抗CD20单克隆抗体治疗难治性自身免疫性溶血性贫血

本研究初步观察抗CD20单克隆抗体利妥昔（rituximab）用于治疗难治性自身免疫性溶血性贫血（AIHA）的疗效和安全性。对1例用糖皮质激素、脾切除治疗无效的AIHA患者,采用利妥昔单克隆抗体,375mg/m2,每周1次,共4次,观察溶血症状的改变并监测血红蛋白（Hb）水平及其它检验指标,同时观察有无不良反应发生。结果表明,首次治疗后11天乳酸脱氢酶（LDH）、总胆红素（TBIL）、直接胆红素（IBIL）逐渐下降,第45天降至正常范围;首剂治疗25天后Hb水平比治疗之前升高到95-100g/L以上。治疗后已4月余,患者仍处于缓解状态。治疗过程中未发生明显不良反应。结论：抗CD20单克隆抗体利妥昔用于治疗难治性自身免疫性溶血性贫血是有效而且安全的。     

Erythropoietin May Improve Anemia in Patients with Autoimmune Hemolytic Anemia Associated with Reticulocytopenia

Background

Management of patients with autoimmune hemolytic anemia (AIHA) and reticulocytopenia remains challenging.

Case Reports

Two patients with decompensated AIHA who were receiving immunosuppressive drugs were treated with erythropoietin (EPO). Administration of EPO increased reticulocyte counts and hemoglobin concentrations in both cases. One patient completely recovered following a short course of treatment. Hemolysis could be compensated in the second patient using only mild doses of immunosuppressive drugs in combination with EPO.

Conclusion

The administration of EPO should be considered in patients with therapy-refractory AIHA, particularly in the presence of reticulocytopenia.     

慢性B细胞淋巴增殖性疾病合并自身免疫性溶血性贫血

本研究探讨慢性B细胞淋巴增殖性疾病（B-CLPD）并发自身免疫溶血性贫血（AIHA）的临床特征,提高对该疾病的认识。回顾性分析2000年至2012年治疗的B-CLPD合并AIHA患者14例,分析其临床特征、实验室检查结果、治疗及转归。结果表明,14例AIHA患者中慢性淋巴细胞白血病（CLL）9例、淋巴瘤5例;溶血发作时血红蛋白中位数61（33-84）g/L,网织红计数比例中位数12.0（3.1-35.0）%,Coombs试验阳性率100%;1例患者单用糖皮质激素治疗,5例采用化疗联合糖皮质激素治疗,8例采用利妥昔单抗免疫化疗联合糖皮质激素治疗,有效率达100%,其中完全缓解率78.6%（11/14）,部分缓解率21.4%（3/14）;随访至今,35.7%（5/14）出现溶血再发,经用既往治疗方案仍有效,应用过利妥昔单抗治疗的病例仅1例复发;14例中已有6例死亡,1例失访,其余7例存活。结论：AIHA是B-CLPD的常见并发症,可在疾病不同阶段出现。糖皮质激素免疫抑制剂疗效较好,但长期缓解率低,停药或减量后易复发,单克隆抗体具有较好的应用前景。     

Fatal Immune Hemolytic Anemia Following Allogeneic Stem Cell Transplantation: Report of 2 Cases and Review of Literature

Immune hemolytic anemia is a well-recognized complication after allogeneic hematopoietic stem cell transplantation (HSCT). There are 4 possible causes for this complication. First, antibodies present in the recipient destroy donor cells. Second, donor red cell antibodies at the time of stem cell infusion are transferred to the recipient. Third, sometimes, engrafted donor lymphocytes cause active production of red cell antibodies. Fourth, another cause of hemolysis after allogeneic HSCT is autoimmune hemolytic anemia (AIHA). It is thought to be due to antibodies produced by the donor’s immune system against antigens on red cells of donor origin. Autoimmune hemolytic anemia after allogeneic HSCT is rare, it is still not well characterized, and it represents a life-threatening situation. We describe 2 patients with acute myeloid leukemia treated with intensive chemotherapy and umbilical cord blood stem cell transplantation (UCBT). One patient developed AIHA at day + 182 and the other at day + 212 after receiving UCBT. Patients received 5 and 7 line treatment options, respectively, including continuous corticosteroids, intravenous immunoglobulin, splenectomy, cyclophosphamide, plasma exchange, rituximab, bortezomib, and eculizumab. However, both patients died because of massive hemolysis after 85 and 106 days of intensive treatment, respectively. These cases reflect the extreme difficulty in the therapeutic management of patients with AIHA following UCBT. After an extensive review of the literature, the exact physiopathologic mechanisms of AIHA after allogeneic HSCT in general, and after UCBT in particular, and therefore an effective treatment remain unknown.     

