Fulminant hepatic failure following bone marrow transplantation for hepatitis-associated aplastic anemia

A case of aplastic anemia associated with non-A, non-B hepatitis was initially successfully treated by bone marrow transplantation. The patient subsequently developed fulminant hepatic failure. Fulminant hepatic failure is rare in bone marrow transplantation and only occurs in association with aplastic anemia associated with viral hepatitis. This case helps to highlight the relationships between the immune system, hepatitis, and bone marrow failure.     

Successful ATG and bolus methylprednisolone therapy towards severe aplastic anemia with splenomegaly

A 22-year-old female patient with severe aplastic anemia was treated by ATG.bolus methylprednisolone therapy. After the therapy, anemia and thrombocytopenia began to recover within a month. The frequency of blood transfusion decreased thereafter. Since anemia due to splenomegaly was certified, bolus methylprednisolone therapy was performed in good response. Suppressor T-cells towards hemopoiesis were confirmed in this case, and hemopoietic potential was augmented by ATG.bolus methylprednisolone therapy. In spite of discontinuation of any therapy in 1986, she is being in good health more than five years.     

Changes in bone marrow MRI patterns in aplastic anemia before and after successful treatment with ATG]

In order to evaluate the usefulness of MRI in estimating bone marrow cellularity, we performed MRI of the lumbar spine in two patients with severe aplastic anemia, before and after successful treatment with antithymocyte globulin (ATG). Case 1, a 25-year-old man with idiopathic aplastic anemia, was treated with ATG 6 months after the onset. One month after treatment, his peripheral blood count and bone marrow cellularity recovered, and the MRI bone marrow pattern became normal. Case 2, a 78-year-old woman with drug-induced aplastic anemia, was treated with ATG 4 months after the onset. Three months after treatment, her peripheral blood count improved. Five months after treatment, her bone marrow cellularity recovered and the MRI bone marrow pattern was normal for her age. Seven months after treatment, when her peripheral blood count was almost normal, we observed hypercellular bone marrow restoration at the periphery of the vertebrae. MRI seems to be an effective method of evaluating bone marrow recovery in aplastic anemia.     

Changes in bone marrow and peripheral blood lymphocyte subset findings with onset of hepatitis-associated aplastic anemia

Rationale:Hepatitis-associated aplastic anemia (HAAA) is a rare illness that results in bone marrow failure following hepatitis development. The etiological agent remains unknown in most HAAA cases. However, clinical features of the disease and immunotherapy response indicate that immune-mediated factors play a central role in the pathogenesis of HAAA. Activation of cytotoxic T cells and increase in CD8 cells could exert cytotoxic effects on the myelopoietic cells in the bone marrow.Patient concerns:A 15-month-old boy was brought to our hospital with complaints of generalized petechiae and purpura observed a week prior to hospitalization. His liver was palpated 3 cm below the costal margin, platelet count was 0 × 10⁴/μL, and alanine aminotransferase level was 1346 IU/L. A blood test indicated cytomegalovirus infection, and 3 bone marrow examinations revealed progressive HAAA. As the disease progressed to the 3^rd, 6^th, and 9^th week after onset, CD4⁺ T cells were markedly decreased, CD8⁺ T cells were markedly increased, and the CD4/CD8 ratio was significantly decreased. The number of B cells and natural killer cells decreased with time, eventually reaching 0.0%.Diagnosis:HAAA.Interventions:Rabbit antithymocyte globulin and eltrombopag olamine (a thrombopoietin receptor agonist) were administered.Outcomes:The patient''s platelet count returned to normal, and bone marrow transplantation was avoided. The peripheral blood lymphocytes (PBLs) improved as the patient''s general condition recovered.Lessons:This case demonstrates that HAAA induced by cytomegalovirus infection features decreasing CD4⁺ and increasing CD8⁺ PBLs as the bone marrow hypoplasia progresses. The PBLs return to their normal levels with the recovery from the disease. Our case findings thus support the involvement of immunological abnormality in HAAA.     

Lack of known hepatitis virus in hepatitis-associated aplastic anemia and outcome after bone marrow transplantation

