Original Article
Hepatitis-Associated Aplastic Anemia
N Engl J Med 1997; 336:1059-1064April 10, 1997
- Abstract
Background
Hepatitis-associated aplastic anemia is a variant of aplastic anemia in which aplastic anemia follows an acute attack of hepatitis. The aplastic anemia, however, is often fatal if untreated. To characterize the illness, investigate the role of hepatitis viruses, and assess the response to immunosuppressive treatment, we studied patients with the syndrome who were referred to the National Institutes of Health (NIH).
Methods
Standard hematologic and biochemical tests and measurements of bone marrow cellularity were used to monitor the patients' response to treatment. Serum was assayed for antibodies and antigens related to hepatitis A, B, and C viruses and for the RNA of hepatitis C and GB virus C by the polymerase chain reaction. All patients were treated with antithymocyte globulin and cyclosporine.
Results
Ten patients with hepatitis-associated aplastic anemia were referred to the NIH between 1990 and 1996; all had the typical features of this syndrome. There was evidence of activated CD8 T lymphocytes in the blood. Serologic tests for hepatitis A, B, and C viruses were negative; RNA of hepatitis C virus was undetectable in all patients, but RNA of GB virus C was detected in three patients. Seven of the patients responded to intensive immunosuppressive treatment; the three who did not respond all died within one year of treatment, two from complications of stem-cell or marrow transplantation.
Conclusions
The hepatitis of the hepatitis-associated aplastic anemia does not appear to be caused by any of the known hepatitis viruses. We recommend immunosuppressive treatment for patients who do not have an HLA-matched related donor available for bone marrow transplantation. Several features of the syndrome suggest that it is mediated by immunopathologic mechanisms.
Media in This Article
Figure 2
Hematologic Values before and Six Months after Treatment with Antithymocyte Globulin and Cyclosporine Was Begun.Figure 1
Flow-Cytometric Analysis of Peripheral-Blood Lymphocytes from Patients before Treatment with Antithymocyte Globulin and Cyclosporine.Article Activity
- Article
Hepatitis-associated aplastic anemia was first described in 2 case histories in 1955,1,2 and by 1975 more than 200 cases had been reported.3 As a syndrome of bone marrow failure, hepatitis-associated aplastic anemia is not uncommon, with hepatitis documented in 2 to 5 percent of cases of aplastic anemia in the West4,5 and 4 to 10 percent in the Far East.6 In a Taiwanese study, a quarter of childhood cases of aplastic anemia were preceded by signs of hepatitis for which no cause was clearly evident.7 Hepatitis-associated aplastic anemia most often affects adolescent boys and young men,3 who present with severe pancytopenia two to three months after an episode of acute hepatitis. The marrow failure can be precipitous and severe and is usually fatal if untreated.3 There is no known association with blood transfusions, drugs, or toxins, and most patients have been seronegative for hepatitis A, B, and C.8,9
Aplastic anemia is also not uncommon after orthotopic liver transplantation performed for fulminant non-A, non-B hepatitis in young patients. In a study conducted at the University of Pittsburgh, aplastic anemia developed in 28 percent of such patients (9 of 32), as compared with none of 1463 patients undergoing liver transplantation for other causes.10 In a study at the University of Nebraska, aplastic anemia developed in 33 percent of children (6 of 18) who required liver transplantation for fulminant non-A, non-B, non-C hepatitis.11 The cause of fulminant seronegative hepatitis is unknown.12
We performed a retrospective analysis of patients with hepatitis-associated aplastic anemia who were referred to the Clinical Center at the National Institutes of Health (NIH).
Methods
Patients
Between June 1990 and June 1996, 10 patients were referred to the NIH for the evaluation of severe aplastic anemia that had developed within three months after documented hepatitis. Severe aplastic anemia was defined as pancytopenia with at least two of the following abnormalities: an absolute neutrophil count of less than 500 per cubic millimeter, a platelet count of less than 20,000 per cubic millimeter, and a reticulocyte count of less than 60,000 per cubic millimeter, in association with a bone marrow cellularity of less than 30 percent. Hepatitis was defined as an increase in serum aminotransferase levels to at least three times the upper limit of the normal range (normal range for alanine aminotransferase, 6 to 41 U per liter; normal range for aspartate aminotransferase, 9 to 34 U per liter). A complete response was defined as normal or near-normal blood counts within a year after the initiation of therapy (hemoglobin concentration, >10 g per deciliter; absolute neutrophil count, >1000 per cubic millimeter; and platelet count, >100,000 per cubic millimeter).
All the patients received intensive immunosuppression with equine antithymocyte globulin (Upjohn, Kalamazoo, Mich.) at a dose of 40 mg per kilogram of body weight per day intravenously for four days combined with a six-month course of cyclosporine (12 to 15 mg per kilogram per day orally, with adjustment of the dose to maintain a blood level between 200 and 400 ng per milliliter).13 Beginning in 1995, cyclosporine treatment was continued at tapering doses for a further 26-week period. Patient 9 followed this regimen before his referral, and at the NIH he received cladribine (2-chlorodeoxyadenosine), given as an intravenous infusion of 0.1 mg per kilogram per day for seven days, as experimental treatment for refractory aplastic anemia. The protocols were approved by the institutional review board of the National Heart, Lung, and Blood Institute, and all patients gave written informed consent before their participation. The following is a representative case history.
