Eculizumab
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| CD55 | This gene encodes a protein involved in the regulation of the complement cascade.
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| CD59 | This protein is a potent inhibitor of the complement membrane attack complex, whereby it binds complement C8 and/or C9 during the assembly of this complex, thereby inhibiting the incorporation of multiple copies of C9 into the complex, which is necessary
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| PIG-A | This gene encodes a protein required for synthesis of N-acetylglucosaminyl phosphatidylinositol (GlcNAc-PI), the first intermediate in the biosynthetic pathway of GPI anchor.
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| GPI | Defects in the GPI anchors synthesis occur in the rare diseases paroxysmal nocturnal hemoglobinuria (PNH) and hyperphosphatasia with mental retardation syndrome (HPMR). In PNH a clonal defect in blood stem cells in the gene PIGA, that is required for GPI
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| PNH | Paroxysmal nocturnal hemoglobinuria (PNH), is an acquired clonal disorder caused by a somatic mutation of the PIG-A gene in hematopoetic stem cells.
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| Somatic Mutations | Alterations in DNA that occur after conception. Somatic mutations can occur in any of the cells of the body except the germ cells (sperm and egg) and therefore are not passed on to children. These alterations can (but do not always) cause cancer or other
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| Hemolysis | Hemolysis (or haemolysis)—from the Greek αἷμα (aima, haema, hemo-) meaning "blood" and λύσις (lusis, lysis, -lysis) meaning a "loosing", "setting free" or "releasing"[1]—is the rupturing of erythrocytes (red blood cells) and the release of their contents
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| CD55 | Decay accelerating factor is a 70 kDa membrane protein that regulates the complement system on the cell surface. It prevents the assembly of the C3bBb complex (the C3-convertase of the alternative pathway) or accelerates the disassembly of preformed conve
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| MAC | The membrane attack complex (MAC) is typically formed on the surface of pathogenic bacterial cells as a result of the activation of the host's alternative pathway and the classical pathway of the complement system, and it is one of the effector proteins o
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| LDH | LDH is often used as a marker of tissue breakdown as LDH is abundant in red blood cells and can function as a marker for hemolysis. A blood sample that has been handled incorrectly can show false-positively high levels of LDH due to erythrocyte damage.
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| Flow Cytometry | is a laser-based, biophysical technology employed in cell counting, cell sorting, biomarker detection and protein engineering, by suspending cells in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multipara
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| Thrombosis | Thrombosis (Greek: θρόμβωσις) is the formation of a blood clot (thrombus; Greek: θρόμβος) inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel is injured, the body uses platelets (thrombocytes) and fibri
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| Stem Cell | Stem cells are biological cells found in all multicellular organisms, that can divide (through mitosis) and differentiate into diverse specialized cell types and can self-renew to produce more stem cells.
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| FLAER | a multiparameter fluorescent aerolysin (FLAER)-based flow assay using CD45, CD33, and CD14 that accurately identified PNH monocyte and neutrophil clones in PNH, AA, and MDS.
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| complement system | helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system[1] that is not adaptable and does not change over the course of an individual's life
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| complement pathway | In all three pathways, C3-convertase cleaves and activates component C3, creating C3a and C3b, and causing a cascade of further cleavage and activation events. C3b binds to the surface of pathogens, leading to greater internalization by phagocytic cells b
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| Eculizumab | is a humanized monoclonal antibody that is a first-in-class terminal complement inhibitor Eculizumab inhibits the cleavage of C5 to C5a (a potent anaphylatoxin with prothrombotic and proinflammatory properties) and C5b by the C5 convertase, which prevents
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| Eculizumab C5 blockade MOA | Eculizumab specifically binds to the terminal Complement component 5, or C5, which acts at a late stage in the complement cascade.
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| 51% | In Brodsky there was a 51% reduction in transfusions (PNH)
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| aHUS Renal More than 50% of patients progress to end-stage renal disease | Elevated creatinine
Proteinuria
Edema
malignant hypertension
Decreased estimated glomerular filtration rate (eGFR)
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| aHUS CNS 48% of patients experience neurological symptoms | Confusion
Stroke
Encephalopathy
Seizure
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| aHUS Cardiovascular 43% of patients experience cardiovascular symptoms | Myocardial infarction
Hypertension
Diffuse vasculopathy,
Peripheral gangrene
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| aHUS Gastrointestinal Up to 30% of patients experience | diarrhea
Colitis
Nausea/Vomiting
Pancreatitis
Abdominal pain
Gastroenteritis
Liver necrosis
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| aHUS Blood | Thrombocytopenia
Decreased haptoglobin
Elevated lactate dehydrogenase (LDH)
Decreased hemoglobin
Schistocytes
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| aHUS Pulmonary | Dyspnea
Pulmonary hemorrhage
Pulmonary edema
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| Mechanism of Disease (MOD) for aHUS | atypical hemolytic uremic syndrome (aHUS) is a chronic, genetic disease of systemic, complement-mediated thrombotic microangiopathy (TMA) with catastrophic consequences
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| Common coexisting diseases and conditions aHUS Overlap | Malignant hypertension (30%)
TMA with history of transplant* (23%)
TMA associated with pregnancy (21%)
Glomerulopathy (17%)
Systemic disease
Scleroderma
Systemic lupus erythematosus (SLE)
3 (6%)
Malignancy‡ 1 (2%)
TOTAL 47 (100%)
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