Efficacy of anti-thymocyte globulin and cyclosporin A combined therapy in aplastic anemia complicated with limited cutaneous systemic sclerosis]

We reported here on a case of limited cutaneous systemic sclerosis (lcSSc) with aplastic anemia treated by anti-thymocyte globulin and cyclosporin A. The use of this therapy resulted not only in marrow recovery but also in resolution of the skin sclerosis. A 68 year-old woman was diagnosed as lcSSc accompanied by Hashimoto's thyroiditis and primary biliary cirrhosis. Treatment by D-penicillamine was started. After 11 months, She complained of nasal bleeding and subcutaneous bleeding. Her laboratory data revealed pancytopenia. White blood cell count, hemoglobin concentration and platelet count were decreased at 2300/microl, 8.2 g/dl, and 3000/microl respectively. Bone marrow was severely hypoplastic, suggesting aplastic anemia. The etiology of hypopastic marrow was considered to be D-penicillamine which had been frequently reported to cause hematopoietic cell suppression. We immediately started methylprednisolone pulse therapy combined with G-CSF and cyclosporin A, which showed little effectiveness. Next we tried the anti-thymocyte globulin therapy combined with G-CSF and cyclosporin A. Her blood cell counts gradually improved. After 4 months, she did not need the blood transfusion anymore. Furthermore, the sclerosis of her skin began to improve gradually, and the titer of anti-centromere antibody also decreased. Thus, anti-thymocyte globulin and cyclosporin A combined therapy can be considered among the therapies of systemic sclerosis.     

Membranous nephropathy after allogeneic hematopoietic stem cell transplantation in a patient with aplastic anemia: a case report

Nephrotic syndrome has been described as one of the clinical forms of chronic graft-versus-host disease (cGVHD), but a limited number of cases have been described. We experienced a young female patient with nephrotic syndrome developed 22 months after allogeneic hematopoietic stem cell transplantation (HSCT) for severe aplastic anemia. She had been well after successful management for gut-limited cGVHD until she developed a clinical nephrotic syndrome with hypoalbuminemia of 2.0 g/dL and 24-hr urine protein of 6.88 g/dL. On physical examination and laboratory findings, there was no other evidence of cGVHD. Clinical and renal biopsy findings were consistent with cGVHD-related membranous nephropathy, and immunosuppressive agents with cyclosporine and prednisone were prescribed. After 3 month of treatment, the proteinuria decreased to normal range; and the patient from nephrotic syndrome nearly recovered. We recommend cGVHD-related glomerulonephritis should be considered in all patients with hypoalbuminemia following allogeneic HSCT, even if there is no other evidence of clinical GVHD.     

再障患者细胞因子与对应血象三系水平测定的临床意义

目的：评价再障患者外周血象白细胞（WBC）、红细胞（RBC）、血小板（PLT）三系数量与其各自对应的细胞因子水平的关系，探讨细胞因子对再生障碍性贫血（AA）发病的影响及其临床意义。方法：用放射免疫分析检测外周血中粒细胞-巨噬细胞集落刺激因子（GM—CSF）、白细胞介素-2（IL-2）、血小板生成素（TPO）水平；用化学发光免疫法检测外周血促红细胞生成素（EPO）；用全自动五分类血球计数仪检测血象。统计：所有数据采用SPSS10．0统计软件处理。结果：AA组外周血中WBC数：量、RBC数量、PLT数量及白细胞因子GM—CSF（P〈0．05）水平明显低于正常对照组；而IL-2、EPO、TPO（P〈0．05）细胞因子水平均明显高于正常对照组；GM—CSF与外周血WBC有正相关性，EPO与外周血RBC有一定的负相关性；TPO与PLT亦呈负相关。结论：再障患者外周血象兰系数量与对应细胞因子水平有一定的相关性。     

Anemia prevalence and associated risk factors in a single-center ambulatory HIV clinical cohort

