RBC Hemolysis and Platelet Activation in Paroxysmal Nocturnal Hemoglobinuria Are Mediated by Oxidative Stress That Can Be Ameliorated by Antioxidants.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1049-1049
Author(s):  
Eitan Fibach ◽  
Orly Zelig ◽  
Johnny Amer
Keyword(s):  
Oxidative Stress ◽  
Platelet Activation ◽  
Bacterial Infections ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Membrane Lipid ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Blood Samples

Abstract Paroxysmal Nocturnal Hemoglobinuria (PNH) is an acquired stem cell disorder characterized by the unique triad of intravascular hemolysis, bone marrow failure and thrombosis. Complement-mediated hemolysis in PNH is explained by a deficiency in glycosylphosphotidylinositol (GPI)-anchored proteins, CD55 and CD59 on the RBC surface. Using flow cytometry for simultaneous measurement of oxidative-state markers in RBC and platelets, we studied blood samples obtained from normal donors and PNH patients. Reactive oxygen species (ROS), reduced glutathione (GSH), membrane lipid peroxidation and phosphatidylserine (PS) exposure were measured by staining with dichlorofuorescein, mercury orange, fluor-DHPE and Annexin V, respectively, followed by gating based on size and granularity. The results of blood samples obtained from normal donors (N=25) and PNH patients (N=11) indicated that the RBC from the patients had higher levels of ROS (1.4-fold) and lipid peroxides (3.5-fold) and lower GSH levels (two-fold) than those of normal RBC. Similar results were obtained with platelets from the same samples, indicating that both cell types are in a state of oxidative stress. Within each cell type, cells with the PNH immunophenotype (CD55− CD59−) had higher ROS levels and PS exposure than cells with the normal (CD55+CD59+) phenotype. These results support the direct relationship between the PNH phenotype and intracellular oxidative stress. Oxidants, such as hydrogen peroxide, phenylhydrazine, hemin, ferric ammonium citrate, increased the oxidative status of the cells and caused concentration-dependent RBC lysis and platelet activation. Complement-containing plasma had a similar effect. The RBC lysis and platelet activation were preceded by a burst of ROS and were more prominent in cells with the PNH phenotype. Incubation of PNH-cells with antioxidants such as N-acetyl cysteine, vitamin C and tocotrinol, prevented the complement-mediated lysis. We previously reported that cellular oxidative stress, prevalent in conditions such as thalassemia, may be associated with RBC hemolysis, platelet activation and a decreased PMN antibacterial potential. Oxidative stress in RBC, platelets and neutrophils in PNH could in part account for clinical manifestations such as hemolysis, a hypercoagulable state and recurrent bacterial infections. Our present results, indicating that incubation with antioxidants ameliorates such stress and its adverse consequences, suggest the possibility of using antioxidants for treatment of PNH and similar conditions.

Platelets and PMN as Well as RBC of Patients with Sickle Cell Anemia Exhibit Oxidative Stress Which Can Be Corrected by Antioxidants.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3575-3575
Author(s):  
Johnny Amer ◽  
Hussam Ghoti ◽  
Eliezer Rachmilewitz ◽  
Koren Ariel ◽  
Eitan Fibach
Keyword(s):  
Oxidative Stress ◽  
Flow Cytometry ◽  
Sickle Cell ◽  
Clinical Manifestations ◽  
Oxidative Status ◽  
Polymorphonuclear Neutrophils ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Beta Thalassemia ◽  
Mercury Orange