Autoimmune hemolytic anemia in pediatric liver or combined liver and small bowel transplant patients: a case series and review of the literature

BACKGROUND: Autoimmune hemolytic anemia (AIHA) occurring after solid organ transplantation is an infrequently reported entity. We describe in this report six cases of AIHA in pediatric liver or combined liver and small bowel transplant patients. STUDY DESIGN AND METHODS: We retrospectively identified and reviewed the records of pediatric liver or combined liver and small bowel transplant patients with both serologic and clinical evidence of AIHA. We also performed an English language literature review for prior publications of AIHA occurring after solid organ transplantation. RESULTS: We identified six patients presenting with severe hemolysis 9 months to 14 years after transplantation. All six developed warm AIHA, and two had concomitant cold agglutinins. All except one patient received various therapeutic combinations including steroids, intravenous immune globulin, rituximab, plasmapheresis, splenectomy, and vincristine. Five patients achieved remission 2 weeks to 3 months after presentation. Although tacrolimus has been speculated to play a causative role in the development of AIHA after organ transplantation, our case series demonstrated slightly better outcomes despite continuing tacrolimus compared to published cases where most patients either received significantly reduced doses of tacrolimus or were switched to a different immunosuppressant (83% vs. 76% cumulative literature remission rate). CONCLUSION: AIHA may occur in solid organ transplant patients at a much higher frequency than previously believed. Hemolysis is often severe and resistant to steroid treatment alone. Thus early diagnosis and institution of aggressive multimodality treatment, including the use of rituximab, may be needed to achieve remission.     

伴有自身免疫性溶血性贫血及纯红系再生障碍性贫血的血管免疫母细胞性T细胞淋巴瘤

血管免疫母细胞性T细胞淋巴瘤（AITL）是一种外周T细胞淋巴瘤,常合并自身免疫现象,如免疫相关性血细胞减少症,是NHL中的少见类型。为了研究AITL的临床特征,病理表现和有效的治疗方法,对1例37岁男性患者进行了血常规检查、骨髓检测、单个核细胞的流式细胞术检测、Coombs试验、血清学检测、CT和免疫组织化学测定等。结果查明,患者有广泛淋巴结肿大、肝脾肿大,颈部淋巴结活检表明为血管免疫母细胞性T细胞淋巴瘤;患者重度贫血,网织红细胞降低,Coombs实验阳性,骨髓红系增生低下,提示并发温抗体型自身免疫性溶血性贫血（AIHA）和纯红系再生障碍性贫血（PRCA）;经过CHOP-E方案化疗后,合并的AIHA和PRCA以及AITL浸润症状均消失。结论：成功地确诊了合并有AIHA和PRCA的AITL,淋巴结活检和骨髓检测意义大,CHOP-E化疗方案对此种AITL有一定治疗效果。     

AIHA患者应用两种配血方法的输血疗效比较

目的 通过比较自身免疫性溶血性贫血(AIHA)患者分别采用微柱凝集法和体外溶血试验两种配血方法进行输血的疗效,为AIHA患者寻找一种安全有效的配血方法。方法 选取北京大学深圳医院2010年1月～2014年12月诊断为AIHA并且需要输血治疗的患者75例,随机分为A组40例与B组35例,A组采用微柱凝集法配血共输血65人次,B组采用体外溶血试验配血共输血63人次,比较两组患者输血疗效。结果 两组患者输血治疗后RBC计数与Hb水平均有上升,TBIL含量均下降。B组患者RBC计数,Hb水平升高幅度及TBIL含量下降幅度明显高于A组患者; 两组Hb水平输血前比较差异无统计学意义(P>0.05),输血后比较差异有统计学意义(P<0.05),表明B组输血疗效优于A组。A组输注总有效率为67.69%,B组输注总有效率为93.65%,B组总有效率明显高于A组,两组比较差异有统计学意义(P<0.05)。结论AIHA患者采用体外溶血试验配血方法可以筛选到更适合的供者红细胞,确保患者输血安全有效。     

