Fatal intravascular autoimmune hemolytic anemia after fludarabine treatment for chronic lymphocytic leukemia

We report the case of a patient with chronic lymphocytic leukemia (CLL) who developed fatal intravascular autoimmune hemolytic anemia (AIHA) after fludarabine treatment. He had previously received several treatments including two courses of fludarabine. The direct antiglobulin test (DAT) was negative at diagnosis but was found to be positive with anti-IgG after the first fludarabine treatment. When the patient was treated again with fludarabine nine months later, the DAT became positive with anti-IgG and anti-C3d antiglobulins after the second course of treatment. Abrupt, fatal intravascular hemolysis occurred after the third course. The occurrence of severe AIHA in CLL patients treated with fludarabine has been reported by several authors. Physicians should be aware of the risk of severe AIHA in CLL patients with a history of AIHA or positivation of the DAT during previous fludarabine administration, or in case of secondary fixation of complement to the red cell membrane occurring during fludarabine treatment.     

Fatal intravascular autoimmune hemolytic anemia after fludarabine treatment for chronic lymphocytic leukemia

We report the case of a patient with chronic lymphocytic leukemia (CLL) who developed fatal intravascular autoimmune hemolytic anemia (AIHA) after fludarabine treatment. He had previously received several treatments including two courses of fludarabine. The direct antiglobulin test (DAT) was negative at diagnosis but was found to be positive with anti-IgG after the first fludarabine treatment. When the patient was treated again with fludarabine nine months later, the DAT became positive with anti-IgG and anti-C3d antiglobulins after the second course of treatment. Abrupt, fatal intravascular hemolysis occurred after the third course. The occurrence of severe AIHA in CLL patients treated with fludarabine has been reported by several authors. Physicians should be aware of the risk of severe AIHA in CLL patients with a history of AIHA or positivation of the DAT during previous fludarabine administration, or in case of secondary fixation of complement to the red cell membrane occurring during fludarabine treatment.     

Autoimmune hemolytic anemia in patients with liver transplants for primary biliary cirrhosis: Three case reports and a review of the literature

BACKGROUND: Hemolytic anemia is rare after liver transplant and is usually associated with ABO mistmatch, post-transplant lymphoproliferative disorders, or medications. CASE REPORTS: We report three patients who had undergone successful liver transplants for primary biliary cirrhosis (PBC) and developed direct antibody test positive autoimmune hemolytic anemia (AIHA) several years into uncomplicated post-transplant management. For two of the patients, the hemolysis responded to steroids and rituximab. One patient required a surgical splenectomy. DISCUSSION: AIHA is an immune-mediated hemolysis that has been reported in patients with PBC. There are no reports of AIHA in patients following liver transplantation for this disease. AIHA should be considered in stable PBC patients who develop anemia years after liver transplant.     

Autoimmune hemolytic anemia in a patient with idiopathic interstitial pneumonia

We report a rare case of autoimmune hemolytic anemia (AIHA) complicated by idiopathic interstitial pneumonia (IIP). A sixty-year-old man was diagnosed as having IIP in January 2009. In March, when he was hospitalized for the introduction of home oxygen therapy, severe anemia was detected. Based on the findings showing elevated levels of lactate dehydrogenase and indirect bilirubin, a decreased level of haptoglobin, positive Coombs test, and splenomegaly, a diagnosis of AIHA was made. Although anti-DNA antibody was found, diagnostic criteria for systemic lupus erythematosus and other collagen diseases were not fulfilled. Therefore, we concluded that AIHA coexisted with IIP. Treatment with prednisolone led to improvement of both AIHA and IIP. There has not been any exacerbation even after a gradual reduction of prednisolone to 7.5 mg/day. Coexistence of AIHA and IIP is rare, and accumulation of case reports is needed to gain a better understanding of this condition.     

Autoimmune hemolytic anemia in a case of chronic hepatitis type C 56 weeks after initiation of second line treatment with pegylated interferon alpha2b/ribavirin combination therapy

A 49-year-old man with chronic type C hepatitis had agreed to undergo pegylated interferon alpha2b/ribavirin (RBV) combination therapy during 48 weeks, but his hepatitis relapsed. Despite of second line treatment with the same combination, 56 weeks later, his hemoglobin decreased and the dose of RBV was decreased. He was then admitted to our hospital because of increasing anemia and this combination therapy was stopped. The results of blood chemistry and immunological examination revealed he had contracted autoimmune hemolytic anemia (AIHA). In cases of deterioration of anemia during this combination, we must discuss about not only RBV-induced hemolytic anemia but also AIHA.     

