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PNH hemolytic anemia

After finishing my fourth Babesia textbook, a number of people came to me reporting that their Babesia treatment helped "cure" their Babesia. I only report what they report.

1. Am J Clin Pathol. 2009 Oct;132(4):564-72.

Use of a FLAER-based WBC assay in the primary screening of PNH clones.

Sutherland DR, Kuek N, Azcona-Olivera J, Anderson T, Acton E, Barth D, Keeney M.

Laboratory Medicine Program, Toronto General Hospital 11E-416, Toronto, Ontario M5G 2C4, Canada.

Diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) with flow cytometry traditionally involves the analysis of CD55 and CD59 on RBCs and neutrophils. However, the ability to accurately detect PNH RBCs is compromised by prior hemolysis and/or transfused RBCs. Patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS) can also produce PNH clones. We recently described 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. Here, we compared the efficiency of this WBC assay with a CD59-based assay on RBCs during a 3-year period. PNH clones were detected with the FLAER assay in 63 (11.8%) of 536 samples tested, whereas PNH RBCs were detected in only 33 (6.2%), and always with a smaller clone size. The FLAER assay on WBCs is a more sensitive and robust primary screening assay for detecting PNH clones in clinical samples.

PMID: 19762534 [PubMed - indexed for MEDLINE]

2. J Stroke Cerebrovasc Dis. 2009 Sep-Oct;18(5):409-10.

Recurrent ischemic stroke in paroxysmal nocturnal hemoglobinuria: paroxysmal nocturnal hemoglobinuria or missed patent foramen ovale?

Tiu R, Yacoub H, Maciejewski J, Sila CA.

Department of Hematologic Oncology and Blood Disorders, Taussig Cancer Institute, Cleveland Clinic, Ohio 44195, USA. tiur@ccf.org

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired bone-marrow disorder characterized by hemolytic anemia, hemoglobinuria, and cytopenia. Most patients die from venous thrombotic events. Stroke is a common cause of morbidity and mortality in PNH and it is almost exclusively a result of cerebral venous thrombosis. Case reports of ischemic stroke complicating PNH have implicated a similar propensity for arterial events caused by the disease. We present a case of recurrent cerebral infarctions complicating PNH initially attributed to arterial thrombosis but ultimately determined to be a result of the disease and a concomitant patent foramen ovale identified only after repeated evaluations. This case emphasizes the pitfalls of diagnostic testing and the importance of a persistent search for a venous cause for cerebral embolic events in patients with hematologic diseases not classically known to involve the arterial system.

PMID: 19717030 [PubMed - in process]

3. BMC Blood Disord. 2009 Aug 13;9:5.

Profile of hematological abnormalities of Indian HIV infected individuals.

Dikshit B, Wanchu A, Sachdeva RK, Sharma A, Das R.

Department of Internal Medicine, Postgraduate Institute of Medical Education & Research, Chandigarh, India. awanchu@yahoo.com.

ABSTRACT: BACKGROUND: Hematological abnormalities are a common complication of HIV infection. These abnormalities increase as the disease advances. Bone marrow abnormalities occur in all stages of HIV infection. METHODS: Two hundred HIV infected individual were screened for hematological abnormalities from March 2007-March 2008. Absolute CD4 cell count analysis was carried out by flowcytometry. Depending on the results of the primary screening further investigations were performed, like iron studies, hemolytic work up, PNH work up and bone marrow evaluation. Other investigations included coagulation profile, urine analysis, blood culture (bacterial, fungal, mycobacterial), serology for Epstein Barr virus (EBV), Cytomegalovirus (CMV), Hepatitis B and C, and Parvo B19 infection. RESULTS: The most common hematological abnormality was anemia, seen in 65.5% (131/200) patients. Iron deficiency anemia was seen in 49.2% (/200) cases while anemia of chronic disease occurred in 50.7% (/200) cases. Bone marrow evaluation was carried out in 14 patients out of which staging marrow was performed in 2 cases of non-Hodgkin's lymphoma (NHL) and did not show any bone marrow infiltration. In remaining12 cases bone marrow was done for evaluation of pancytopenia. Among patients with pancytopenia 50% (6/12) showed granulomas (4 were positive for AFB, 2 were positive for fungal cryptococci), 25% (3/12) showed hemophagocytosis. There was a strong negative correlation between anemia and CD4 counts in this study. Thrombocytopenia was seen in 7% (14/200) cases and had no significant correlation with CD4 counts. No patient had absolute neutrophil count (ANC) < 800 cells/muL. No case of coagulation abnormalities was found. CONCLUSION: Anemia in HIV patients can be a good clinical indicator to predict and access the underlying immune status. Patients should be investigated for hematological manifestations and appropriate steps should be taken to identify and treat the reversible factors.

PMCID: 2741436 PMID: 19678930 [PubMed - in process]

4. Br J Haematol. 2009 Sep;146(5):538-45. Epub 2009 Jul 6.

NKG2D-mediated immunity underlying paroxysmal nocturnal haemoglobinuria and related bone marrow failure syndromes.

Hanaoka N, Nakakuma H, Horikawa K, Nagakura S, Tsuzuki Y, Shimanuki M, Kojima K, Yonemura Y, Kawaguchi T.

Department of Haematology/Oncology, Wakayama Medical University, Wakayama, Japan.

It is considered that a similar immune mechanism acts in the pathogenesis of bone marrow (BM) failure in paroxysmal nocturnal haemoglobinuria (PNH) and its related disorders, such as aplastic anaemia (AA) and myelodysplastic syndromes (MDS). However, the molecular events in immune-mediated marrow injury have not been elucidated. We recently reported an abnormal expression of stress-inducible NKG2D (natural-killer group 2, member D) ligands, such as ULBP (UL16-binding protein) and MICA/B (major histocompatibility complex class I chain-related molecules A/B), on granulocytes in some PNH patients and the granulocyte killing by autologous lymphocytes in vitro. The present study found that the expression of NKG2D ligands was common to both granulocytes and BM cells of patients with PNH, AA, and MDS, indicating their exposure to some incitement to induce the ligands. The haematopoietic colony formation in vitro by the patients' marrow cells significantly improved when their BM cells were pretreated with antibodies against NKG2D receptor, suggesting that the antibodies rescued haematopoietic cells expressing NKG2D ligands from damage by autologous lymphocytes with NKG2D. Clinical courses of patients with PNH and AA showed a close association of the expression of NKG2D ligands with BM failure and a favourable response to immunosuppressive therapy. We therefore propose that NKG2D-mediated immunity may underlie the BM failure in PNH and its-related marrow diseases.

PMID: 19594748 [PubMed - indexed for MEDLINE]

5. Biol Blood Marrow Transplant. 2009 Jun;15(6):656-61. Epub 2009 Feb 12.

Current status of allogeneic hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria.

Matos-Fernandez NA, Abou Mourad YR, Caceres W, Kharfan-Dabaja MA.

Department of Blood and Marrow Transplantation, Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.

Treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) has been traditionally empirical, primarily aiming at ameliorating symptoms or treating complications resulting from the disease. Novel therapies such as eculizumab result in stabilization of hemoglobin levels and improvement in quality of life, but does not cure PNH. Nonrandomized studies suggest that long-term remissions are achievable when using myeloablative or nonmyeloablative/reduced-intensity (NMT/RIC) allogeneic hematopoietic stem cell transplantation (HSCT) as treatment for PNH. Nevertheless, patients with previous life-threatening complications from PNH may be more appropriately treated with an NMT/RIC regimen, rather than a myeloablative approach, because of the increased transplant mortality associated with the latter. The decision to perform an allogeneic HSCT (allo-HSCT) should weigh disease prognosis, by incorporating known adverse prognostic factors such as previous history of thrombosis and/or evolution to pancytopenia, among others, against the risk of transplant-related complications. Selection of the appropriate candidate and, equally important, the right time to perform an allo-HCT are important questions that need to be answered in the context of large prospective randomized trials.

PMID: 19450749 [PubMed - indexed for MEDLINE]

6. Pediatr Blood Cancer. 2009 Sep;53(3):472-4.

Splenic infarction and subsequent splenic rupture in a patient with paroxysmal nocturnal hemoglobinuria and heparin-induced thrombocytopenia.

Magnan H, Kayton ML, DiMichele DM, Araten DJ, Kernan NA, Boulad F.

Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

We describe a patient with paroxysmal nocturnal hemoglobinuria (PNH) and no previous history of thrombosis who presented with hepatic venous thromboses and subsequently developed splenic infarction and rupture requiring splenectomy while on anticoagulation therapy for the hepatic thromboses. The patient's anticoagulation was complicated by heparin-induced thrombocytopenia (HIT) highlighting the unique management challenge presented by PNH in combination with HIT. (c) 2009 Wiley-Liss, Inc.

PMID: 19415735 [PubMed - indexed for MEDLINE]

7. Liver Transpl. 2009 May;15(5):540-3.

Successful liver transplantation for Budd-Chiari syndrome in a patient with paroxysmal nocturnal hemoglobinuria treated with the anti-complement antibody eculizumab.