Abstract Sickle cell disease (SCD) is caused by an abnormal hemoglobin (HbS), which results mainly in sickling and hemolysis of RBC. However, the platelets and the polymorphonuclear neutrophils (PMN) are also involved in the pathophysiology of the disease. Similar to the findings in thalassemia, some patients develop thromboembolic phenomena with hypercoagulable state, which is due in part to platelet activation. In addition, a growing body of evidence suggests that WBC, particularly PMN, are abnormal; their number is elevated during painful crises and the severity of the disease increases with their number. Several aspects of the changes in the three blood lineages are thought to result from oxidative stress, which represents the imbalance between enhanced generation of reactive oxygen species (ROS) and a low cellular content of antioxidants such as reduced glutathione (GSH), the major intracellular scavenger of ROS. In SCD, oxidative stress results primarily from the premature precipitation of the unstable HbS and the accumulation of excess iron, a catalyst in the formation of ROS. Accumulation of ROS may result in hemolysis of RBC, activation of platelets and a respiratory burst of PMN. We developed flow cytometry techniques for measuring oxidative-state markers, ROS generation and GSH content, simultaneously in RBC, platelets and PMN. Peripheral blood samples obtained from 15 normal donors, 10 patients with SCD and 5 SCD/beta-thalassemia patients (two with the IVS2-1 mutation and 3 with the IVS1-6 mutation) were studied. Out of the 15 SCD patients, 5 were splenectomized, and all were treated with folic acid, except one who was treated with hydroxyurea. The blood was mixed with 3% gelatin, and following 30 min. incubation the upper layer, containing RBC, platelets and WBC, was collected. ROS and GSH were measured by FACS analysis following staining with 2′, 7′-dichlorofuoresceine (DCF) and mercury orange, respectively. Cells were gated on the basis of size and granularity to include platelets, RBC or PMN, exclusively. The cells in each gate were analyzed for green (DCF) or orange (mercury orange) fluorescence and the Mean Fluorescence Channel (MFC) was calculated. The results showed that ROS production increased by 10 to 30-fold in RBC, platelets and PMN from SCD patients compared with that of their normal counterparts. Concomitantly, the GSH content decreased by 20–50% in the SCD cells. It was possible to modulate the oxidative status of cells from both normal donors and SCD patients: Exposure of the cells to oxidants such as hydrogen peroxide (2 mM), hemin (0.1 mM) or iron (ferric ammonium citrate - 0.1 mM) increased the oxidative status in all cell types, while antioxidants such as N-acetyl cysteine, vitamin C (both at 1 mM) and vitamin E (0.2 mM) significantly decreased the oxidative stress. Our results indicate that similar to the findings in thalassemia, in SCD, RBC and platelets, as well as PMN, are in a state of oxidative stress, which could in part account for the clinical manifestations. Addition of antioxidants, which reduced the ROS and enhanced the GSH content of the cells, could protect against oxidative damage. The flow cytometry techniques we developed may prove useful for studying the effects of various antioxidants and for monitoring the patient’s oxidative status during therapy thereby providing an objective, quantitative evaluation of their efficacy.

scholarly journals Paroxysmal Nocturnal Hemoglobinuria with a Distinct Molecular Signature Diagnosed Ten Years after Allogenic Bone Marrow Transplantation for Acute Myeloid Leukemia

2019 ◽  
Vol 2019 ◽  
pp. 1-3
Author(s):  
Alberto Santagostino ◽  
Laura Lombardi ◽  
Gerard Dine ◽  
Pierre Hirsch ◽  
Srimanta Chandra Misra
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Somatic Mutation ◽  
Myeloid Leukemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Clonal Selection ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Hematopoietic Stem ◽  
Acute Myeloid