The prevalence of anemia in HIV-infected persons has not been well characterized in the HAART era. In a single-center, retrospective study, anemia prevalence and risk factors, including use of HAART, were assessed in an ambulatory clinical cohort of 758 HIV-infected patients for the calendar year 2000. The relationships between anemia (hemoglobin level less than 12.5 g/dL) and demographic variables, antiretroviral treatment regimens, and disease markers were analyzed. Mean baseline patient characteristics were hemoglobin level, 13.7 +/- 1.9 g/dL; CD4+ cell count, 405 +/- 293/microL; and HIV RNA level, 77,841 +/- 148,394 copies/mL. Overall anemia prevalence was 30.3%. Multivariate logistic regression analysis demonstrated that anemia was associated with a CD4+ cell count below 50/microL, female sex, black race, a viral load above 100,000 copies/mL, zidovudine use, and older age. Severe anemia was less prevalent in this study population than in historical comparators; however, mild to moderate anemia rates remain high.     

Severe aplastic anemia induced by ticlopidine: report of two cases.

Aplastic anemia is a rare side-effect associated with ticlopidine therapy. We report two cases of severe aplastic anemia developed after the use of ticlopidine. A 51-year-old woman took ticlopidine at 500 mg/day for 49 days to prevent a secondary stroke. She developed fever and dizziness within 49 days of initiating ticlopidine therapy. A 70-year-old woman was started on ticlopidine after coronary stent insertion. Fifty days after starting ticlopidine, she developed fever and dizziness. Both patients showed pancytopenia and were diagnosed as aplastic anemia which were confirmed by bone marrow examination. Both patients were hospitalized and received antibiotics, blood products and hematopoietic growth factors. Four and seven weeks after the withdrawal of ticlopidine, the hematologic parameters of each patient improved. A complete blood count should be monitored during ticlopidine therapy to check for cytopenia.     

Posttransplant thrombopoiesis predicts survival in patients undergoing autologous hematopoietic progenitor cell transplantation.

The frequency and clinical significance of secondary thrombocytopenia following initial engraftment in autologous hematopoietic progenitor cell transplantation (HPCT) is unknown. An institutional review board approved retrospective study of thrombopoiesis was performed in 359 patients transplanted with autologous blood (97%) or marrow (3%) who achieved platelet engraftment to >50,000/microL. Idiopathic secondary posttransplant thrombocytopenia (ISPT) was defined as >50% decline in blood platelets to <100,000/microL in the absence of relapse or sepsis. ISPT occurred at a median of day +35 posttransplant in 17% of patients. Patients with ISPT had similar initial platelet engraftment (median 17 days) versus non-ISPT patients (18 days; P=NS) and recovered platelet counts (median 123,00 K/microL) by day 110 posttransplant. Four factors were independently associated with post-transplant death in a multivariate model: disease status at transplant; the number of prior chemotherapy regimens, failure to achieve a platelet count of >150,000/microL posttransplant, and the occurrence of ISPT. A prognostic score was developed based upon the occurrence of ISPT and posttransplant platelet counts of <150,000/microL. Survival of patients with both factors (n=25) was poor (15% alive at 5 years); patients with 1 factor (n=145) had 49% 5-year survival; patients with 0 factors (n=189) had 72% 5-year survival. Patients who failed to achieve a platelet count of >150,000/microL received significantly fewer CD34+ cells/kg (P<.001), whereas patients with ISPT received fewer CD34+CD38- cells/kg (P=.0006). The kinetics of posttransplant thrombopoiesis is an independent prognostic factor for long-term survival following autologous HPC. ISPT and lower initial posttransplant platelet counts reflect poor engraftment with long-term and short-term repopulating CD34+ hematopoietic stem cells, respectively, and are associated with an increased risk of death from disease relapse.     

