Warm Autoimmune Hemolytic Anemia Research Articles

Warm Autoimmune Hemolytic Anemia: Clinical Profile and Management.

BackgroundAutoimmune hemolytic anemia (AIHA) is a rare autoimmune disease in which autoantibodies target red blood cells leading to marked decrease in their lifespan. The classification of AIHA is based on the immunochemical properties of the RBC autoantibody. Warm antibody AIHA (wAIHA) accounts for 75-80% of all adult AIHA cases. The treatment of wAIHA is mainly corticosteroids. Our retrospective study aimed to study the clinical profile and management of wAIHA.MethodsData of 75 patients admitted with wAIHA or presented to outpatient department (previous medical records) with wAIHA between January 2003 and January 2016 were analyzed.ResultsIn our study, females constituted 12 and 26 patients of primary and secondary wAIHA, while males constituted 17 and 20 patients of primary and secondary wAIHA, respectively. Mean hemoglobin level at AIHA onset was found to be 7.1 ± 1.7 g/dL in primary wAIHA group and 6.3 ± 1.2 g/dL in secondary wAIHA group, which is statistically significant. Splenectomy was used as mode of treatment in one (3.4%) patient of primary wAIHA group and 15 (32.60%) patients of secondary wAIHA group, which is statistically significant. Mean age of wAIHA onset was 69.7 ± 21.5 years in wAIHA group secondary to lymphoma and 54.3 ± 25.7 years in other wAIHA group, which is statistically significant.ConclusionThe most common causes of secondary wAIHA are B-cell lymphoma, systemic lupus erythematosus, rheumatoid arthritis, chronic lymphocytic leukemia (CLL), common variable immune deficiency, renal cell carcinoma and secondary to drug usage (alpha methyldopa and carbamazepine), respectively. Reducing the cumulative dose of corticosteroids with second line treatment whenever possible and therefore reducing the risk of sepsis, specifically in older patients with comorbidities will reduce morbidity and mortality.

Warm autoimmune hemolytic anemia: experience from a single referral center in Mexico City.

BackgroundAutoimmune hemolytic anemia (AIHA) is characterized by an autoimmune-mediated destruction of red blood cells. Warm AIHA (wAIHA) represents 60% of AIHA cases and is associated with the positive detection of IgG and C3d in the direct antiglobulin test (DAT). This study aimed to assess the clinical and laboratorial differences between primary and secondary wAIHA patients from a referral center in Mexico City.MethodsAll patients diagnosed with wAIHA in our institution from January 1992 to December 2015 were included and received corticosteroids as the first-line treatment. We analyzed the response to the first-line treatment, relapse-free survival, and time to splenectomy.ResultsEighty-nine patients were included. Secondary wAIHA represented 55.1% of the cases. At diagnosis, secondary wAIHA patients showed a DAT mixed pattern more frequently than primary wAIHA patients (36.7 vs. 17.5%, P<0.001). In the survival analysis, patients with secondary wAIHA had a lower time to response (18 vs. 37 days, P=0.05), median disease-free survival (28.51 vs. 50.95 weeks, P=0.018), and time to splenectomy (43.5 vs. 61 wks, P=0.029) than those with primary wAIHA. Due to economic constraints, rituximab was considered as the third-line treatment in only two patients.ConclusionSecondary wAIHA may benefit from a longer low-dose steroid maintenance period mainly due to its shorter time to relapse and time to splenectomy than primary wAIHA.

Progress in diagnosis and treatment of autoimmune hemolytic disorders.

Discovery of the Coombs' test was an epoch-making event in the history of managing autoimmune hemolytic anemia (AIHA). The Coombs' test allows immune-related hemolytic anemia to be distinguished from nonimmune acquired hemolytic anemia, but also creates a complicated category; Coombs-negative AIHA. To resolve this problem, several trials have been conducted to detect immunoglobulin (Ig) G molecules on erythrocytes (RBC-IgG) that the Coombs' test cannot detect. In Japan, RBC-IgG can be quantitated using a radioimmunoassay, but this procedure is time-consuming and expensive. Convenient quantitative analysis of RBC-IgG has recently been reported using flow cytometry, a semi-quantitative method. In the treatment of warm AIHA, corticosteroids represent the first-line therapy. For refractory and relapsed cases, the choice may be between splenectomy and rituximab, which is becoming the preferred second-line treatment. Progress in the treatment of warm AIHA is also reviewed in this article.