Viral infection has been shown to induce aplastic anemia, unidentified types of hepatitis being the most common cause for aplastic anemia-associated viral hepatitis. The survival rate for this group of patients after bone marrow transplantation with stem cells from an HLA-matched sibling is not well known. The aim of this study was to determine the prevalence of hepatitis G virus (HGV) and transfusion transmitted virus (TTV) infection in non-A, non-B, non-C hepatitis associated-aplastic anemia (HAAA) patients, and to define the role of bone marrow transplantation (BMT) as a therapeutic modality for this disease. Sixty-eight patients (43 males and 25 females) with aplastic anemia, underwent allogeneic BMT at the Hadassah University Hospital between 1981 and 1997. Onset of hepatitis was defined as jaundice and elevated alanine aminotransaminase (ALT) levels. Onset of aplastic anemia was defined as the first date on which varying degrees of pancytopenia occurred: hemoglobin level below 10 g/dl, WBC below 2 x 10(9)/l and low platelet count 10 x 10(10)/l. Serial serum samples from HAAA patients were assayed for virological and/or serological markers of hepatitis A, B, C, D, E, G viruses, TTV and parvovirus B19. Seventeen of the 68 patients with aplastic anemia (25%) suffered from hepatitis, 12 males and five females, ages 5 to 36 years. The mean interval between onset of hepatitis and first indication of aplastic anemia was 62 days (range 14-225 days). The development of aplastic anemia was unrelated to age, sex or severity of hepatitis. Ten of the 17 patients (59%) achieved complete ALT recovery prior to the diagnosis of aplastic anemia. Serum samples were available for 15 patients; none had evidence of acute or active hepatitis A, B, C, D, E, G and TTV virus infection at the time of diagnosis. Parvovirus B19 DNA sequences were not detectable in 10 of 12 tested cases; two positive results were detected in serum samples obtained after blood transfusion, making the analysis of these positive results difficult. All 17 patients underwent BMT. The mean post-BMT follow-up period was 38 months (range 1 day-123 months), five patients (30%) died 1 to 160 days post BMT, and 12 (70%) are alive 31 to 123 months after BMT. Relapsing hepatitis was not observed in any of the patients. In conclusion, HAAA is a disease of the young and the etiologic agent associated with HAAA remains unknown. HGV, TTV and parvovirus B19 sequences were not detected in any of the HAAA cases. The survival rate after BMT with stem cells from an HLA-matched sibling is similar to that for patients with non-hepatitis-associated aplastic anemia.     

Successful bone marrow transplantation for severe aplastic anemia following orthotopic liver transplantation: long-term follow-up and outcome

Severe aplastic anemia (SAA) is well described in children following liver transplantation for fulminant hepatic failure (FHF) secondary to non-A, non-B, non-C hepatitis, and is associated with a high mortality rate. Successful immunosuppressive treatment of SAA following liver transplantation has been reported, but death from infectious complications is not uncommon. We report the 8-year follow-up of a 3.5-year-old boy who underwent successful HLA-identical sibling donor bone marrow transplant for SAA 7 months following orthotopic liver transplant for non-A, non-B, non-C hepatitis. His post-bone marrow transplantation course was uneventful with no evidence of liver toxicity. Eight months following BMT he developed renal cell carcinoma metastatic to lymph nodes which was treated surgically. Six years following BMT he developed a mucoepidermoid carcinoma of the parotid gland also treated surgically. Despite these malignancies, he is currently well 8 years following liver and bone marrow transplantation, without signs of GVHD, growth failure or liver graft rejection. This is the first report of long-term follow-up of bone marrow transplantation for SAA following liver transplantation. The occurrence of two subsequent malignancies in this child underscores the need for close follow-up of future similar cases.     

Treatment of adults with severe aplastic anemia: primary therapy with antithymocyte globulin (ATG) and rescue of ATG failures with bone marrow transplantation.

PURPOSE: To evaluate a policy of immunosuppression with antithymocyte globulin (ATG) as primary therapy for adults with severe aplastic anemia (SAA) regardless of the availability of an HLA-identical bone marrow donor. PATIENTS AND METHODS: Thirty-one consecutive adults with SAA who satisfied the age criteria for allogeneic bone marrow transplantation (BMT) (age less than 51 years) were treated with ATG 20 mg/kg/day for 10 days along with high-dose corticosteroids. Patients with an HLA-identical donor received a transplant if they did not respond to ATG or if they developed life-threatening complications during or soon after ATG administration. Eight patients with no response to ATG were also treated with oral cyclosporine 12.5 mg/kg/day. RESULTS: Eleven patients had a complete and five a partial response to ATG; two patients improved with cyclosporine treatment, resulting in an overall response rate of 58% to immunosuppression. Nine of 14 patients with donors received a BMT: seven because they did not respond to ATG and two because of serious infections. Seven grafts were obtained from related and two from unrelated donors. There was no significant difference in survival between those with and without a related HLA-identical donor (log-rank p value = 0.969). At a median follow-up of 58 months, 26 of 31 are alive with an actuarial survival of 80% at 5 years. Two patients died of infection, two died from complications of BMT, and one remains transfusion-dependent. One patient died of refractory leukemia at 30 months; one patient relapsed with hypoplasia 95 months after initial therapy with ATG. He showed a complete response to treatment with cyclosporine. No other late hematologic events have occurred. CONCLUSIONS: This treatment approach resulted in the restoration of hematopoiesis and independence from transfusion in 80% of patients with SAA entered into the study. The efficacy of allogeneic BMT in salvaging cases in which ATG failed does not appear to be compromised. Follow-up for the development of clonal hematologic disorders remains an important part of this treatment policy.     