异基因造血干细胞移植治疗重型再生障碍性贫血

背景：近年来随着造血干细胞移植技术的提高和免疫抑制剂的使用,重型再生障碍性贫血的治疗效果有了明显改善,尤其是亲缘间HLA配型全相合异基因造血干细胞移植,取得了较高的治愈率。 目的：观察异基因造血干细胞移植治疗重型再生障碍性贫血的疗效。 方法：自2009至2011年采用异基因造血干细胞移植治疗重型再生障碍性贫血患者20例,HLA配型全相合12例,不全相合8例。移植预处理采用氟达拉滨+兔抗人胸腺细胞免疫球蛋白+环磷酰胺。除1例为非血缘外周血干细胞移植外,其他患者干细胞来源为动员后的骨髓和外周血干细胞联合移植。HLA全相合移植物抗宿主病预防采用环孢素联合短程甲氨蝶呤,不全相合患者采用环孢素、短程甲氨蝶呤联合吗替麦考酚酸酯。 结果与结论：移植后中性粒细胞恢复> 0.5×109 L-1平均为12.5 d,血小板恢复> 20×109 L-1平均为+18 d。20例患者随访24-60个月,总生存率75%(15例),治愈率70%(14例),死亡5例;12例全相合患者中83%治愈(10例),8例不全相合患者治疗有效率62%(5例),治愈率50%(4例)。20例患者中发生急性及慢性移植物抗宿主病5例,治疗中并发败血症4例,侵袭性真菌感染3例。结果可见异基因干细胞移植是治疗重型再生障碍性贫血的有效方法之一,尤以HLA全相合效果良好,移植后恢复快,移植物抗宿主病发生率低。中国组织工程研究杂志出版内容重点：干细胞;骨髓干细胞;造血干细胞;脂肪干细胞;肿瘤干细胞;胚胎干细胞;脐带脐血干细胞;干细胞诱导;干细胞分化;组织工程全文链接：     

Secondary failure of platelet recovery after hematopoietic stem cell transplantation.

After primary recovery of platelet counts after transplantation, there can be a late persistent decline called secondary failure of platelet recovery (SFPR), which may occur although the counts of other cell lineages remain within the normal range. SFPR was defined as a decline of platelet counts below 20,000/microL for 7 consecutive days or requiring transfusion support after achieving sustained platelet counts > or = 50,000/microL without transfusions for 7 consecutive days after hematopoietic stem cell transplantation (HSCT). The study population consisted of 2871 consecutive patients receiving transplants from January 1990 to March 1997. After primary recovery of platelet counts, SFPR not due to relapse of the underlying disease was observed in 285 of 1401 (20%) patients undergoing allogeneic transplantation and 36 (8%) of 444 patients undergoing autologous transplantation, with a median time of onset after transplantation at day 63 (range, day 21-156) and day 44 (range, day 24-89), respectively. Concomitant neutropenia was seen in 57 (20%) of 285 patients undergoing allogeneic HSCT and 7 (19%) of 36 patients undergoing autologous HSCT with SFPR. By multivariable analysis, the following were factors significantly associated with SFPR after allogeneic HSCT: a transplant from an unrelated donor; a graft-versus-host disease (GVHD) prophylaxis other than methotrexate and cyclosporine; development of grade 2 through 4 acute GVHD; impaired renal or liver function; conditioning with the combination of busulfan, cyclophosphamide, and total body irradiation; stem cell dose; and infections. Cytomegalovirus infection after engraftment and source of stem cells were the only significant risk factors after autologous HSCT. The hazard rate of death was significantly higher in patients who experienced SFPR (hazard ratio = 2.6 for allogeneic HSCT; hazard ratio = 2.2 for autologous HSCT). SFPR was associated with serious complications and poor outcome after transplantation. The identification of the characteristics and risk factors for SFPR could improve patient counseling and management and lead to the design of effective treatment strategies.     

Eltrombopag for Post-Transplant Poor Graft Function in East Asian Patients

Poor graft function (PGF) is a serious, potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation. Eltrombopag has shown multilineage responses in patients with refractory severe aplastic anemia, supporting the idea that it may improve cytopenia in patients with PGF. This retrospective, single center analysis included 8 Korean patients receiving eltrombopag for PGF. Median interval between transplant and eltrombopag treatment was 73 days, and the median duration treatment was 3.5 weeks. With median maximum daily dose of 50 mg, the time to best response was 93 days. Median hemoglobin increased from 8.2 g/dL to 10.9 g/dL, platelet from 18.5 × 10⁹/L to 54 × 10⁹/L, and absolute neutrophil count from 1.25 × 10⁹/L to 3.32 × 10⁹/L. In conclusion, eltrombopag is a good option for PGF in Korean patients, even at a lower dose compared to western patients.     