Singer AL, Locke JE, Stewart ZA, Lonze BE, Hamilton JP, Scudiere JR, Anders RA, Rother RP, Brodsky RA, Cameron AM.

Department of Surgery, Comprehensive Transplant Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. asinger1@jhmi.edu

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hemolytic anemia caused by somatic mutations in the phosphatidylinositol glycan-complementation class A gene and the resulting absence of a key complement regulatory protein, CD59. Affected red blood cells in patients with PNH undergo intravascular complement-mediated lysis with resulting anemia, hemoglobinuria, and venous thromboses. Hepatic venous outflow thrombosis [Budd-Chiari syndrome (BCS)] is especially common in PNH patients and often fatal. The few case reports of outcomes in patients undergoing liver transplant for BCS secondary to PNH detail instances of recurrent BCS as well as early thrombotic portal vein occlusion and hepatic artery thrombosis requiring retransplantation. PNH is therefore generally considered a contraindication to liver transplantation. Here we present the first report of a patient with PNH and BCS undergoing successful liver transplantation while receiving eculizumab, a humanized monoclonal antibody that blocks the activation of the terminal complement at C5.

PMID: 19399743 [PubMed - indexed for MEDLINE]

8. Blood. 2009 Jun 25;113(26):6522-7. Epub 2009 Apr 16.

How I treat paroxysmal nocturnal hemoglobinuria.

Brodsky RA.

Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA. brodsro@jhmi.edu

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.

PMCID: 2710914 PMID: 19372253 [PubMed - indexed for MEDLINE]

9. J Pediatr Hematol Oncol. 2009 Apr;31(4):274-6.

Primary/de novo paroxysmal nocturnal hemoglobinuria in a child from north India: a case report with review of literature.

Naseem S, Varma N, Trehan A.

Hemato-Oncology Unit, Advanced Pediatric Center, Post Graduate Institute of Medical Education and Research, Chandigarh, India.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder, characterized by intravascular hemolysis, thrombosis, or bone marrow failure. It is very rare in children. The clinical manifestations are due to deficiency of a family of membrane proteins that are anchored into the cell membrane through glycosylphosphatidylinositol (GPI). Currently, flow cytometric analysis of GPI-linked proteins has replaced the traditional Ham test (acidified-serum lysis test) and sucrose lysis test, it being a quantitative and more sensitive method. The only curative treatment of the disease is stem cell transplantation. We are reporting a case of de novo pediatric PNH, presenting with hemoglobinuria and a sizeable clone of GPI-anchor deficient blood cells, along with review of reported cases of PNH in pediatric patients. PNH can occur in children and has varied clinical and hematologic presentations; the presence of PNH should be considered in every child with an acquired bone marrow failure, unexplained hemoglobinuria and/or unexpected serious thrombosis. Pediatricians should keep this disorder in mind, when patients present with above features.

PMID: 19346880 [PubMed - indexed for MEDLINE]

10. Hematol Oncol Clin North Am. 2009 Apr;23(2):333-46.

Bone marrow failure syndromes: paroxysmal nocturnal hemoglobinuria.

Parker CJ.

Division of Hematology and Bone Marrow Transplantation, Department of Medicine, University of Utah School of Medicine, 50 North Medical Drive, Salt Lake City, UT 84132, USA. charles.parker@hsc.utah.edu

This article discusses the etiology of paroxysmal nocturnal hemoglobinuria (PNH) and its relationship to marrow hyperplasia. The author posits that the defining clinical pathology of PNH (ie, complementmediated intravascular hemolysis) is an epiphenomenon that is a consequence of an orchestrated response (ie, natural selection of PIGA-mutant stem cells) to a specific type of bone marrow injury (ie, immune mediated). Management of PNH is discussed also.

PMID: 19327587 [PubMed - indexed for MEDLINE]

11. Ter Arkh. 2009;81(1):48-51.

[Density-specific distribution of erythrocytes in different types of anemia]

[Article in Russian]

Shurkhina ES, Nesterenko VM, Kolodeĭ SV, Tsvetaeva NV, Ermakova TA, Nikulina OF, Kolosheĭnova TI, Ataullakhanov FI.

AIM: To study density-specific distribution of erythrocytes (DSDE) in different types of anemia. MATERIAL AND METHODS: DSDE was determined in anemic patients by fractionation of the whole blood in hematocritic capillaries in the presence of mixtures of dimethyl- and dibutylphthalates with known density. RESULTS: Parameters are proposed which characterize DSDE changes typical for each type of anemia: mean erythrocyte density (MED)--mean density of total erythrocytic population; DSDE width (W)--a characteristic of erythrocytic population heterogeneity; light fraction of erythrocytes (LEF)--% of the cells with density less than 1.086 g/ml (hypochromic cells and reticulocytes); dense fraction of erythrocytes (DEF)--% of cells with density over 1.112 g/ml (hyperchromic cells forming as a result of erythrocyte dehydration). DSDE parameters for different types of anemia differed: reduced MED was typical for iron deficiency anemia (IDA) and paroxysmal nocturnal hemoglobinuria (PNH), increased DEF was seen in microspherocytic anemia (MSA), autoimmune hemolytic anemia (AHA), deficiency of glucose-6-phosphate dehydrogenase, increased LEF was observed in reticulocytosis in all anemia types except MSA, DSDE W was larger in MSA, AHA, PNA. CONCLUSION: DSDE is determined by proportion of erythropoiesis and sequestration of erythrocytes as well as pathological impacts leading to impairment of membrane permeability for cations and erythrocytic metabolism. Informative value of DSDE parameters makes them effective for diagnostic screening of anemias and control over course of different diseases.

PMID: 19253711 [PubMed - indexed for MEDLINE]

12. Am J Hematol. 2009 Apr;84(4):221-7.

Balancing role of nitric oxide in complement-mediated activation of platelets from mCd59a and mCd59b double-knockout mice.

Qin X, Hu W, Song W, Blair P, Wu G, Hu X, Song Y, Bauer S, Feelisch M, Leopold JA, Loscalzo J, Halperin JA.

Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. xuebin_qin@hms.harvard.edu

CD59 is a membrane protein inhibitor of the membrane attack complex (MAC) of complement. mCd59 knockout mice reportedly exhibit hemolytic anemia and platelet activation. This phenotype is comparable to the human hemolytic anemia known as paroxysmal nocturnal hemoglobinuria (PNH), in which platelet activation and thrombosis play a critical pathogenic role. It has long been suspected but not formally demonstrated that both complement and nitric oxide (NO) contribute to PNH thrombosis. Using mCd59a and mCd59b double knockout mice (mCd59ab(-/-) mice) in complement sufficient (C3(+/+)) and deficient (C3(-/-)) backgrounds, we document that mCd59ab(-/-) platelets are sensitive to complement-mediated activation and provide evidence for possible in vivo platelet activation in mCd59ab(-/-) mice. Using a combination of L-NAME (a NO-synthase inhibitor) and NOC-18 or SNAP (NO-donors), we further demonstrate that NO regulates complement-mediated activation of platelets. These results indicate that the thrombotic diathesis of PNH patients could be due to a combination of increased complement-mediated platelet activation and reduced NO-bioavailability as a consequence of hemolysis. Copyright 2009 Wiley-Liss, Inc.

PMID: 19229985 [PubMed - indexed for MEDLINE]

13. Dtsch Med Wochenschr. 2009 Feb;134(9):404-9. Epub 2009 Feb 17.

[Paroxysmal nocturnal hemoglobinuria (PNH). Pathogenesis, diagnosis and treatment]

[Article in German]

Röth A, Dührsen U, Schrezenmeier H, Schubert J.

Klinik für Hämatologie, Universitätsklinikum Essen, Universität Duisburg-Essen. alexander.roeth@uni-due.de

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the classic clinical triad of corpuscular hemolytic anemia, thrombophilia and cytopenia. This is caused by an acquired mutation of the PIG(phosphatidylinositol glycan)-A gene of the pluripotent hematopoetic stem cell. This results in a deficiency of GPI(glycosylphosphatidylinositol)-anchors and GPI-anchored proteins on the surface of affected blood cells. Flow cytometry is the standard for diagnosis and measurement of type and size of the PNH clone. Treatment of PNH is mainly symptomatic. Allogeneic bone marrow transplantation is the only curative option in case of severe complications during the course of the diseases. A new targeted treatment strategy is the inhibition of the terminal complement cascade with a monoclonal antibody (eculizumab). As shown in clinical studies this is efficient to reduce complement mediated intravascular hemolysis, reduce the need for transfusions, improve the quality of life in patients with PNH and reduce the risk for thromboembolic complications, which are the main cause of mortality in PNH.

PMID: 19224425 [PubMed - indexed for MEDLINE]

14. Blood. 2009 Apr 23;113(17):4094-100. Epub 2009 Jan 29.

Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab.

Risitano AM, Notaro R, Marando L, Serio B, Ranaldi D, Seneca E, Ricci P, Alfinito F, Camera A, Gianfaldoni G, Amendola A, Boschetti C, Di Bona E, Fratellanza G, Barbano F, Rodeghiero F, Zanella A, Iori AP, Selleri C, Luzzatto L, Rotoli B.