Patient 7, a 15-year-old student from Colorado, presented in July 1995 with nausea and abdominal pain followed 10 days later by jaundice (bilirubin level, 14.4 mg per deciliter [246 μmol per liter]; aspartate aminotransferase level, 1777 U per liter; and alanine aminotransferase level, 3372 U per liter). One month later liver function had improved slightly, but cytopenia had developed (hemoglobin concentration, 12.1 g per deciliter; leukocyte count, 1400 per cubic millimeter; neutrophil count, 710 per cubic millimeter; and platelet count, 44,000 per cubic millimeter). On admission to the NIH in late August, the patient's liver-enzyme levels were still abnormal (aspartate aminotransferase level, 1892 U per liter; and alanine aminotransferase level, 1956 U per liter), and he had pancytopenia (hemoglobin concentration, 9.3 g per deciliter; leukocyte count, 600 per cubic millimeter; neutrophil count, 468 per cubic millimeter; and platelet count, 30,000 per cubic millimeter). An examination of bone marrow confirmed the presence of aplastic anemia, and treatment with antithymocyte globulin, cyclosporine, and granulocyte colony-stimulating factor was started. Within a month liver function was normal, and by three months the hematologic values had improved (hemoglobin concentration, 11.1 g per deciliter; leukocyte count, 2700 per cubic millimeter; neutrophil count, 1500 per cubic millimeter; and platelet count, 117,000 per cubic millimeter). In August 1996 his bone marrow was slightly hypocellular for his age but showed normal trilineage maturation, the hemoglobin concentration was 13.2 g per deciliter, the leukocyte count was 3300 per cubic millimeter, the neutrophil count was 2100 per cubic millimeter, and the platelet count was 134,000 per cubic millimeter. The patient remains well 18 months after the initiation of treatment. There is no evidence of paroxysmal nocturnal hemoglobulinuria or myelodysplastic syndrome.
Immunologic Testing
Peripheral-blood mononuclear cells were examined by flow cytometry to quantitate the number and phenotype of B and T lymphocytes with directly conjugated monoclonal antibodies against CD2, CD3, CD4, CD8, CD19, and HLA-DR (Becton Dickinson, Mountain View, Calif.).
Serologic Analysis
Standard commercial assays were used to test serum samples for hepatitis A antibody (IgM and IgG), hepatitis B surface antigen and antibody, hepatitis B core antibody, and hepatitis C antibody. In addition, hepatitis C virus (HCV) RNA and GB virus C (GBV-C) RNA14,15 were tested for by reverse transcription followed by the polymerase chain reaction (PCR) as previously described.16,17
Results
Clinical Features
On admission to the NIH all 10 patients had evidence of severe aplastic anemia, as indicated by blood counts and bone marrow findings. All but one were children or young adults (<30 years of age), and seven were male (Table 1Table 1
Clinical Characteristics of Patients with Hepatitis-Associated Aplastic Anemia.). The clinical features were similar in all cases; none of the patients had a history of exposure to toxins or chemicals, blood transfusion, or parenteral treatment of any kind before the onset of illness. All had markedly elevated liver-enzyme levels, generally with aminotransferase levels in the thousands of units per liter, and the interval between hepatitis and the onset of aplasia was short (less than one week to seven weeks). In seven patients without pancytopenia at presentation, liver function appeared to be improving at the time of the onset of aplasia.Immunologic Features
Flow-cytometric analysis showed abnormalities of the CD4 and CD8 counts in all patients. The mean (±SD) absolute counts were 99.5±182 CD4 cells per cubic millimeter (range, <4 to 602), 140±157 CD8 cells per cubic millimeter (range, <7 to 545), and 40±36 HLA-DR–positive CD8 cells per cubic millimeter (range, <1 to 101). The percentage of CD4 cells was below the normal range in all patients; in nine patients the percentage of CD8 T cells was above normal. All patients had an increased percentage of HLA-DR–positive CD8 cells, indicating activation of cytotoxic T cells (Figure 1Figure 1
Flow-Cytometric Analysis of Peripheral-Blood Lymphocytes from Patients before Treatment with Antithymocyte Globulin and Cyclosporine.).Response to Immunosuppressive Treatment
All the patients were treated with a four-day course of intravenous antithymocyte globulin and a six-month course of oral cyclosporine.13 Liver-enzyme levels returned to normal within one month after treatment was begun in all patients except Patient 9, whose aminotransferase levels fell (but not to normal) two weeks after antithymocyte globulin was given and then rose again. The aminotransferase levels returned to normal in Patient 9 after treatment with cladribine. Hematologic improvement after antithymocyte globulin treatment was slower: in five patients the blood counts returned toward normal within six months after treatment was begun (Figure 2Figure 2
Hematologic Values before and Six Months after Treatment with Antithymocyte Globulin and Cyclosporine Was Begun.), and two other patients were transfusion-independent at nine months. Of the three patients who did not respond to treatment with antithymocyte globulin, Patient 2 was subsequently shown to have monosomy 7, and Patient 8 was critically ill before starting therapy and underwent stem-cell transplantation within one month after treatment was begun. Patient 9 did not respond to two courses of immunosuppression (Table 2Table 2
Response of Patients to Immunosuppressive Therapy.).Patient 6 responded to the immunosuppressive treatment, but one year after receiving antithymocyte globulin therapy and one month after the discontinuation of cyclosporine, his aminotransferase levels rose again; two months later cytopenia developed (neutrophil count, 312 per cubic millimeter; platelet count, 9000 per cubic millimeter) with an aplastic marrow. He received a second course of antithymocyte globulin and cyclosporine, with a full hepatic and hematologic response (Table 2). None of the other patients have relapsed to date, nor has paroxysmal nocturnal hemoglobulinuria or myelodysplasia developed in any of them.