Paroxysmal nocturnal hemoglobinurea (PNH) is a rare disorder of complement regulation due to somatic mutation of PIGA (phosphatidylinositol glycan anchor) gene. We herewith report a case who developed a symptomatic PNH long after an allogenic marrow transplant. Some reasonable arguments concerning the origin of PNH clone have been discussed. The molecular studies revealed presence of JAK2 and TET2 mutations without a BCOR mutation. The literature review has been performed to probe into the complex interplay of autoimmunity and clonal selection and expansion of PNH cells, which occurs early in hematopoietic differentiation. The consequent events such as hypoplastic and/or hemato-oncologic features could further be explained on the basis of next-generation sequencing (NGS) studies. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder of hematopoietic stem cells, characterized by a somatic mutation of the phosphatidylinositol glycan-class A (PIGA). The PIGA gene products are crucial for biosynthesis of glycosylphosphatidylinositol (GPI) anchors, which attaches a number of proteins to the plasma membrane of the cell. Amongst these proteins, the CD55 and CD59 are complement regulatory proteins. The CD55 inhibits C3 convertase whereas the CD59 blocks the membrane attack complex (MAC) by inhibiting the incorporation of C9 to MAC. The loss of complement regulatory protein renders the red cell susceptible to complement-mediated lysis leading to intravascular and extravascular hemolysis. The intravascular hemolysis explains most of the morbid clinical manifestations of the disease. The clinical features of syndrome of PNH are recurrent hemolytic episodes, thrombosis, smooth muscle dystonia, and bone marrow failure; other important complications include renal failure, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML). The most used therapies were blood transfusions, immunosuppressive, and steroid. Allogeneic stem cell transplantation was also practiced. At present, the therapy of choice is eculizumab (Soliris, Alexion Pharmaceuticals), a humanized monoclonal antibody that blocks activation of the terminal complement at C5. The limiting factor for this therapy is breakthrough hemolysis and the frequent dosing schedule. Ravulizumab (ALXN1210) is the second generation terminal compliment inhibitor which seems to provide a sustained control of hemolysis without breakthrough hemolysis and with a longer dosing interval.

Efficacy of Alpha-Lipoic Acid in Iron-Induced Oxidative Stress.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3599-3599
Author(s):  
Ashutosh Lal ◽  
Jung H. Suh ◽  
Bruce N. Ames
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Lipoic Acid ◽  
Iron Content ◽  
Redox State ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Dependent Manner ◽  
Intracellular Iron ◽  
Dose Dependent

Abstract Antioxidant supplementation could reduce organ damage and premature death in patients with iron overload. We evaluated the improvement in iron-induced oxidative stress with α-Lipoic acid (LA), a multifunctional thiol antioxidant and inducer of phase II enzymes, and compared it with benzylhydroxylamine (BH), a reducing agent that protects against free radicals. Human fibroblasts (IMR-90) were grown in regular cell culture medium or with ferric ammonium citrate (FAC). The intracellular iron content was measured by inductively-coupled plasma spectrometry (ICP). Either LA or BH was added on day 2, and cells grown to confluence. Oxidative stress was assessed by dichlorodihydrofluorescein diacetate fluorescence (DCF-fl). GSH:GSSG was measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The total intracellular iron content (mean±SEM, ng per 5x10^6 cells) increased from 66.95±6.51 in control cells to 262.26±4.69 after exposure to 25 μM FAC, and 556.26±21.15 after exposure to 125 μM FAC. The increase in iron-content of the IMR-90 fibroblasts caused significant rise in oxidant appearance at the highest concentration, as evidenced by 27.8±2.6% increase in steady-state DCF-fl compared with control cells (p <.001). Addition of increasing concentrations of LA attenuated iron-mediated rise in DCF-fl in dose dependent manner. LA at concentrations above 25 μM completely abolished the iron-dependent rise in DCF-fl (91.9±2.3% for FAC+LA, p <.001). BH treated cells also exhibited a dose-dependent decrease in DCF-fl, but a much higher concentration (>200 μM) was needed for complete attenuation of iron-induced rise in DCF-fl (108.3±3.4%, p <.001). These results suggest that LA is more effective than BH in ameliorating iron-mediated increase in oxidative stress. To further understand the basis for the efficacy of LA, intracellular GSH and GSSG were measured. Results show that LA improved the total GSH levels and its redox state in a dose dependent manner. LA and BH attenuated iron-mediated oxidant production, with LA exhibiting greater efficacy. This effect may be due to potent ability of LA to improve intracellular GSH levels and redox state. Our results suggest LA may be useful in reducing complications from iron overload.