Glycogen storage disease type Ia: Linkage of glucose,glycogen, lactic acid,triglyceride, and uric acid metabolism

A female presented in infancy with hypotonia, undetectable serum glucose, lactic acidosis, and triglycerides >5000 mg/dL. The diagnosis of type 1A glycogen storage disease was made via the result of a liver biopsy, which showed increased glycogen and absent glucose-6-phosphatase enzyme activity. The patient was treated with dextrose administered orally, which was replaced by frequent feedings of cornstarch, which resulted in an improvement of her metabolic parameters. At age 18 years of age, she had marked hypertriglyceridemia (3860 mg/dL) and eruptive xanthomas and was treated with fenofibrate, atorvastatin, and fish oil. At age 29 years she was noted to have multiple liver adenomas, severe anemia, and hyperuricemia. Aggressive cornstarch therapy was commenced with a goal of maintaining her blood glucose levels >75 mg/dL and lactate levels <2 mmol/L. After 15 months on this regimen, her lipids levels (measured in mg/dL) off all medications were as follows: total cholesterol 222, triglycerides 179, high-density lipoprotein cholesterol 32, and calculated low-density lipoprotein cholesterol 154. Her weight was stable with a body mass index of 24.8 kg/m². Her liver adenomas had decreased in size, and her anemia and hyperuricemia had improved. She was homozygous for the R83C missense mutation in G6PC. Our data indicate that optimized metabolic control to maintain blood glucose levels >75 mg/dL is critical in the management of this disease.     

Emergence of chronic myelogenous leukemia in a patient with primary thrombocythemia and absence of BCR/ABL rearrangement

A 65-year-old woman presented with clinical features of primary thrombocythemia (PT), and absence of the BCR/ABL fusion gene. She responded to hydroxyurea treatment, although after 1 year she required progressive increases in the dose. Six years later, she maintained a high platelet count despite hydroxyurea at 2 g/day and treatment was changed to anagrelide. After 3 weeks, both platelet and leukocyte counts increased. A karyotype study detected the Philadelphia chromosome in all of the 24 metaphases studied. Fluorescent in situ hybridization (FISH) analysis revealed the BCR/ABL rearrangement. The patient was treated with imatinib mesylate and achieved a normal platelet and leukocyte count in 3 weeks. Patients presenting clinical features of PT expressing the Ph chromosome or the BCR/ABL fusion gene have been well documented but, to our knowledge, this is the first report of evolution from typical PT to chronic myeloid leukemia.     

Complete hematopoietic recovery after continuous iron chelation therapy in a patient with severe aplastic anemia with secondary hemochromatosis

A 16-yr-old male patient with hemochromatosis due to multiple packed red blood cell transfusions was referred to our emergency center for the treatment of severe aplastic anemia and dyspnea. He was diagnosed with aplastic anemia at 11-yr of age. He had received continuous transfusions because an HLA-matched marrow donor was unavailable. Following a continuous, approximately 5-yr transfusion, he was noted to develop hemochromatosis. He had a dilated cardiomyopathy and required diuretics and digitalis, multiple endocrine and liver dysfunction, generalized bleeding, and skin pigmentation. A total volume of red blood cell transfusion before deferoxamine therapy was about 96,000 mL. He received a regular iron chelation therapy (continuous intravenous infusion of deferoxamine, 50 mg/kg/day for 5 days q 3-4 weeks) for approximately seven years after the onset of multiple organ failures. His cytopenia and organ dysfunctions began to be gradually recovered since about 2002, following a 4-yr deferoxamine treatment. He showed completely normal ranges of peripheral blood cell counts, heart size, and liver function two years ago. He has not received any transfusions for the last four years. This finding suggests that a continuous deferoxamine infusion may play a role in the immune regulation in addition to iron chelation effect.     

Tetraphocomelia in the syndrome of thrombocytopenia with absent radii (TAR syndrome)

We report on an infant with the syndrome of Thrombocytopenia with Absent Radii (TAR) with severe lower-limb involvement. Amegakaryocytic thrombocytopenia was detected at 6 days when the platelet count was 11,000/microL. The platelet count increased steadily to 100,000/microL at 3 years. The patient required bilateral above-knee amputations for femorotibial synostoses. We recommend postponement of all elective operations until platelet counts are normal.     