自身免疫性溶血性贫血患者的血型检定研究

为了观察自身抗体对ABO和RhD血型检定的干扰，对38例自身免疫性溶血性贫血(autoimmune hemolytic anemia，AIHA)患者血液标本进行ABO和RhD常规定型，氯奎放散试验后定型及基因定型。结果表明：38例AIHA患者中，ABO血型难定者11例(31.6％)，均为间接抗球蛋白试验阳性及正反定型不合。RhD(-)误定RhD( )1例，并含抗-D。采用氯奎放散试验后血型皆正确检定。结论：AIHA患者的自身抗体干扰血型检定，必须采用多种技术才能正确检定血型，确保安全输血。     

自身免疫溶血性贫血患者抗体筛选观察

为了观察自身免疫溶血性贫性(AIHA)患者的同种抗体，用氯奎放散试验检测自身抗体掩盖的同种抗体，用乙醚放散试验检测自身抗体的特异性。结果表明：38例AIHA病人中，间抗阳性者19例．其中含同种抗体者7例(抗-D1例，抗-E4例，抗-CE2例)，自身抗体具有D-型特异性者5例(抗-E3例．抗-C1例．抗-c 1例)。结论：采用氯奎放散试验、乙醚放散试验等检测被自身抗体掩盖的同种抗体，对AIHA患者的安全输血很重要。     

61例自身免疫性溶血性贫血患者血型血清学特征及输血疗效评估

本研究旨在分析自身免疫性溶血性贫血患者的血型血清学特征及红细胞不相容输注的疗效及安全性.通过回顾性分析特发性（21例）或继发性自身免疫性溶血性贫血患者（40例）血型血清学特征、输血不良反应发生情况,按照自身抗体类型、接受不同红细胞成分分别评价不相合输血疗效和安全性.结果表明：61例中单独IgM类冷自身抗体8例（13.1％）,单独IgG类温自身抗体50例（82.0％）,IgM冷自身抗体联合IgG温自身抗体3例（4.9％）,合并存在同种抗体18例（29.5％）;其中36例自身免疫性溶血性贫血患者在排除同种抗体干扰情况下共进行不相合红细胞输注113次,总有效率56.6％,总部分有效率15.1％,总无效率28.3％.按输注红细胞成分差异分为ABO同型非洗涤红细胞组和O型洗涤红细胞组,ABO同型非洗涤红细胞组有效率57.6％,部分有效率13.0％,无效率29.4％;O型洗涤红细胞组有效率53.6％,部分有效率21.4％,无效率25.0％,两组输注疗效比较差异无显著性（P＞0.05）.按患者自身抗体类型分为IgM冷自身抗体组和IgG温自身抗体组,其中IgM冷自身抗体组有效率46.2％,部分有效率30.8％,无效率23.0％;IgG温自身抗体组有效率56.7％,部分有效率13.4％,无效率29.9％,两组输注疗效比较差异无显著性（P＞0.05）.所有输血病例均无溶血性输血反应发生.结论：对于重度贫血的自身免疫性溶血性贫血患者在排除同种抗体干扰的情况下,采用同型非洗涤红细胞或O型洗涤细胞输注都是相对安全的,两种方式疗效差异无显著性,选择同型非洗涤红细胞输注更方便、快捷,还能避免O型红细胞的过度使用.     

Refractory autoimmune hemolytic anemia in a systemic lupus erythematosus patient: A clinical case report

Warm autoimmune hemolytic anemia (AIHA) is a hematologic disorder with an incidence of 1–3 per 10⁵ individuals/year. Patients with systemic lupus erythematosus (SLE) develop AIHA in 3% of adult cases and 14% of pediatric cases. We report a case of AIHA refractory to multiple lines of treatment in a patient with SLE, who eventually responded to a proteasome inhibitor‐based combination. A patient with systemic lupus erythematous was diagnosed with symptomatic autoimmune hemolytic anemia. The patient was refractory to multiple lines of treatment including prednisone, intravenous immune globulin, methylprednisolone, rituximab, cyclophosphamide, mycophenolate mofetil, and splenectomy. She eventually had a beneficial response to a proteasome inhibitor‐based combination with bortezomib plus mycophenolate mofetil. The treatment of refractory autoimmune hemolytic anemia can be challenging. Patients with AIHA refractory to primary or secondary treatments must resort to receiving novel therapeutic modalities including combinations targeting plasma cell, T‐ and B‐cell proliferation.     

