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PNH Paroxysmal Nocturnal Hemoglobinuria

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https://www.readbyqxmd.com/read/27913482/update-on-the-diagnosis-and-management-of-paroxysmal-nocturnal-hemoglobinuria
#1
Charles J Parker
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...
December 2, 2016: Hematology—the Education Program of the American Society of Hematology
https://www.readbyqxmd.com/read/27903532/acquired-somatic-mutations-in-pnh-reveal-long-term-maintenance-of-adaptive-nk-cells-independent-from-hspc
#2
Marcus A F Corat, Heinrich Schlums, Chuanfeng Wu, Jakob Theorell, Diego A Espinoza, Stephanie E Sellers, Danielle M Townsley, Neal S Young, Yenan T Bryceson, Cynthia E Dunbar, Thomas Winkler
Natural killer (NK) cells have long been considered short-lived effectors of innate immunity. However, recent animal models and human studies suggest that subsets of NK cells have adaptive features. We investigate clonal relationships of various NK cell subsets, including the adaptive population, by taking advantage of naturally occurring X-linked somatic PIGA mutations in hematopoietic stem and progenitor cells (HSPC) from patients with paroxysmal nocturnal hemoglobinuria (PNH). The affected HSPCs and their progeny lack expression of glycosylphosphatidylinositol (GPI) anchors on their cell surfaces, allowing quantification of PIGA-mutant (GPI-negative) HSPC-derived peripheral blood cell populations...
November 30, 2016: Blood
https://www.readbyqxmd.com/read/27837250/development-of-a-disease-specific-quality-of-life-questionnaire-for-patients-with-aplastic-anemia-and-or-paroxysmal-nocturnal-hemoglobinuria-qlq-aa-pnh-report-on-phases-i-and-ii
#3
Martha Groth, Susanne Singer, Cathrin Niedeggen, Andrea Petermann-Meyer, Alexander Röth, Hubert Schrezenmeier, Britta Höchsmann, Tim H Brümmendorf, Jens Panse
Acquired aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) are interrelated ultra-rare diseases. Quality of life (QoL) evaluation tools used in studies for AA and PNH are unspecific and designed for cancer patients (e.g., the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, EORTC QLQ-C30). Given the complexity of AA and PNH, variation in symptoms and treatments, younger age of many patients, and the fact that AA and PNH are not classified as malignant diseases, it is likely that cancer-specific questionnaires are inappropriate...
November 11, 2016: Annals of Hematology
https://www.readbyqxmd.com/read/27812245/paroxysmal-nocturnal-hemoglobinuria-from-bench-to-bed
#4
REVIEW
Amrallah A Mohammed, Hani El-Tanni, Tariq Al-Malki Atiah, Arwa Al-Malki Atiah, Marwan Al-Malki Atiah, Ayman A Rasmy
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia with highly variable clinical symptoms making the diagnosis and prediction of its outcome difficult. It is caused by the expansion of a hematopoietic progenitor cell that has acquired a mutation in the X-linked phosphatidylinositol glycan class A (PIGA) gene that results in deficiency of the glycosylphosphatidylinositol anchor structure responsible for fixing a wide spectrum of proteins particularly CD55 and CD59. The clinical features of this disease arise as a result of complement-mediated hemolysis in unprotected red cells, leukocytes, and platelets as well as the release of free hemoglobin...
December 2016: Indian Journal of Hematology & Blood Transfusion
https://www.readbyqxmd.com/read/27780113/the-dysfunction-of-platelets-in-paroxysmal-nocturnal-hemoglobinuria
#5
Rong Fu, Yinping Meng, Yihao Wang, Hui Liu, Yi Liu, Lijuan Li, Shaoxue Ding, Guojin Wang, Jia Song, Zonghong Shao
INTRODUCTION: Thrombosis is a dangerous complication of paroxysmal nocturnal hemoglobinuria (PNH) and has a high mortality rate. However, the mechanism underlying the development of thrombosis in PNH remains unclear. To explore this, platelet function and serum complement activity were investigated in 14 patients with classical PNH, 11 with PNH aplastic anemia (AA) and 30 healthy controls. MATERIAL AND METHODS: Serum concentrations of the terminal complement complex (sC5b-9) were determined by enzyme-linked immunofluorescence assay (ELISA), and the levels of C5b-9, CD61 and CD62p on platelet membranes were determined by flow cytometry...
