Read by QxMD icon Read

PNH Paroxysmal Nocturnal Hemoglobinuria

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
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
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
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...
September 26, 2016: Bioconjugate Chemistry
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
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 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
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
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
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
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
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
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
Antonio M Risitano, Serena Marotta
The introduction in the clinic of anti-complement agents represented a major achievement which gave to physicians a novel etiologic treatment for different human diseases. Indeed, the first anti-complement agent eculizumab has changed the treatment paradigm of paroxysmal nocturnal hemoglobinuria (PNH), dramatically impacting its severe clinical course. In addition, eculizumab is the first agent approved for atypical Hemolytic Uremic Syndrome (aHUS), a life-threatening inherited thrombotic microangiopathy. Nevertheless, such remarkable milestone in medicine has brought to the fore additional challenges for the scientific community...
June 2016: Seminars in Immunology
Yarden S Fraiman, Nathan Cuka, Denise Batista, Milena Vuica-Ross, Alison R Moliterno
Paroxysmal nocturnal hemoglobinuria (PNH), a disease characterized by intravascular hemolysis, thrombosis, and bone marrow failure, is associated with mutations in the PIG-A gene, resulting in a deficiency of glycosylphosphatidylinositol-anchored proteins. Many hypotheses have been posed as to whether PNH and PIG-A mutations result in an intrinsic survival benefit of CD55(-)/CD59(-) cells or an extrinsic permissive environment that allows for their clonal expansion within the bone marrow compartment. Recent data have identified the concurrence of PIG-A mutations with additional genetic mutations associated with myeloproliferative disorders, suggesting that some presentations of PNH are the result of a stepwise progression of genetic mutations similar to other myelodysplastic or myeloproliferative syndromes...
2016: Journal of Blood Medicine
Iuri Marinov, Andrea J Illingworth, Miroslav Benko, D Robert Sutherland
BACKGROUND: CD157 has been recently reported as a useful glycosylphosphatidylinositol (GPI)-linked marker for the detection of paroxysmal nocturnal hemoglobinuria (PNH) clones in patients with suspected paroxysmal nocturnal hemoglobinuria by flow cytometry as it targets both neutrophils and monocytes. The aim of this study is to test the feasibility of a non-fluorescent aerolysin (FLAER) approach and propose an alternative for laboratories, where FLAER is not available. METHODS: We validated a non-FLAER-based single-tube, 6-color assay targeting the GPI-linked structures CD157, CD24, and CD14...
June 13, 2016: Cytometry. Part B, Clinical Cytometry
Ken Ishiyama
Acquired aplastic anemia (AA) is a hematopoietic dyscrasia characterized by pancytopenia and bone marrow hypoplasia. AA is considered to be caused mainly by T-cell attacks on hematopoietic stem cells, as assumption based on good responses to T-cell specific immunosuppressive therapy (IST). Several markers, such as HLA-DRB1(*)1501 and an increase in the percentage of paroxysmal nocturnal hemoglobinuria (PNH) phenotype cells, have been shown to represent the immune pathophysiology of AA. However, little is known about the pathogenesis of AA...
May 2016: [Rinshō Ketsueki] the Japanese Journal of Clinical Hematology
Rong Fu, Shao-Xue Ding, Y I Liu, Li-Juan Li, Hui Liu, Hong-Lei Wang, Tian Zhang, Zong-Hong Shao
Paroxysmal nocturnal hemoglobinuria/aplastic anemia (PNH/AA) syndrome presents a markedly increased population of cells deficient in glycophosphatidylinositol (GPI(-) cells) and signs of bone marrow failure, which requires treatment with hematopoiesis-stimulating factors, such as granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF). However, little is known about the effects of these stimulating factors on GPI(-) cells. In order to explore the effects of stimulating factors in PNH/AA, G-CSF receptor (CD114) and SCF receptor (CD117) expression levels on GPI(+) and GPI(-) hematopoietic stem cells (HSCs) were measured by flow cytometry (FCM)...
May 2016: Experimental and Therapeutic Medicine
John Chapin, Hunter S Terry, Dorothy Kleinert, Jeffrey Laurence
OBJECTIVE: The objective of this study was to describe complement activation in hemostatic and pathologic states of coagulation and in the acquired and congenital hemolytic anemias. METHODS AND RESULTS: We review published and emerging data on the involvement of the classic, alternative and lectin-based complement pathways in coagulation and the hemolytic anemias. The alternative pathway in particular is always "on," at low levels, and is particularly sensitive to hyper-activation in a variety of physiologic and pathologic states including infection, autoimmune disorders, thrombosis and pregnancy, requiring tight control predicated on a variety of soluble and membrane bound regulatory proteins...
April 2016: Transfusion and Apheresis Science
Abdelmalek Dahmani, Hervé Roudot, Florence Cymbalista, Rémi Letestu
OBJECTIVES: Diagnostic tests for paroxysmal nocturnal hemoglobinuria (PNH) are currently based on flow cytometry techniques. Typically, these tests use antibodies against glycosylphosphatidylinositol (GPI)-anchored proteins, but a new approach has been described recently, using a novel reagent named FLAER (fluorescently labeled aerolysin). In this work, we evaluate the performance and highlight the peculiarities of using this new reagent. RESULTS: We investigated the general conditions of staining and explored optimal labeling settings...
March 2016: American Journal of Clinical Pathology
Seishi Ogawa
Clonal hematopoiesis (CH) in aplastic anemia (AA) has been closely linked to the evolution of late clonal disorders, including paroxysmal nocturnal hemoglobinuria and myelodysplastic syndromes (MDS)/acute myeloid leukemia (AML), which are common complications after successful immunosuppressive therapy (IST). With the advent of high-throughput sequencing of recent years, the molecular aspect of CH in AA has been clarified by comprehensive detection of somatic mutations that drive clonal evolution. Genetic abnormalities are found in ∼50% of patients with AA and, except for PIGA mutations and copy-neutral loss-of-heterozygosity, or uniparental disomy (UPD) in 6p (6pUPD), are most frequently represented by mutations involving genes commonly mutated in myeloid malignancies, including DNMT3A, ASXL1, and BCOR/BCORL1 Mutations exhibit distinct chronological profiles and clinical impacts...
July 21, 2016: Blood
Fetch more papers »
Fetching more papers... Fetching...
Read by QxMD. Sign in or create an account to discover new knowledge that matter to you.
Remove bar
Read by QxMD icon Read

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"