A patient with mixed type Evans syndrome: efficacy of rituximab treatment

Mixed type Evans syndrome is a very rare hematologic disease. Although mixed type Evans syndrome may initially respond well to steroids, this disease usually runs a chronic course with intermittent exacerbations. We describe here a 46-yr-old female with the steroid-refractory, mixed type Evans syndrome, and she had a prompt response to rituximab. She was diagnosed as having the mixed type Evans syndrome with the clinical features of symptomatic anemia, jaundice and thrombocytopenia. Prednisone therapy was commenced and her hemoglobin and platelet level returned to the normal. However, after 15 weeks, she relapsed with hemolytic anemia and thrombocytopenia. We started rituximab at the dose of 375 mg/m(2) once weekly for a total of 4 doses, which was well-tolerated and this induced the normalization of hemoglobin, bilirubin and lactic dehydrogenase, and there was also a significant increase of the platelet count.     

Impact on hemoglobin of starting combination antiretroviral therapy with or without zidovudine in anemic HIV-infected patients

OBJECTIVE: To evaluate, among anemic patients with HIV, the impact on hemoglobin (Hb) of initiating zidovudine (AZT)-containing and non-AZT-containing combination antiretroviral therapy (cART). METHODS: We used medical records data collected in 11 US cities from 1998 to 2004. Baseline anemia was described as mild (10 < Hb < or = 12 [women] or 14 [men] g/dL), moderate (8 < Hb < or = 10 g/dL), or severe (Hb < or = 8 g/dL). Improvement of anemia was a > or =1-g/dL increase in Hb, with a decrease in categoric severity. We excluded patients previously treated with erythropoietin or transfusion, and used Cox proportional hazards regression to describe factors associated with hazard of improvement of anemia. RESULTS: For 1620 patients initiating cART, more than half (54%) of patients had improvement of anemia. Time to improvement of anemia was longer for those initiating AZT-containing regimens and blacks and was shorter for those with moderate and severe anemia or CD4 counts <200 cells/microL. CONCLUSIONS: Most anemic patients initiating cART (with or without AZT) had increases in Hb-especially those with more severe anemia or immunosuppression. Initiation of AZT-containing cART may be considered, even for patients with preexisting anemia; however, improvement of anemia may be delayed for black patients and for patients with mild disease.     

Effect of c-mpl ligands after total body irradiation (TBI) with and without allogeneic hematopoietic stem cell transplantation: low-dose TBI does not prevent sensitization.

This study investigates the potential role of the recombinant c-mpl ligands (recombinant human thrombopoietin [rhTPO] and pegylated recombinant human megakaryocyte growth and development factor [PEG-rhMGDF]) on the recovery of platelet counts after TBI with and without allogeneic hematopoietic stem cell transplantation (HSCT) in an established canine model. Initially, 3 cohorts, each with 2 nonirradiated dogs, received increasing doses of rhTPO (5 microg/kg per day; 10 microg/kg per day; 20 microg/kg per day) for 7 days to determine the optimal dose. The dose of 10 microg/kg per day of rhTPO was selected for subsequent studies. Ten dogs then received either rhTPO or placebo for 28 days after 200 cGy TBI without HSCT. The rhTPO group had fewer days with platelet counts <20,000/microL (9.8 days versus 17.8 days, P < .05) and significantly increased granulocyte counts (n = 5) compared to the controls (n = 5). RhTPO-specific antibodies developed in 2 dogs, which caused a significant but transient decrease of the platelet counts. Retreatment of these sensitized dogs with rhTPO resulted in profound transient decreases in platelet counts. In the next study, 20 dogs received either PEG-rhMGDF or placebo for 21 days after 920 cGy TBI and allogeneic HSCT. The median time to platelet recovery (>20,000/microL) for the PEG-rhMGDF group (n = 10) was 14.0 days compared to 15.5 days for the control group (n = 10; log rank, P = .35). There were no significant differences in the total time to platelet counts <20,000/microL or in the time to recover neutrophil counts >500/microL. The effects of rhTPO on recovery of platelet and granulocyte counts after sublethal TBI were modest, and no effects of PEG-rhMGDF were observed on hematopoietic recovery after high-dose TBI and allogeneic HSCT. The significant effect that rhTPO-specific antibodies had on the platelet counts may limit the clinical role of recombinant c-mpl ligands unless sensitization can be prevented.     