Virologic Assays
Patient 10 had evidence of previous infection with hepatitis B (tests were positive for hepatitis B surface and core antibody and negative for hepatitis B surface antigen). In the other nine patients serologic tests for hepatitis A, hepatitis B, and HCV were all negative, confirming that none had evidence of recent or current infection with any of these viruses. The reverse-transcription PCR for HCV RNA was negative in all patients but was positive for GBV-C RNA in three patients (Patients 4, 5, and 9) at the time of admission to the NIH. All three of these patients had received multiple blood transfusions before testing as part of their treatment (16, 20, and 35 units, respectively). Serum was available from 12 of the 16 units donated to Patient 4, and one of these samples was found to contain GBV-C.
Discussion
Our patients had the typical features of hepatitis-associated aplastic anemia. All had acute hepatitis that was followed within two months by aplastic anemia or pancytopenia.3 Most were young males,3 and 7 of the 10 patients had a complete response to immunosuppressive treatment within one year. The hepatitis was clinically indistinguishable from a typical viral hepatitis, but no specific cause could be identified: there was no evidence of active or recent hepatitis A or B infection and no antibody or PCR evidence of hepatitis C. GBV-C RNA was detected in three patients, but they had received multiple blood transfusions; in one patient serum from one of the transfused units contained the virus. None of the remaining patients had detectable GBV-C viremia, even early in the course of their illness. These negative results were obtained with three different assays for viral sequences from the 5' untranslated region and polymerase regions of the viral genome (data not shown). Thus, GBV-C does not appear to be the etiologic agent of hepatitis-associated aplastic anemia.
Our results, especially the response to immunosuppressive treatment, suggest that the liver and marrow abnormalities in hepatitis-associated aplastic anemia are immune-mediated. At presentation, all patients had activated CD8 cells in the blood, in several cases before the transfusion of any blood products. Levels of activated CD8 cells fell with treatment in all patients, except Patient 9, who had no response to immunosuppressive treatment. In Patient 6, the number of activated CD8 cells declined, but not to normal, despite one year of treatment with cyclosporine. After immunosuppressive therapy was stopped the number of activated CD8 cells again rose, this time in parallel with an elevation in serum aminotransferase levels that heralded a relapse. With retreatment the levels again declined.
In this study, activated lymphocytes stained brightly with a fluorescent anti-CD8 antibody, a reaction that is consistent with the presence of a T-cell phenotype, but we cannot rule out the possibility that this population also included natural killer cells. We did not determine whether the activated CD8 cells could inhibit or kill hepatic or hematopoietic target cells, but previous studies have shown that lymphocytes from patients with aplastic anemia suppress the in vitro proliferation of hematopoietic progenitor cells from patients and normal donors.18 Moreover, in aplastic anemia activated cytotoxic lymphocytes localize in the bone marrow,19,20 and there are increased levels of interferon gamma, a lymphokine product of activated CD8 and CD4 T cells, in the bone marrow.21,22 T-cell activation is common in viral infection, and cytotoxic T cells are thought to mediate the liver inflammation in hepatitis B and hepatitis C infection,23,24 but lymphocytes do not appear to be activated in uncomplicated seronegative hepatitis.25 The rapid improvement of hepatitis with immunosuppressive treatment in our patients is consistent with an immune-mediated pathophysiology.
The extremely poor prognosis of patients with hepatitis-associated aplastic anemia has prompted others to recommend immediate bone marrow transplantation.26,27 Studies involving single centers have reported survival rates of patients with severe aplastic anemia of up to 90 percent after transplantation with HLA-matched bone marrow from sibling donors, with larger studies showing survival rates of 66 percent.28-30 In registries that included more than 50 patients with post-hepatitis aplasia, the hepatitis did not affect the overall rates of graft failure,30 the rate of acute or chronic graft-versus-host disease,31 or long-term survival.32 These results justify the use of bone marrow transplantation in the minority of young patients for whom an HLA-identical sibling is available.28-30,32,33 Unfortunately, long-term survival after transplantation of HLA-matched marrow from unrelated donors is only about half that with HLA-matched transplants from sibling donors.31,34,35 Our results with antithymocyte globulin and cyclosporine are equivalent to those in patients with uncomplicated severe aplastic anemia who received such treatment and to the results with HLA-identical marrow transplantation for aplastic anemia regardless of the cause.7,11,36,37 Treatment with antithymocyte globulin and cyclosporine can be safely initiated immediately after diagnosis, allowing time to search for an alternative donor in patients without an HLA-identical sibling.
Our study confirms that hepatitis-associated aplastic anemia is a distinct type of aplastic anemia with a stereotypical pattern. The clinical features and, particularly, the response to immunosuppressive therapy strongly suggest that immunologic mechanisms mediate the marrow aplasia. The cause of the hepatitis is unknown, but it does not appear to be due to any of the known hepatitis viruses. In contrast to previous reports, in our study the outcome was not invariably fatal and most patients responded well to immunosuppressive therapy, without exacerbation of the hepatitis.
We are indebted to Stacie Anderson, Martha Kirby, and Susan Wong for sample analysis, and to Mary Caples, Janice Kimball, and the 2 West nursing staff at the NIH.
Source Information
From the Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, Md.
Address reprint requests to Dr. Brown at Bldg. 10, Rm. 7C218, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892-1652.
