苯中毒致再生障碍性贫血的细胞免疫功能研究

目的:探讨细胞免疫功能与苯中毒性再生障碍性贫血(再障)发生、发展及转归的关系。方法:根据16例苯中毒再障患者T淋巴细胞亚群有无异常,分为A组和B组。T细胞亚群正常的患者为A组,CD4 /CD8 比值降低者为B组。A组应用雄激素、粒细胞集落刺激因子(G-CSF)和促红细胞生成素(Epo)联合治疗,B组应用以上方案联合环孢素A(CsA)治疗。外周血细胞水平恢复正常后G-CSF、Epo及CsA逐渐减量。结果:所有病例治疗后外周血细胞计数、骨髓涂片正常,治疗前CD4 /CD8 降低者,治疗后恢复正常。结论:部分苯中毒性再障患者,即使无免疫抑制剂的应用,造血干细胞的损伤也能逐渐恢复。因此,对苯中毒性再障患者,常规检查外周血T淋巴细胞及其亚群的变化,以预测应用免疫抑制剂的可行性及其有效性。     

Lymphoproliferative disease of granular T lymphocytes presenting as aplastic anemia

Lymphoproliferative disease of granular T lymphocyte (T-LDGL), also known as T-cell large granular lymphocyte leukemia, is a clonal disorder of cytotoxic T lymphocytes that is clinically manifested as chronic neutropenia and anemia. Association with autoimmune disorders is common. In 9 patients, T-LDGL is reported as presenting as aplastic anemia. The clinical characteristics were similar to acquired aplastic anemia. Morphologic evidence of increased granular lymphocytes in the peripheral blood and an excess of CD3(+)/CD8(+)/CD57(+) cells in the bone marrow were found in most cases. Cyclophosphamide was ineffective, but noncytotoxic immunosuppressive agents generally produced a good response. After a median follow-up of 49 months, 5 patients had died from the disease or related complications. Median survival was 40 months. Aplastic anemia can be a presenting manifestation of T-LDGL, and T-LDGL should be considered in the differential diagnosis of acquired aplastic anemia.     

The prognosis in aplastic anemia.

The biphasic shape of the survival curve of 99 patients with aplastic anemia suggested that there may be at least two subgroups of patients with this disease, one with a very short survival and another with a longer survival. Patients who survived for 4 mo or less after the first clinic visit (group A) were different from the patients who survived longer (group B) with respect to their modes of onset, sex, intervals from the onset of symptoms to first clinic visit, and initial hematologic values. These differences suggested that short survival could be predicted from data available at the first contact with the physician. From these measurements, a prognostic index could be calculated which was useful in identifying the patients in group A. Although this method of prognostication needs further testing, if validated, it may prove useful in selecting patients for therapeutic trials and could explain the divergent results in previous studies of androgen treatment of aplastic anemia. When our androgen-treated subjects were compared with subjects with a similar prognostic index who had not received androgens, a beneficial effect of androgen therapy on survival could not be demonstrated.     

The pathophysiology of aplastic anemia.

No single cause can explain aplastic anemia. Two major factors are involved: An intrinsic derangement of hemopoietic proliferation capacity that is essentially compatible with life, but has to be considered a premalignant condition. This primarily diseased tissue can be destroyed by immune mechanisms in an attempt to achieve self-cure. Therefore, immunosuppressive therapy can mitigate this immune reaction but leaves the patient with a poorly proliferating bone marrow that is prone to late complications. The clinical presentation and course depend on the balance of these two major factors: If the immune reaction is strong, acute severe aplasia occurs, whereas in patients with a weak immune reaction the disease will present itself rather as chronic pancytopenia with myelodysplastic traits. Co-involvement of environmental cells in the disease process is an additional factor. Poor production of hemopoietic growth factors may aggravate aplasia and poor immune competence may allow abnormal clones to proliferate. All these pathophysiological factors are genetically determined.     

Fetal liver transplantation in aplastic anemia.

Fetal liver transplantation was attempted in 7 patients with aplastic anemia. 4 of these patients showed a partial response as evidenced by decrease in blood transfusion requirements and increase in the peripheral blood counts and hematopoietic cells in the bone marrow. Bone marrow culture studies revealed evidence of a temporary mixed lymphoid chimerism (cases 1 and 3). While case 1 lived for 16 months, case 3 is surviving at 17 months. None of the patients showed apparent graft-versus-host disease. Increased incidence of infections was noticed. Possible causes for the same are discussed. 3 patients failed to respond. Fetal liver transplant may be of therapeutic value in management of aplastic anemia.     

Complement-sensitive red cells in aplastic anemia.

In view of the clinical association of aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH), the complement-dependent lysis of the youngest red cells of AA patients was studied. A complement-sensitive population of young red cells was found in five of six patients with AA. These cells were rapidly cleared from the circulation and were undetectable in the oldest cell fraction. Such cells were not found in normal controls or in a variety of hematologic disorders, with the exception of PNH. This study suggests that in most patients with AA, even without any clinical manifestations of PNH, there is a population of dyserythropoietic, short-lived complement-sensitive cells.     