Autoimmune cytopenias associated with inflammatory bowel diseases: Insights from a multicenter retrospective cohort

IntroductionAutoimmune cytopenias (AIC) including autoimmune hemolytic anemia (AIHA) and immunologic thrombocytopenia (ITP) are rare immunologic disorders, scarcely reported in inflammatory bowel diseases (IBD). We conducted a multicentric retrospective study, including a case-control analysis, that aimed to describe the characteristics and outcomes of patients affected by AIC and IBD. MethodForty cases were recruited from 4 IBD centers and 2 AIC tertiary centers. Controls were recruited from the MICISTA registry. ResultsFrom the MICISTA registry, incidences were estimated at 4.1/100,000 patient-years and 12.5/100,000 patient-years after IBD diagnosis for AIHA and ITP, respectively. All AIHA patients (n=14) had colonic involvement (13/14 with UC), whereas CD (52%) and UC (48%) diagnoses were evenly distributed among ITP patients. Compared to control IBD patients, cases were characterized by a higher frequency of extra-intestinal manifestations (37.5% vs 17%, p<0.001) and by the presence of IBD severity’s hallmark. AIHA and IBD ran mainly in parallel, and 12 out of 14 AIHA were warm AIHA. In isolated cases, rituximab and infliximab were efficient to treat IBD and AIC, respectively. IBD surgery may induce AIC remission in some cases. ConclusionAlthough low, incidence of AIC appears higher in IBD patients compared to the general population. The association seems to be mainly non-fortuitous, especially for colitis-associated AIHA.

High Incidence of Venous Thromboembolism Events during Warm Autoimmune Hemolytic Anemia

▪Introduction. Thrombotic manifestations are a hallmark of many hemolytic disorders such as sickle cell disease and paroxysmal nocturnal hemoglobinuria. However, the risk of venous thromboembolism events (VTE) associated with warm autoimmune hemolytic anemia (wAIHA) has only been investigated in few studies and reported to occur in up to 15 to 33%.1-4 Moreover, risk factors of VTE during wAIHA have not been clearly identified, except for antiphospholipid antibodies and splenectomy. The aim of this study was to characterize VTE in wAIHA and to determine predictive factors of occurrence.Methods. Medical records of patients with wAIHA taken in charge in our university hospital between March 2006 and March 2016 were retrospectively analyzed. Inclusion criteria were 1) patients older than 18, with 2) wAIHA defined as hemoglobin below 120 g/L, low haptoglobin level and a positive direct antiglobulin test (DAT) for IgG alone or with complement. Exclusion criteria were known constitutional hemolysis, negative DAT or positive DAT for complement alone, or presence of cold agglutinins. Demographic, clinical and biological characteristics of patients and treatments were recorded. All VTE were proven by ultrasound scan for deep vein thrombosis (DVT) or CT scan for pulmonary embolism (PE). Thromboses of the portal system following splenectomy were not considered. The study was approved by the ethical committee. Quantitative data are reported by median [interquartile range] and compared by Mann-Whitney test. Qualitative data are reported as percentage and compared by Khi2. p<0.05 was considered significant.Results. Forty-eight patients were included, among which 26 (54%) had a secondary wAIHA (15 lymphomas, 5 autoimmune diseases, 3 infections, 2 myeloproliferative neoplasms and 1 myelodysplastic syndrome). Median age was 65 [44-78], with 51% of female. Median hemoglobin level was 73 g/L [63-90]. Clinical and biological parameters were not significantly different between primary and secondary wAIHA, notably the frequency of VTE was similar (27.3 vs. 19.2%; p=0.5).Overall, the incidence of VTE was 22.9% (n=11): 3 patients had PE, 3 had DVT alone and 5 had both DVT and PE. Only one patient was splenectomized at the time of VTE. VTE occurred at a median time of 4 weeks [1.7-7] after the diagnosis of wAIHA, with an active hemolysis in 91% cases (10/11). The Padua score was used to quantify clinical risk factors for VTE and was not different between the two groups.The frequency of jaundice was higher in patients with VTE (44.4 vs. 7.1%; p=0.02), confirmed by a higher bilirubin level (41 [32-47.5] vs. 31 [25-39] mmol/L; p=0.04). Despite similar levels of hemoglobin (74 [56-89] vs. 72 g/L [63-89]; p=0.9), hemolysis and erythropoiesis tended to be higher in the VTE group, as the LDH level (768 [464-1254] vs. 461 UI/L [296-704]; p=0.09) and reticulocyte count (288 [147-341] vs. 158x109/L [115-249]; p=0.06) tended to be higher. Platelet count was not different between the two groups (283 [165-364] vs. 228x109/L [156-310]; p=0.5). In the VTE group, a higher leucocyte count was observed (11.9 [8.6-18.1] vs. 7.3x109/L [5.4-10.5]; p=0.02). Antiphospholipid antibodies were screened in 9/11 patients with VTE and were negative.Conclusion. A high incidence of VTE (22.9%) was observed during wAIHA. VTE preferentially occurred in the first weeks of diagnosis. As no clinically relevant predictive factors could be determined, a systematic screening for DVT at diagnosis and the use of a prophylactic anticoagulation until the hemolysis is controlled are recommended.

