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Gene Expression and Function of the Cellular Receptor for u-PA (u-PAR)
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Vincent Ellis, Michael Ploug, Torben Plesner, Keld Danø
Cell surface associated u-PAR is absent from peripheral blood cells in the hematological condition, paroxysmal nocturnal hemoglobinuria (PNH),84 an acquired clonal stem cell disorder resulting in defective and deficient hematopoiesis.89 The somatic mutation responsible for the PNH phenotype is thought to cause a defect in the post-translational processing of proteins destined to become GPI-anchored,89 and consequently other GPI-anchored proteins are also absent from peripheral blood cells. Despite this biosynthetic defect the proteins are apparently still synthesized and an active, i.e., u-PA binding, soluble truncated form of u-PAR has been detected in the plasma of these patients but not in normal individuals.90 The clinical manifestations of PNH are diverse, but affected individuals have a high incidence of recurrent venous thrombosis, with thromboembolic complications being the major cause of death. It has been speculated that lack of leukocyte u-PAR may be causally related to these thrombotic events.84 The notion that u-PAR-mediated plasminogen activation is involved in the fibrinolytic process and the maintenance of hemostasis is given a foundation by the observations that leukocyte accumulation in thrombi in vivo is an active process mediated by P-selectin on activated platelets91 and that neutrophils in whole-blood clots in vitro accumulate fibrin degradation products.92
Hemolytic Anemia Associated with Red Cell Membrane Defects
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Most PNH patients develop thrombocytopenia or granulocytopenia during the course of their disease. PNH may progress to aplastic anemia, often a fatal complication. Three to five percent of patients with PNH develop acute leukemia. Leukemic cells derive from the PNH clone.
Miscellaneous Forms of Acquired Red Cell Aplasia and Erythropoietic Failure in Childhood
Published in Stephen A. Feig, Melvin H. Freedman, Clinical Disorders and Experimental Models of Erythropoietic Failure, 2019
Melvin H. Freedman, Stephen A. Feig
Paroxysmal nocturnal hemoglobinuria (PNH) is a relatively uncommon disorder that is most frequently diagnosed in adults between the second and fourth decades, but about 10% of cases occur in patients younger than 21 years of age.108 PNH is an acquired, clonal disease affecting the hematopoietic stem cell, resulting in defective and deficient hematopoiesis involving all three myeloid lineages. The hallmark of PNH is an increased sensitivity of red cells to the hemolytic action of complement that may lead to intermittent episodes of hemoglobinuria. The biochemical defects that have been implicated in producing the clinical manifestations of PNH were summarized by Ware et al.109 Several proteins are missing from the membrane of the abnormal blood cells in PNH: molecules that regulate complement activation (CD55, CD59, and C8-binding protein); immunologic molecules (Fey III receptor, lympho-cyte-function antigen 3, and CD14); and enzymes (red cell acetylcholinesterase, leukocyte alkaline phosphatase, and lymphocyte 5-ectonucleotidase). Apparently, PNH cells cannot synthesize the common chemical “anchor” that fixes each of these proteins to the cell membrane and, hence, appears to be the central biochemical defect in this disorder.109
Evaluating ravulizumab for the treatment of children and adolescents with paroxysmal nocturnal hemoglobinuria
Published in Expert Review of Hematology, 2022
Justin J. Yoo, Satheesh Chonat
Paroxysmal nocturnal hemoglobinuria is a complex clonal hemolytic disease that can vary in severity from mild hemolytic anemia to bone marrow failure. The management of PNH includes supportive care with blood products and anticoagulation, while bone marrow transplantation is the only curative option. The discovery that uncontrolled complement pathway activation plays a crucial role in the pathogenesis of PNH, and the development of eculizumab with remarkable efficacy and acceptable safety profile changed the face of the management of PNH. Till recently, the standard of care for symptomatic PNH is eculizumab. However, with the advent of ravulizumab, which demonstrated non-inferiority to eculizumab in multiple clinical trials [25,28,29], it is now increasingly considered the treatment of choice in adults with PNH. Currently, ravulizumab is the only FDA-approved drug for the treatment of PNH in children and adolescents [39]. This is strongly recommended for those patients with PNH experiencing intravascular hemolytic anemia, chronic fatigue, pain, dyspnea with or without thrombosis.
Cutting edge approaches to detecting brain mosaicism associated with common focal epilepsies: implications for diagnosis and potential therapies
Published in Expert Review of Neurotherapeutics, 2021
Zimeng Ye, Mark F. Bennett, Melanie Bahlo, Ingrid E. Scheffer, Samuel F. Berkovic, Piero Perucca, Michael S. Hildebrand
Genetic analysis of the paired PNH- and blood-derived DNA samples failed to detect any variants in known familial or sporadic PNH genes but did reveal a mosaic MEN1 duplication (c.1546dupC) variant predicted to lead to frameshift (p.R615PfsX15) in 16.7% of sequenced reads in PNH DNA. The presence of this variant in PNH DNA, and its absence from blood, was confirmed independently by Sanger sequencing. This variant had been reported at high frequency as a germline heterozygous change in patients with multiple endocrine neoplasia type 1 (MEN1) syndrome with in vitro functional studies confirming that it impairs nuclear localization [62]. Germline mutations in MEN1 are well known to cause MEN1 syndrome and double-hit mutations (a constitutional germline mutation with a second somatic mutation) in MEN1 can cause MEN1 syndrome-related tumors such as ependymoma, lipoma, and parathyroid tumor [63,64]. However, this gene is not related to PNH. It is possible that constitutional mutation or double-hit mutations in MEN1 can cause MEN1 syndrome, while mosaicism may lead to other phenotypes (e.g. PNH) through mechanisms like cellular interference between cell populations with and without mutations, already established for some X-linked disorders [65–67].
Safety of current treatments for paroxysmal nocturnal hemoglobinuria
Published in Expert Opinion on Drug Safety, 2021
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, progressive, and life-threatening hematopoietic stem cell disorder whose clinical manifestations include intravascular hemolysis, thrombosis, and bone marrow failure [1]. The disease arises as a consequence of a somatic mutation in the phosphatidylinositol glycan class A (PIG-A) gene that prevents synthesis of N-acetyl-D-glucosamine phosphatidylinositol, an essential component of glycosylphosphatidylinositol anchor protein (GPI-AP) [2]. Deficiency of GPI-anchored complement-inhibitor proteins, especially CD55 (decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis), causes chronic intravascular hemolysis, a hallmark clinical manifestation of PNH that is mediated by the alternative pathway of complement (APC). The APC cascade can be divided into amplification of the C3 and C5 convertases and the cytolytic membrane attack complex (MAC). CD55 regulates the formation and stability of the C3 and C5 convertases, and CD59 blocks the formation of the MAC [3]. Chronic hemolysis leads to release of free hemoglobin, which causes nitric oxide depletion, reactive oxygen species increases, endothelial dysfunction, and platelet and monocyte activation [4,5]. Consequently, PNH is typically characterized by thrombosis and organ damage, as well as severe hemolytic anemia, and symptoms include hemoglobinuria, severe fatigue, abdominal pain, dysphagia, erectile dysfunction, renal dysfunction, and pulmonary hypertension [6,7]. Despite best supportive care, PNH is associated with high morbidity and mortality [6,8–10].