Bone marrow mast cell reaction in preleukaemic myelodysplasia and in aplastic anaemia

Summary The relationship of bone marrow mast cell counts to prognosis was investigated in 48 patients with preleukaemic myelodysplasia, in 59 patients with aplastic anemia and in a DMBA induced myelodysplasia/leukaemia rat model. In patients with myelodysplasia terminating in overt leukaemia the number of mast cells per square millimeter was not correlated to duration of the preleukaemic course. Leukaemia development probabilities of patients at risk were not different for low and elevated mast cell counts. In aplastic anaemia, however, a lower bone marrow mast cell count was related to a higher survival probability and longer survival time. In the animal model no significant differences could be found between myelodysplastic, leukaemic, and control animals.     

Resolution of chronic severe refractory thrombocytopenia after treatment of hypothyroidism

The case of a 52 year old woman with chronic severe refractory thrombocytopenia is presented. Over a three year period, her platelet count was persistently less than 20 x 10(9)/litre (normal range, 150-400). She required repeated hospital admission for management of bleeding and received multiple blood transfusions. She was given repeated courses of steroids, immunosuppression, immunoglobulin, and splenectomy, without success, in an attempt to stop the chronic blood loss. Eventually, she was found to be profoundly hypothyroid. On correction of her thyroid deficiency the platelet count returned to the normal range and all bleeding stopped. The platelet count remains in the normal range three years later.     

Severe Rejection of an HL-A Identical Sibling Renal Transplant

A twenty-year-old patient with end-stage pyelonephritis received an HL-A identical renal transplant from her brother. She remained well for 28 days and then suffered a severe rejection episode while on decreased immunosuppressive therapy because of low white blood counts, reducing renal function to a creatinine clearance of 32 ml/min. Two weeks later she suffered a second major rejection episode which was arrested at a clearance of 10 ml/min. For the last 10 months renal function has remained stable at this level.     

Granulocyte-macrophage colony-stimulating factor in the sera of patients with aplastic anemia

Summary To clarify the role of growth factors in the pathophysiology of aplastic anemia we measured serum granulocyte-macrophage colony-stimulating factor (GM-CSF) levels in 33 aplastic anemia patients by a specific and sensitive enzyme-linked immunosorbent assay. GM-CSF serum levels of patients with aplastic anemia were significantly higher than in healthy volunteers. GM-CSF levels were correlated with the severity of aplastic anemia but not with the absolute neutrophil count. Since T lymphocytes are one of the main sources of GM-CSF, our data provide further evidence for in vivo T lymphocyte activation in aplastic anemia. GM-CSF serum levels are higher in patients responding to immunosuppressive treatment than in nonresponders. Elevated serum GM-CSF might be predictive of a good response to immuno-suppressive therapy. GM-CSF serum levels are lower immediately after treatment with antilymphocyte globulin/antithymocyte globulin (ALG/ATG) than corresponding pretreatment values. Thus we cannot confirm the hypothesis that ALG/ATG effects in vivo are mediated by stimulating the release of growth factors. We conclude that in aplastic anemia the primary defect is a failure in GM-CSF response rather than in GM-CSF supply.Abbreviations AA aplastic anemia - ALG antilymphocyte globulin - ATG antithymocyte globulin - CyA cyclosporine A - ELISA enzyme-linked immunosorbent assay - Epo erythropoietin - G-CSF granulocyte colony-stimulating factor - GM-CSF granulocyte-macrophage colony-stimulating factor - IFN- interferon- - IL interleukin - MP methylprednisolone - nSAA nonsevere aplastic anemia - rh recombinant human - SAA severe aplastic anemia - TNF- tumor necrosis factor- Dedicated to Prof. Dr. N. Zöllner on the occasion of his 70th birthday