Glucocorticoid-induced thrombotic microangiopathy in paroxysmal nocturnal hemoglobinuria:A case report and review of literature

BACKGROUND Thrombotic microangiopathy(TMA)is a group of disorders that converge on excessive platelet aggregation in the microvasculature,leading to consumptive thrombocytopenia,microangiopathic hemolysis and ischemic end-organ dysfunction.In predisposed patients,TMA can be triggered by many environmental factors.Glucocorticoids(GCs)can compromise the vascular endothelium.However,GC-associated TMA has rarely been reported,which may be due to the lack of awareness of clinicians.Given the high frequency of thrombocytopenia during GC treatment,particular attention should be given to this potentially fatal complication.CASE SUMMARY An elderly Chinese man had a 12-year history of aplastic anemia(AA)and a 3-year history of paroxysmal nocturnal hemoglobinuria(PNH).Three months earlier,methylprednisolone treatment was initiated at 8 mg/d and increased to 20 mg/d to alleviate complement-mediated hemolysis.Following GC treatment,his platelet counts and hemoglobin levels rapidly decreased.After admission to our hospital,the dose of methylprednisolone was increased to 60 mg/d in an attempt to enhance the suppressive effect.However,increasing the GC dose did not alleviate hemolysis,and his cytopenia worsened.Morphological evaluation of the marrow smears revealed increased cellularity with an increased percentage of erythroid progenitors without evident dysplasia.Cluster of differentiation(CD)55 and CD59 expression was significantly decreased on erythrocytes and granulocytes.In the following days,platelet transfusion was required due to severe thrombocytopenia.Observation of platelet transfusion refractoriness indicated that the exacerbated cytopenia may have been caused by the development of TMA due to GC treatment because the transfused platelet concentrates had no defects in glycosylphosphatidylinositol-anchored proteins.We examined blood smears and found a small number of schistocytes,dacryocytes,acanthocytes and target cells.Discontinuation of GC treatment resulted in rapidly increased platelet counts and steady increases in hemoglobin levels.The patient’s platelet counts and hemoglobin levels returned to the levels prior to GC treatment 4 weeks after GC discontinuation.CONCLUSION GCs can drive TMA episodes.When thrombocytopenia occurs during GC treatment,TMA should be considered,and GCs should be discontinued.

Leukemic transformation during anti-tuberculosis treatment in aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome:A case report and review of literature

BACKGROUND Accumulating evidence demonstrates that autoimmune hematopoietic failure and myeloid neoplasms have an intrinsic relationship with regard to clonal hematopoiesis and disease evolution.In approximately 10%-15%of patients with severe aplastic anemia(SAA),the disease phenotype is transformed into myeloid neoplasms following antithymocyte globulin plus cyclosporine-based immunosuppressive therapy.In some of these patients,myeloid neoplasms appear during or shortly after immunosuppressive therapy.Leukemic transformation in SAA patients during anti-tuberculosis treatment has not been reported.CASE SUMMARY A middle-aged Chinese female had a 6-year history of non-SAA and a 2-year history of paroxysmal nocturnal hemoglobinuria(PNH).With aggravation of systemic inflammatory symptoms,severe pancytopenia developed,and her hemoglobinuria disappeared.Laboratory findings in cytological,immunological and cytogenetic analyses of bone marrow samples met the diagnostic criteria for“SAA.”Definitive diagnosis of disseminated tuberculosis was made in the search for infectious niches.Remarkable improvement in hematological parameters was achieved within 1 mo of anti-tuberculosis treatment,and complete hematological remission was achieved within 4 mo of treatment.Frustratingly,the hematological response lasted for only 3 mo,and pancytopenia reemerged.At this time,cytological findings(increased bone marrow cellularity and an increased percentage of myeloblasts that accounted for 16.0%of all nucleated hematopoietic cells),immunological findings(increased percentage of cluster of differentiation 34+cells that accounted for 12.28%of all nucleated hematopoietic cells)and molecular biological findings(identification of somatic mutations in nucleophosmin-1 and casitas B-lineage lymphoma genes)revealed that“SAA”had transformed into acute myeloid leukemia with mutated nucleophosmin-1.The transformation process suggested that the leukemic clones were preexistent but were suppressed in the PNH and SAA stages,as development of symptomatic myeloid neoplasm through acquisition and accumulation of novel oncogenic mutations is unlikely in an interval of only 7 mo.Aggravation of inflammatory stressors due to disseminated tuberculosis likely contributed to the repression of normal and leukemic hematopoiesis,and the relief of inflammatory stressors due to anti-tuberculosis treatment contributed to penetration of neoplastic hematopoiesis.The concealed leukemic clones in the SAA and PNH stages raise the possibility of an inflammatory stress-fueled antileukemic mechanism.CONCLUSION Aggravated inflammatory stressors can repress normal and leukemic hematopoiesis,and relieved inflammatory stressors can facilitate penetration of neoplastic hematopoiesis.