scholarly journals How I treat paroxysmal nocturnal hemoglobinuria

Blood ◽  
2009 ◽  
Vol 113 (26) ◽  
pp. 6522-6527 ◽  
Author(s):  
Robert A. Brodsky
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Failure ◽  
Allogeneic Bone Marrow Transplantation ◽  
Clinical Manifestations ◽  
Allogeneic Bone ◽  
Curative Therapy ◽  
Blood Disorder

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal blood disorder that manifests with hemolytic anemia, bone marrow failure, and thrombosis. Many of the clinical manifestations of the disease result from complement-mediated intravascular hemolysis. Allogeneic bone marrow transplantation is the only curative therapy for PNH. Eculizumab, a monoclonal antibody that blocks terminal complement activation, is highly effective in reducing hemolysis, improving quality of life, and reducing the risk for thrombosis in PNH patients. Insights into the relevance of detecting PNH cells in PNH and other bone marrow failure disorders are highlighted, and indications for treating PNH patients with bone marrow transplantation and eculizumab are explored.

Chronic Oxidative Stress Reduces the Oxidative Burst Response of Thalassemic Polymorphonuclear Neutrophils.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3811-3811
Author(s):  
Johnny Amer ◽  
Eitan Fibach
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Respiratory Burst ◽  
Bacterial Infections ◽  
Polymorphonuclear Neutrophils ◽  
Abnormal Behavior ◽  
Ammonium Citrate ◽  
Ros Generation ◽  
Chronic Oxidative Stress ◽  
Increased Susceptibility

Abstract Bacterial infections are a serious complication in the beta-thalassemia syndrome, but the mechanisms underlying the increased susceptibility to these infections are not fully understood. Factors, likely to be involved are anemia, splenectomy, iron-overload, alterations in immune responses and defective phagocytic cells. Polymorphonuclear neutrophils (PMN) destroy microbial organisms by a burst of reactive oxygen species (ROS) in response to bacterial components as well as to phorbol myristate acetate (PMA). The respiratory burst is mediated by a multi-component enzyme - NADPH oxidase. We previously showed that in thalassemia, RBC and platelets are under oxidative stress, which may affect their functionality and integrity, leading to premature hemolysis and platelet activation. In the present study, we utilized flow cytometric techniques to compare ROS generation in normal (n=18) and in beta-thalassemic (n=10) PMN and to assess respiratory burst in response to stimulation by PMA. Peripheral blood samples were mixed with 3% gelatin, and following 30 min incubation the upper layer, containing PMN, platelets and some RBC, was collected. ROS generation was measured by FACS analysis following staining of the cells with 2′-7′-dichlorofluorescein (DCF). PMN were “gated” according to granularity and size. The identity of the cells in the PMN gate was verified by immuno-staining for CD11b and CD15, specific PMN antigens. The intensity of the resultant ROS-mediated cell fluorescence was linearly related to the height (intensity) of the respiratory burst. The average mean fluorescence channel (MFC) of DCF-stained PMN of thalassemia patients and of normal donors at basal level was 39 and 10, respectively. Upon activation with 100 ng/ml PMA for 15 min. at 37°C, while the average MFC of the normal PMN increased by 36-fold, the thalassemic PMN increased by only two and a half fold. These results indicate high basal ROS generation by thalassemic PMN, but a reduced response to PMA. To determine whether this abnormal behavior of thalassemic PMN was due to oxidative stress, normal PMN were treated with various oxidants followed by DCF staining. Pre-treatment with hydrogen peroxide (1 mM), butyl-hydroxyperoxide (0.6 mM), hemin (0.1 mM) or ferric ammonium citrate (0.1 mM) increased the basal level of ROS generation (5 to 22-fold, but decreased the PMA response by 20–30%. In contrast, overnight treatment of thalassemic PMN with antioxidants such as N-acetyl-L-cysteine and vitamin C (both at 0.05 mM) reduced the basal ROS level and enhanced the PMN response to PMA. Our findings suggest that the oxidative status of PMN plays an important role in the defense mechanism against bacterial infections. PMN that are under chronic oxidative stress, such as in thalassemia (e.g., as a result of iron-overload) have a reduced capacity to elicit a respiratory burst. This may explain the increased susceptibility of thalassemic patients to bacterial infections. Consequently, these findings raise the possibility of using antioxidants in thalassemia and other conditions associated with recurrent bacterial infections.