Can Rituximab be Useful for Treating SLE-Associated Immune Cytopenias ? Results from a Retrospective Multicentre Study on 62 Patients

Introduction: Autoimmune cytopenias and mostly immune thrombocytopenia (ITP) are common manifestations of systemic lupus erythematosus (SLE). Rituximab (RTX) is used off-label in many countries for treating primary ITP and warm autoimmune hemolytic anemia (AIHA). In SLE, the place of RTX is controversial and the aim of this study was to assess the efficacy and safety of RTX for treating SLE-associated immune cytopenias.Materials and methods: A multicentre retrospective study was performed throughout the French network of adult’ immune cytopenias. Patients aged >18 years, with a definite diagnosis of SLE according to the usual criteria, treated by RTX from 2005 to 2015 specifically for a SLE-associated immune cytopenia could be included. SLE-associated ITP was defined as platelet count ≤ 50 x 109L after exclusion of any other cause of thrombocytopenia. AIHA was defined by a hemoglobin level (Hb) ≤100 g/l with markers of hemolysis and a positive direct antiglobulin test. To assess treatment efficacy, the following criteria were used: for ITP, complete response (CR) and response (R) were defined according to the consensus international criteria. For AIHA, a CR was defined by a normal Hb level in the absence of recent transfusion and without ongoing haemolysis, and a response (R) by a Hb level ≥100 g/l with an increase of at least 20 g/l from baseline. CR and PR could be retained only for patients who were treated with corticosteroids and/or other immunosuppressive agents at a stable or decreasing dose.Results: Sixty-two patients, 55 women (88.7%), with a median age of 36 years [range 31-49] were included. The median duration of SLE at time of first RTX administration was 6.7 years [3.4-11.4] and the reason for using RTX was ITP in 40 cases (64.5%), AIHA in 15 cases (24.2%) and Evan’s syndrome in 6 cases (9.7%). One patient was treated for a SLE-associated pure red cell aplasia. Other SLE-related manifestations were: articular (54.8%), cutaneous (49.2%), serositis (14.5%), renal (11.1%) and/or neurological (14.5%). Patients had received an average of 3.1 ± 1.3 treatments prior to RTX including steroids (100%), and hydroxychloroquine (90.3%). The overall initial response rate to RTX was 82% (87% for ITP, 86% for AIHA, and 50% for Evan’s syndrome) including 59% CR. Median follow-up after the first injection of RTX was 24.6 months [12.6-61.2]. Twenty-one (41%) of the initial responders relapsed and re-treatment with RTX was successful in 94%. Severe infections occurred after rituximab in three adults with no fatal outcome. No cases of of opportunistic infections of RTX-induced neutropenia were observed.Discussion: RTX appears to be an effective and relatively safe option for the treatment of SLE-associated immune cytopenias. DisclosuresMichel:Roche: Research Funding.

