Autoimmune Processes as an Important Parameter for the Pathogenesis of Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

Bone marrow (BM) hypoplasia is a major cause of death in paroxysmal nocturnal hemoglobinuria (PNH). However, little is known about the molecular events leading to the hypoplasia. Considering the close pathologic association between PNH and aplastic anemia (AA), it is suggested that a similar mechanism operates in the development of their BM failure. Recent reports have indicated apoptosis-mediated BM suppression in AA. It is thus conceivable that apoptosis also operates to cause BM hypoplasia in PNH. If this is the case, PNH clones need to survive apoptosis and show considerable expansion leading to clinical manifestations. We report here that granulocytes obtained from 11 patients with PNH were apparently less susceptible than those from 20 healthy individuals to both spontaneous apoptosis without any ligands and that induced by anti-FAS (CD95) antibody in vitro. The patients' BM CD34+ cells were also resistant to apoptosis induced by treatment with tumor necrosis factor-α, interferon-γ, and subsequently with anti-FAS antibody. In lymphocytes, the pathologic resistance was not discriminated from inherent resistance to apoptosis. Granulocytes from 13 patients with AA and 12 patients with myelodysplastic syndrome (MDS) exhibited similar resistance to apoptosis. CD34+ cells from MDS-BM also showed similar tendency. Thus, the comparative resistance to apoptosis supports the pathogenic implication of apoptosis in marrow injury of PNH and related stem cell disorders.

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Paroxysmal Nocturnal Hemoglobinuria Clones Are Infrequent in Hepatitis-Associated Aplastic Anemia at the Time of Diagnosis

Blood ◽

10.1182/blood-2019-125620 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5016-5016

Author(s):

Wenrui Yang ◽

Xin Zhao ◽

Guangxin Peng ◽

Li Zhang ◽

Liping Jing ◽

...

Keyword(s):

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Clonal Evolution ◽

Extrinsic Factors ◽

Clone Size ◽

Hematopoietic Stem ◽

Over Time ◽

Pnh Clone

Aplastic anemia (AA) is an immune-mediated bone marrow failure, resulting in reduced number of hematopoietic stem and progenitor cells and pancytopenia. The presence of paroxysmal nocturnal hemoglobinuria (PNH) clone in AA usually suggests an immunopathogenesis in patients. However, when and how PNH clone emerge in AA is still unclear. Hepatitis associated aplastic anemia (HAAA) is a special variant of AA with a clear disease course and relatively explicit immune pathogenesis, thus serves as a good model to explore the emergence and expansion of PNH clone. To evaluate the frequency and clonal evolution of PNH clones in AA, we retrospectively analyzed the clinical data of 90 HAAA patients that were consecutively diagnosed between August 2006 and March 2018 in Blood Diseases Hospital, and we included 403 idiopathic AA (IAA) patients as control. PNH clones were detected in 8 HAAA patients (8.9%,8/90) at the time of diagnosis, compared to 18.1% (73/403) in IAA. Eight HAAA patients had PNH clone in granulocytes with a median clone size of 3.90% (1.09-12.33%), and 3 patients had PNH clone in erythrocytes (median 4.29%, range 2.99-10.8%). Only one HAAA patients (1/8, 12.5%) had a PNH clone larger than 10%, while 24 out of 73 IAA patients (32.9%) had larger PNH clones. Taken together, we observed a less frequent PNH clone with smaller clone size in HAAA patients, compared to that in IAAs. We next attempted to find out factors that associated with PNH clones. We first split patients with HAAA into two groups based on the length of disease history (≥3 mo and < 3mo). There were more patients carried PNH clone in HAAA with longer history (21.4%, 3/14) than patients with shorter history (6.6%, 5/76), in line with higher incidence of PNH clone in IAA patients who had longer disease history. Then we compared the PNH clone incidence between HAAA patients with higher absolute neutrophil counts (ANC, ≥0.2*109/L) and lower ANC (< 0.2*109/L). Interestingly, very few VSAA patients developed PNH clone (5%, 3/60), while 16.7% (5/30) of non-VSAA patients had PNH clone at diagnosis. We monitored the evolution of PNH clones after immunosuppressive therapy, and found increased incidence of PNH clone over time. The overall frequency of PNH clone in HAAA was 20.8% (15/72), which was comparable to that in IAA (27.8%, 112/403). Two thirds of those new PNH clones occurred in non-responders in HAAA. In conclusion, PNH clones are infrequent in HAAA compared to IAA at the time of diagnosis, but the overall frequency over time are comparable between the two groups of patients. In SAA/VSAA patients who are under the activated abnormal immunity, longer clinical course and relatively adequate residual hematopoietic cells serve as two important extrinsic factors for HSCs with PIGA-mutation to escape from immune attack and to expand. Disclosures No relevant conflicts of interest to declare.