Hematology, Department of Biochemistry and Medical Biotechnologies, Federico II University, Naples, Italy. amrisita@unina.it

In paroxysmal nocturnal hemoglobinuria (PNH) hemolytic anemia is due mainly to deficiency of the complement regulator CD59 on the surface of red blood cells (RBCs). Eculizumab, an antibody that targets complement fraction 5 (C5), has proven highly effective in abolishing complement-mediated intravascular hemolysis in PNH; however, the hematologic benefit varies considerably among patients. In the aim to understand the basis for this variable response, we have investigated by flow cytometry the binding of complement fraction 3 (C3) on RBCs from PNH patients before and during eculizumab treatment. There was no evidence of C3 on RBCs of untreated PNH patients; by contrast, in all patients on eculizumab (n = 41) a substantial fraction of RBCs had C3 bound on their surface, and this was entirely restricted to RBCs with the PNH phenotype (CD59(-)). The proportion of C3(+) RBCs correlated significantly with the reticulocyte count and with the hematologic response to eculizumab. In 3 patients in whom (51)Cr labeling of RBCs was carried out while on eculizumab, we have demonstrated reduced RBC half-life in vivo, with excess (51)Cr uptake in spleen and in liver. Binding of C3 by PNH RBCs may constitute an additional disease mechanism in PNH, strongly enhanced by eculizumab treatment and producing a variable degree of extravascular hemolysis.

PMID: 19179465 [PubMed - indexed for MEDLINE]

15. Hematology. 2009 Feb;14(1):33-7.

Abnormalities in the expression of CD55 and CD59 surface molecules on peripheral blood cells are not specific to paroxysmal nocturnal hemoglobinuria.

Ruiz-Delgado GJ, Vázquez-Garza E, Méndez-Ramírez N, Gómez-Almaguer D.

Departament of Hematology, Hospital Universitario de Monterrey, Universidad Autónoma de Nuevo León, Monterrey, NL, Mexico.

The regulatory proteins CD55 and CD59 are glycolsylphosphatidylinositol-anchored, type I cell surface proteins, which inhibit formation of the C3 convertases and prevent the terminal polymerization of the membrane attack complexes, respectively. Paroxysmal nocturnal hemoglobinuria (PNH) is a genetic disorder due to the impaired conformation of the glycolsylphosphatidylinositol anchor, which results in the deficient expression of CD55 and CD59 leading to excessive destruction of red cells and leukocytes. We have studied the expression of these two molecules in red blood cells, granulocytes and platelets in patients with PNH (two patients), autoimmune hemolytic anemia (AIHA) (seven patients), autoimmune thrombocytopenia (ATP) (22 patients), systemic lupus erythematosus (SLE) (19 patients), aplastic anemia (AA) (eight patients), and Evans syndrome (ES) (two patients). A diminished expression of CD55 and CD59 was found in the three cell lines of the two patients with PNH. In the seven patients with AIHA two were found with CD59 diminished expression in red blood cells and one with CD59 diminished expression in granulocytes. In the patients with ATP one was found with CD55 diminished expression in red blood cells, one with CD59 diminished expression granulocytes and one with a CD59 diminished expression in the platelets. In the subset of patients with SLE only one was found with a CD55 diminished expression in the red blood cells. In the patients with AA, a diminished expression in red blood cells was not found; however, one patient was found with a diminished expression of CD59 in granulocytes, and one patient with a diminished expression of CD55 in the platelets. In the two patients with ES we did not found changes in the expression of CD55 and CD59. We conclude that the diminished expression of the glycolsylphosphatidylinositol-anchored type I cell surface proteins CD55 and CD59 is not specific to PNH and that it can be found in patients with a variety of autoimmune disorders. Additional studies are needed to define the role of the deficiencies of CD55 and CD59 in the pathogenesis of autoimmune hemocytopenias.

PMID: 19154662 [PubMed - indexed for MEDLINE]

16. Lancet. 2009 Feb 28;373(9665):759-67. Epub 2009 Jan 12.

Eculizumab for paroxysmal nocturnal haemoglobinuria.

Parker C.

Hematology and Bone Marrow Transplant, University of Utah School of Medicine, Salt Lake City, UT, USA.

The complement system plays a central part in both innate and acquired immunity, but the contribution of complement activation to pathobiology is largely ancillary. An exception to the non-dominant role of complement in disease is the haemolytic anaemia of paroxysmal nocturnal haemoglobinuria (PNH). The intravascular haemolysis that is the clinical hallmark of PNH is a consequence of deficiency of the complement inhibitory proteins decay accelerating factor (DAF, CD55) and membrane inhibitor of reactive lysis (MIRL, CD59). Eculizumab is a humanised monoclonal antibody that binds and prevents activation of complement C5 and the subsequent formation of the cytolytic membrane attack complex of complement. Eculizumab inhibits the intravascular haemolysis of PNH, reduces transfusion requirements, stabilises haemoglobin concentration, and improves quality of life. Although chronic treatment with eculizumab increases the risk of infections with Neisseria meningitides, the drug is generally safe and well tolerated. But as is the case with other drugs developed for treatment of ultra-orphan diseases, eculizumab is expensive, and treatment must continue indefinitely because C5 inhibition does not affect the process (ie, clonal proliferation of haemopoietic stem cells with a mutant phosphatidylinositol glycan complementation class A [PIGA] gene) that underlies PNH. Moreover, due to the heterogeneous nature of the disease, treatment with eculizumab is not appropriate for all patients with PNH.

PMID: 19144399 [PubMed - indexed for MEDLINE]

17. Indian J Pathol Microbiol. 2009 Jan-Mar;52(1):38-41.

PNH revisited: Clinical profile, laboratory diagnosis and follow-up.

Gupta PK, Charan VD, Kumar H.

Department of Transfusion Medicine, Armed Forces Medical College, Department of Clinical Hematology, Command Hospital (SC), Pune 40, Maharashtra, India. paw_5671@hotmail.com

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by intravascular hemolysis, marrow failure, nocturnal hemoglobinuria and thrombophila. This acquired disease caused by a deficiency of glycosylphosphatidylinositol (GPI) anchored proteins on the hematopoietic cells is uncommon in the Indian population. MATERIALS AND METHODS: Data of patients diagnosed with PNH in the past 1 year were collected. Clinical data (age, gender, various presenting symptoms), treatment information and follow-up data were collected from medical records. Results of relevant diagnostic tests were documented i.e., urine analysis, Ham's test, sucrose lysis test and sephacryl gel card test (GCT) for CD55 and CD59. RESULTS: A total of 5 patients were diagnosed with PNH in the past 1 year. Presenting symptoms were hemolytic anemia (n=4) and bone marrow failure (n=1). A GCT detected CD59 deficiency in all erythrocytes in 4 patients and CD55 deficiency in 2 patients. A weak positive PNH test for CD59 was seen in 1 patient and a weak positive PNH test for CD55 was seen in 3 patients. All patients were negative by sucrose lysis test. Ham's test was positive in two cases. Patients were treated with prednisolone and/or androgen and 1 patient with aplastic anemia was also given antithymocyte globulin. A total of 4 patients responded with a partial recovery of hematopoiesis and 1 patient showed no recovery. None of the patients received a bone marrow transplant. CONCLUSION: The study highlights the diagnostic methods and treatment protocols undertaken to evaluate the PNH clone in a developing country where advanced methods like flowcytometry immunophenotyping (FCMI) and bone marrow transplants are not routinely available.

PMID: 19136777 [PubMed - indexed for MEDLINE]

18. Med Clin (Barc). 2008 Nov 8;131(16):617-30.

[Paroxysmal nocturnal hemoglobinuria.]

[Article in Spanish]

Hernández-Campo PM, Almeida J, Orfao A.

Servicio General de Citometría, Centro de Investigación del Cáncer (IBMCC-USAL/CSIC), Hospital Universitario de Salamanca, Departamento de Medicina, Universidad de Salamanca, Salamanca, España.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder characterized by the existence of somatic mutations in the PIG-A (phosphatidylinositolglycan complementation class A) gene, which encodes for a protein involved in the biosynthesis of the glycosyl phosphatidylinositol (GPI) molecule that serves as an anchor for many cell surface proteins. This genetic alteration translates into a total or partial deficiency in the PNH clone of surface proteins attached to the cell by a GPI anchor. Evaluation of deficient expression of GPI-associated proteins is currently used for the diagnosis of paroxysmal nocturnal hemoglobinuria. Among other proteins, deficiency of CD55 and CD59 leads to an increased susceptibility of PNH cells to complement-mediated cell lysis. Variable degrees of cytopenia, an increased susceptibility to infections and recurrent thrombotic events are other symptoms of the disease. In this paper we review the recent advances in the knowledge about the pathogenic mechanisms of the disease and the current approaches for the diagnosis and monitoring of PNH patients.