July 22, 2016: Thrombosis Research
https://www.readbyqxmd.com/read/27775713/small-molecule-factor-d-inhibitors-targeting-the-alternative-complement-pathway
#6
Jürgen Maibaum, Sha-Mei Liao, Anna Vulpetti, Nils Ostermann, Stefan Randl, Simon Rüdisser, Edwige Lorthiois, Paul Erbel, Bernd Kinzel, Fabrice A Kolb, Samuel Barbieri, Julia Wagner, Corinne Durand, Kamal Fettis, Solene Dussauge, Nicola Hughes, Omar Delgado, Ulrich Hommel, Ty Gould, Aengus Mac Sweeney, Bernd Gerhartz, Frederic Cumin, Stefanie Flohr, Anna Schubart, Bruce Jaffee, Richard Harrison, Antonio Maria Risitano, Jörg Eder, Karen Anderson
Complement is a key component of the innate immune system, recognizing pathogens and promoting their elimination. Complement component 3 (C3) is the central component of the system. Activation of C3 can be initiated by three distinct routes-the classical, the lectin and the alternative pathways-with the alternative pathway also acting as an amplification loop for the other two pathways. The protease factor D (FD) is essential for this amplification process, which, when dysregulated, predisposes individuals to diverse disorders including age-related macular degeneration and paroxysmal nocturnal hemoglobinuria (PNH)...
October 24, 2016: Nature Chemical Biology
https://www.readbyqxmd.com/read/27766064/characteristics-of-taiwanese-patients-of-pnh-in-the-international-pnh-registry
#7
Wen-Chien Chou, Wei-Han Huang, Ming-Chung Wang, Chao-Sung Chang, Shih-Peng Yeh, Tzeon-Jye Chiou, Yeu-Chin Chen, Tseng-Hsi Lin, Ming-Ching Shen
BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and acquired hematopoietic stem cell disease, with florid clinical presentations. Although this disease has been characterized in the western countries, its clinical and laboratory features in Taiwan have not yet been reported. RESULTS: As a part of an international prospective, non-interventional, observational registration trial of PNH, we have analyzed 63 patients recruited between 2009 and 2015 in Taiwan, with comparison to the 3857 patients in the rest of the world (ROW)...
2016: Thrombosis Journal
https://www.readbyqxmd.com/read/27757214/positive-impact-of-eculizumab-therapy-on-surgery-for-budd-chiari-syndrome-in-a-patient-with-paroxysmal-nocturnal-hemoglobinuria-and-a-long-term-history-of-thrombosis
#8
Silvia De-la-Iglesia, Hugo Luzardo, Angelina Lemes, Melissa Torres, Maria Teresa Gómez-Casares, Naylen Cruz, Teresa Molero
Paroxysmal nocturnal hemoglobinuria (PNH) is associated with severe end-organ damage and a high risk of thrombosis. Budd-Chiari syndrome, which develops after thrombotic occlusion of major hepatic blood vessels, is relatively common in PNH and has been associated with increased mortality. We report the case of a 46-year-old male with PNH who presented with Budd-Chiari syndrome associated with portal cavernoma, portal hypertension and hypersplenism. In September 2010, the patient suffered gastrointestinal bleeding, hematuria, and elevated plasma lactate dehydrogenase; he started eculizumab therapy with a good response...
September 28, 2016: Hematology Reports
https://www.readbyqxmd.com/read/27743175/evaluation-of-efficacy-of-alemtuzumab-in-5-patients-with-aplastic-anemia-and-or-myelodysplastic-neoplasm
#9
Wolfgang Füreder, Sabine Cerny-Reiterer, Wolfgang R Sperr, Leonhard Müllauer, Eva Jäger, Ilse Schwarzinger, Klaus Geissler, Peter Valent
Patients with aplastic anemia or hypoplastic myelodysplastic syndrome (MDS) may respond to immunosuppressive therapy, including the anti-CD52 antibody alemtuzumab. We analyzed treatment responses to alemtuzumab in 5 patients with MDS or aplastic anemia (AA) evolving to MDS. Two patients with hypoplastic MDS (hMDS) showed a partial response (PR) to alemtuzumab. In both responding patients, a concomitant paroxysmal nocturnal hemoglobinuria (PNH) clone was detected before therapy. One responder relapsed after 15 months and underwent successful allogeneic stem cell transplantation...
October 14, 2016: Wiener Klinische Wochenschrift
https://www.readbyqxmd.com/read/27725586/pathogenesis-of-paroxysmal-nocturnal-hemoglobinuria
#10
Yoshiko Murakami
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired GPI deficiency caused by somatic mutation of the PIGA gene in one or several hematopoietic stem cells. Recently, PNH caused by somatic mutation of one allele of the PIGT gene in combination with a germline mutation of the other allele was reported, showing that PIGA is not the only gene responsible for PNH, though other causes are rare. These mutant cells become GPI deficient, expand clonally and differentiate into all of the hematopoietic lineages. When GPI deficient erythrocytes increase in proportion, massive hemolysis occurs due to activated complement attack during infection...