BAFF and CD4 T-Cells Are Major Survival Factors for Splenic Plasma Cells in B Cell Depletion Context: Implications for Autoimmune Diseases

The use of monoclonal anti-CD20 antibody (Rituximab) has greatly improved the treatment of B-cell mediated autoimmune diseases, albeit with variable outcomes. Our previous data in humans suggested that Rituximab induced paradoxically the settlement of splenic long-lived plasma cells (LLPC) in the context of 2 autoimmune cytopenia, immune thrombocytopenia and warm autoimmune hemolytic anemia (1) (2). The presence of splenic autoreactive LLPC explained the failure of Rituximab treatment. To investigate whether this mechanism could have a general relevance and decipher the cellular and molecular mechanism of this process, we used both non auto-immune and auto-immune mouse models.We have taken advantage of the knock-in transgenic mouse model AID-CreERT2-EYFP, which allows the irreversible expression of EYFP in B cells engaged in a germinal center-dependent immune response after tamoxifen regimen, to follow plasma cells (PC) at different times of immunization by sheep red blood cells, and upon anti-CD20 regimen (clone 18B12, Biogen Idec), in the spleen and bone marrow (3).By using a set of diagnostic genes that allowed us to distinguish short-lived and long-lived plasma cells, we compared the transcriptional program by multiplex PCR of EYFP+ B220- PC from controls and anti-CD20 treated mice, immunized and analyzed at the same time, corresponding to the nadir of B-cell depletion. While splenic PC of untreated mice displayed an intermediate profile between short-lived and long-lived plasma cells, splenic PC from anti-CD20 treated mice composed a homogeneous population that displayed a more mature program, similar to the one of natural long-lived bone marrow PC. The absolute number of splenic EYFP+ B220- did not change upon anti-CD20 treatment indicating that B-cell depletion promoted PC differentiation rather than a long-lived PC selection. We identified BAFF (B-cell activating factor) as a major player of this process. Indeed, as described in human spleens, we observed that BAFF level was increased in the supernatants of splenocytes after B-cell depletion. Above all, combination of anti-CD20 and anti-BAFF (clone 10F4, GSK) antibodies dramatically reduced the number of splenic EYFP+B220- LLPC (decrease >5 fold compared with anti-CD20 and control groups, P < 0.001). Targeting BAFF had no major impact on protective long-lived bone marrow PC as IgG1 level in the sera remained unchanged after combination therapy. We identified neutrophils as the main source of BAFF production in the spleen. Finally, CD4+ T-cells also appeared to play a key role in context of B-cell depletion for supporting plasma cell survival in the spleen as they appeared to closely interact with EYFP+ plasma cells by confocal microscopy. Moreover, their depletion (clones YTS 191.1 or GK 1.5, Bioxcell) in vivo induced a significant decrease in the number of splenic LLPCs (decrease > 2 fold compared with anti-CD20 group, P < 0.05). To assess whether B-cell depletion could also modify the splenic plasma cell program in an auto-immune context characterized by an ongoing immune response, we used NZB/NZW mice that spontaneously develop a disease closely resembling human systemic lupus. In line with our previous findings, anti-CD20 treatment also promoted the differentiation of LLPC in the spleen of the NZB/NZW model, while a treatment combining anti-CD20 with anti-BAFF induced a marked reduction in total PC numbers(decrease > 3 fold compared with anti-CD20 group, P < 0.05).In conclusion, the process of PC maturation upon anti-CD20 treatment appeared to be a general mechanism, both in non auto-immune and auto-immune models. We identified BAFF and CD4+ T-cells as key factors in the splenic environment responsible for the emergence of such LLPC. Finally, our results suggest that interfering with the plasma cell survival niche with monoclonal anti-BAFF antibody at the time of B-cell depletion might greatly improve the response rate in B-cell mediated auto-immune cytopenia.(1) Mahevas M, et al, Journal of Clinical Investigation , 2013(2) Mahevas M, et al, Journal of Autoimmunity, 2015(3) Dogan I, et al, Nature Immunology, 2009 DisclosuresNo relevant conflicts of interest to declare.

Real World Experience of Clinical Profile and Outcomes of Autoimmune Hemolytic Anemia: Single Centre Experience

