In vitro proliferation and differentiation of megakaryocytic progenitors in patients with aplastic anemia, paroxysmal nocturnal hemoglobinuria, and the myelodysplastic syndromes.
(73/995)
It has previously been shown that patients with aplastic anemia (AA) have a stem cell defect both of proliferation and differentiation. This has been shown by long-term bone marrow (BM) culture, long-term initiating cell assays, and committed progenitor assays. We present, for the first time, data on megakaryocyte (Mk) colony formation from purified BM CD34(+) cells from patients with AA. The results are compared with those from normal controls and from patients with paroxysmal nocturnal hemoglobinuria (PNH) and the myelodysplastic syndromes (MDSs). Those treated for AA had previously received immunosuppression (antithymocyte globulin and/or cyclosporin). No patients had received bone marrow transplantation. A total of 13 AA patients (five untreated, eight treated), six PNH, six MDS, and 13 normal donors were studied. BM CD34(+) cells were purified by indirect labeling and then cultured in a collagen-based Mk assay kit (MegaCult-C, StemCell Technologies). The cultures were fixed on day 12, and the Mk colonies were identified by the alkaline phosphatase anti-alkaline phosphatase technique using the monoclonal antibody CD41 (GP IIb/IIIa). The slides were scored for Mk colony-forming units (CFU-Mks) (3-20 and >20 cells), Mk burst-forming units (BFU-Mks) (>50 cells), and mixed colonies. The results show that total Mk colony formation in AA was significantly lower than in normal donors (p<0.0001), both in untreated patients/nonresponders to treatment (p = 0.0001) and in complete/partial responders (p<0.002). There was no significant difference in Mk colony formation in treated and untreated patients (p = 0.05). Patients with AA had a lower total colony formation than PNH patients (p = 0.0002). PNH patients exhibited lower colony formation than normal controls (p = 0.03), as shown by MDS patients, although the considerable number of variables resulted in a lack of statistically significant difference from normal controls (p = 0.2). We have now shown that Mk colony formation from purified BM CD34(+) cells is significantly reduced, supporting previous evidence that AA results from a stem cell defect. (+info)
T cell lymphoproliferative disorder following bone marrow transplantation for severe aplastic anemia.
(74/995)
Post-transplant lymphoproliferative disorder (PTLD) is uncommonly of T cell origin, especially following BMT. We describe a 13-year-old boy with severe aplastic anemia (SAA) and no evidence of Fanconi's anemia who underwent BMT at 11 years of age using CY 10 mg/kg once daily i.v. on days -5, -4, antilymphocyte globulin (ALG) 30 mg/kg once daily i.v. on days -5 approximately -3 and CsA from day -1 as conditioning. The BMT failed and he received a further peripheral blood stem cell transplant (PBSCT) 240 days after BMT. Conditioning was with CY 50 mg/kg once daily i.v. on days -5 approximately -2, and ALG 15 mg/kg once daily i.v. on days -4 approximately -2. GVHD prophylaxis included CsA and MTX. Engraftment was later confirmed by cytogenetic studies. Desquamation and ulcers of the oral mucosa and mouth angle developed in the 13th month post PBSCT. A buccal mucosa biopsy on day +524 revealed only plasmacytosis. Immunosuppressants were discontinued at that point. Generalized lymphadenopathy, prolonged fever (waxing and waning) and facial swelling developed in the 18th month post PBSCT. A neck lymph node biopsy on day +601 showed T cell lymphoma of diffuse large cell type with monoclonal TCR gamma-chain gene rearrangement. A FISH study showed that the malignant T cells were of recipient origin. EBV in situ hybridization was negative. He did not receive further treatment apart from discontinuation of immunosuppressants. He was followed up in our out-patient clinic and showed good performance 1170 days post PBSCT. We speculate that a different mechanism was operating in the pathogenesis of T cell lymphoma in this case. Risk factors include SAA and two transplants, conditioned with CY and ALG, long term use of CsA and treatment with azathioprine. (+info)
Umbilical cord blood transplantation from unrelated HLA-matched donor in an adult with severe aplastic anemia.
(75/995)
A 23-year-old male suffering from severe aplastic anemia (SAA) weighing 60 kg was successfully treated by unrelated allo-CBSCT (cord blood stem cell transplantation). A six-loci HLA-identical umbilical cord blood (UCB) was infused after conditioning with low-dose cyclophosphamide (CTX) and antilymphocyte globulin (ALG). The prophylaxis of GVHD consisted of CsA and MTX. The infused cord blood provided 1.89 x 10(7) nucleated cells per kg, CD34-positive cells: 0.89%. Neutrophils >0.5 x 10(9)/l were reached 10 days after transplant, and platelets greater than 50.0 x 10(9)/l at day 26. RBC and platelet transfusion independence were reached on days 15 and 18. The patient developed grade 1 skin GVHD 10 months after engraftment of the donor cells. Microsatellite DNA fingerprinting indicated a stable and persistent donor-recipient mixed chimerism, whilst the circulating red cells remain of host origin. (+info)
Association of complementation group and mutation type with clinical outcome in fanconi anemia. European Fanconi Anemia Research Group.