PMID: 19080854 [PubMed - indexed for MEDLINE]

19. Hematology Am Soc Hematol Educ Program. 2008:116-23.

The role of complement inhibition in PNH.

Hillmen P.

St James's University Hospital, Leeds, UK. peter.hillmen@nhs.net

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, chronic, debilitating, acquired disorder that most frequently presents in early adulthood and usually continues throughout the life of a patient. PNH results in the death of approximately half of affected individuals, mainly through thrombotic complications, and until recently had no specific therapy. In 2007 eculizumab, an anti-complement antibody targeting the C5 complement component was approved for PNH by both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA). Eculizumab is very effective in the treatment of intravascular hemolysis and all its sequelae, which include most of the symptoms and complications of PNH. Eculizumab has revolutionized our approach to hemolytic PNH and as it markedly reduces the principal complications of PNH, namely thrombosis and renal failure, should have a significant impact on survival. However, the development of eculizumab presents new challenges in PNH, such as how to avoid complications of therapy, how to overcome some of the problems associated with treatment and who to select for treatment, as only a proportion of patients with a PNH clone will benefit. This article will review the evidence behind the use of eculizumab in PNH, the effect it will have on the complications of the disease, the most appropriate selection of patients for therapy, the optimal management and the potential complications of the therapy.

PMID: 19074068 [PubMed - indexed for MEDLINE]

20. Hematology Am Soc Hematol Educ Program. 2008:111-5.

Paroxysmal nocturnal hemoglobinuria: stem cells and clonality.

Brodsky RA.

Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-0185, USA. brodsro@jhmi.edu

Paroxysmal nocturnal hemoglobinuria is a clonal hematopoietic stem cell disease that manifests with intravascular hemolysis, bone marrow failure, thrombosis, and smooth muscle dystonias. The disease can arise de novo or in the setting of acquired aplastic anemia. All PNH patients to date have been shown to harbor PIG-A mutations; the product of this gene is required for the synthesis of glycosylphosphatidylinositol (GPI) anchored proteins. In PNH patients, PIG-A mutations arise from a multipotent hematopoietic stem cell. Interestingly, PIG-A mutations can also be found in the peripheral blood of most healthy controls; however, these mutations arise from progenitor cells rather than multipotent hematopoietic stem cells and do not propagate the disease. The mechanism of whereby PNH stem cells achieve clonal dominance remains unclear. The leading hypotheses to explain clonal outgrowth in PNH are: 1) PNH cells evade immune attack possibly, because of an absent cell surface GPI-AP that is the target of the immune attack; 2) The PIG-A mutation confers an intrinsic resistance to apoptosis that becomes more conspicuous when the marrow is under immune attack; and 3) A second mutation occurs in the PNH clone to give it an intrinsic survival advantage. These hypotheses may not be mutually exclusive, since data in support of all three models have been generated.

PMID: 19074067 [PubMed - indexed for MEDLINE]

21. Hematology Am Soc Hematol Educ Program. 2008:104-10.

The pathophysiology of disease in patients with paroxysmal nocturnal hemoglobinuria.

Bessler M, Hiken J.

Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. mbessler@im.wustl.edu

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia caused by the expansion of a hematopoietic progenitor cell that has acquired a mutation in the X-linked PIGA gene. PNH occurs on the background of bone marrow failure. Bone marrow failure and the presence of the abnormal cells account for the clinical phenotype of patients with PNH including hemolysis, cytopenia, and thrombophilia. PIGA is essential for the synthesis of glycosyl phosphatidylinositol (GPI) anchor molecules. PNH blood cells are therefore deficient in all proteins that use such an anchor molecule for attachment to the cell membrane. Two of these proteins regulate complement activation on the cell surface. Their deficiency therefore explains the exquisite sensitivity of PNH red blood cells to complement-mediated lysis. Complement-mediated lysis of red blood cells is intravascular, and intravascular hemolysis contributes significantly to the morbidity and mortality in patients with this condition. PNH is an outstanding example of how an increased understanding of pathophysiology may directly improve the diagnosis, care, and treatment of disease.

PMID: 19074066 [PubMed - indexed for MEDLINE]

22. Hematology Am Soc Hematol Educ Program. 2008:93-103.

Paroxysmal nocturnal hemoglobinuria: an historical overview.

Parker CJ.

Division of Hematology and Bone Marrow Transplantation, University of Utah School of Medicine, Salt Lake City, UT 84148, USA. charles.parker@hsc.utah.edu

The clinical hallmark of paroxysmal nocturnal hemoglobinuria (PNH) is episodic hemoglobinuria, and it was this feature that captured the attention of European physicians in the latter half of the 19th century, resulting in careful observational studies that established PNH as an entity distinct from paroxysmal cold hemoglobinuria and march hemoglobinuria. Curiosity about the etiology of the nocturnal aspects of the hemoglobinuria led the German physician Paul Strübing to develop the prescient hypothesis that the erythrocytes of PNH are abnormally sensitive to hemolysis when the plasma is acidified during sleep because of accumulation of carbon dioxide and lactic acid as a result of slowing of the circulation. Investigation of the intricate pathophysiology that underlies the abnormal sensitivity of PNH erythrocytes to hemolysis in acidified serum produced a number of remarkable scientific achievements that involved discovery of the alternative pathway of complement, identification of the membrane proteins that regulate complement, discovery of a novel mechanism for attachment of proteins to the cell surface, and identification of the genetic basis of the disease. These discoveries were made steadily over a period of more than 100 years, and each generation of physicians and scientists made important contributions to the field. The mysteries of PNH have been solved in a particularly satisfying way because the precision and orderliness of the solutions made clearly understandable what had seemed at the times prior to resolution to be problems of nearly insurmountable complexity. The history of PNH is an inspirational reminder of the elegant complexity of nature, the rewards of curiosity and the power and beauty of science.

PMID: 19074065 [PubMed - indexed for MEDLINE]

23. Hematology Am Soc Hematol Educ Program. 2008:92.

Paroxysmal nocturnal hemoglobinuria (PNH): an historical perspective.

Benz EJ Jr.

PMID: 19074064 [PubMed - indexed for MEDLINE]

24. Hematology Am Soc Hematol Educ Program. 2008:35.

Which patients with paroxysmal nocturnal hemoglobinuria (PNH) should be treated with eculizumab? ASH evidence-based review 2008.

Haspel RL, Hillmen P.

Beth Israel Deaconess Hospital, Department of Pathology, Boston, MA 02215, USA. haspelr@yahoo.com

PMID: 19074053 [PubMed - indexed for MEDLINE]

25. Exp Hematol. 2009 Jan;37(1):42-51. Epub 2008 Nov 14.

Glycosylphosphatidylinositol-anchored protein deficiency confers resistance to apoptosis in PNH.

Savage WJ, Barber JP, Mukhina GL, Hu R, Chen G, Matsui W, Thoburn C, Hess AD, Cheng L, Jones RJ, Brodsky RA.

Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA.

OBJECTIVE: Investigate the contribution of PIG-A mutations to clonal expansion in paroxysmal nocturnal hemoglobinuria (PNH). MATERIALS AND METHODS: Primary CD34+ hematopoietic progenitors from PNH patients were assayed for annexin-V positivity by flow cytometry in a cell-mediated killing assay using autologous effectors from PNH patients or allogeneic effectors from healthy controls. To specifically assess the role of the PIG-A mutation in the development of clonal dominance and address confounders of secondary mutation and differential immune attack that can confound experiments using primary cells, we established an inducible PIG-A CD34+ myeloid cell line, TF-1. Apoptosis resistance was assessed after exposure to allogeneic effectors, NK92 cells (an interleukin-2-dependent cell line with the phenotype and function of activated natural killer [NK] cells), tumor necrosis factor (TNF)-alpha, and gamma-irradiation. Apoptosis was measured by annexin-V staining and caspase 3/7 activity. RESULTS: In PNH patients, CD34+ hematopoietic progenitors lacking glycosylphosphatidylinositol (GPI)-anchored proteins (GPI-AP(-)) were less susceptible than GPI-AP+ CD34+ precursors to autologous (8% vs 49%; p < 0.05) and allogeneic (28% vs 58%; p < 0.05) cell-mediated killing from the same patients. In the inducible PIG-A model, GPI-AP(-) TF-1 cells exhibited less apoptosis than induced, GPI-AP+ TF-1 cells in response to allogeneic cell-mediated killing, NK92-mediated killing, TNF-alpha, and gamma-irradiation. GPI-AP(-) TF-1 cells maintained resistance to apoptosis when effectors were raised against GPI-AP(-) cells, arguing against a GPI-AP being the target of immune attack in PNH. NK92-mediated killing was partially inhibited with blockade by specific antibodies to the stress-inducible GPI-AP ULBP1 and ULBP2 that activate immune effectors. Clonal competition experiments demonstrate that the mutant clone expands over time under proapoptotic conditions with TNF-alpha. CONCLUSION: PIG-A mutations contribute to clonal expansion in PNH by conferring a survival advantage to hematopoietic progenitors under proapoptotic stresses.