Construction of gene/protein interaction networks and enrichment pathway analysis for paroxysmal nocturnal hemoglobinuria and aplastic anemia

Background:To develop a protein-protein interaction network of Paroxysmal nocturnal hemoglobinuria(PNH)and Aplastic anemia(AA)based on genetic genes and to predict pathways underlying the molecular complexes in the network.Methods:In this research,the PNH and AA-related genes were screened through Online Mendelian Inheritance in Man(OMIM).The plugins and Cytoscape were used to search literature and build a protein-protein interaction network.Results:The protein-protein interaction network contains two molecular complexes that are five higher than the correlation integral values.The target genes of this study were obtained:CD59,STAT3,TERC,TNF,AKT1,C5AR1,EPO,IL6,IL10 and so on.We also found that many factors regulate biological behaviors:neutrophils,macrophages,vascular endothelial growth factor,immunoglobulin,interleukin,cytokine receptor,interleukin-6 receptor,tumor necrosis factor,and so on.This research provides a bioinformatics foundation for further explaining the mechanism of common development of both.Conclusion:This indicates that the PNH and AA is a complex process regulated by many cellular pathways and multiple genes.

Allogeneic stem cell transplantation-A curative treatment for paroxysmal nocturnal hemoglobinuria with PIGT mutation:A case report

BACKGROUND Patients with paroxysmal nocturnal hemoglobinuria(PNH)have a clonal population of blood cells deficient in glycosylphosphatidylinositol-anchored(GPIanchored)proteins,most of the time resulting from a mutation in the X-linked gene PIGA.We report a patient with PNH resulting from a rare biallelic PIGT mutation on chromosome 20.CASE SUMMARY A 47-year-old man was referred to our hospital for febrile pancytopenia.The patient reported a history of recurrent urticaria and arthralgia and he presented during 3 mo recurrent acute dermo-hypodermitis and aseptic meningitidis.Based on clinical cases published with PIGT-PNH,with clinically typical PNH and autoinflammatory symptoms,we treated our patients with repeated infusions of eculizumab to decrease autoinflammatory symptoms and then we performed an allogeneic stem cell transplantation(allo-SCT)with a mismatched unrelated donor.Our patient experienced no acute Graft vs Host disease(GvHD)and a moderate chronic GvHD and is now considered cured at 24 mo after allo-SCT.CONCLUSION This case report suggests that allo-SCT should be considered to cure PIGT-PNH patients.

Posthepatectomy jaundice induced by paroxysmal nocturnal hemoglobinuria: A case report