自身免疫性溶血性贫血患者外周血B-1a细胞的研究

目的：研究自身免疫性溶血性贫血患者外周血B-1a细胞的变化。方法：用CD5CD19双标抗体和流式细胞仪检测20例正常对照、13例自身免疫性溶血性贫血（AIHA）发病初期患者、4例脾切除术后AIHA患者以及10例外伤后脾切除患者的外周血B细胞和13-1a细胞占外周血单个核细胞的百分比。结果：正常对照外周血昏1a细胞占外周血单个核细胞的比例为（0．78±0．16）％，AIHA患者发病初期外周血B-1a细胞百分比为（2．58±0．63）％，AIHA患者脾切除术后外周血B-1a细胞百分比降至（0．58±0．37）％，外伤后脾切除患者外周血B-1a细胞百分比为（0．65±0．43）％。结论：AIHA患者外周血B-1a细胞比例明显增高，且AIHA患者接受脾切除手术溶血得到控制后，B-1a细胞比例明显下降。     

Bovine Blood and Neuromuscular Paralysis as a Bridge to Recovery in a Patent with Severe Autoimmune Hemolytic Anemia

Hemoglobin solutions have several advantages as substitutes for erythrocyte transfusions. They have a prolonged shelf life, do not require cross‐matching, are associated with few transfusion reactions, and are effective in delivering oxygen to the tissues. Despite the potential clinical utility of these solutions, they have not achieved widespread use. HbOC‐201 (Hemopure, Biopure, Cambridge, MA, USA) is a bovine hemoglobin solution that has been FDA approved for compassionate use in Jehovah''s witness patients requiring transfusions. Here we report a case of a patient with hemoglobin H disease who developed a severe life‐threatening mixed warm and cold antibody mediated autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) who was successfully treated with HbOC‐201 as an adjunct to blood transfusion.     

P31Mixed‐Type Autoimmune Haemolytic Anemia (AIHA)

The diagnosis of mixed‐type AIHA is based on demonstrating the presence of ‘warm’ IgG auto‐antibody and high thermal amplitude ‘cold’ IgM auto‐antibody reacting at or >30 °C. Mixed‐type AIHA is uncommon. In general, patient with mixed‐type AIHA responds to steroids and reported to be associated with SLE and lymphoma. Awareness of this condition is important as management may be different from either treating warm AIHA or cold haemmagglutinin disease (CHAD). We report two unusual cases of mixed‐type AIHA. Management and outcome of these cases are discussed. An 88‐year‐old, patient was admitted with low Hb and raised bilirubin. He was already on steroids 15 mg daily for joint pain. In view of the strong red cell agglutination in the blood film (CHAD) was suspected initially and were investigated to exclude the secondary causes of CHAD. Three days later Hb dropped to 6.6 g dL^?1. Samples were forwarded to the reference laboratory. The DAT was positive with IgG, IgM and C3d. Serological evidence of mixed‐AIHA was confirmed at the reference laboratory. In view of the ongoing haemolysis, steroids were increased to 40 mg daily, and transfusion was given, together with intravenous immunoglobulin (IVIg). Haemolysis ceased and the patient was discharged on decreasing doses of steroid. This case was unusual as the patient developed AIHA while on steroids medication. An 85‐year‐old patient, was admitted with Hb level of 5.7 g dL^?1 and evidence of haemolysis. Laboratory investigation confirmed mixed‐type AIHA. A CT scan showed splenomegaly, with small volume lympadenopathy, which were too small to biopsy. A bone marrow biopsy showed no evidence of lymphoma infiltration. The patient was treated with steroids, IVIg, followed by chemotherapy (cyclophosphamide, vincrestine and steroids) with no response. Rituximab (357 mg m^?2 weekly for 2 weeks) resulted in no response. The patient received 33 units of red cells over a 9 week period. She underwent splenectomy with resolution of haemolysis and Hb sustained at 11 g dL^?1. Splenic biopsy revealed T cell angioimmunoblastic Non‐Hodgkins lymphoma. Splenectomy should be considered in resistant mixed‐type AIHA.     