Plasmapheresis for fulminant autoimmune hemolytic anemia with rapidly progressing disturbance of consciousness

A 64-year-old male was diagnosed as having autoimmune hemolytic anemia (AIHA) in December 2001. The diagnosis of AIHA was established based on the presence of anemia, hyperbilirubinemia, reticulocytosis, positive Coombs test and serum LDH elevation. Although he received steroid pulse therapy, disturbance of consciousness appeared and the anemia and icterus did not improve. Plasma exchange was carried out to eliminate antibodies as an emergency measure. The patient's symptoms were ameliorated following four courses of plasma exchange. This case represents a case of aggressive AIHA with disturbance of consciousness and refractory to conventional corticosteroid therapy. Plasma exchange rapidly led to complete remission.     

Chronic hepatitis C associated with Coombs-positive hemolytic anemia

Hepatitis C virus (HCV) is a recognized cause of significant extrahepatic disease. Induction of autoimmune hemolytic anemia (AIHA) has been reported, either during or after interferon (IFN) treatment of HCV infection. We herein report a 56-year-old patient with HCV infection who developed severe Coombs-positive AIHA in the absence of treatment with IFN. Prednisone therapy was initiated, but intravenous immunoglobulins were added because of persistent hemolysis. Clinical course was complicated by rapid deterioration and the development of Creutzfeldt-Jakob disease. Having discarded other possible causes of AIHA, we suggest a possible association between AIHA and infection by HCV.     

Successful Treatment with Cyclosporine and High-Dose Gamma Immunoglobulin for Persistent Parvovirus b19 Infection in a Patient with Refractory Autoimmune Hemolytic Anemia

We describe a patient with persistent pure red cell aplasia due to human parvovirus B19 (HPVB19) infection during immunosuppressive therapy for refractory autoimmune hemolytic anemia (AIHA). The patient had been given corticosteroid (CS) and/or azathioprine for AIHA. During the course of treatment, reticulocyte count and hemoglobin levels decreased suddenly. Bone marrow aspirate showed erythroid lineage-specific aplasia with a few giant proerythroblasts, suggesting the presence of HPVB19 infection. The diagnosis of aplastic crisis due to HPVB19 infection was based on positive test results by polymerase chain reaction for HPVB19 immunoglobulin M (IgM) antibody and B19 DNA. Although splenectomy followed by administration of high-dose gamma globulin (HDIG) and plasma exchange were performed, the crisis and hemolysis recurred. Aplastic crises occurred several times when the B19 IgG result became negative and the CD4+ lymphocyte count was less than 300/microL. The patient showed complete recovery from anemia after CS was switched to cyclosporin A (CsA) and intermittent administration of HDIG. The result for B19 IgG antibody was continuously positive, and the DNA result became negative after these treatments. The results in this case indicated that concomitant administration of CsA and intermittent administration of HDIG can lead to cure of chronic anemia due to HPVB19 infection in patients with refractory AIHA.     

Successful control of refractory and life-threatening autoimmune hemolytic anemia with intravenous immunoglobulins in a man with the primary antiphospholipid syndrome

 A 58-year old man with a history of hypothyroidism and primary antiphospholipid syndrome (with recurrent thromboembolic disease and therapy-refractory autoimmune thrombocytopenic purpura) presented with a life-threatening crisis of warm autoimmune hemolytic anemia (AIHA) while under chronic low-dose steroid therapy. The exacerbation was eventually controlled with a 5-day course of intravenous immunoglobulin (IVIG, Sandoglobulin) (400 mg/kg per day) but hemolysis rapidly recurred, despite therapy with steroids, azathioprine, and cyclosporin, necessitating a second course of IVIG. Control of packed cell transfusion needs for about 7 months was achieved by weekly administration of IVIG (800 mg/kg), although there is no direct evidence that IVIG therapy reduced the production of anticardiolipin or RBC antibodies. Three months after discontinuation of IVIG and change to maintenance with intermediate-dose corticosteroids plus cyclosporin A, the patient succumbed to duodenal perforation with peritonitis and invasive pulmonary aspergillosis. The case illustrates that IVIG therapy may be helpful in selected life-threatening and refractory cases of AIHA. It also sadly illustrates the long-term toxicity of standardly used therapeutics in refractory AIHA. Received: 15 April 1996 / Accepted: 6 August 1996     