Increased frequency of HLA-DR2 in patients with paroxysmal nocturnal hemoglobinuria and the PNH/aplastic anemia syndrome

Blood ◽  
2001 ◽  
Vol 98 (13) ◽  
pp. 3513-3519 ◽  
Author(s):  
Jaroslaw P. Maciejewski ◽  
Dean Follmann ◽  
Ryotaro Nakamura ◽  
Yogen Saunthararajah ◽  
Candido E. Rivera ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Normal Incidence ◽  
Primary Diagnosis ◽  
Hla Alleles ◽  
Predictors Of Response ◽  
Pnh Clone

Abstract Many autoimmune diseases are associated with HLA alleles, and such a relationship also has been reported for aplastic anemia (AA). AA and paroxysmal nocturnal hemoglobinuria (PNH) are related clinically, and glycophosphoinositol (GPI)–anchored protein (AP)–deficient cells can be found in many patients with AA. The hypothesis was considered that expansion of a PNH clone may be a marker of immune-mediated disease and its association with HLA alleles was examined. The study involved patients with a primary diagnosis of AA, patients with myelodysplastic syndrome (MDS), and patients with primary PNH. Tests of proportions were used to compare allelic frequencies. For patients with a PNH clone (defined by the presence of GPI-AP–deficient granulocytes), regardless of clinical manifestations, there was a higher than normal incidence of HLA-DR2 (58% versus 28%; z = 4.05). The increased presence of HLA-DR2 was found in all frankly hemolytic PNH and in PNH associated with bone marrow failure (AA/PNH and MDS/PNH). HLA-DR2 was more frequent in AA/PNH (56%) than in AA without a PNH clone (37%;z = 3.36). Analysis of a second cohort of patients with bone marrow failure treated with immunosuppression showed that HLA-DR2 was associated with a hematologic response (50% of responders versus 34% of nonresponders; z = 2.69). Both the presence of HLA-DR2 and the PNH clone were independent predictors of response but the size of PNH clone did not correlate with improvement in blood count. The results suggest that clonal expansion of GPI-AP–deficient cells is linked to HLA and likely related to an immune mechanism.

scholarly journals α-Lipoic Acid Reduces Iron-induced Toxicity and Oxidative Stress in a Model of Iron Overload

2019 ◽  
Vol 20 (3) ◽  
pp. 609 ◽  
Author(s):  
Giuseppina Camiolo ◽  
Daniele Tibullo ◽  
Cesarina Giallongo ◽  
Alessandra Romano ◽  
Nunziatina Parrinello ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Lipoic Acid ◽  
Inductively Coupled Plasma ◽  
National Health System ◽  
Human Mesenchymal Stem Cells ◽  
Iron Accumulation ◽  
Organ Injury ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate

Iron toxicity is associated with organ injury and has been reported in various clinical conditions, such as hemochromatosis, thalassemia major, and myelodysplastic syndromes. Therefore, iron chelation therapy represents a pivotal therapy for these patients during their lifetime. The aim of the present study was to assess the iron chelating properties of α-lipoic acid (ALA) and how such an effect impacts on iron overload mediated toxicity. Human mesenchymal stem cells (HS-5) and animals (zebrafish, n = 10 for each group) were treated for 24 h with ferric ammonium citrate (FAC, 120 µg/mL) in the presence or absence of ALA (20 µg/mL). Oxidative stress was evaluated by reduced glutathione content, reactive oxygen species formation, mitochondrial dysfunction, and gene expression of heme oxygenase-1b and mitochondrial superoxide dismutase; organ injury, iron accumulation, and autophagy were measured by microscopical, cytofluorimetric analyses, and inductively coupled plasma‒optical mission Spectrometer (ICP-OES). Our results showed that FAC results in a significant increase of tissue iron accumulation, oxidative stress, and autophagy and such detrimental effects were reversed by ALA treatment. In conclusion, ALA possesses excellent iron chelating properties that may be exploited in a clinical setting for organ preservation, as well as exhibiting a good safety profile and low cost for the national health system.