- References
References
1
Lorenz E ,Quaiser K . Panmyelopathie nach Hepatitis epidemica. Wien Med Wochenschr 1955;105:19-22
Medline2
Fomina LG . K voprosu obizmenenii krovetvoreniia pri zabolevaniiakh pecheni. Sov Med 1955;19:28-31
Medline3
Hagler L ,Pastore RA ,Bergin JJ ,Wrensch MR . Aplastic anemia following viral hepatitis: report of two fatal cases and literature review. Medicine (Baltimore) 1975;54:139-164
Web of Science | Medline4
Bottiger LE ,Westerholm B . Aplastic anaemia. III. Aplastic anaemia and infectious hepatitis. Acta Med Scand 1972;192:323-326
CrossRef | Web of Science | Medline5
Mary JY ,Baumelou E ,Guiguet M . Epidemiology of aplastic anemia in France: a prospective multicentric study. Blood 1990;75:1646-1653
Web of Science | Medline6
Young NS ,Issaragrisil S ,Chieh CW ,Takaku F . Aplastic anaemia in the Orient. Br J Haematol 1986;62:1-6
CrossRef | Web of Science | Medline7
Liang DC ,Lin KH ,Lin DT ,Yang CP ,Hung KL ,Lin KS . Post-hepatitis aplastic anaemia in children in Taiwan, a hepatitis prevalent area. Br J Haematol 1990;74:487-491
CrossRef | Web of Science | Medline8
Hibbs JR ,Frickhofen N ,Rosenfeld SJ , et al. Aplastic anemia and viral hepatitis: non-A, non-B, non-C? JAMA 1992;267:2051-2054
CrossRef | Web of Science | Medline9
Pol S ,Driss F ,Devergie A ,Brechot C ,Berthelot P ,Gluckman E . Is hepatitis C virus involved in hepatitis-associated aplastic anemia? Ann Intern Med 1990;113:435-437
Web of Science | Medline10
Tzakis AG ,Arditi M ,Whitington PF , et al. Aplastic anemia complicating orthotopic liver transplantation for non-A, non-B hepatitis. N Engl J Med 1988;319:393-396
Full Text | Web of Science | Medline11
Cattral MS ,Langnas AN ,Markin RS , et al. Aplastic anemia after liver transplantation for fulminant liver failure. Hepatology 1994;20:813-818
CrossRef | Web of Science | Medline12
Sallie R ,Silva AE ,Purdy M , et al. Hepatitis C and E in non-A non-B fulminant hepatic failure: a polymerase chain reaction and serological study. J Hepatol 1994;20:580-588
CrossRef | Web of Science | Medline13
Rosenfeld SJ ,Kimball J ,Vining D ,Young NS . Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia. Blood 1995;85:3058-3065
Web of Science | Medline14
Simons JN ,Leary TP ,Dawson GJ , et al. Isolation of novel virus-like sequences associated with human hepatitis. Nat Med 1995;1:564-569
CrossRef | Web of Science | Medline15
Linnen J ,Wages J Jr ,Zhang-Keck ZY , et al. Molecular cloning and disease association of hepatitis G virus: a transfusion-transmissible agent. Science 1996;271:505-508
CrossRef | Web of Science | Medline16
Hibbs JR ,Issaragrisil S ,Young NS . High prevalence of hepatitis C viremia among aplastic anemia patients and controls from Thailand. Am J Trop Med Hyg 1992;46:564-570
Web of Science | Medline17
Leary TP ,Muerhoff AS ,Simons JN , et al. Consensus oligonucleotide primers for the detection of GB virus C in human cryptogenic hepatitis. J Virol Methods 1996;56:119-121
CrossRef | Web of Science | Medline18
Kagan WA ,Ascensao JA ,Pahwa RN , et al. Aplastic anemia: presence in human bone marrow of cells that suppress myelopoiesis. Proc Natl Acad Sci U S A 1976;73:2890-2894
CrossRef | Web of Science | Medline19
Zoumbos NC ,Gascon P ,Djeu JY ,Trost SR ,Young NS . Circulating activated suppressor T lymphocytes in aplastic anemia. N Engl J Med 1985;312:257-265
Full Text | Web of Science | Medline20
Maciejewski JP ,Hibbs JR ,Anderson S ,Katevas P ,Young NS . Bone marrow and peripheral blood lymphocyte phenotype in patients with bone marrow failure. Exp Hematol 1994;22:1102-1110
Web of Science | Medline21
Nakao S ,Yamaguchi M ,Shiobara S , et al. Interferon-gamma gene expression in unstimulated bone marrow mononuclear cells predicts a good response to cyclosporine therapy in aplastic anemia. Blood 1992;79:2532-2535
Web of Science | Medline22
Nistico A ,Young NS . Gamma-interferon gene expression in the bone marrow of patients with aplastic anemia. Ann Intern Med 1994;120:463-469
Web of Science | Medline23
Chisari FV ,Ferrari C . Hepatitis B virus immunopathogenesis. Annu Rev Immunol 1995;13:29-60
CrossRef | Web of Science | Medline24
Liaw YF ,Lee CS ,Tsai SL , et al. T-cell-mediated autologous hepatocytotoxicity in patients with chronic hepatitis C virus infection. Hepatology 1995;22:1368-1373
Web of Science | Medline25
Kojima S ,Matsuyama K ,Kodera Y ,Okada J . Circulating activated suppressor T lymphocytes in hepatitis-associated aplastic anaemia. Br J Haematol 1989;71:147-151
CrossRef | Web of Science | Medline26
Camitta BM ,Nathan DG ,Forman EN ,Parkman R ,Rappeport JM ,Orellana TD . Posthepatic severe aplastic anemia -- an indication for early bone marrow transplantation. Blood 1974;43:473-483
Web of Science | Medline27
Gluckman E ,Devergie A ,Faille A ,Bussel A ,Benbunan M ,Bernard J . Antilymphocyte globulin treatment in severe aplastic anemia -- comparison with bone marrow transplantation: report of 60 cases. Haematol Bluttransfus 1979;24:171-17928
May WS ,Sensenbrenner LL ,Burns WH , et al. BMT for severe aplastic anemia using cyclosporine. Bone Marrow Transplant 1993;11:459-464
Web of Science | Medline29
Storb R ,Etzioni R ,Anasetti C , et al. Cyclophosphamide combined with antithymocyte globulin in preparation for allogeneic marrow transplants in patients with aplastic anemia. Blood 1994;84:941-949
Web of Science | Medline30
Champlin RE ,Horowitz MM ,van Bekkum DW , et al. Graft failure following bone marrow transplantation for severe aplastic anemia: risk factors and treatment results. Blood 1989;73:606-613
Web of Science | Medline31
Bradley BA, Hows JM, Gore SM, et al. Current status of unrelated-donor bone marrow transplantation: the International Marrow Unrelated Search and Transplant (IMUST) Study. Clin Transpl 1992:91-107.