Direct antiglobulin test-negative autoimmune hemolytic anemia in a patient with β-thalassemia minor during pregnancy: A case report

BACKGROUNDSevere refractory anemia during pregnancy can cause serious maternal and fetal complications. If the cause cannot be identified in time and accurately, blind symptomatic support treatment may cause serious economic burden. Thalassemia minor pregnancy is commonly considered uneventful, and the condition of anemia rarely progresses during pregnancy. Autoimmune hemolytic anemia (AIHA) is rare during pregnancy with no exact incidence available. CASE SUMMARYWe report the case of a 30-year-old β-thalassemia minor multiparous patient experiencing severe refractory anemia throughout pregnancy. We monitored the patient closely, carried out a full differential diagnosis, made a diagnosis of direct antiglobulin test-negative AIHA, and treated her with prednisone and intravenous immunoglobulin. The patient gave birth to a healthy full-term baby.CONCLUSIONCoombs-negative AIHA should be suspected in cases of severe hemolytic anemia in pregnant patients with and without other hematological diseases.     

12例急性自身免疫性溶血性贫血患者体外溶血试验配血与输血研究

本研究采用体外溶血试验配血方法,为微柱凝胶抗人球蛋白法配血困难的急性自身免疫性溶血性贫血（AIHA）患者筛查配血相容的红细胞。对照组选择26例AIHA患者,采用微柱凝胶抗人球蛋白法,确定配血结果凝集强度最弱的同型供血者红细胞输注。实验组为12例微柱凝胶抗人球蛋白法配血困难的急性AIHA患者,采用体外溶血试验配血法,选取配血结果出现不溶血的同型供血者红细胞输注。结果表明,体外溶血试验法输血组与微柱凝胶抗人球蛋白法配血组输血效果相比较,差异有显著性意义（P〈0.01）。实验组患者平均每次输注去白细胞红细胞悬液2.26单位,输血后患者血红蛋白、网织红细胞及总胆红素等指标变化与输血前相比较,差异有显著性意义（P〈0.01）。结论：在微柱凝胶抗人球法配血困难时,采取体外溶血试配血可以顺利为AIHA患者筛查到相容红细胞。     

Autoimmune hemolytic anemia

Diagnosis of autoimmune hemolytic anemia (AIHA) requires both serologic evidence of an autoantibody and hemolysis. Based on the characteristic temperature reactivity of the autoantibody to red cell membranes, AIHA is classified into warm AIHA or cold AIHA (cold agglutinin disease and paroxysmal cold hemoglobinuria). Sensitized RBCs are destructed by intravascular and/or extravascular hemolysis. On the basis of etiology, AIHA are classified as idiopathic or secondary. The common cause of secondary AIHA is lymphoproliferative disorders, autoimmune diseases, and infections. The first line therapy of patients with warm AIHA is glucocorticoids and primary treatment for cold AIHA is avoiding cold exposure. The other standard treatments include splenectomy and immunosuppressive drugs. Recently, rituximab, a monoclonal anti-CD20 antibody, has been used in refractory AIHA with excellent responses.     