Significance of p53 overexpression in bone marrow biopsies from patients with bone marrow failure: aplastic anemia, hypocellular refractory anemia, and hypercellular refractory anemia

 Among patients with bone marrow failure, differentiating acquired aplastic anemia (AA) from hypocellular refractory anemia (hypo RA) can be a difficult and challenging task. Morphological, cytochemical, immunocytochemical, and cytogenetic studies may provide tools for discriminating between both entities. In addition, differences in the pattern of proliferation and apoptosis of bone marrow cells in AA and in the myelodysplastic syndrome have been reported. Because of the correlation between p53 and apoptosis, we examined the overexpression of p53 on bone marrow biopsies in RA and AA. Our study included 14 patients with hypo RA, 14 patients with hypercellular (hyper) RA, ten patients with classic acquired AA, and 37 hematologically normal individuals. p53 was overexpressed in eight (57%) hypo RA patients and 11 (79%) hyper RA patients. All normal individuals and patients with AA showed no overexpression of p53 in their marrow. These results were statistically significant:p<0.01 (AA vs hypo RA),p<0.001 (AA vs hyper RA), while the difference between hypo RA and hyper RA was not statistically significant. We conclude that p53 overexpression in bone marrow biopsies is a valuable tool for studying bone marrow failure and may provide additional information to help differentiate hypo RA from acquired AA. Received: March 13, 1998 / Accepted: August 13, 1998     

Successful bone marrow transplantation in children with severe aplastic anemia using HLA-partially matched family donors

Bone marrow transplantation (BMT) using HLA-partially matched family donors has produced disappointing results (25–30% of long-term survivors) in patients with severe aplastic anemia. We describe two children affected by severe aplastic anemia, not responsive to immunosuppressive therapy, who underwent allogeneic bone marrow transplantation using a HLA-partially matched family donor. Both cases presented 2 first class HLA-antigens (A and B) disparity between donor and recipient. The pretransplant conditioning regimen consisted of cyclophosphamide, thoracoabdominal irradiation, cytosine-arabinoside, and antilymphocyte globulin. As graft versus host disease (GVHD) prophylaxis, Cyclosporine-A was administered at usual dosages for 6 months. A full marrow engraftment was observed in both cases. Only grade I acute GVHD, promptly responsive to corticosteroid therapy, developed with no chronic GVHD. Five months after transplant, both children progressively developed hypertension, renal function impairment, thrombocytopenia, and severe normochromic anemia, with erythropoietin serum levels lower than expected for the haematocrit. After antihypertension treatment and supportive therapy, the clinical picture progressively improved, while treatment with recombinant human erythropoietin completely corrected the long-lasting anemia. The two children are alive and well 28 months after the transplant, with a Karnofsky score of 100% and a normal peripheral blood count. The authors suggest that, once immunosuppressive therapy has failed, BMT from donors other than HLA-identical sibling is a feasible approach in children affected by severe aplastic anemia, not having an HLA-identical donor. © 1993 Wiley-Liss, Inc.     

Successful bone marrow plus cord blood stem cell transplantation in a girl who developed myelodysplastic syndrome from hepatitis-associated aplastic anemia treated with long-term immunosuppressants and growth factors

A 9-year-old girl who had hepatitis-associated aplastic anemia was treated intermittently with methylprednisolone pulse therapy and growth factors (granulocyte-colony stimulating factor (G-CSF), recombinant human erythropoietin (rhEpo) and cyclosporin A (CyA) for over two years. At this time, there was hematological improvement, but chromosome analysis revealed monosomy 7. After six months, there was progression to myelodysplastic syndrome (MDS) (stage in refractory anemia of excess blasts (RAEB)) with monosomy 7, monosomy 6, marker chromosome and with hematological deterioration. She received bone marrow (1.57 x 10(5) cells kg(-1) (patient body weight)) plus cord blood cell (0.3 x 10(7) cells kg(-1) (patient body weight)) transplantation from her brother, 2 years and 7 months after the diagnosis of hepatitis-associated aplastic anemia. Engraftment was achieved after two weeks, and acute graft-versus-host disease occurred in a mild form after four weeks. Hematological remission has been continuous for 20 months after bone marrow transplantation. Transformation of hepatitis-associated aplastic anemia to MDS with the monosomy 7, monosomy 6 and marker chromosome in this patient was considered to have been related to the administration of high doses of immunosuppressive drugs plus growth factors.     