PMCID: 2628761 PMID: 19013003 [PubMed - indexed for MEDLINE]

26. Proc Natl Acad Sci U S A. 2008 Nov 25;105(47):18496-500. Epub 2008 Nov 14.

Neutral evolution in paroxysmal nocturnal hemoglobinuria.

Dingli D, Luzzatto L, Pacheco JM.

Division of Hematology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA. dingli.david@mayo.edu

Paroxysmal nocturnal hemoglobinuria is an acquired hematopoietic stem cell (HSC) disorder characterized by the partial or complete deficiency of glycosyl-phosphatidylinositol (GPI)-linked membrane proteins, which leads to intravascular hemolysis. A loss of function mutation in the PIG-A gene, required for GPI biosynthesis, explains how the deficiency of many membrane proteins can result from a single genetic event. However, to date the mechanism of expansion of the GPI(-) clone has not been fully understood. Two hypotheses have been proposed: A selective advantage of GPI(-) cells because of a second mutation or a conditional growth advantage of GPI(-) cells in the presence of an immune attack on normal (GPI(+)) HSCs. Here, we explore a third possibility, whereby the PNH clone does not have a selective advantage. Simulations in a large virtual population accurately reproduce the known incidence of the disease; and the fit is optimized when the number of stem cells is decreased, reflecting a component of bone marrow failure in PNH. The model also accounts for the occurrence of spontaneous cure in PNH, consequent on clonal extinction. Thus, a clonal advantage may not be always necessary to explain clonal expansion in PNH.

PMCID: 2587638 PMID: 19011109 [PubMed - indexed for MEDLINE]

27. Exp Hematol. 2008 Dec;36(12):1616-24. Epub 2008 Oct 26.

Increased soluble urokinase plasminogen activator receptor (suPAR) is associated with thrombosis and inhibition of plasmin generation in paroxysmal nocturnal hemoglobinuria (PNH) patients.

Sloand EM, Pfannes L, Scheinberg P, More K, Wu CO, Horne M, Young NS.

National Heart Lung and Blood Institute, Hematology Branch, Office of Biostatistics Research, Division of Prevention and Population Sciences, National Institutes of Health, Bethesda, MD 20892-1260, USA. Sloande@nhlbi.nih.gov

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired genetic disorder of the bone marrow that produces intravascular hemolysis, proclivity to venous thrombosis, and hematopoietic failure. Mutation in the PIG-A gene of a hematopoietic stem cell abrogates synthesis of glycosylphosphoinositol (GPI) anchors and expression of all GPI-anchored proteins on the surface of progeny erythrocytes, leukocytes, and platelets. Urokinase plasminogen activator receptor (uPAR), a GPI-linked protein expressed on neutrophils, mediates endogenous thrombolysis through a urokinase-dependent mechanism. Here we show that membrane GPI-anchored uPAR is decreased or absent on granulocytes and platelets of patients with PNH, while soluble uPAR (suPAR) levels are increased in patients' plasma. Serum suPAR concentrations correlated with the number of GPI-negative neutrophils and were highest in patients who later develop thrombosis. In vitro, suPAR is released from PNH hematopoietic cells and from platelets upon activation, suggesting that these cells are the probable source of plasma suPAR in the absence of GPI anchor synthesis and trafficking of uPAR to the cell membrane. In vitro, the addition of recombinant suPAR results in a dose-dependent decrease in the activity of single-chain urokinase. We hypothesized that suPAR, prevents the interaction of urokinase with membrane-anchored uPAR on residual normal cells.

PMID: 18954937 [PubMed - indexed for MEDLINE]

28. Leuk Res. 2009 Jun;33(6):e4-5. Epub 2008 Oct 25.

Paroxysmal nocturnal hemoglobinuria (PNH) and pregnancy in the era of eculizumab.

Danilov AV, Smith H, Craigo S, Feeney DM, Relias V, Miller KB.

PMID: 18952283 [PubMed - indexed for MEDLINE]

29. Transfus Med. 2008 Oct;18(5):308-11.

Paroxysmal nocturnal haemoglobinuria presenting as cerebral venous sinus thrombosis.

Misra UK, Kalita J, Bansal V, Nair PP.

Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India. ukmisra@sgpgi.ac.in

Paroxysmal nocturnal haemoglobinuria (PNH) is associated with anaemia, intravascular haemolysis and venous thrombosis. Cerebral venous sinus thrombosis (CVST) is a late but serious complication of PNH. We for the first time report a young man who presented with CVST and was diagnosed to have PNH after 11 months. We highlight the reasons for delay in the diagnosis and discuss the special issues in the management.

PMID: 18937739 [PubMed - indexed for MEDLINE]

30. Curr Vasc Pharmacol. 2008 Oct;6(4):347-53.

Thrombosis in paroxysmal nocturnal hemoglobinuria at a glance: a clinical review.

Ziakas PD, Poulou LS, Pomoni A.

Bone Marrow Transplantation Unit, Hygeia Diagnostic & Therapeutic Centre, Athens, Greece. zpanos@otenet.gr

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired stem cell disorder, with its primary clinical manifestations being hemolytic anemia, marrow failure and thrombophilia. Chronic hemolysis, failures of the fibrinolytic system, increased leukocyte-derived tissue factor levels in plasma, procoagulant microparticles generated through complement-mediated damage of platelets and venous endothelium are related to the acquired hypercoagulable state. Visceral thrombosis (including hepatic veins and mesenteric veins), cerebrovascular events and pulmonary embolism predict a poor outcome. Thrombosis is also associated with significant morbidity during pregnancy. Depending on the sites of thrombosis, a score-based probability to predict outcome can be assigned. Abdominal vein thromboses account for the majority of morbidity and mortality related to thrombosis, and time-dependent trends suggest that mortality rates tend to decline, with the advent of evolution of therapeutic and diagnostic strategies. In contrast, mortality rates from cerebrovascular events display no significant decline. Prompt diagnosis requires both clinical suspicion and sophisticated imaging techniques, along with multidisciplinary therapeutic intervention. In the eculizumab era, a significant reduction of thrombotic events was observed during therapy, and long-term follow up is needed to establish any benefit in rates and pattern of this complication. However, up to now, only bone marrow transplantation permanently abolishes the coagulation defect.

PMID: 18855722 [PubMed - indexed for MEDLINE]

31. J Coll Physicians Surg Pak. 2008 Aug;18(8):512-4.

Paroxysmal nocturnal hemoglobinuria.

Mehmood A, Sharif MA, Murtaza B.

Department of Department of Medicine, Combined Military Hospital, Bahawalnagar, Pakistan.

Paroxysmal Nocturnal Hemoglobinuria (PNH) literally means to have episodes of hemoglobin in the urine during the night. It is a Coomb's negative rare hemolytic disorder characterized by non-malignant clonal expansion of haemopoietic stem cells due to acquired genetic mutations. A 30 years old male patient presented with 5 years history of transfusion dependent anemia with intermittent episodes of passing dark colored urine in the morning. Blood complete picture showed decreased hemoglobin and reticulocytosis upto 30%. Coomb's test was negative with unconjugated hyperbilirubinemia and markedly raised serum LDH. Urine analysis showed marked hemosiderinuria and flow cytometry revealed 60% RBCs deficient for CD-59, confirming the diagnosis of paroxysmal nocturnal hemoglobinuria. The management of the patient depends on whether anemia is due to hemolysis or as consequence of impaired erythropoiesis. Corticosteroids at a dose of 0.25-1 mg/kg/day was selected as it is amongst the various treatment options in patients with predominant hemolysis.

PMID: 18798591 [PubMed - indexed for MEDLINE]

32. Oncologist. 2008 Sep;13(9):993-1000. Epub 2008 Sep 10.

FDA report: eculizumab (Soliris) for the treatment of patients with paroxysmal nocturnal hemoglobinuria.

Dmytrijuk A, Robie-Suh K, Cohen MH, Rieves D, Weiss K, Pazdur R.

Office of Oncology Drug Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993, USA. andrew.dmytrijuk@fda.hhs.gov

On March 16, 2007, eculizumab (Soliris; Alexion Pharmaceuticals, Inc. Cheshire, CT), a humanized monoclonal antibody that binds to the human C5 complement protein, received accelerated approval by the U.S. Food and Drug Administration for the treatment of patients with paroxysmal nocturnal hemoglobinuria (PNH) to reduce hemolysis. Eculizumab was studied in a randomized, double-blind, placebo-controlled clinical trial in 87 RBC transfusion-dependent adult PNH patients and in a supportive single-arm study in 96 patients. The eculizumab dose was 600 mg as a 35-minute i.v. infusion administered weekly for the first 4 weeks followed by 900 mg (week 5) then 900 mg every 14 days thereafter. Hemoglobin stabilized in 21 of 43 (48.8%) eculizumab-treated patients, compared with none of 44 placebo-treated patients. Eculizumab-treated patients required significantly fewer RBC transfusions than placebo-treated patients (median, 0 versus 10 units). There was also a significant reduction in the serum lactate dehydrogenase area under the curve with eculizumab compared with placebo treatment. Results of the phase II supportive study were similar to those of the phase III study. The safety database included 196 adult patients with PNH. Significant findings included the development of human anti-human antibody responses in three patients and serious meningococcal infections in three patients. Patients should undergo meningococcal vaccination at least 2 weeks prior to receiving the first eculizumab treatment and have revaccination according to current medical guidelines. Patients must be monitored and evaluated immediately for early signs of meningococcal infections and treated with antibiotics as indicated.