Erythropoietin in aplastic anemia

Summary The level of erythropoietin (Ep) was measured in sera and urine from aplastic anemia patients. Increased levels of E_p were demonstrated in sera from all 25 patients studied. An elevated level of E_p was found in the urine of 17 of 23 patients in whom the urine was tested. No correlation between blood hemoglobin and E_p level was observed. A higher serum E_p level was noted in patients with aplastic anemia than in patients with sideropenic anemia of the same severity. To explain the discrepancy, diminished E_p consumption in bone marrow of aplastic anemia patients is discussed.This work was supported by a grant form the Medical Scientific Fund of Serbia     

Acquired aplastic anemia

In aplastic anemia, hematopoiesis fails: Blood cell counts are extremely low, and the bone marrow appears empty. The pathophysiology of aplastic anemia is now believed to be immune-mediated, with active destruction of blood-forming cells by lymphocytes. The aberrant immune response may be triggered by environmental exposures, such as to chemicals and drugs or viral infections and, perhaps, endogenous antigens generated by genetically altered bone marrow cells. In patients with post-hepatitis aplastic anemia, antibodies to the known hepatitis viruses are absent; the unknown infectious agent may be more common in developing countries, where aplastic anemia occurs more frequently than it does in the West. The syndrome paroxysmal nocturnal hemoglobinuria (PNH) is intimately related to aplastic anemia because many patients with bone marrow failure have an increased population of abnormal cells. In PNH, an entire class of proteins is not displayed on the cell surface because of an acquired X-chromosome gene mutation. The PNH cells may have a selective advantage in resisting immune attack. In contrast, the disease myelodysplasia can be confused with aplasia and can also evolve from aplastic anemia. The occurrence of cytogenetic abnormalities in patients years after presentation implies that genomic instability is a feature of this immune-mediated disease. Aplastic anemia can be effectively treated by stem-cell transplantation or immunosuppressive therapy. Transplantation is curative but is best used for younger patients who have histocompatible sibling donors. Antithymocyte globulin and cyclosporine restore hematopoiesis in approximately two thirds of patients. However, recovery of blood cell count is often incomplete, recurrent pancytopenia requires retreatment, and some patients develop late complications (especially myelodysplasia).     

Ticlopidine-associated aplastic anemia

 Serious hematologic complications associated with ticlopidine have been reported, including aplastic anemia. We report here an additional case of fatal aplastic anemia due to ticlopidine. A 66-year-old male patient developed fever and pancytopenia 2 months after ticlopidine was started. Despite the administration of granulocyte colony-stimulating factor (G-CSF) and broad-spectrum antibiotics, as well as aggressive red cell and platelet transfusions, the patient died 16 days after admission due to septic shock. Eighteen other cases of ticlopidine-induced aplastic anemia published in the English literature are also reviewed and presented here. Eight of the total 19 patients (including the one reported here) have died, mostly due to infection. Of the seven who received supportive treatment only, four had spontaneous recovery. Nine cases were treated with G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF), and response was observed in only four of them. Several other cases were treated with high-dose corticosteroids or androgens; however, it was not possible to evaluate the efficacy of these treatments because of the limited number of cases. In the absence of satisfactory treatment for ticlopidine-induced aplastic anemia at present, it may be reasonable to try antilymphocyte globulin or cyclosporine. Also, great efforts should be made in the prevention and management of infection accompanying this disease. Received: 2 November 1997 / Accepted: 12 January 1998     

Hodgkin lymphoma accompanied by aplastic anemia and polyclonal expansion of large granular lymphocytes

Immunologic abnormalities have been described in patients with Hodgkin lymphoma, including autoimmune hemolytic anemia and immune thrombocytopenic purpura. The concurrent diagnoses of Hodgkin lymphoma and acquired aplastic anemia, however, is extremely rare. We report a 56-year-old Japanese female patient with severe aplastic anemia and increased large granular lymphocytes prior to the recurrence of Hodgkin lymphoma. After being in remission for 10 years from Hodgkin lymphoma, she developed progressive pancytopenia. The large granular lymphocytes (expressed CD3+ CD8+ TCRalphabeta+) had a polyclonal distribution, the serum-soluble FasL concentration was significantly elevated, and bone marrow biopsy showed severely hypocellular bone marrow without infiltration of abnormal lymphocytes. No lymphadenopathy was observed that would suggest a relapse of Hodgkin lymphoma. A diagnosis of aplastic anemia was made, and treatment with corticosteroids and cyclosporine was initiated. Two months later, she suddenly developed celiac and mediastinal lymphadenopathy. She underwent one cycle of chemotherapy before she died of progressive pancytopenia. Autopsy revealed the recurrence of Hodgkin lymphoma, nodular sclerosis in the lymph nodes and markedly hypocellular bone marrow. Although autoimmune disorders are described in Hodgkin lymphoma, our case shows a rare instance of a patient who had aplastic anemia as the first manifestation of a relapse of Hodgkin lymphoma.     

Prognosis in acquired aplastic anemia

To study prognostic factors 38 consecutive patients with aplastic anemia were evaluated until death or over a follow-up period of at least 4 years. A prognostic formula was devised by multivariate analysis for prediction of short-term survivors at diagnosis of aplastic anemia: Using the initial percentage of nonmyeloid cells in the marrow aspirate and the neutrophil count in peripheral blood, survival of less than 4 months is predicted with a probability of 89% (sensitivity 80%). The lowest blood counts during the course of the disease are useful to predict the outcome in more chronic courses of aplastic anemia: A reticulocytopenia below 5 X 10(9)/1, a neutropenia below 0.1 X 10(9)/1 or a thrombocytopenia below 5 X 10(9)/1 all resulted in an ultimate mortality of over 90%. However, if none of these threshold values were reached, a 4 year survival of 71% was observed. Thus, 5 X 10(9) reticulocytes/1, 0.1 X 10(9) neutrophils/1 and 5 X 10(9) platelets/1 form a group of risk factors to predict a fatal or favorable outcome throughout the course of the disease.