2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
https://www.readbyqxmd.com/read/27644115/extravascular-hemolysis-and-complement-consumption-in-paroxysmal-nocturnal-hemoglobinuria-patients-undergoing-eculizumab-treatment
#11
Marta Subías Hidalgo, Hector Martin Merinero, Alicia López, Jaouad Anter, Sheila Pinto García, Fernando Ataúlfo Gonzalez-Fernández, Rafael Forés, Margarita Lopez-Trascasa, Ana Villegas, Emilio Ojeda, Santiago Rodríguez de Córdoba
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by complement-mediated intravascular hemolysis that is effectively treated with eculizumab. However, treatment responses are reported heterogeneous with some patients presenting residual hemolysis and requiring RBC transfusions. Recent reports have shown that both extravascular hemolysis and incomplete C5 blockade can explain these suboptimal hematological responses. Here we have tested our eculizumab-treated PNH patients (n=12) for signs of hemolysis and assessed complement biomarkers...
September 13, 2016: Immunobiology
https://www.readbyqxmd.com/read/27598771/pasylated-coversin-a-c5-specific-complement-inhibitor-with-extended-pharmacokinetics-shows-enhanced-anti-hemolytic-activity-in-vitro
#12
Nadine Kuhn, Christoph Q Schmidt, Martin Schlapschy, Arne Skerra
The Ornithodoros moubata Complement Inhibitor (OmCI) binds complement component 5 (C5) with high affinity and, thus, selectively prevents proteolytic activation of the terminal lytic complement pathway. A recombinant version of OmCI (also known as Coversin and rEV576) has proven efficacious in several animal models of complement-mediated diseases and successfully completed a phase Ia clinical trial. Coversin is a small 17 kDa lipocalin protein which has a very short plasma half-life if not bound to C5; therefore, the drug requires frequent dosing...
October 19, 2016: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/27598686/diagnostic-screening-of-paroxysmal-nocturnal-hemoglobinuria-prospective-multicentric-evaluation-of-the-current-medical-indications
#13
Marta Morado, Alex Freire Sandes, Enrique Colado, Dolores Subirá, Paloma Isusi, María Soledad Noya, María Belén Vidriales, Amparo Sempere, José Ángel Díaz, Alfredo Minguela, Beatriz Álvarez, Cristina Serrano, Teresa Caballero, Mercedes Rey, Ana Pérez Corral, María Cristina Fernández Jiménez, Elena Magro, Angelina Lemes, Celina Benavente, Helena Bañas, Juana Merino, Celine Castejon, Olivier Gutierrez, Pilar Rabasa, Matheus Vescosi Gonçalves, Martin Perez-Andres, Alberto Orfao
BACKGROUND: Although consensus guidelines have been proposed in 2010 for the diagnostic screening of paroxysmal nocturnal hemoglobinuria (PNH) by flow cytometry (FCM), so far no study has investigated the efficiency of such medical indications in multicentric vs. reference laboratory settings. METHODS: Here we evaluate the efficiency of consensus medical indications for PNH testing in 3,938 peripheral blood samples submitted to FCM testing in 24 laboratories in Spain and one reference center in Brazil...
September 6, 2016: Cytometry. Part B, Clinical Cytometry
https://www.readbyqxmd.com/read/27570707/pesg-pnh-diagnosis-follow-up-and-treatment-guidelines
#14
REVIEW
Fahri Sahin, Olga Meltem Akay, Mesut Ayer, Mehmet Sinan Dal, Sehmus Ertop, Osman Ilhan, Volkan Karakus, Mehmet Ali Ozcan, Vildan Ozkocaman, Hayri Ozsan, Ozan Salim, Mahmut Tobu, Anil Tombak, Tulin Firatli Tuglular, Mehmet Yilmaz, Ali Unal, Mustafa Nuri Yenerel, Guray Saydam
PNH Education and Study Group (PESG) have been established in December 2013 as a non-profit, independent, medical organization www.pesg.org. Paroxysmal Nocturnal Hemoglobinuria (PNH) is a multi-systemic disease that should be treated with a multidisciplinary approach. Patients may apply to the clinics other than the hematology due to variability and diversity of clinical findings which lower the rate of diagnosis due to low awareness about PNH. PNH might be overlooked and diagnosis might be delayed. Regarding these, PESG was established with the collaboration of Immunology, Cardiology, Thorax Diseases (Pulmonology), Neurology, Gastroenterology, General Surgery and Urology specialists in addition to hematologists dealing with PNH...
2016: American Journal of Blood Research
https://www.readbyqxmd.com/read/27536121/eculizumab-in-the-management-of-paroxysmal-nocturnal-hemoglobinuria-patient-selection-and-special-considerations
#15
REVIEW
Fatimah Al-Ani, Ian Chin-Yee, Alejandro Lazo-Langner
Paroxysmal nocturnal hemoglobinuria (PNH) is a nonmalignant clonal disorder resulting from somatic mutation in the PIG-A gene leading to a deficiency of the membrane-anchoring molecule glycosylphosphatidylinositol. The lack of expression of two glycosylphosphatidylinositol-anchored proteins involved in the regulation of the complement system renders PNH erythrocytes susceptible to complement-mediated lysis. Clinical manifestations include thromboembolic disease, chronic kidney injury, pulmonary hypertension, smooth muscle dysfunction, and chronic hemolysis...