32
Passweg JR, Socié G, Hinterberger W, et al. Bone marrow transplantation for severe aplastic anemia: has outcome improved? Blood (in press).
33
Gluckman E ,Horowitz MM ,Champlin RE , et al. Bone marrow transplantation for severe aplastic anemia: influence of conditioning and graft-versus-host disease prophylaxis regimens on outcome. Blood 1992;79:269-275
Web of Science | Medline34
Kernan NA ,Bartsch G ,Ash RC , et al. Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med 1993;328:593-602
Full Text | Web of Science | Medline35
Margolis D ,Camitta B ,Pietryga D , et al. Unrelated donor bone marrow transplantation to treat severe aplastic anaemia in children and young adults. Br J Haematol 1996;94:65-72
CrossRef | Web of Science | Medline36
Shannon K ,Koehne W ,Heyman MB ,Koerper MA . Relapsing post-hepatitis aplastic anemia: immunosuppressive therapy. Clin Pediatr (Phila) 1990;29:25-29
CrossRef | Web of Science | Medline37
Shimokawa T ,Suzue T . Successful treatment of a case of hepatitis-associated severe aplastic anemia by anti-lymphocyte globulin (ALG). Rinsho Ketsueki 1990;31:1836-1839
Medline
- Citing Articles (70)
Citing Articles
1
Sammy Saab. 2012. Hematopoietic Abnormalities and Hemostasis. , 405-413.
CrossRef2
Anna S. F. Lok, Francesco Negro. 2011. Hepatitis B and D. , 537-581.
CrossRef3
Rebecca J. Deyell, Evan B. Shereck, Ruth A. Milner, Kirk R. Schultz. (2011) Immunosuppressive Therapy Without Hematopoietic Growth Factor Exposure in Pediatric Acquired Aplastic Anemia. Pediatric Hematology-Oncology 28:6, 469-478
CrossRef4
Ann Ming Yeh, Amirkaveh Mojtahed, Dorsey Bass. (2011) Acute Liver Failure and Aplastic Anemia in an 11-Year-Old Girl. Digestive Diseases and Sciences 56:8, 2237-2240
CrossRef5
Pramod K. Mistry, Dhanpat Jain. 2011. Haematological Disorders of the Liver. , 48-69.
CrossRef6
Eon Chul Han, Nam-Joon Yi, Geun Hong, Min Su Park, Young Rok Choi, Heyoung Kim, Kwang Woong Lee, In Ho Kim, Yoon Jun Kim, Jae Sung Ko, Kyung Duk Park, Hoan Jong Lee, Eun Hwa Choi, Jeong Kee Seo, Kyoung-Bun Lee, Kyung Suk Suh. (2011) Serongative Acute Hepatic Failure-associated Aplastic Anemia in Pediatric Liver Transplantation. The Journal of the Korean Society for Transplantation 25:4, 276
CrossRef7
Philip Lanzkowsky. 2011. Bone Marrow Failure. , 123-167.
CrossRef8
Francois P. Aspesberro, Joan S. Roberts, Thomas V. Brogan. 2011. Hematology and Oncology Problems in the Intensive Care Unit. , 1151-1161.