Investigation of SEN virus infection in patients with cryptogenic acute liver failure, hepatitis-associated aplastic anemia, or acute and chronic non-A-E hepatitis

SEN virus (SENV) has been tentatively linked to transfusion-associated non-A-E hepatitis. We investigated SENV's role in unexplained hepatitis in other settings. Polymerase chain reaction amplification was used to detect 2 SENV variants (SENV-D and SENV-H) in 1706 patients and control subjects. SENV was detected in 54 (22%) of 248 patients with acute or chronic non-A-E hepatitis, 9 (35%) of 26 patients with hepatitis-associated aplastic anemia, and 0 of 17 patients with cryptogenic acute liver failure, compared with 150 (24%) of 621 control subjects with liver disease and 76 (10%) of 794 healthy control subjects. When controlling for geographic region, the prevalence of SENV among case and control subjects was not significantly different. The severity of acute or chronic hepatitis A, B, or C was not influenced by coexisting SENV infection. No etiological role for SENV in the cause of cryptogenic hepatitis could be demonstrated.     

原发性骨髓衰竭性贫血

原发性骨髓衰竭性贫血是一组极易误诊的造血系统重症.它包含再生障碍性贫血、纯红细胞再障、免疫相关性全血细胞减少、免疫相关性贫血、低增生阵发性睡眠性血红蛋白尿症、骨髓增生异常综合征和意义未明的原发性血细胞减少.该组疾病的正确诊断基于对患者详尽的问史查体、全面的血象骨髓象和病理机制检查以及必要的试验性治疗.提高该组疾病疗效有赖于及时去症、合理治本、足疗程刺激造血等.     

Successful allogeneic bone marrow transplantation in a 6.5-year-old male for severe aplastic anemia complicating orthotopic liver transplantation for fulminant non-A-non-B hepatitis

We report the case of a 6.5-year-old male who received an unrelated orthotopic liver transplant for hepatic failure and encephalopathy following non-A-non-B hepatitis and subsequently developed severe aplastic anemia. For treatment of his aplastic anemia, he received a successful marrow transplant from his 9-year-old genotypically HLA-identical sister following conditioning with cyclophosphamide 200 mg/kg and anti-thymocyte globulin 90 mg/kg. Significant veno-occlusive disease of the liver and graft-versus-host disease did not occur. The patient remains alive without clinical chronic active hepatitis or need for blood product therapy. His hematocrit is 36%, white blood cell count 9.7 x 10(3)/mm3, and platelet count 1.7 x 10(5)/mm3 almost 2 years after marrow transplantation.     

Veno-occlusive disease of the liver after allogeneic bone marrow transplantation for severe aplastic anemia

There are few reports about the occurrence of hepatic VOD after BMT for severe aplastic anemia (SAA). We prospectively studied 17 patients with SAA after allogeneic BMT for the occurrence and severity of VOD. Plasma levels of protein C, protein S, antithrombin III, vWF, t-PA and PAI-1 were determined before preparative chemotherapy, on the day of marrow infusion, and on days 7, 14 and 21. VOD occurred in seven patients (41.2%) at a median of day 1 (range, day -2 to 15). Five had mild, and two moderate VOD. Platelet transfusion requirements were higher in the patients with VOD. The plasma levels of natural anticoagulants such as protein C, free protein S and antithrombin III decreased significantly on day 0 from the baseline levels. Plasma levels of t-PA, PAI-1 and vWF increased significantly in the early post-transplant period compared to the baseline levels. The mean plasma levels of t-PA on day 7 (P = 0.016) and PAI-1 on days 0 and 7 (P = 0.016, 0.032) were higher in the patients with VOD. In summary, we observed hypercoagulability and a high incidence of VOD after allogeneic BMT for SAA. Levels of t-PA and PAI-1 were significantly higher in the patients with VOD after BMT.     

Magnetic resonance imaging of the bone marrow in patients with aplastic anemia and myelodysplastic syndrome]

Magnetic resonance imaging (MRI) of bone marrow was performed in 16 patients with aplastic anemia (AA) and myelodysplastic syndrome (MDS). Sagittal images from the lower thoracic and lumbar vertebral marrow were evaluated on short TI IR sequences (STIR, IR 2000/160/20). Four distinct patterns of signal intensity (SI) of the STIR images corresponding with active red marrow were classified as follows: pattern I, homogeneously low SI (4 cases); II, marginally high SI (2 cases); III, heterogeneously high SI (8 cases); IV, homogeneously high SI (2 cases). The SI distribution of STIR images strongly correlated with the cellularity of clot specimens of aspirates from sternum using the Wiebel test plate. In all three patients with AA, the STIR images revealed pattern I. In 8 of 13 cases of MDS patients, the STIR images were classified into pattern III. In one patient with hypoplastic MDS, the STIR image showed low SI. The STIR images of two AA patients at clinical remission after treatment showed marginally high SI similar to those of normal marrow. MRI of bone marrow can be a useful technique for the diagnosis of AA and MDS and for monitoring therapeutic effects.