Bendamustine and rituximab combination in the management of chronic lymphocytic leukemia‐associated autoimmune hemolytic anemia: A multicentric retrospective study of the French CLL intergroup (GCFLLC/MW and GOELAMS)

We report our experience on bendamustine and rituximab (BR) combination in 26 patients with chronic lymphocytic leukemia (CLL) complicated by autoimmune hemolytic anemia (AIHA). At the time of BR initiation, 88% of the patients had already been treated for AIHA and CLL was progressive regardless of AIHA in all patients but one. Overall response rates were 81% for AIHA and 77% for CLL. Median time to next treatment was 28.3 months and 26.2 months for AIHA and CLL, respectively. BR therapy may represent a good and safe therapeutic option in this setting where adequate control of CLL seems important for long‐term AIHA response. Am. J. Hematol. 90:204–207, 2015. © 2014 Wiley Periodicals, Inc.     

Successful treatment of autoimmune hemolytic anemia associated with multicentric Castleman disease by anti-interleukin-6 receptor antibody (tocilizumab) therapy

We describe herein the successful treatment of severe autoimmune hemolytic anemia (AIHA) in a patient with multicentric Castleman disease (MCD) by humanized anti-interleukin-6 (IL-6) receptor antibody (tocilizumab) therapy. Inflammatory anemia is commonly reported; however, AIHA is a very rare complication of MCD. In 1996, a 45-year-old Japanese woman was referred to our hospital because of generalized lymphadenopathy, anemia and skin eruptions. Lymph node biopsy demonstrated MCD. She was treated with prednisolone (1 mg/kg/day), which improved the anemia and skin eruptions. In 2009, she suddenly developed Coombs-positive hemolytic anemia. The blood count was as follows: hemoglobin 4.7 g/dl, platelets 490 × 10(9)/l and white blood cell count 9.8 × 10(9)/l. Both direct and indirect Coombs' tests were strongly positive. She was treated with 8 mg/kg tocilizumab every 2 weeks. One month later, her hemoglobin levels rose dramatically to 10.9 g/dl and her haptoglobin level, hypergammaglobulinemia and clinical symptoms had also markedly improved. To the best of our knowledge, this is the first report of the efficacy of tocilizumab in AIHA associated with MCD. The well-established role of IL-6 in the pathogenesis of MCD may have been responsible for the improvement in the AIHA associated with MCD. Anti-IL-6 receptor antibody treatment could be an attractive therapeutic approach for AIHA associated with MCD.     

Autoimmune hemolytic anemia in an elderly patient with primary Sjögren's syndrome

Primary Sj?gren's syndrome is an autoimmune disease characterized by lymphocytic infiltration of the salivary glands and lacrimal glands. The histological features of chronic inflammation in primary Sj?gren's syndrome may be associated with B cell hyper-reactivity. This syndrome also has various manifestations associated with other exocrine glands and nonglandular tissues. The hematological abnormalities usually seen in Sj?gren's syndrome are lymphopenia, leucopenia, and thrombocytopenia. Although the direct Coomb's test is often positive, the occurrence of autoimmune hemolytic anemia (AIHA) is rare. Here, we report an elderly patient with primary Sj?gren's syndrome who developed AIHA during the clinical course.     

Late onset of autoimmune hemolytic anemia and pure red cell aplasia after allogeneic hematopoietic stem cell transplantation using in vivo alemtuzumab

Hemolytic anemia and pure red cell aplasia (PRCA) after allogeneic hematopoietic stem cell transplantation (HSCT) have been reported to be mainly related to ABO-incompatibility between donor and recipient. Autoimmune hemolytic anemia (AIHA) without ABO-incompatibility has been also reported after allogeneic HSCT, especially with T-cell depletion. However, optimal management of AIHA or PRCA remains unclear. A 54-year-old male with myelodysplastic syndrome (MDS) underwent haploidentical human leukocyte antigen-mismatched HSCT using in vivo alemtuzumab and developed AIHA and PRCA simultaneously 15 months after transplantation, following the administration of cidofovir and probenecid for persistent cytomegalovirus (CMV) antigenemia and retinitis. AIHA was successfully treated with rituximab, and subsequently PRCA with cyclosporine without relapse of MDS or recurrence of CMV infection. The clinical course suggested that AIHA was mainly caused by humoral immune response, while PRCA was mainly caused by cell-mediated immune response in this patient, although these immune responses might be related to each other.     