BACKGROUND Jaundice is a major manifestation of posthepatectomy liver failure,a feared complication after hepatic resection.Herein,we report a case of posthepatectomy jaundice that was not caused by liver failure but by paroxysmal nocturnal hemoglobinuria(PNH)-induced hemolysis.CASE SUMMARY A 56-year-old woman underwent right hepatectomy and biliary tract exploration surgery due to hepatic duct stones.Prior to surgery,the patient was mildly anemic.The direct antiglobulin test was negative.A bone marrow biopsy showed mild histiocyte hyperplasia.After surgery,the patient suffered a progressive increase in serum bilirubin.Meanwhile,the patient developed hemolytic symptoms after blood transfusion.She was ultimately diagnosed with PNH.PNH is a rare bone marrow failure disorder that manifests as complement-dependent intravascular hemolysis with varying severity.After steroid treatment,the patient’s jaundice gradually decreased,and the patient was discharged on the 35th postoperative day.CONCLUSION PNH-induced hemolysis is a rare cause of posthepatectomy jaundice.It should be suspected in patients having posthepatectomy hyperbilirubinemia without other signs of liver failure.Steroid therapy can be considered for the treatment of PNH in such cases.

Association analysis of cytokine polymorphisms and plasma level in Northern Chinese Han patients with paroxysmal nocturnal hemoglobinuria

Background While the incidence of paroxysmal nocturnal hemoglobinuria （PNH） is relatively high in Northern China, the exact mechanism of the disease remains unknown. Immunoregulatory cytokine polymorphisms can directly regulate the expression levels of cytokines, which play a crucial role in many diseases. The purpose of this study was to study cytokine gene single nucleotide polymorphisms （SNPs） and the correlated cytokine expression levels in relationship to the PNH pathogenesis.Methods Peripheral blood samples were collected from 30 PNH patients and 40 healthy donors; all of the samples were collected from the Han people of Northern China. Eight SNP loci in five cytokine genes, including tumor necrosis factor-αlpha （TNF-α）, interferon-γamma （IFN-γ）, transforming growth factor-βeta （TGF-β）, interleukin-6 （IL-6）, and IL-10, and aplastic anemia （AA） were assessed. TNF-α, TGF-β, IFN-γ, IL-6, and IL-10 were analyzed by sequence-specific primer polymerase chain reaction （PCR-SSP）. The plasma protein levels of TNF-α, TGF-β, and IFN-γ were assessed by an ELISA.Results The PNH patients had a lower frequency of the TC/GG genotype of the TGF-β gene （P 〈0.01） and a higher frequency of the C allele in the TGF-β gene （＋10） compared to the controls （P 〈0.05）. The predominant genotype of the ＋874 locus of the IFN-γ gene was TA in the PNH patients, while that in the predominant genotype was AA in the control group and was statistically significant （P 〈0.001）. The frequency of the T allele in the IFN-γ gene was dramatically higher in the PNH patients than in the controls （P 〈0.05）. The PNH patients had a reduced frequency of the GC and CC genotypes, as well as the C allele at locus –174 of the IL-6 gene compared to the controls （P 〈0.01）. In addition, the plasma concentrations of TNF-α, TGF-β, and IFN-γ were significantly higher in the PNH group compared to the control group （P 〈0.01）.Conclusions Expression levels of the TNF-α, TGF-β, and IFN-γ cytokines play an important role in PNH. The GC and CC genotypes, as well as the C allele of the IL-6 gene may protect the Han people of Northern China against PNH. Additionally, the TC/GG genotype of the TGF-β gene may be the protective allele. In contrast, the TA genotype and the T allele for the IFN-γ gene, as well as the C allele of TGF-β may be susceptible to PNH. However, SNPs in the TNF-α and IL-10 genes did not correlate with PNH development. Alternatively, the increased plasma concentrations of TNF-α, TGF-β, and IFN-γ in PNH patients may also be related to PNH development.

Detection of CD59-deficient granulocytes in a patient with advanced myelodysplastic syndrome

Aplastic anemia （AA）, myelodysplastic syndrome （MDS）, and paroxysmal noctumal hemoglobinuria （PNH） are bone marrow failure disorders closely related to each other. PNH often occurs in the course of AA or MDS-refractory anemia （RA）. Acquired AA patients, particularly with PNH clones, have benefited from the immunosuppressive therapy （IST）. Although the possible immune abnormality was not considered as the core mechanism in MDS pathology,1 MDS-RA cases with PNH clones also reflected a high probability of response to IST. We report here one rare case of advanced MDS with PNH clones diagnosed by flow cytometry （FCM）.