CrossRef9
Carolus Schenke, Miguel A Alejandre-Alcázar, Wolfgang Holter, Klaus Korn, Thomas Papadopoulos, Henrik Köhler. (2010) Aplastic Anemia Following Hepatitis Associated With Human Herpesvirus 6. Journal of Pediatric Gastroenterology and Nutrition 51:4, 527-529
CrossRef10
Masataka Ishimura, Shouichi Ohga, Masako Ichiyama, Koichi Kusuhara, Hidetoshi Takada, Toshiro Hara, Masaharu Takahashi, Hiroaki Okamoto. (2010) Hepatitis-associated aplastic anemia during a primary infection of genotype 1a torque teno virus. European Journal of Pediatrics 169:7, 899-902
CrossRef11
Anna Locasciulli, Andrea Bacigalupo, Barbara Bruno, Barbara Montante, Judith Marsh, André Tichelli, Gerard Socié, Jakob Passweg, . (2010) Hepatitis-associated aplastic anaemia: epidemiology and treatment results obtained in Europe. A report of The EBMT aplastic anaemia working party. British Journal of Haematology 149:6, 890-895
CrossRef12
Sherilyn A. Gross, Richard D. Irons, A. Robert Schnatter, John Ryder, Xiao Qin Wang, G. Bruce Copley, Thomas W. Armstrong. (2010) A hospital-based case control study of aplastic anemia in Shanghai, China. Chemico-Biological Interactions 184:1-2, 165-173
CrossRef13
Vicky Rowena Breakey, Stephen Meyn, Vicky Ng, Christopher Allen, Inderjeet Dokal, Peter M. Lansdorp, Oussama Abla, Yigal Dror. (2009) Hepatitis-associated Aplastic Anemia Presenting as a Familial Bone Marrow Failure Syndrome. Journal of Pediatric Hematology/Oncology 31:11, 884-887
CrossRef14
Judith C. W. Marsh, Sarah E. Ball, Jamie Cavenagh, Phil Darbyshire, Inderjeet Dokal, Edward C. Gordon-Smith, Jane Keidan, Andrew Laurie, Anna Martin, Jane Mercieca, Sally B. Killick, Rhona Stewart, John A. L. Yin, . (2009) Guidelines for the diagnosis and management of aplastic anaemia. British Journal of Haematology 147:1, 43-70
CrossRef15
R. GONZALEZ-CASAS, L. GARCIA-BUEY, E. A. JONES, J. P. GISBERT, R. MORENO-OTERO. (2009) Systematic review: hepatitis-associated aplastic anaemia - a syndrome associated with abnormal immunological function. Alimentary Pharmacology & Therapeutics 30:5, 436-443
CrossRef16
Maria Scalzone, Paola Coccia, Palma Maurizi, Giorgio Attinà, Lucia Liotti, Maria Giuseppina Cefalo, Antonio Ruggiero, Riccardo Riccardi. (2009) Aplastic anaemia in childhood. Description of two cases and review of the literature. Central European Journal of Medicine 4:3, 363-368
CrossRef17
Magnus P. Stalder, Alicia Rovó, Jörg Halter, Dominik Heim, Tobias Silzle, Jakob Passweg, Johannes Rischewski, Martin Stern, Caroline Arber, Andreas Buser, Sandrine Meyer-Monard, André Tichelli, Alois Gratwohl. (2009) Aplastic anemia and concomitant autoimmune diseases. Annals of Hematology 88:7, 659-665
CrossRef18
Rupali Agnihotri, Khandige Mahalinga Bhat, Giliyar Subraya Bhat, Pratibha Pandurang. (2009) Periodontal management of a patient with severe aplastic anemia: a case report. Special Care in Dentistry 29:3, 141-144
CrossRef19
M D Aljurf, S Z Zaidi, H El Solh, F Hussain, A Ghavamzadeh, H K Mahmoud, T Shamsi, T Ben Othman, M M Sarhan, D Dennison, A Ibrahim, S Benchekroun, N Chaudhri, B Labar, M Horowitz, D Niederwieser, A Gratwohl. (2009) Special issues related to hematopoietic SCT in the Eastern Mediterranean region and the first regional activity report. Bone Marrow Transplantation 43:1, 1-12
CrossRef20
(2008) Chimerism and Tolerance in a Recipient of a Deceased-Donor Liver Transplant. New England Journal of Medicine 358:19, 2075-2075
Full Text21
Jean P Molleston, Terry A Vik, Steven J Steiner, Kevin M Kernek. (2008) Non-ABC Acute Hepatic Failure Associated With Aplastic Anemia Can Be Treated With Immunosuppression. Journal of Pediatric Gastroenterology and Nutrition 46:2, 216-219
CrossRef22
Nedim Hadžić, Susan Height, Sarah Ball, Mohamed Rela, Nigel D. Heaton, Paul Veys, Giorgina Mieli-Vergani. (2008) Evolution in the management of acute liver failure-associated aplastic anaemia in children: A single centre experience. Journal of Hepatology 48:1, 68-73
CrossRef23
Tsuyoshi Muta, Yoshinori Tanaka, Eiji Takeshita, Yuichi Kobayashi, Takahito Tokuyama, Yoko Ueda, Koji Joko, Tomoaki Fujisaki, Eisuke Yokota. (2008) Recurrence of Hepatitis-Associated Aplastic Anemia after a 10-year Interval. Internal Medicine 47:19, 1733-1737
CrossRef24
William J. Savage, Patricia A. DeRusso, Linda M. Resar, Allen R. Chen, Meghan A. Higman, David M. Loeb, Richard J. Jones, Robert A. Brodsky. (2007) Treatment of hepatitis-associated aplastic anemia with high-dose cyclophosphamide. Pediatric Blood & Cancer 49:7, 947-951
CrossRef25
Emma Honkaniemi, Britt Gustafsson, Björn Fischler, Antal Nemeth, Britt-Marie Frost, Nikos Papadogiannakis, Jacek Winiarski. (2007) Acquired aplastic anaemia in seven children with severe hepatitis with or without liver failure. Acta Paediatrica 96:11, 1660-1664
CrossRef26
Cem Cengiz, Nesrin Turhan, O. Faruk Yolcu, Sevinc Yılmaz. (2007) Hepatitis Associated with Aplastic Anemia: Do CD8(+) Kupffer Cells Have a Role in the Pathogenesis?. Digestive Diseases and Sciences 52:9, 2438-2443
CrossRef27
Rosa Sanchez, Philip Rosenthal, Robert Goldsby. (2007) Immunotherapy for severe aplastic anemia following orthotopic liver transplantation in children. Pediatric Blood & Cancer 49:1, 93-98
CrossRef28
Elisabetta Cariani, Anna Maria Pelizzari, Anna Rodella, Franco Gargiulo, Luisa Imberti, Nino Manca, Giuseppe Rossi. (2007) Immune-mediated hepatitis-associated aplastic anemia caused by the emergence of a mutant hepatitis B virus undetectable by standard assays. Journal of Hepatology 46:4, 743-747
CrossRef29
Jason T. Blackard, Nyingi Kemmer, Kenneth E. Sherman. (2006) Extrahepatic replication of HCV: Insights into clinical manifestations and biological consequences. Hepatology 44:1, 15-22
CrossRef30
Gregory Fischer, Linda Shore-Lesserson. 2006. Hematologic Diseases. , 359-376.