PMID: 18784156 [PubMed - indexed for MEDLINE]

33. Curr Protoc Cytom. 2002 May;Chapter 6:Unit 6.11.

Immunophenotypic analysis of PNH cells.

Richards SJ, Hillmen P.

Haematological Malignancy Diagnostic Service, Leeds, United Kingdom.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hematopoietic stem-cell disorder in which a gene mutation results in cellular inability to synthesize the glycosylphosphatidylinositol (GPI) anchors needed to attach various proteins to the cell membrane. Traditional clinical laboratory PNH screening and diagnosis are based upon demonstration of increased erythrocyte susceptibility to lysis by activated complement. These methods are neither very specific nor very sensitive, and have largely been superseded by the rapid, sensitive, and specific flow cytometric analysis of GPI-linked antigen expression. The protocols in this unit cover immunophenotypic analysis of red blood cells, peripheral blood granulocytes, and peripheral blood monocytes, as well as a four-color modification for simultaneous analysis of peripheral blood granulocytes and monocytes.

PMID: 18770768 [PubMed - indexed for MEDLINE]

34. Indian J Pediatr. 2008 Jun;75(6):575-8. Epub 2008 Aug 31.

Paroxysmal nocturnal hemoglobinuria in childhood and adolescence--a retrospective analysis of 18 cases.

Naithani R, Mahapatra M, Dutta P, Kumar R, Pati HP, Choudhry VP.

Department of Hematology, All India Institute of Medical Sciences, New Delhi, India.

OBJECTIVE: To assess the clinical and hematological profile of PNH in children. METHODS: Clinical and laboratory features of children with PNH diagnosed in the past six years at our centre were reviewed. Various investigations done included a complete blood count and peripheral smear examination, plasma hemoglobin, urine hemosiderin, acid ham test, sucrose lysis test, immunophenotyping of erythrocytes by sephadex column gel card and of granulocytes by flow cytometry. There were 18 children with a marked male predominance (M 14: F 4). RESULTS: Pallor, jaundice, dark urine and bleeding manifestations were the major presenting complaints. One girl suffered an arterial stroke. All children had cytopenia in at least one cell line. Children were treated with danazol, stanazolol, prednisolone and cyclosporin A variously. Overall response rate was 61%. Children with classical PNH performed slightly better with response rates of 66% (6/9) as compared to aplastic anemia-PNH group which has a response rate of 55% (5/9). Amongst various variables only danazol correlated with better response (p=0.029). CONCLUSION: PNH is an uncommon disease in children and should be included in the differential diagnosis of children presenting with cytopenia.

PMID: 18759084 [PubMed - indexed for MEDLINE]

35. Am J Health Syst Pharm. 2008 Sep 1;65(17):1609-15./p>


Davis J.

University of Pennsylvania Health System, Philadelphia, USA.

PURPOSE: The pharmacology, pharmacokinetics, indications, clinical efficacy, adverse effects, drug interactions, and dosage and administration of eculizumab are reviewed. SUMMARY: Eculizumab, a recombinant, humanized, monoclonal, immunoglobulin G antibody produced from murine myeloma cells, is the first agent to be approved for labeling by the Food and Drug Administration for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). Eculizumab works by inhibiting the complement cascade. It binds specifically to complement protein C5 and inhibits cleavage to C5a and C5b, resulting in the prevention of terminal complex formation and therefore cell lysis. In clinical studies, the effect of eculizumab on hemolysis was measured by a reduction in serum lactase dehydrogenase levels. The effect on hemolysis was evident after one week of treatment. The safety and efficacy of eculizumab were evaluated in a series of three trials. Results from the trials indicated that eculizumab reduces hemolysis and improves symptoms such as the number of paroxysms, dysphagia, and abdominal pain. The most frequent adverse reactions reported in the clinical trials included headache, nasopharyngitis, back pain, and nausea. The recommended i.v. dosing regimen is 600 mg weekly for four weeks, followed by a 900-mg dose at week 5, and 900 mg every 14 days as a maintenance dose. The manufacturer recommends that patients who have not received meningococcal vaccine be vaccinated at least two weeks before starting therapy because eculizumab is associated with a high risk of meningococcal infection. CONCLUSION: Eculizumab represents a major advancement in the treatment of PNH. While clinical experience is limited, long-term studies in patients with PNH have supported the safe and effective use of eculizumab with few serious adverse effects.

PMID: 18714106 [PubMed - indexed for MEDLINE]

36. Rinsho Ketsueki. 2008 Jul;49(7):498-504.

[Immunosuppressive therapy with antithymocyte globulin and cyclosporine for paroxysmal nocturnal hemoglobinuria]

[Article in Japanese]

Nakasone H, Iijima K, Asano H, Nakamura F, Kida M, Izutsu K, Urabe A, Usuki K.

Division of Hematology, Kanto Medical Center NTT EC.

Immunosuppressive therapy (IST) for paroxysmal nocturnal hemoglobinuria (PNH) has been infrequently reported. Four PNH cases were treated with antithymocyte globulin (ATG) at our center. We assessed and reviewed the efficacy and safety of IST for PNH. ATG therapy was performed for progression of cytopenia in 3 classical-type and 1 marrow failure-type PNH cases. ATG was administered at a dose of 15 mg/kg for 5 consecutive days. Hydration and anticoagulant therapy were given as prophylaxis for thrombosis during ATG therapy. Cyclosporine was also given to the 3 classical-type PNH patients. Three patients showed hemolytic exacerbation and thrombocytopenia during ATG administration, and all needed to receive transfusions of red blood cells and platelets; however, renal failure and thrombosis did not occur. Anemia improved in all cases within 1 year, but thereafter, recurred in 2 cases. ATG therapy is a choice of treatment for PNH, although its mechanism remains unknown.

PMID: 18709982 [PubMed - indexed for MEDLINE]

37. Bone Marrow Transplant. 2008 Oct;42(8):523-7. Epub 2008 Jul 14.

Reduced intensity HLA-haploidentical BMT with post transplantation cyclophosphamide in nonmalignant hematologic diseases.

Brodsky RA, Luznik L, Bolaños-Meade J, Leffell MS, Jones RJ, Fuchs EJ.

Division of Hematology, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. brodsro@jhmi.edu

Allogeneic blood or marrow transplantation (BMT) is potentially curative for a variety of life-threatening nonmalignant hematologic diseases such as paroxysmal nocturnal hemoglobinuria (PNH) and hemoglobinopathies. The application of BMT to treat these disorders is limited by the lack of suitable donors and often end-organ damage from the underlying disease. We treated three patients with thrombotic PNH, one of whom also had sickle cell disease, with a nonmyeloablative, HLA-haploidentical BMT with post-transplant CY. Rapid engraftment without GVHD occurred in two of the patients, including the patient with sickle cell disease. Both patients are disease free with full donor chimerism and require no immunosuppressive therapy, with follow-up of 1 and 4 years, respectively. Nonmyeloablative, HLA-haploidentical BMT with post-transplant CY is a promising approach for patients with life-threatening nonmalignant hematologic disease who lack an HLA-matched sibling donor.

PMID: 18622413 [PubMed - indexed for MEDLINE]

38. Leuk Res. 2009 Mar;33(3):e3-5. Epub 2008 Jul 1.

Coexistence of paroxysmal nocturnal hemoglobinuria (PNH) and acute lymphoblastic leukemia (ALL): Is PNH a prodrome of ALL?

Isoda A, Ogawa Y, Matsumoto M, Sawamura M.

PMID: 18597843 [PubMed - indexed for MEDLINE]

39. Blood. 2008 Sep 1;112(5):2160-2. Epub 2008 Jul 2.

Expansion of donor-derived hematopoietic stem cells with PIGA mutation associated with late graft failure after allogeneic stem cell transplantation.

Mochizuki K, Sugimori C, Qi Z, Lu X, Takami A, Ishiyama K, Kondo Y, Yamazaki H, Okumura H, Nakao S.

Cellular Transplantation Biology, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, Ishikawa, Japan.

A small population of CD55(-)CD59(-) blood cells was detected in a patient who developed donor-type late graft failure after allogeneic stem cell transplantation (SCT) for treatment of aplastic anemia (AA). Chimerism and PIGA gene analyses showed the paroxysmal nocturnal hemoglobinuria (PNH)-type granulocytes to be of a donor-derived stem cell with a thymine insertion in PIGA exon 2. A sensitive mutation-specific polymerase chain reaction (PCR)-based analysis detected the mutation exclusively in DNA derived from the donor bone marrow (BM) cells. The patient responded to immunosuppressive therapy and achieved transfusion independence. The small population of PNH-type cells was undetectable in any of the 50 SCT recipients showing stable engraftment. The de novo development of donor cell-derived AA with a small population of PNH-type cells in this patient supports the concept that glycosyl phosphatidylinositol-anchored protein-deficient stem cells have a survival advantage in the setting of immune-mediated BM injury.

