How Do Red Blood Cells Die?

Normal human red blood cells have an average life span of about 120 days in the circulation after which they are engulfed by macrophages. This is an extremely efficient process as macrophages phagocytose about 5 million erythrocytes every second without any significant release of hemoglobin in the circulation. Despite large number of investigations, the precise molecular mechanism by which macrophages recognize senescent red blood cells for clearance remains elusive.

Results of a pilot study of isoniazid in patients with erythropoietic protoporphyria.

Erythropoietic protoporphyria (EPP), the most common porphyria of childhood and the third most common porphyria of adulthood, is characterized clinically by painful, non-blistering cutaneous photosensitivity. Two distinct inheritance patterns involving mutations affecting genes that encode enzymes of the heme biosynthetic pathway underlie the clinical phenotype. Aminolevulinic acid synthase 2 (ALAS2), the rate limiting enzyme of the heme pathway in the erythron, is a therapeutic target in EPP because inhibiting enzyme function would reduce downstream production of protoporphyrin IX (PPIX), preventing accumulation of the toxic molecule and thereby ameliorating symptoms.

Cirrhosis in Hemochromatosis: Independent Risk Factors in 368 HFE p.C282Y Homozygotes.

Introduction And Aim: We sought to identify independent risk factors for cirrhosis in HFE p.C282Y homozygotes in a cross-sectional study.

Material And Methods: We evaluated 368 p.

Dynamic dosing of romiplostim in patients with immune thrombocytopenia purpura: Two case reports.

Romiplostim is a thrombopoietin receptor agonist approved for the treatment of immune thrombocytopenia purpura. When following FDA-approved romiplostim prescribing recommendations to withhold treatment for platelet counts above 400k/µL, some patients exhibit a precipitous decline in their platelet count potentially causing patient harm. We present two cases where stable platelet counts were achieved only through persistent weekly dosing of romiplostim despite platelet counts above 400k/µL on the day of administration.

GNPAT p.D519G is independently associated with markedly increased iron stores in HFE p.C282Y homozygotes.

Background: GNPAT p.D519G positivity is significantly increased in HFE p.C282Y homozygotes with markedly increased iron stores.

Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria.

Once suspected, the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) is straightforward when flow cytometric analysis of the peripheral blood reveals a population of glycosyl phosphatidylinositol anchor protein-deficient cells. But PNH is clinically heterogeneous, with some patients having a disease process characterized by florid intravascular, complement-mediated hemolysis, whereas in others, bone marrow failure dominates the clinical picture with modest or even no evidence of hemolysis observed. The clinical heterogeneity is due to the close, though incompletely understood, relationship between PNH and immune-mediated bone marrow failure, and that PNH is an acquired, nonmalignant clonal disease of the hematopoietic stem cells.

The D519G Polymorphism of Glyceronephosphate O-Acyltransferase Is a Risk Factor for Familial Porphyria Cutanea Tarda.

Unlabelled: Both familial and sporadic porphyria cutanea tarda (PCT) are iron dependent diseases. Symptoms of PCT resolve when iron stores are depleted by phlebotomy, and a sequence variant of HFE (C282Y, c.843G>A, rs1800562) that enhances iron aborption by reducing hepcidin expression is a risk factor for PCT.

Exome sequencing for molecular characterization of non-HFE hereditary hemochromatosis.

Diagnostic genetic testing for hereditary hemochromatosis is readily available for clinically relevant HFE variants (i.e., those that generate the C282Y, H63D and S65C HFE polymorphisms); however, genetic testing for other known causes of iron overload, including mutations affecting genes encoding hemojuvelin, transferrin receptor 2, HAMP, and ferroportin is not.

Rare event counting of CD59- red cells in human blood: A 47-month experience using PNH consensus guidelines for WBC and RBC testing in a reference lab.

Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disorder characterized by increased complement-mediated lysis of erythrocytes (RBCs) because of low/absent glycophosphatidylinositol (GPI) anchors of numerous cell surface proteins.

Methods: Rare event analysis was applied to 120 million RBCs (12 normal individuals) and 102 million RBCs (102 normal individuals) to establish a reference range and verify a methodology for rare event analysis. Patient PNH testing (n = 10,984) was performed over 47 months using the 2010 consensus guidelines with CD59-PE and glycophorin A-FITC for RBCs and FLAER-Alexa 488, CD33-PerCP-Cy5.

Paroxysmal nocturnal hemoglobinuria.

Purpose Of Review: The aim is to report on recent observations related to the natural history of paroxysmal nocturnal hemoglobinuria (PNH) and to review new therapeutic strategies for controlling the hemolysis of PNH.

Recent Findings: This review focuses on studies designed to characterize the long-term outcome of patients with PNH treated with eculizumab and to define the relationship between PNH and bone marrow failure syndromes. New therapeutic strategies aimed at controlling extravascular as well as intravascular hemolysis are also examined.

Methylation of AR locus does not always reflect X chromosome inactivation state.