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Adolescent with Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria

Leukemia Research ◽

10.1016/s0145-2126(17)30346-6 ◽

2017 ◽

Vol 55 ◽

pp. S134-S135

Author(s):

G. García-Donas ◽

E. Arbelo ◽

C. Muñiz ◽

K. Kestler ◽

N. Dominguez ◽

...

Keyword(s):

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria

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Aplastic Anemia, Paroxysmal Nocturnal Hemoglobinuria, and Pure Red Cell Aplasia

Evidence-Based Hematology ◽

10.1002/9781444300857.ch23 ◽

2009 ◽

pp. 189-196

Author(s):

Shivani Srivastava ◽

Richard W. Childs

Keyword(s):

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Pure Red Cell Aplasia ◽

Red Cell ◽

Red Cell Aplasia

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Impaired Hematopoiesis in Paroxysmal Nocturnal Hemoglobinuria/Aplastic Anemia Is Not Associated With a Selective Proliferative Defect in the Glycosylphosphatidylinositol-Anchored Protein-Deficient Clone

Blood ◽

10.1182/blood.v89.4.1173 ◽

1997 ◽

Vol 89 (4) ◽

pp. 1173-1181 ◽

Cited By ~ 84

Author(s):

Jaroslaw P. Maciejewski ◽

Elaine M. Sloand ◽

Tadatsugu Sato ◽

Stacie Anderson ◽

Neal S. Young

Keyword(s):

Protein Expression ◽

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Surface Proteins ◽

In Vitro Assays ◽

Normal Numbers ◽

Normal Volunteers ◽

Cd34 Cells ◽

Cd59 Expression

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) results from somatic mutations in the PIG-A gene, leading to poor presentation of glycosylphosphatidylinositol (GPI)-anchored surface proteins. PNH frequently occurs in association with suppressed hematopoiesis, including frank aplastic anemia (AA). The relationship between GPI-anchored protein expression and bone marrow (BM) failure is unknown. To assess the hematopoietic defect in PNH, the numbers of CD34+ cells, committed progenitors (primary colony-forming cells [CFCs]), and long-term culture-initiating cells (LTC-ICs; a stem cell surrogate) were measured in BM and peripheral blood (PB) of patients with PNH/AA syndrome or patients with predominantly hemolytic PNH. LTC-IC numbers were extrapolated from secondary CFC numbers after 5 weeks of culture, and clonogenicity of LTC-ICs was determined by limiting dilution assays. When compared with normal volunteers (n = 13), PNH patients (n = 14) showed a 4.7-fold decrease in CD34+ cells and an 8.2-fold decrease in CFCs. LTC-ICs in BM and in PB were decreased 7.3-fold and 50-fold, respectively. Purified CD34+ cells from PNH patients had markedly lower clonogenicity in both primary colony cultures and in the LTC-IC assays. As expected, GPI-anchored proteins were decreased on PB cells of PNH patients. On average, 23% of monocytes were deficient in CD14, and 47% of granulocytes and 58% of platelets lacked CD16 and CD55, respectively. In PNH BM, 27% of CD34+ cells showed abnormal GPI-anchored protein expression when assessed by CD59 expression. To directly measure the colony-forming ability of GPI-anchored protein-deficient CD34+ cells, we separated CD34+ cells from PNH patients for the GPI+ and GPI− phenotype; CD59 expression was chosen as a marker of the PNH phenotype based on high and homogeneous expression on fluorescent staining. CD34+CD59+ and CD34+CD59− cells from PNH/AA patients showed similarly impaired primary and secondary clonogeneic efficiency. The progeny derived from CD34+CD59− cells were both CD59− and CD55−. A very small population of CD34+CD59− cells was also detected in some normal volunteers; after sorting, these CD34+CD59− cells formed normal numbers of colonies, but their progeny showed lower CD59 levels. Our results are consistent with the existence of PIG-A–deficient clones in some normal individuals. In PNH/AA, progenitor and stem cells are decreased in number and function, but the proliferation in vitro is affected similarly in GPI-protein–deficient clones and in phenotypically normal cells. As measured in the in vitro assays, expansion of PIG-A– clones appears not be caused by an intrinsic growth advantage of cells with the PNH phenotype.