A persistent severe autoimmune hemolytic anemia despite apparent direct antiglobulin test negativization.

BACKGROUND AND OBJECTIVE: Not all cases of autoimmune hemolytic anemia (AIHA) are diagnosed by the direct antiglobulin test (DAT). We present and discuss a simple method of enhancing the sensitivity of the standard DAT. DESIGN AND METHODS: We report the case of a five-month-old child diagnosed with a severe IgG-mediated AIHA, characterized by quick DAT negativization despite clinical worsening. Warm AIHA with negative DAT, possibly due to a low affinity autoantibody, unresponsive to conventional therapy, was hypothesized. RESULTS: The DAT resulted strongly positive with anti-IgG serum using a 4C saline for erythrocyte washing, to reduce the dissociation of the supposed low affinity autoantibody. Very intensive cytoreductive treatment was administered twice until clinical remission was obtained. INTERPRETATION AND CONCLUSIONS: The clinical course of AIHA can be dissociated by the DAT. Since autoantibody-mediated hemolysis with negative DAT rarely occurs, once other causes of high reticulocyte count anemia have been ruled out, the DAT after ice-cold saline washing could be a useful and easy means of corroborating the diagnosis of AHIA, when traditional methods fail.     

抗β2糖蛋白I抗体在系统性红斑狼疮合并自身免疫性溶血性贫血中的意义

目的检测抗β2糖蛋白I抗体(β2 glycoprotein I,aβ2GPI)等多种自身抗体在系统性红斑狼疮(systemic lupus erythematous,SLE)并发自身免疫性溶血性贫血(autoimmune hemolytic anemia,AIHA)患者的阳性率,评估aβ2GPI在并发AIHA的SLE患者中的意义。方法收集2008年12月至2013年4月福建医科大学附属第一医院风湿科门诊和病房SLE患者资料,根据有无发生AIHA分为SLE-AIHA组和SLE-non-AIHA组。选取AIHA患者为AIHA组。检测IgM和IgG类的aβ2GPI、抗心磷脂抗体(anticardiolipin,ACL),以及抗Sm抗体、核小体抗体、组蛋白抗体、核糖体P蛋白抗体等多种自身抗体,采用SPSS11.5软件统计分析。结果共纳入SLE患者104例,SLE-AIHA组22例,SLE-non-AIHA组82例;AIHA组20例。SLE-AIHA组和SLE-non-AIHA组在年龄、性别、病程、受累器官等方面均无统计学差异;而SLE-AIHA组的IgG类aβ2GPI阳性率达45.5%,显著高于SLE-non-AIHA组的15.9%,差异有统计学意义(P0.01);两组患者的IgM类aβ2GPI、IgM和IgG类ACL、抗Sm抗体、核小体抗体、组蛋白抗体、核糖体P蛋白抗体阳性率比较差异均无统计学意义(均P0.05);SLE-AIHA组和AIHA组患者aβ2GPI和ACL阳性率比较差异均无统计学意义(均P0.05);SLE-AIHA组IgG类aβ2GPI阳性患者肾损害发生率高于该抗体阴性者,差异有统计学意义(P0.05)。结论 IgG类aβ2GPI在并发AIHA SLE患者和原发性AIHA患者中均表现较高阳性率,可能是SLE并发AIHA的重要血清学特征;同时该抗体可能是继溶血事件后加重狼疮患者肾损害的重要因素之一。     

Old DAT and new data: Positive direct antiglobulin test identifies a subgroup with poor outcome among chronic lymphocytic leukemia stage A patients

Only a minority of chronic lymphocytic leukemia (CLL) patients harboring a positive direct antiglobulin test (DAT) will develop autoimmune hemolytic anemia (AIHA). In a single institution cohort of 378 CLL patients, 56 patients (14.8%) had at least one positive DAT during the course of the disease, either at diagnosis or later. We found no relationship between the time of the first positive DAT and overall survival (OS). However, patients with a positive DAT who did not develop AIHA had the same adverse outcome as patients who developed AIHA. Of the patients who were in Binet stage A at diagnosis, those with a positive DAT had a significantly shorter OS, regardless of their IGHV mutational status, however, there was a strong association with VH1‐69. By multivariate analysis, a positive DAT was found to be an independent adverse prognostic factor for OS. Thus, DAT represents a strong adverse prognostic factor and its determination should be repeated during follow‐up. Am. J. Hematol. 90:E5–E8, 2015. © 2014 Wiley Periodicals, Inc.     