(76/995)
Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder. Clinical care is complicated by variable age at onset and severity of hematologic symptoms. Recent advances in the molecular biology of FA have allowed us to investigate the relationship between FA genotype and the nature and severity of the clinical phenotype. Two hundred forty-five patients from all 7 known complementation groups (FA-A to FA-G) were studied. Mutations were detected in one of the cloned FANC genes in 169 patients; in the remainder the complementation group was assigned by cell fusion or Western blotting. A range of qualitative and quantitative clinical parameters was compared for each complementation group and for different classes of mutation. Significant phenotypic differences were found. FA-G patients had more severe cytopenia and a higher incidence of leukemia. Somatic abnormalities were less prevalent in FA-C, but more common in the rare groups FA-D, FA-E, and FA-F. In FA-A, patients homozygous for null mutations had an earlier onset of anemia and a higher incidence of leukemia than those with mutations producing an altered protein. In FA-C, there was a later age of onset of aplastic anemia and fewer somatic abnormalities in patients with the 322delG mutation, but there were more somatic abnormalities in patients with IVS4 + 4A --> T. This study indicates that FA patients with mutations in the FANCG gene and patients homozygous for null mutations in FANCA are high-risk groups with a poor hematologic outcome and should be considered as candidates both for frequent monitoring and early therapeutic intervention. (Blood. 2000;96:4064-4070) (+info)
Normocytic anemia.
(77/995)
Anemia is a common problem that is often discovered on routine laboratory tests. Its prevalence increases with age, reaching 44 percent in men older than 85 years. Normocytic anemia is the most frequently encountered type of anemia. Anemia of chronic disease, the most common normocytic anemia, is found in 6 percent of adult patients hospitalized by family physicians. The goals of evaluation and management are to make an accurate and efficient diagnosis, avoid unnecessary testing, correct underlying treatable causes and ameliorate symptoms when necessary. The evaluation begins with a thorough history and a careful physical examination. Basic diagnostic studies include the red blood cell distribution width, corrected reticulocyte index and peripheral blood smear; further testing is guided by the results of these studies. Treatment should be directed at correcting the underlying cause of the anemia. A recent advance in treatment is the use of recombinant human erythropoietin. (+info)
Pancytopenia--a clinico-hematologic analysis of 77 cases.
(78/995)
The present study was conducted in the department of Haematology and Transfusion Medicine, Government Medical College & Hospital, Chandigarh over a period of 32 months. During this period pancytopenia was an indication for bone marrow (aspiration and or trephine) in 77 out of a total of 205 cases (37.6%). The most common cause of pancytopenia as revealed by bone marrow was megaloblastic anaemia (68%) followed by aplastic anaemia (7.70%). This study also revealed few uncommon and rare, but interesting causes of pancytopenia like drug induced agranulocytosis, hemophagocytic syndrome and waldenstroms macroglobinemia. (+info)
Improved survival in severe acquired aplastic anemia of childhood.
(79/995)
Multi-agent immunosuppressive therapy has produced improved survival for severe acquired aplastic anemia in children. Recently, some investigators have suggested that immunosuppressive therapy may replace bone marrow transplantation as first-line therapy for this disorder. To assess its validity, we compared the outcomes of bone marrow transplantation vs immunosuppressive therapy in one institution from 1987 to 1997. We studied 46 consecutive patients less than 18 years of age who presented between January 1987 and April 1997. Inherited marrow failure syndromes and myelodysplastic syndromes were excluded. Patients received immunosuppressive therapy vs bone marrow transplantation based on availability of HLA-matched donors. The main outcome measures were survival, complete marrow and hematological remission, or partial remission but achieving independence from transfusional support. Twenty patients received multi-agent immunosuppressive therapy (cyclosporine, antithymocyte globulin and methylprednisolone); 11 attained complete remission and three partial remission for a transfusion-independent survival of 70%. Six patients died of infectious and hemorrhagic complications. Twenty-six patients were transplanted and 24 (93%) achieved complete remission; one achieved a PR, 25 remain transfusion independent with a median follow-up of 5.9 years or 70 months. One patient developed AML 34 months after successful transplant and one patient died due to graft failure and complications of transplant. There has been a striking improvement in survival for pediatric patients treated with multi-agent immunosuppression in the last decade. However, transplantation results have also improved and this remains the definitive first-line therapy for severe acquired aplastic anemia in this age group. (+info)
An immunological syndrome featuring transverse myelitis, Evans syndrome and pulmonary infiltrates after unrelated bone marrow transplant in a patient with severe aplastic anemia.
(80/995)
A patient with severe aplastic anemia underwent a matched unrelated bone marrow transplant, following which he developed a complex autoimmune syndrome. This featured transverse myelitis, immune mediated Coombs positive hemolytic anemia and immune thrombocytopenia (Evans syndrome), pulmonary infiltrates, eosinophilia, muscle pains and cramps and lichenoid dermatitis all of which may represent manifestations of graft-versus-host disease as they showed response to immunosuppression. Thus, although immune-mediated cytopenias after an allogeneic bone marrow transplant are rare, they should be considered as a possible cause of cytopenia in post-transplant patients. (+info)