2016: Therapeutics and Clinical Risk Management
https://www.readbyqxmd.com/read/27509843/stratification-of-responders-towards-eculizumab-using-a-structural-epitope-mapping-strategy
#16
Anna-Luisa Volk, Francis Jingxin Hu, Magnus M Berglund, Erik Nordling, Patrik Strömberg, Mathias Uhlen, Johan Rockberg
The complement component 5 (C5)-binding antibody eculizumab is used to treat patients with paroxysmal nocturnal hemoglobinuria (PNH) and atypical haemolytic uremic syndrome (aHUS). As recently reported there is a need for a precise classification of eculizumab responsive patients to allow for a safe and cost-effective treatment. To allow for such stratification, knowledge of the precise binding site of the drug on its target is crucial. Using a structural epitope mapping strategy based on bacterial surface display, flow cytometric sorting and validation via haemolytic activity testing, we identified six residues essential for binding of eculizumab to C5...
2016: Scientific Reports
https://www.readbyqxmd.com/read/27465155/generation-of-induced-pluripotent-stem-cells-as-a-potential-source-of-hematopoietic-stem-cells-for-transplant-in-pnh-patients
#17
Tanapol Phondeechareon, Methichit Wattanapanitch, Yaowalak U-Pratya, Chanapa Damkham, Nuttha Klincumhom, Chanchao Lorthongpanich, Pakpoom Kheolamai, Chuti Laowtammathron, Surapol Issaragrisil
Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by lack of CD55 and CD59 on blood cell membrane leading to increased sensitivity of blood cells to complement. Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for PNH, however, lack of HLA-matched donors and post-transplant complications are major concerns. Induced pluripotent stem cells (iPSCs) derived from patients are an attractive source for generating autologous HSCs to avoid adverse effects resulting from allogeneic HSCT...
October 2016: Annals of Hematology
https://www.readbyqxmd.com/read/27464489/interim-analysis-of-post-marketing-surveillance-of-eculizumab-for-paroxysmal-nocturnal-hemoglobinuria-in-japan
#18
Haruhiko Ninomiya, Naoshi Obara, Shigeru Chiba, Kensuke Usuki, Kaichi Nishiwaki, Itaru Matsumura, Tsutomu Shichishima, Shinichiro Okamoto, Jun-Ichi Nishimura, Kazuma Ohyashiki, Shinji Nakao, Kiyoshi Ando, Yoshinobu Kanda, Tatsuya Kawaguchi, Hideki Nakakuma, Daisuke Harada, Hirozumi Akiyama, Taroh Kinoshita, Keiya Ozawa, Mitsuhiro Omine, Yuzuru Kanakura
Data characterizing the safety and effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) are limited. We describe the safety and effectiveness of eculizumab in PNH patients enrolled in a post-marketing surveillance study. Types and frequencies of observed adverse events were similar to those reported in previous clinical trials and no meningococcal infection was reported. Effectiveness outcomes included the reduction of intravascular hemolysis, the change in hemoglobin (Hb) level, the withdrawal of transfusion and corticosteroids, the change of renal function, and overall survival...
July 27, 2016: International Journal of Hematology
https://www.readbyqxmd.com/read/27400971/paroxysmal-nocturnal-hemoglobinuria-the-future-of-complement-based-therapies
#19
Antonio Risitano
Since its introduction in the clinic, the first complement inhibitor eculizumab has changed the paradigm of PNH treatment. However, a ten-year experience has also taught us that there are same pitfalls which represent a challenge to improve the current anti-complement treatment. The most obvious unmet clinical need remain residual anemia, because one third of patients remains transfusion-dependent, and an additional third still lives with moderate anemia. It has been demonstrated that uncontrolled activation of early steps of the complement plays a major role in this reduced clinical benefit, making C3-mediated extravascular hemolysis the next challenge of PNH treatment...
July 11, 2016: Current Drug Targets
https://www.readbyqxmd.com/read/27371974/modeling-complement-driven-diseases-in-transgenic-mice-values-and-limitations
#20
REVIEW
Yoshiyasu Ueda, Damodar Gullipalli, Wen-Chao Song
Remarkable advances have been made over past decades in understanding the pathogenesis of complement-mediated diseases. This has led to development of new therapies for, and in some cases re-classification of, complement-driven diseases. This success is due to not only insight from human patients but also studies using transgenic animal models. Animal models that mimic human diseases are useful tools to understand the mechanism of disease and develop new therapies but there are also limitations due to species differences in their complement systems...
October 2016: Immunobiology
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