Autoimmune hemolytic anemia in patients with SCID after T cell-depleted BM and PBSC transplantation

We report a high incidence (19.5%) of autoimmune hemolytic anemia (AIHA) in 41 patients with SCID who underwent a T cell-depleted haploidentical transplant. Other than infections, AIHA was the most common post-transplant complication in this patient cohort. Clinical characteristics and treatment of eight patients who developed AIHA at a median of 8 months after the first T cell-depleted transplant are presented. All patients had warm-reacting autoantibodies, and two of eight had concurrent cold and warm autoantibodies. Clinical course was most severe in two patients who had cold and warm autoantibodies. Five patients received specific therapy for AIHA. Successful taper off immunosuppressive therapy for AIHA coincided with T cell reconstitution. Delayed reconstitution of T cell immunity, due to T cell depletion, immunosuppressive conditioning and CsA, as well as paucity of regulatory T cells, are the likely explanations for the occurrence of AIHA in our patient cohort. Screening of the population at risk may prevent morbidity and mortality from AIHA.     

Rituximab in the treatment of refractory autoimmune cytopenias in adults

We report the results of four cycles of rituximab therapy in eleven patients with chronic warm antibody type autoimmune hemolytic anemia (AIHA) and six patients with chronic idiopathic thrombocytopenia (ITP). The overall response rate was 64% in the AIHA group (3 complete responses and 4 partial responses) and 83% in the ITP group (4 complete responses, 1 partial response). Responses in AIHA patients with underlying lymphoproliferative disorders receiving rituximab with chemotherapy were generally better sustained, whereas responses in ITP were often transient.     

Rituximab for the treatment of refractory autoimmune hemolytic anemia in children

Autoimmune hemolytic anemia (AIHA) in children is sometimes characterized by a severe course, requiring prolonged administration of immunosuppressive therapy. Rituximab is able to cause selective in vivo destruction of B lymphocytes, with abrogation of antibody production. In a prospective study, we have evaluated the use of rituximab for the treatment of AIHA resistant to conventional treatment. Fifteen children with AIHA were given rituximab, 375 mg/m(2)/dose for a median of 3 weekly doses. All patients had previously received 2 or more courses of immunosuppressive therapy; 2 patients had undergone splenectomy. After completing treatment, all children received intravenous immunoglobulin for 6 months. Treatment was well tolerated. With a median follow-up of 13 months, 13 patients (87%) responded, whereas 2 patients did not show any improvement. Median hemoglobin levels increased from 7.7 g/dL to a 2-month posttreatment level of 11.8 g/dL (P <.001). Median absolute reticulocyte counts decreased from 236 to 109 x 10(9)/L (P <.01). An increase in platelet count was observed in patients with concomitant thrombocytopenia (Evans syndrome). Three responder patients had relapse, 7, 8, and 10 months after rituximab infusion, respectively. All 3 children received a second course of rituximab, again achieving disease remission. Our data indicate that rituximab is both safe and effective in reducing or even abolishing hemolysis in children with AIHA and that a sustained response can be achieved in the majority of cases. Disease may recur, but a second treatment course may be successful in controlling the disease.     

A case of autoimmune hemolytic anemia and bullous pemphigoid-like skin lesion combined with idiopathic thrombocytopenic purpura

A case of autoimmune hemolytic anemia (AIHA) and bullous pemphigoid (BP)-like skin lesion combined with Idiopathic thrombocytopenic purpura (ITP) is reported. A 25-years-old male, who had been diagnosed as ITP and treated at another hospital, was admitted in this hospital recently complaining of disseminated bullous-vesicular eruptions on the whole body and autoimmune hemolytic anemia. Examinations, disclosed that RBC was 364 X 10(4)/microliters, reticulocyte 40, platelet 3000/microliters, direct and indirect Coombs test positive, and platelet Coombs consumption test was positive leading to the diagnosis of AIHA and ITP, known as "Evans syndrome." Vesicular biopsy-findings and immunofluorescence study showed suspicion of BP, but clinical course and blister was not improved though the administration of prednisolone was performed. Reports of cases of BP complicated by Evans syndrome are very few. AIHA, ITP and BP are considered to have autoimmune disorders and their pathogenetic mechanism are discussed. This patient consulted another hospital one year later, when we heard that skin eruptions already had disappeared.