PMID: 18596225 [PubMed - indexed for MEDLINE]

40. Drugs. 2008;68(10):1341-6.

Eculizumab in paroxysmal nocturnal haemoglobinuria.

Charneski L, Patel PN.

Department of Pharmacy Practice and Science, University of Maryland, Shady Grove Campus, Rockville, Maryland 20850, USA. lcharnes@rx.umaryland.edu

Eculizumab is a monoclonal antibody that binds with high affinity to the complement protein C5, preventing terminal complement-mediated intravascular haemolysis in patients with paroxysmal nocturnal haemoglobinuria (PNH). In three well designed clinical trials in patients with PNH, eculizumab blocked serum haemolytic activity and decreased transfusion rates. Pooled data from the three clinical trials demonstrated that eculizumab treatment decreased the overall thromboembolism rate in patients with PNH. Eculizumab carries a black box warning for the potential increased risk of meningococcal infections and requires patients to receive the meningococcal vaccine at least 2 weeks before starting treatment. Eculizumab is the first drug to be approved by the US FDA for the treatment of PNH and is a novel treatment that offers a new option for patients with PNH.

PMID: 18578555 [PubMed - indexed for MEDLINE]

41. Br J Haematol. 2008 Jul;142(3):413-22. Epub 2008 Jun 9.

Altered lipid raft composition and defective cell death signal transduction in glycosylphosphatidylinositol anchor-deficient PIG-A mutant cells.

Szpurka H, Schade AE, Jankowska AM, Maciejewski JP.

Experimental Haematology and Haematopoiesis Section, Taussig Cancer Centre, Cleveland Clinic, Cleveland, OH 44195, USA.

Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal disorder of haematopoietic stem cells caused by somatic PIGA mutations, resulting in a deficiency in glycosylphosphatidylinositol-anchored proteins (GPI-AP). Because GPI-AP associate with lipid rafts (LR), lack of GPI-AP on PNH cells may result in alterations in LR-dependent signalling. Conversely, PNH cells are a suitable model for investigating LR biology. LR from paired, wild-type GPI(+), and mutant GPI(-) cell lines (K562 and TF1) were isolated and analysed; GPI(-) LR contained important anti-apoptotic proteins, not found in LR from GPI(+) cells. When methyl-beta-cyclodextrin (MbetaCD) was utilized to probe for functional differences between normal and GPI(-) LR, increased levels of phospho-p38 mitogen-activated protein kinase (MAPK), and phospho-p65 nuclear factor NF-kappaB were found in control and GPI(-) cells respectively. Subsequent experiments addressing the inhibition of phosphoinositide-3-kinase (PI3K) suggest that the PI3K/AKT pathway may be responsible for the resistance of K562 GPI(-)cells to negative effects of MbetaCD. In addition, transduction of tumour necrosis factor-alpha (TNF-alpha) signals in a LR-dependent fashion increased induction of p38 MAPK in GPI(+) and increased pro-survival NF-kappaB levels in K562 GPI(-) cells. Therefore, we suggest that the altered LR-dependent signalling in PNH-like cells may induce different responses to pro-inflammatory cytokines from those observed in cells with intact GPI-AP.

PMID: 18544084 [PubMed - indexed for MEDLINE]

42. Br J Haematol. 2008 Jul;142(3):427-35. Epub 2008 Jun 3.

Clinical impact of HLA-DR15, a minor population of paroxysmal nocturnal haemoglobinuria-type cells, and an aplastic anaemia-associated autoantibody in children with acquired aplastic anaemia.

Yoshida N, Yagasaki H, Takahashi Y, Yamamoto T, Liang J, Wang Y, Tanaka M, Hama A, Nishio N, Kobayashi R, Hotta N, Asami K, Kikuta A, Fukushima T, Hirano N, Kojima S.

Department of Paediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Aplastic anaemia (AA) is defined as a pancytopenia caused by bone marrow failure, and its pathogenesis is thought to involve autoimmune processes. Several predictive markers of the response to immunosuppressive therapy (IST) have been proposed, which appear to reflect the immune pathophysiology. We prospectively investigated the presence of human leucocyte antigen (HLA)-DR15, a minor population of paroxysmal nocturnal haemoglobinuria (PNH)-type cells, and antibodies to the recently identified autoantigen postmeiotic segregation increased 1 (PMS1) in 103 children with AA enrolled in a multicentre study. In contrast to adults, children with AA did not show an increased frequency of HLA-DR15. In addition, a sensitive flow cytometric assay revealed that children with AA have a much lower prevalence of PNH-type cells (21.4%) than reported for adults with this disease. An immunoblotting assay detected anti-PMS1 antibody in 15 of 103 (14.6%) of the children. Finally, the response rate to IST was not significantly different between patients with and without DR15 (45.5% vs. 54.0%), PNH-type cells (68.2% vs. 53.1%) or anti-PMS1 antibody (40.0% vs. 59.1%). The current study did not confirm a correlation between these markers and the response to IST, suggesting that there is a difference in the pathophysiologies of adult and paediatric AA.

PMID: 18537977 [PubMed - indexed for MEDLINE]

43. Blood. 2008 Oct 15;112(8):3099-106. Epub 2008 Jun 5.

Paroxysmal nocturnal hemoglobinuria: natural history of disease subcategories.

de Latour RP, Mary JY, Salanoubat C, Terriou L, Etienne G, Mohty M, Roth S, de Guibert S, Maury S, Cahn JY, Socié G; French Society of Hematology; French Association of Young Hematologists.

Service d'Hématologie-Greffe, Université Paris 7, France.

The natural history of paroxysmal nocturnal hemoglobinuria (PNH) clinical subcategories (classic PNH and aplastic anemia [AA]/PNH syndrome) is still unknown. We retrospectively studied 460 PNH patients diagnosed in 58 French hematologic centers from 1950 to 2005. The median (SE) follow-up time was 6.8 (0.5) years. The median survival time (SE) was 22 (2.5) years. We identified 113 patients with classic PNH, 224 patients with AA-PNH syndrome, and 93 (22%) intermediate patients who did not fit within these 2 categories. At presentation, classic PNH patients were older, with more frequent abdominal pain and displayed higher levels of GPI-AP-deficient granulocytes. A time-dependent improved survival was observed. In classic PNH, diagnoses before 1986 (hazard ratio [HR]: 3.6; P = .01) and increasing age (P < .001) were associated with worse survival prognoses, whereas use of androgens within the first year after diagnosis was protective (HR, 0.17; P = .01). Transfusions before 1996 (HR, 2.7; P = .007) led to lower survival rates in patients with AA-PNH syndrome, whereas immunosuppressive treatment was associated with better outcomes (HR, 0.33; P = .03). Evolution to thrombosis affected survival in both subcategories (classic PNH: HR, 7.8 [P < .001]; AA-PNH syndrome: HR, 33.0 [P < .001]). Evolution to bicytopenia or pancytopenia for classic PNH (HR, 7.3, P < .001) and malignancies for AA-PNH syndrome (HR, 48.8; P < .001) were associated with worse outcomes. Although clinical presentation and prognosis factors are different, classic PNH and AA-PNH syndrome present roughly similar outcomes, affected mainly by complications.

PMID: 18535202 [PubMed - indexed for MEDLINE]

44. Biologics. 2008 Jun;2(2):205-22.

Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents.

Risitano AM, Rotoli B.

Hematology, Department of Biochemistry and Medical Biotechnologies, Federico II, University of Naples, Italy.

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal non-malignant hematological disease characterized by the expansion of hematopoietic stem cells (HSCs) and progeny mature cells, whose surfaces lack all the proteins linked through the glycosyl-phosphatidyl inositol anchor. This defect arises from an acquired somatic mutation in the X-linked phosphatidylinositol glycan class A gene, with subsequent clonal expansion of the mutated HSCs as a result of a concomitant, likely immune-mediated, selective pressure. The disease is characterized by complement-mediated chronic intravascular hemolysis, resulting in hemolytic anemia and hemosiderinuria; capricious exacerbations lead to recurrent gross hemoglobinuria. Additional cardinal manifestations of PNH are a variable degree of bone marrow failure and an intrinsic propensity to thromboembolic events. The disease is markedly invalidating, with chronic symptoms requiring supportive therapy - usually including periodical transfusions; possible life-threatening complications may also ensue. The biology of PNH has been progressively elucidated in the past few years, but therapeutic strategies remained unsatisfactory for decades, the only exception being stem cell transplantation, which is restricted to selected patients and retains significant morbidity and mortality. Recently, a biological agent to treat PNH has been developed - the terminal complement inhibitor eculizumab - which has been tested in a number of clinical trials, with exciting results. All the data from worldwide clinical trials confirm that eculizumab radically modifies the symptoms, the biology, and the natural history of PNH, strongly improving the quality of life of PNH patients.