Relationships and distinctions in iron-regulatory networks responding to interrelated signals

Blood ◽  
2003 ◽  
Vol 101 (9) ◽  
pp. 3690-3698 ◽  
Author(s):  
Martina Muckenthaler ◽  
Alexandra Richter ◽  
Niki Gunkel ◽  
Dieter Riedel ◽  
Maria Polycarpou-Schwarz ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Line ◽  
Iron Metabolism ◽  
Target Genes ◽  
Regulatory Protein ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Hfe Gene ◽  
Response Patterns ◽  
Altered Expression

Specialized cDNA-based microarrays (IronChips) were developed to investigate complex physiological gene-regulatory patterns in iron metabolism. Approximately 115 human cDNAs were strategically selected to represent genes involved either in iron metabolism or in interlinked pathways (eg, oxidative stress, nitric oxide [NO] metabolism, or copper metabolism), and were immobilized on glass slides. HeLa cells were treated with iron donors or iron chelators, or were subjected to oxidative stress (H2O2) or NO (sodium nitroprusside). In addition, we generated a stable transgenic HeLa cell line expressing the HFE gene under an inducible promoter. Gene-response patterns were recorded for all of these interrelated experimental stimuli, and analyzed for common and distinct responses that define signal-specific regulatory patterns. The resulting regulatory patterns reveal and define degrees of relationship between distinct signals. Remarkably, the gene responses elicited by the altered expression of the hemochromatosis protein HFE and by pharmacological iron chelation exhibit the highest degree of relatedness, both for iron-regulatory protein (IRP) and non-IRP target genes. This finding suggests that HFE expression directly affects the intracellular chelatable iron pool in the transgenic cell line. Furthermore, cells treated with the iron donors hemin or ferric ammonium citrate display response patterns that permit the identification of the iron-loaded state in both cases, and the discrimination between the sources of iron loading. These findings also demonstrate the broad utility of gene-expression profiling with the IronChip to study iron metabolism and related human diseases.

scholarly journals Eculizumab in the treatment of complement system disorders including paroxysmal nocturnal hemoglobinuria

2020 ◽  
Vol 19 (2) ◽  
pp. 193-199
Author(s):  
B. A. Bakirov ◽  
D. A. Kudlay ◽  
V. N. Pavlov
Keyword(s):  
Complement System ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Clinical Symptoms ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
New Drugs ◽  
Main Function ◽  
Hematopoietic Stem ◽  
Blood Disorder ◽  
The Complement System

The main function of the complement system is to provide humoral defence against foreign pathogens. It contributes to immune response and is a crucial component of innate immunity that provides immediate non-specific immune defence. Inherited or acquired deficiencies of the complement system associated with excessive activation or other impairments of complement activity have varied clinical manifestations. Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired clonal blood disorder that clinically manifests with anemia, thrombosis, chest and abdominal pain, chronic kidney disease and bone marrow failure. The complement-mediated hemolysis due to the lack of membrane-bound complement-regulatory proteins CD55 and CD59 is a central underlying mechanism of the disease and mortality associated with PNH. The severity of clinical symptoms determines the type of treatment which may include allogeneic hematopoietic stem cell transplantation and pathogenetic treatment through the inhibition of the complement system. Eculizumab, a humanized monoclonal anti-C5 antibody, has become the first complement inhibitor to show effectiveness in treating any of complement-mediated hemolytic anemias and now serves as a standard of treatment for patients with PNH. Brisk development of biotechnological methods for the production of new drugs in Russia has enabled the initiation of drug discovery efforts and the creation of the world's first biosimilar of Eculizumab.

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