Autoimmune pancytopenia after liver transplantation: A case report

IntroductionAutoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia (AIN) are reported in the literature after liver, intestinal, heart, pancreas, and kidney transplants. We report a case of autoimmune pancytopenia (AIHA, AIN and ITP) 9 years after liver transplantation with confirmed erythrocyte and neutrophil auto-antibodies.Case reportA 49 years old man was admitted to our hospital presented with dysentery and fever, with history of liver transplantation in 2008. Laboratory evaluation demonstrated hemoglobin: 7.2 g/dL, granulocytes: 0.10 × 10⁹/L and platelets: 15 × 10⁹/mm³; indirect bilirubin: 3.62 mg/dL; lactate dehydrogenase: 603 U/L. Direct antiglobulin test revealed a monospecific anti-IgG plus C3 and the acid eluate was reactive to all panel red cells, consistent with an AIHA. Granulocyte immunofluorescence test (GIFT) and agglutination test (GAT) were reactive for granulocytes. Test with Luminex technology for human neutrophil antigen (HNA) antibody detection was strong reactive with beads expressing HNA-1a, -1b, -1c, -2, -4a and -5a antigens. HNA genotyping revealed the presence of the corresponding antigens, confirming the autoantibodies. Test with Luminex technology for human leucocyte antigen (HLA) antibody detection was negative. Monoclonal antibody immobilization of platelet antigens (MAIPA) assay was negative. Viral causes were excluded. The condition was compatible with clinical onset of autoimmune pancytopenia. Prednisone was administered at an initial dose of 1 mg/kg/day and immunosuppressive therapy was adjusted. This treatment resulted in rapid resolution of pancytopenia.ConclusionCombined autoimmune pancytopenia (AIHA, AIN and ITP) is a rare condition that may occur after liver transplantation. Early recognition of this phenomenon permits appropriate treatment.     

Clinical significance of serologic markers related to red blood cell autoantibodies production after red blood cell transfusion—severe autoimmune hemolytic anemia occurring after transfusion and alloimmunization: successful treatment with rituximab

BACKGROUND: The association of autoantibody formation with blood transfusion was previously noted. Severe autoimmune hemolytic anemia (AIHA) diagnosed after red blood cell (RBC) transfusion determined us to undertake this study and investigate the incidence and clinical significance of autoantibodies occurring after transfusion by a retrospective review of blood bank and medical records.
STUDY DESIGN AND METHODS: We report a lymphoma patient who developed severe autohemolysis after blood transfusion and alloantibody production. The hemolysis was refractory to steroids and chemotherapy and ceased after rituximab. We also retrospectively assessed the blood bank records for a 2-year period to identify the patients who developed autoantibodies after blood transfusion and examined laboratory, clinical features, and outcome.
RESULTS: From January 2005 through December 2006, 375 direct antiglobulin tests (DATs) and 3409 indirect antiglobulin tests (IATs) were found to be positive. Thirty-eight patients with positive DATs and IATs had demonstrable RBC warm-type autoantibodies occurring after blood transfusion; 27 of them had also one or more alloantibodies. Clinical and laboratory signs of hemolysis were absent in all patients (except the case reported). In another 5 patients alloantibodies were retrieved from RBC eluate and serum without evidence of autoantibodies; therefore, a delayed serologic transfusion reaction was diagnosed.
CONCLUSION: RBC autoantibodies are quite commonly found after blood transfusion. Nevertheless, clinically significant AIHA is a rare but at times a life-threatening phenomenon. We describe a first case of successful treatment with rituximab of refractory posttransfusion AIHA. Rituximab must be further evaluated for this indication.     

Osteoporosis and Fractures After Solid Organ Transplantation: A Nationwide Population-Based Cohort Study

ObjectiveTo investigate the incidence of bone disorders after solid organ transplantation (SOT).Participants and MethodsWe used Taiwan's National Health Insurance Research Database to identify 9428 recipients of SOT and 38,140 sex- and age- matched control subjects between January 1, 1997, and December 31, 2010, to compare the incidence and risk of bone disorders between groups.ResultsRecipients of SOT had a significantly higher incidence of osteoporosis and related fractures compared with the non-SOT group. The overall hazard ratio (HR) of osteoporosis after SOT was 5.14 (95% CI, 3.13-8.43), and the HR of related fractures was 5.76 (95% CI, 3.80-8.74). The highest HRs were observed in male patients (HR, 7.09; 95% CI, 3.09-16.3) and in those aged 50 years or younger (HR, 7.38; 95% CI, 2.46-22.1). In addition, SOT patients without any comorbidities had a 9.03-fold higher risk of osteoporosis than non-SOT participants (HR, 9.03; 95% CI, 5.29-15.4). To compare the risk of osteoporosis and related fractures in different recipients of SOT, the highest risk of osteoporosis and fractures was noted in patients receiving lung transplantation, followed by other types of SOT.ConclusionWe report high rates of metabolic bone disorders after SOT in chronic transplant patients over a long follow-up. Both underlying bone disorders before transplantation and use of immunosuppressant agents may contribute to bone disorders after transplantation.