CrossRef31
Takashi Goto, Hiroki Ishikawa, Akira Saeki, Naruhiko Ikari, Mariko Fukuta, Naota Taura, Daisuke Nishimura, Tatsuki Ichikawa, Keisuke Hamasaki, Kazuhiko Nakao, Katsumi Eguchi. (2006) Two cases of hepatitis-associated aplastic anemia. Kanzo 47:6, 298-303
CrossRef32
M. BHATTACHARYYA, H. OAKERVEE, C. DALLEY, M. GLYNN, J. CAVENAGH. (2005) Hepatitis-associated aplastic anaemia treated successfully with antilymphocyte globulin. Clinical and Laboratory Haematology 27:5, 331-333
CrossRef33
S. R. Rajwal, S. M. Davison, M. D. Stringer, S. E. Kinsey, P. McClean. (2005) Successful recovery of aplastic anemia following orthotopic liver transplantation for non-A-E acute liver failure. Pediatric Transplantation 9:4, 537-540
CrossRef34
Kosuke Oyaizu, Fumi Mineshiba, Junji Mineshiba, Hirokazu Takaya, Fusanori Nishimura, Ichiro Tanimoto, Hideo Arai, Shogo Takashiba. (2005) Periodontal Treatment in Severe Aplastic Anemia. Journal of Periodontology 76:7, 1211-1216
CrossRef35
Robert A Brodsky, Richard J Jones. (2005) Aplastic anaemia. The Lancet 365:9471, 1647-1656
CrossRef36
Jacqui L. Dobson, Peter W. Angus, Robert Jones, Peter Crowley, Paul J. Gow. (2005) Flucloxacillin-induced aplastic anaemia and liver failure. Transplant International 18:4, 487-489
CrossRef37
J Starý, F Locatelli, C M Niemeyer. (2005) Stem cell transplantation for aplastic anemia and myelodysplastic syndrome. Bone Marrow Transplantation 35, S13-S16
CrossRef38
Takeshi Hara, Kazuki Ando, Hisashi Tsurumi, Hisataka Moriwaki. (2004) Excessive production of tumor necrosis factor-alpha by bone marrow T lymphocytes is essential in causing bone marrow failure in patients with aplastic anemia. European Journal of Haematology 73:1, 10-16
CrossRef39
J.C.W. Marsh, S.E. Ball, P. Darbyshire, E.C. Gordon-Smith, A.J. Keidan, A. Martin, S.R. McCann, J. Mercieca, D. Oscier, A.W.W. Roques, J.A.L. Yin, . (2003) Guidelines for the diagnosis and management of acquired aplastic anaemia. British Journal of Haematology 123:5, 782-801
CrossRef40
J Maciejewski. (2003) Hematopoietic stem cells in aplastic anemia. Archives of Medical Research 34:6, 520-527
CrossRef41
Paul Krogstad, Mart??n G. Mart??n. (2003) Evaluation of acute liver failure. The Pediatric Infectious Disease Journal 22:9, 831-832
CrossRef42
Klaus Geissler. (2003) Pathophysiology and treatment of aplastic anemia. Wiener Klinische Wochenschrift 115:13-14, 444-450
CrossRef43
Manuel Ramos-Casals, Mario García-Carrasco, Francisco López-Medrano, Olga Trejo, Xavier Forns, Armando López-Guillermo, Carles Muñoz, Miguel Ingelmo, Josep Font. (2003) Severe Autoimmune Cytopenias in Treatment-Naive Hepatitis C Virus Infection. Medicine 82:2, 87-96
CrossRef44
Alejandro Soza, Daryl T.-Y. Lau, Muhammad Farooq Khokhar, Hari Conjeevaram, Yoon Park, Jay H. Hoofnagle. (2003) Resolution of Chronic Hepatitis B-Associated Autoimmune Neutropenia With Interferon-α Therapy. Journal of Pediatric Gastroenterology and Nutrition 36:1, 141-143
CrossRef45
Tadashi Imai, Susumu Itoh, Hitoshi Okada, Shoju Onishi. (2002) Aplastic anemia following hepatitis associated with echovirus 3. Pediatrics International 44:5, 522-524
CrossRef46
Jessica A. Berman, Kashyap Patel, Jaime Caro. (2002) Enhanced response to basiliximab in a patient with aplastic anemia after treatment with standard immunosuppression. American Journal of Hematology 71:1, 64-64
CrossRef47
Senji Kasahara, Takeshi Hara, Hiroyasu Itoh, Kazuki Ando, Hisashi Tsurumi, Michio Sawada, Toshiki Yamada, Hiroo Ohnishi, Hisataka Moriwaki. (2002) Hypoplastic myelodysplastic syndromes can be distinguished from acquired aplastic anaemia by bone marrow stem cell expression of the tumour necrosis factor receptor. British Journal of Haematology 118:1, 181-188
CrossRef48
Hiroko Otsubo, Ken Kaito, Yoji Ogasawara, Takaki Shimada, Noriko Usui, Masayuki Kobayashi. (2002) Successful Immunosuppressive Therapy With Cyclosporine A for Posthepatitis B-Cell Deficiency With Activated Cytoplasmic Interferon-γ—Positive T-Lymphocytes. International Journal of Hematology 75:3, 285-288
CrossRef49
Patrick Itterbeek, Peter Vandenberghe, Frederik Nevens, Johan Fevery, Raymond Aerts, Sing Hiem Yap, Hilde Demuynck, Inge Fourneau, Takaaki Koshiba, Marie-Paule Emonds, Tania Roskams, Marc Boogaerts, Jacques Pirenne. (2002) Aplastic anemia after transplantation for non-A, non-B, non-C fulminat hepatic failure: case report and review of the literature. Transplant International 15:2-3, 117-123