PMCID: 2721357 PMID: 19707355 [PubMed - in process]

45. Int J Lab Hematol. 2008 Jun;30(3):248-53.

A case of paroxysmal nocturnal hemoglobinuria presenting with intra-abdominal bleeding due to splenic rupture, developing renal infarct.

Uzun S, Alpay N, Ozturk GB, Saka B, Yenerel M, Erten N, Karan MA, Taşcioglu C.

Division of General Internal Medicine, Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. drsamiuzun@gmail.com

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder characterized by intravascular hemolysis, hemoglobinuria, and thrombosis. Thrombotic attacks are life threatening and are responsible for nearly 50% of PNH-related deaths. Compared with thrombotic events, bleeding related to thrombocytopenia in PNH is quite rare. This report describes an atypical clinical presentation with problems in the diagnosis and management of a woman who presented with a splenic infarct followed by massive intra-abdominal bleeding due to splenic rupture. She also developed a renal infarct during hospitalization after diagnosis.

PMID: 18479304 [PubMed - indexed for MEDLINE]

46. Med Sci Monit. 2008 May;14(5):CR276-280.

Reduction of CD55 and/or CD59 in red blood cells of patients with HIV infection.

Terpos E, Sarantopoulos A, Kouramba A, Katsarou O, Stavropoulos J, Masouridi S, Karafoulidou A, Meletis J.

Department of Medical Research, 251 General Air Force Hospital, Athens, Greece.

BACKGROUND: Anemia is a common feature in HIV infection. An increased sensitivity of lymphocytes from HIV patients to lysis by complement has been correlated with a decreased expression of CD55 and CD59 in their surface. The aim of this study was to evaluate CD55/CD59 presence in red cells of HIV patients and explore possible correlations with clinical parameters. MATERIAL/METHODS: CD55/CD59 expression was evaluated in erythrocytes of 37 patients (30M/7F, median age: 39 years) with HIV infection (25 also having hemophilia), 121 controls, and 8 PNH patients using the sephacryl-gel microtyping system. Ham and sucrose tests were also performed. RESULTS: Anemia was present in 14/37 (37%) HIV patients. Interestingly, all HIV patients had deficient CD55 and/or CD59 erythrocytes: 8 (21%) for both CD55 andCD59 and 29 (78%) isolated CD55 and/or CD59 negativity. Deficient erythrocytes did not account for more than 10% of the total in the vast majority of patients. In controls, only 2 (1%) had red cells with double CD55/CD59 negativity and 3 (2%) had isolated deficiency. All PNH patients had a simultaneous CD55/CD59 deficiency. Positive Ham and sucrose tests were found only in PNH. There was no correlation between the presence of deficient CD55/CD59 erythrocytes and anemia, hemolysis, antiretroviral therapy, CD4+ counts, viral load, or concomitant hepatitis C infection in HIV patients. CONCLUSIONS: This study provides evidence supporting the presence of erythrocytes with CD55 and/or CD59 deficiency in HIV. Further studies using molecular techniques will be required to clarify the exact role of this deficiency in HIV patients.

PMID: 18443552 [PubMed - indexed for MEDLINE]

47. Int Ophthalmol. 2009 Jun;29(3):187-90. Epub 2008 Apr 24.

Paroxysmal nocturnal hemoglobinuria may cause retinal vascular occlusions.

Scheuerle AF, Serbecic N, Beutelspacher SC.

University Eye Hospital Heidelberg, INF 400, Heidelberg 69120, Germany. alexander.scheuerle@med.uni-heidelberg.de

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the classic triad of haemolytic anaemia, thrombophilia and cytopenia with the majority of cases occurring in adulthood. PNH constitutes a nonmalignant clonal disease of hematopoietic stem cells harboring somatic mutations in the X-linked phosphatidyl inositol glycan complementation group-A (PIG-A) gene. METHODS: We report for the first time retinal venous vascular occlusion as the primary manifestation of PNH. A patient of untypical age for retinal vascular occlusions presented with a history of 4 weeks of progressive reduction in visual acuity. RESULTS: The screening tests for thrombophilia were not successful. However, elevated LDH was detected, leading to the diagnosis of PNH. CONCLUSIONS: To date, no report shows retinal vascular occlusion as the primary symptom leading to the diagnosis PNH. This article describes, for the first time, that this rare disease needs to be considered in the differential diagnosis of retinal vascular occlusions.

PMID: 18437293 [PubMed - indexed for MEDLINE]

48. Transfusion. 2008 Jul;48(7):1403-14. Epub 2008 Apr 16.

Detailed immunophenotypic characterization of different major and minor subsets of peripheral blood cells in patients with paroxysmal nocturnal hemoglobinuria.

Hernández-Campo PM, Almeida J, Acevedo MJ, Sánchez ML, Alberca I, Vidriales B, Martínez E, Romero JR, Orfao A.

Servicio General de Citometría, Departamento de Medicina and Centro de Investigación del Cáncer, Universidad de Salamanca, Salamanca, Spain.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by a deficient expression of glycosylphosphatidylinositol-anchored proteins (GPI-APs), due to somatic mutations of the phosphatidylinositolglycan complementation Class A (PIG-A) gene. STUDY DESIGN AND METHODS: In this study, the expression of a high number of GPI-APs on different subsets of peripheral blood (PB) cells from 14 PNH patients and their potential association with underlying genetic abnormalities has been analyzed. RESULTS: This study confirms the existence of variable patterns of expression of different GPI-APs on both major and minor PB-cell subsets from PNH patients. The size of the PNH clone within PB neutrophils and monocytes was systematically higher than that of other cell populations. Genetic changes were detected in the PIG-A gene in 5 of 13 cases analyzed. Interestingly, the reactivity for many GPI-APs was significantly higher on different subsets of normal PB cells from PNH patients than those observed on healthy volunteers. CONCLUSION: The best combination of markers for the diagnostic screening of PNH would include evaluation of CD14 on monocytes and of CD16 on neutrophils, although further analysis of CD55 and CD59 expression may contain additional clinically useful information. Clear association between the genetic changes detected in the PIG-A gene in 5 of 13 cases analyzed, and the phenotypic profile of PNH cells has not been found. Additionally, an abnormally higher expression of several GPI-APs among normal residual cells from PNH patients in comparison to healthy donors was observed, suggesting that factors other than the PIG-A mutation could determine the phenotypic profile of PB cells in PNH.

PMID: 18422849 [PubMed - indexed for MEDLINE]

49. Hum Immunol. 2008 Mar;69(3):202-6. Epub 2008 Mar 10.

Paroxysmal nocturnal hemoglobinuria: significant association with specific HLA-A, -B, -C, and -DR alleles in an Italian population.

Lombardi ML, Terrazzano G, Cosentini E, Gargiulo L, Risitano A, Camerlingo R, Sica M, Aufiero D, Poggi A, Pirozzi G, Luzzatto L, Rotoli B, Notaro R, Alfinito F, Ruggiero G.

Dipartimento di Oncologia Sperimentale, Istituto Nazionale Tumori di Napoli, Napoli, Italy.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the expansion of a PIG-A mutated hematopoietic stem cell. An immune-mediated origin has been suggested for this disease. Because HLA genes represent a susceptibility factor for autoimmunity, we investigated HLA genotype in 42 Italian PNH patients compared with 301 control subjects of the same ethnic origin. A significantly increased frequency of the HLA class I alleles A*0201 (p < 0.05), B*1402 (p < 0.001), and Cw*0802 (p < 0.005), and of the HLA class II DRB1*1501 (p < 0.01) with the linked DQB1*0602 (p

PMID: 18396213 [PubMed - indexed for MEDLINE]

50. Malays J Pathol. 2006 Dec;28(2):107-12.

Assessing donor chimerism using flow cytometry in paroxysmal nocturnal haemoglobinuria after stem cell transplantation--a case report.

Azma RZ, Hamidah NH, Leong CF, Ainoon O, Cheong SK.

Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia. zahratul@mail.hukm.ukm.my

Paroxysmal nocturnal haemoglobinuria (PNH) is an acquired haemopoietic stem cell disorder arising from somatic mutation of the X-linked PIG-A gene which leads to deficiency of the glycosylphosphatidylinositol (GP1) membrane anchor proteins such as CD 59 (MIRL: membrane inhibitor of reactive lysis) and CD 55 (DAF: decay accelerating factor). Allogeneic peripheral blood stem cell transplant (PBSCT) is a curative mode of treatment in symptomatic PNH patients. Assessment of donor chimerism for PBSCT can be performed by various methods including short tandem repeat loci (STR) and variable number of tandem repeats (VNTR). Flow cytometry, which is much cheaper and faster, also can be used to assess engraftment in patients with PNH. Engrafted patients will show the presence of CD 55 and CD 59 on their red cells and white cells. We describe here the usefulness of flow cytometry in the assessment of donor chimerism following allogeneic PBSCT, in a case of PNH.

PMID: 18376800 [PubMed - indexed for MEDLINE]

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