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Hemopoietic Stem Cell Transplantation (HSCT) for Paroxysmal Nocturnal Hemoglobinuria (PNH) and Acquired Severe Aplastic Anemia (SAA): a report from the SAA Working Party of the European Blood and Marrow Transplant group (EBMT)

Paroxysmal Nocturnal Hemoglobinuria and Related Disorders ◽

10.1007/978-4-431-67867-0_18 ◽

2003 ◽

pp. 211-217

Author(s):

Andrea Bacigalupo ◽

◽

Rosi Oneto ◽

Barbara Bruno

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Working Party ◽

Marrow Transplant ◽

Hemopoietic Stem Cell ◽

Blood And Marrow Transplant ◽

Hemopoietic Stem Cell Transplantation ◽

Acquired Severe Aplastic Anemia

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Progressive, purpuric nodules on a patient with aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH)

Journal of the American Academy of Dermatology ◽

10.1016/j.jaad.2019.06.1141 ◽

2019 ◽

Vol 81 (4) ◽

pp. AB259

Keyword(s):

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria

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Development of a patient-reported outcome questionnaire for aplastic anemia and paroxysmal nocturnal hemoglobinuria (PRO-AA/PNH)

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-020-01532-3 ◽

2020 ◽

Vol 15 (1) ◽

Author(s):

Kimmo Weisshaar ◽

Hannah Ewald ◽

Jörg Halter ◽

Sabine Gerull ◽

Sandra Schönfeld ◽

...

Keyword(s):

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Patient Reported Outcome ◽

Phase Iii ◽

Specific Patient ◽

Patient Reported ◽

Related Quality ◽

Health Related ◽

Core Symptoms ◽

Missing Items

Abstract Background The introduction of new therapy modalities has significantly improved the outcome of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) patients. However, relatively little is known about the exact disease burden of AA/PNH since standardized assessments of symptoms including health-related quality of life (HRQoL) are frequently missing or inadequately designed for this rare patient group. We aimed to develop AA/PNH-specific questionnaires for self-reporting of symptoms, which could be included in electronic platforms for data collection and patient care. Methods By scoping review, we extracted any reported symptoms in AA/PNH and their prevalence from the literature (Phase I). Consensus rounds with patients and medical experts were conducted to identify core symptoms reported in the literature and to add missing items (Phase II). Ultimately, AA/PNH-specific patient-reported outcome (PRO) questionnaires including the selected measures were designed (Phase III). Results AA symptoms from 62 and PNH symptoms from 45 observational studies were extracted from the literature. Twenty-four patients and seven medical experts identified 11 core symptoms including HRQoL issues after three consensus rounds. Significant differences in the symptom ranking of patients versus medical experts could be observed. Therefore, patient- as well as expert-centered PRO questionnaires in AA and PNH were created following the concepts of validated instruments. Conclusion The development of symptom self-reporting questionnaires for AA and PNH was feasible and the disease-specific PRO questionnaires can now be validated within a web-based workflow in a subsequent feasibility study.

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