CrossRef50
Helen A. Papadaki, Judith C.W. Marsh, George D. Eliopoulos. (2002) Bone Marrow Stem Cells and Stromal Cells in Autoimmune Cytopenias. Leukemia & Lymphoma 43:4, 753-760
CrossRef51
Akira Ohara, Seiji Kojima, Jun Okamura, Hiroko Inada, Hisato Kigasawa, Shigeyoshi Hibi, Ichiro Tsukimoto, . (2002) Evolution of myelodysplastic syndrome and acute myelogenous leukaemia in children with hepatitis-associated aplastic anaemia. British Journal of Haematology 116:1, 151-154
CrossRef52
P. F. Whitington, E. M. Alonso. (2001) Fulminant Hepatitis in Children: Evidence for an Unidentified Hepatitis Virus. Journal of Pediatric Gastroenterology and Nutrition 33:5, 529-536
CrossRef53
K. Ashok Shenoy, M. R. Prabha Adhikari, M. Chakrapani, D. Shenoy, A. Pillai. (2001) Pancytopenia after recombinant hepatitis b vaccine - an indian case report. British Journal of Haematology 114:4, 954-962
CrossRef54
Markus Peck-Radosavljevic. (2001) Hypersplenism. European Journal of Gastroenterology & Hepatology 13:4, 317-323
CrossRef55
John Tung, Nedim Hadzic, Mark Layton, Alastair J. Baker, Anil Dhawan, Mohamed Rela, Nigel D. Heaton, Giorgina Mieli-Vergani. (2000) Bone Marrow Failure in Children With Acute Liver Failure. Journal of Pediatric Gastroenterology and Nutrition 31:5, 557-561
CrossRef56
Christoph Sarrazin, Brigitte R
ster, Jung-Hun Lee, Bernd Kronenberger, W. Kurt Roth, Stefan Zeuzem. (2000) Prospective follow-up of patients with GBV-C/HGV infection: Specific mutational patterns, clinical outcome, and genetic diversity. Journal of Medical Virology 62:2, 191-198
CrossRef57
M. A. Sathar, P. N. Soni, D. York. (2000) GB Virus C/Hepatitis G Virus (GBV-C/HGV): still looking for a disease. International Journal of Experimental Pathology 81:5, 305-322
CrossRef58
S.B. Killick, J.C.W. Marsh. (2000) Aplastic anaemia: Management. Blood Reviews 14:3, 157-171
CrossRef59
E. C. Gordon-Smith, J. C. W. Marsh. (2000) Management of Acquired Aplastic Anemia. Reviews in Clinical and Experimental Hematology 4:3, 260-278
CrossRef60
Neal S. Young. (2000) The Etiology of Acquired Aplastic Anemia. Reviews in Clinical and Experimental Hematology 4:3, 236-259
CrossRef61
A. Handa, R. F. Jubran, B. Dickstein, A. Boylan, N. L. C. Luban, N. S. Young, K. E. Brown. (2000) GB Virus C/Hepatitis G Virus Infection Is Frequent in American Children and Young Adults. Clinical Infectious Diseases 30:3, 569-571
CrossRef62
Neal S Young. (2000) Hematopoietic cell destruction by immune mechanisms in acquired aplastic anemia. Seminars in Hematology 37:1, 3-14
CrossRef63
E Palomba, A Bairo, P-A Tovo. (1999) High rate of maternal-infant transmission of hepatitis G virus in HIV-1 and hepatitis C virus-infected women. Acta Paediatrica 88:12, 1392-1395
CrossRef64
Magdalena Robaczewska, Lucyna Cova, Anna J. Podhajska, Bogdan Falkiewicz. (1999) Hepatitis G virus: Molecular organization, methods of detection, prevalence, and disease association. International Journal of Infectious Diseases 3:4, 220-233
CrossRef65
Jean-François Cantaloube, Pierre Gallian, Philippe Biagini, Houssam Attoui, Jacqueline Escher, Jean-Pierre Zappitelli, Yves Delord, Philippe De Micco, Xavier De Lamballerie. (1999) Prevalence of GB virus type C/hepatitis G virus RNA and anti-E2 among blood donors in Southeastern France. Transfusion 39:1, 95-102
CrossRef66
Ronald L. Paquette, Ken Kuramoto, Lawrence Tran, Ghislaine Sopher, Stephen D. Nimer, Jerome B. Zeldis. (1998) Hepatitis C virus infection in acquired aplastic anemia. American Journal of Hematology 58:2, 122-126
CrossRef67
Kenneth G. Hadlock, Steven K.H. Foung. (1998) GBV-C/HGV: A new virus within the Flaviviridae and its clinical implications. Transfusion Medicine Reviews 12:2, 94-108
CrossRef68
Eva C. Guinan. (1997) CLINICAL ASPECTS OF APLASTIC ANEMIA. Hematology/Oncology Clinics of North America 11:6, 1025-1044
CrossRef69
(1997) Hepatitis-Associated Aplastic Anemia. New England Journal of Medicine 337:6, 424-425
Full Text70
Epstein, Franklin H., , Young, Neal S., Maciejewski, Jaroslaw, . (1997) The Pathophysiology of Acquired Aplastic Anemia. New England Journal of Medicine 336:19, 1365-1372
Full Text
- Letters
