin, Oxygen, Gene, Carbon dioxide, Phenotype, Hemolysis, In vitro, Carbon monoxide

28

Antibody binding to red blood cells (RBCs) can induce potentially fatal outcomes, including hemolytic transfusion reactions (HTRs), hemolytic disease of the fetus and newborn, and autoimmune hemolytic anemia. The mechanism(s) of RBC destruction following antibody binding is typically thought to require complement activation and/or the involvement of Fcγ receptors (FcγRs). In the current report, we analyzed mechanisms of HTRs during incompatible transfusions of murine RBCs expressing human glycophorin A (hGPA) into mice with anti-hGPA.

Concepts: Hemoglobin, Blood, Red blood cell, Anemia, Hemolytic anemia, Hemolysis, Hematology, Blood transfusion

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INTRODUCTION: Schistocytes are major signs of micro- and macroangiopathic haemolytic anaemia. The aim was to evaluate automated fragmented red cell (FRC) count compared to visual microscopy, and to assess FRCs in the presence of microcytosis and hypochromia using Sysmex automated counters. METHODS: Schistocytes were determined with visual microscopy after the observation of 1000 erythrocytes, and the automated counting with Sysmex XE-5000. Indices of microcytosis (%MicroR) and hypochromia (%Hypo-He) were also analysed in the XE-5000 analyser. RESULTS: Linear regression analysis showed a good correlation between automated and manual FRC% count (r = 0.824, P < 0.0001), but Bland-Altman's plot revealed an overestimation of FRC of 0.82%. There is a global correlation between %MicroR and FRCs. In subgroup analysis of %MicroR (reference value: 0.3-3%, mild microcytosis: 3.1-7.2% and severe microcytosis: 7.3-56.7%), no correlations with automated %FRC were noticed (P > 0.05). Based on %Hypo-He subgroups (mild hypochromia: 1.2-5.2%, and severe hypochromia: 5.3-35.4%), a significant correlation of automated %FRC with mild hypochromia was found (r = 0.621, P < 0.01). CONCLUSION: Despite the agreement between FRC count and the manual method, the overvaluation of FRC was high, leading to false-positive results. Microcytosis appeared to have no impact on FRC count, whereas mild hypochromia seemed to be related with FRC count. Particular attention is required to assess automated FRCs in samples with mild hypochromia.

Concepts: Hemoglobin, Regression analysis, Linear regression, Red blood cell, Anemia, Hemolytic anemia, Hemolysis, Hematology

27

This study was performed to explore other potential mechanisms underlying hemolysis in addition to pore-formation of tentacle extract (TE) from the jellyfish Cyanea capillata. A dose-dependent increase of hemolysis was observed in rat erythrocyte suspensions and the hemolytic activity of TE was enhanced in the presence of Ca2+, which was attenuated by Ca2+ channel blockers (Diltiazem, Verapamil and Nifedipine). Direct intracellular Ca2+ increase was observed after TE treatment by confocal laser scanning microscopy, and the Ca2+ increase could be depressed by Diltiazem. The osmotic protectant polyethylenglycol (PEG) significantly blocked hemolysis with a molecular mass exceeding 4000 Da. These results support a pore-forming mechanism of TE in the erythrocyte membrane, which is consistent with previous studies by us and other groups. The concentration of malondialdehyde (MDA), an important marker of lipid peroxidation, increased dose-dependently in rat erythrocytes after TE treatment, while in vitro hemolysis of TE was inhibited by the antioxidants ascorbic acid-Vitamin C (Vc)-and reduced glutathione (GSH). Furthermore, in vivo hemolysis and electrolyte change after TE administration could be partly recovered by Vc. These results indicate that lipid peroxidation is another potential mechanism besides pore-formation underlying the hemolysis of TE, and both Ca2+ channel blockers and antioxidants could be useful candidates against the hemolytic activity of jellyfish venoms.

Concepts: Hemoglobin, Cell membrane, Red blood cell, Antioxidant, Reactive oxygen species, Hemolytic anemia, Hemolysis, Glutathione

25

Acute hemolytic anemia (AHA) due to glucose 6-phosphate dehydrogenase (G6PD) deficiency has rarely been recognized as a contributor to the development of frostbite. We discuss a case of frostbite in a 32-year-old male Marine with G6PD deficiency during military training on Mount McKinley in Alaska, which eventually led to a permanent disability. In this report, the pathophysiology of G6PD deficiency, the effects of hemolytic anemia, and factors that contribute to frostbite will be discussed, as well as the clinical findings, treatment course, and the outcome of this case. The patient was evacuated and admitted to Alaska Regional Hospital. He was treated for fourth-degree frostbite, ultimately resulting in the complete or partial amputation of all toes. Although it cannot be proved that AHA occurred in this patient, this case potentially adds frostbite to the list of rare but possible clinical presentations of G6PD deficiency.

Concepts: Hemolytic anemia, Hemolysis, Hematology, Glucose-6-phosphate dehydrogenase deficiency, Pentose phosphate pathway, Glucose-6-phosphate dehydrogenase, Primaquine, Haemolytic anaemias

24

We report the occurrence of autoimmune hemolytic anemia in a patient receiving the anti-PD-1 monoclonal antibody, nivolumab, for metastatic melanoma in the presence of known red cell alloantibodies, despite having received prior ipilimumab without evidence of hemolysis. The patient had a history of multiple red cell alloantibodies and a positive direct antiglobulin test, identified at the time of a prior transfusion, which occurred before treatment with ipilimumab. The patient developed symptomatic warm autoimmune hemolytic anemia after four cycles of treatment with nivolumab. Clinical improvement was noted following cessation of the drug and treatment with corticosteroids. Given that there was no prior history of hemolysis, even during treatment with ipilimumab, we hypothesize that anti-PD-1 therapy disrupted peripheral tolerance, unmasking an underlying autoimmune predisposition.

Concepts: Immune system, Hemoglobin, Red blood cell, Anemia, Hemolytic anemia, Hemolysis, Hematology, Coombs test

24

The synthesis and antibacterial activity of (7S)-7-sulfur-azetidin-3-yl lincomycin derivatives are described. Modification was achieved by a simple reaction of (7R)-7-O-methanesulfonyllincomycin and the corresponding substituted azetidine-2-thiol. Several compounds first showed moderate antibacterial activity against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene as lincomycin derivatives.The Journal of Antibiotics advance online publication, 13 January 2016; doi:10.1038/ja.2015.134.

Concepts: Bacteria, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus, Hemolysis, Activity, Streptococcaceae, 2016

22

In order to investigate the pathophysiology of erythrocyte membrane proteins, 10 patients (6 pre- and 4 post-splenectomy) with hereditary spherocytosis (HS) and other patients with haemolytic anaemia were examined.

Concepts: Hemoglobin, Red blood cell, Anemia, Hemolytic anemia, Hemolysis, Hematology, Hereditary spherocytosis, Spherocytosis