Clonality can be established by a lack of mosaicism in a female because of random inactivation of either the maternal or paternal X chromosome early in embryogenesis. The methylation status of CpG sites close to the trinucleotide repeats in exon 1 of the human androgen receptor (AR) X chromosome gene assay (HUMARA) has been used to determine clonality. This HUMARA at times indicated clonal hematopoiesis in healthy elderly women, thus precluding its applicability.

Management of paroxysmal nocturnal hemoglobinuria in the era of complement inhibitory therapy.

Despite the availability of safe, effective targeted therapy that controls intravascular hemolysis, the management of paroxysmal nocturnal hemoglobinuria (PNH) remains complicated because of disease heterogeneity and close association with BM failure syndromes. The purpose of this review is to provide a framework for individualizing treatment based on disease classification. According to the recommendations of the International PNH Interest Group, patients can be placed into one of the following 3 categories: (1) classic PNH, (2) PNH in the setting of another BM failure syndrome, or (3) subclinical PNH.

In vitro and in vivo characterization of SGI-1252, a small molecule inhibitor of JAK2.

Objective: Constitutive activation of the Janus kinase 2 (JAK2) due to a somatic mutation (JAK2(V617F)) arising in hematopoietic stem cells plays a central role in the pathophysiology of myeloproliferative neoplasms (MPNs). To investigate the hypothesis that drugs that inhibit JAK2 have therapeutic potential, we developed a small molecule inhibitor, SGI-1252, that targets the adenosine triphosphate-binding and solvent pocket of the protein.

Materials And Methods: Established cells lines each expressing different JAK2(V617F) copy numbers, a cell line transfected with wild-type and mutant JAK2, ex vivo expanded erythroid progenitor cells from patients with MPNs, and a murine xenograft model were used to characterize the activity of SGI-1252.

CD4 (+)CD25 (+)Foxp3 (+) regulatory T cells and hematologic malignancies.

Regulatory T cells (Tregs) are an immunosuppressive T cell subset that functions to prevent autoimmunity and to regulate physiologic immune reactions. Tregs are also present in the tumor microenvironment and appear to play an important role in the pathophysiology of malignant processes. Available data suggests that this role is context-dependent, as a higher density of tumor infiltrating Tregs at diagnosis may be associated with either a positive or a negative clinical outcome.

A novel approach to preventing the hemolysis of paroxysmal nocturnal hemoglobinuria: both complement-mediated cytolysis and C3 deposition are blocked by a monoclonal antibody specific for the alternative pathway of complement.

The clinical hallmark of paroxysmal nocturnal hemoglobinuria (PNH) is chronic intravascular hemolysis that is a consequence of unregulated activation of the alternative pathway of complement (APC). Intravascular hemolysis can be inhibited in patients by treatment with eculizumab, a monoclonal antibody that binds complement C5 thereby preventing formation of the cytolytic membrane attack complex of complement. However, in essentially all patients treated with eculizumab, persistent anemia, reticulocytosis, and biochemical evidence of hemolysis are observed; and in a significant proportion, their PNH erythrocytes become opsonized with complement C3.

Bone marrow failure syndromes: paroxysmal nocturnal hemoglobinuria.

This article discusses the etiology of paroxysmal nocturnal hemoglobinuria (PNH) and its relationship to marrow hyperplasia. The author posits that the defining clinical pathology of PNH (ie, complementmediated intravascular hemolysis) is an epiphenomenon that is a consequence of an orchestrated response (ie, natural selection of PIGA-mutant stem cells) to a specific type of bone marrow injury (ie, immune mediated). Management of PNH is discussed also.

Paroxysmal nocturnal hemoglobinuria: an historical overview.

The clinical hallmark of paroxysmal nocturnal hemoglobinuria (PNH) is episodic hemoglobinuria, and it was this feature that captured the attention of European physicians in the latter half of the 19th century, resulting in careful observational studies that established PNH as an entity distinct from paroxysmal cold hemoglobinuria and march hemoglobinuria. Curiosity about the etiology of the nocturnal aspects of the hemoglobinuria led the German physician Paul Strübing to develop the prescient hypothesis that the erythrocytes of PNH are abnormally sensitive to hemolysis when the plasma is acidified during sleep because of accumulation of carbon dioxide and lactic acid as a result of slowing of the circulation. Investigation of the intricate pathophysiology that underlies the abnormal sensitivity of PNH erythrocytes to hemolysis in acidified serum produced a number of remarkable scientific achievements that involved discovery of the alternative pathway of complement, identification of the membrane proteins that regulate complement, discovery of a novel mechanism for attachment of proteins to the cell surface, and identification of the genetic basis of the disease.

Isolation and functional assay of the membrane complement inhibitors CD55 (DAF) and CD59 (MIRL).

The complement system is the primary effector of humoral immunity. Because of its enormous destructive capacity, mechanisms for confining the activity of the system to the desired target and elaborate safeguards for protecting self against complement-mediated injury have evolved. Human cells, particularly those found at sites of inflammation (e.