▪Background: Autoimmune haemolytic anaemia (AIHA) is a relatively uncommon condition for acute fall in haemoglobin with grave consequences if not diagnosed and treated promptly. The literature on the clinical outcome, response to treatment, and occurrence of acute complications is relatively scarce from the real world.Aim: We retrospectively analysed 100 cases of autoimmune haemolytic anaemia (AIHA) for clinic-pathological features and response to therapy.Patients and methods: It is a single centre retrospective analysis of all cases of AIHA managed at our centre from Jan 2010- June 2016. Patients were analysed for the demographic features, presenting complaints, clinical/ pathological findings at diagnosis, types of therapy given and response to therapy. AIHA was diagnosed by features suggestive of haemolysis (anaemia with unconjugated hyperbilirubinemia, raised LDH and reticulocytosis) and/or positive DAT in the absence of any underlying secondary causes for anaemia according to the monospecific-DAT results and the thermal characteristics of the autoantibody, patients were classified as warm AIHA (DAT positive for IgG with or without C3D), cold agglutinin disease (DAT positive for C3D only with cold agglutinins), mixed (DAT positive for IgG and C3d with coexistence of warm autoantibodies and high titre cold agglutinins), or atypical AIHA (either DAT negative). Based on the severity of anaemia, patients were classified into very severe (Hb≤60gm/L), severe (Hb-61 to 80gm/L), moderate (Hb-81 to 100gm/L) and mild (Hb>100gm/L).Results: A total of 100 consecutive patients were included fulfilling the inclusion criteria. The median follow-up of the study population was 17.7months (mean - 28.2m, range-0.3-197m). The median age of the patients was 33y (mean 36.3y: range 13-80y). There was female predominance (n=64, 64%). Easy fatiguability (85%) followed by dyspnoea on exertion (75%) were commonest presenting complaints. The median duration of complaints was 3 months (mean 8.93: range 0.2- 96). Jaundice (58%) and cola coloured urine (11%) were other important manifestations. Preceding history suggestive of viral infections was present in 22% of the patients and only one patient had significant drug history temporally correlating with AIHA. Splenomegaly was present in 67% with a median palpability of 2cm (mean 2.71: range 0- 20) and hepatomegaly in 49% with a median palpability of 1cm (mean 1.402: range 0 - 8) below the coastal margin. Lymphadenopathy was present in 8% of the patients.On severity grading 67% had very severe anaemia, 21% had severe, 9% moderate anaemia and 1% had mild anaemia. 24% of the patients had simultaneous low platelet counts less than 1 lakh. 17% patients had atypical AIHA - DAT negative. 21% patients had secondary AIHA of which eight patients had simultaneous low platelets (suggestive of Evans). The commonest cause for the secondary AIHA was rheumatological disorders (SLE 15 patients, MCTD one patient) followed by lymphomatous disorders in rest.Most common therapeutic modality employed was corticosteroids (methyl prednisolone pulse therapy n-20, prednisolone n-67), followed by IvIg (n-4), chemotherapy (RCHOP-1, RCVP-1, CVP-1) and rituximab (100mg/wk - 1, 375mg/m2/wk - 2). 75% of the patients had some clinical response (CR 47%, PR 22%, SD 6%) to the first line therapy. The median time to response was 1.5 months. 52% of the patients required repeat therapy in the form either steroid-sparing agent, immunosuppressant or repeat course of steroids. Six patients required splenectomy. The response to second-line therapy was seen in 92% of patients (CR 31/52, PR 9/52, SD 8/52). More than two lines/ times of therapy for non-response/relapse was required in 10% of the patients, of whom, 50% of the individuals were steroid dependent. A total of two patients succumbed to the illness (first owing to tuberculosis possible exacerbated by immunosuppressive therapy, and second due to progressive disease).Limitations of the study: All limitations of a retrospective study are applicable to our study as well. The selection of patients with fairer prognosis can explain a lower mortality in our study.Conclusion: Primary AIHA is the commonest form of AIHA. Most secondary AIHA has rheumatological etiology. Response to steroids is good leading to considerable remission but which is not long lasting and majority requiring second line/ second time therapy with same or alternative agents. DisclosuresNo relevant conflicts of interest to declare.

Solving cases in autoimmune haemolytic anaemia

Autoimmune haemolytic anaemia (AIHA) can be classified in different types including warm AIHA (WAIHA), cold haemagglutinin disease (CHAD), mixed‐type AIHA, paroxysmal cold haemoglobinuria and drug‐induced AIHA. Warm AIHA (WAIHA) is the most common type of AHAI characterized by warm autoantibodies primarily IgG (rarely IgM or IgA) reacting best at 37°C. Most are directed against the Rh protein, and over 90% of cases have a positive Direct Antiglobulin Test (DAT). The patient's plasma contains autoantibodies that appear as a panagglutinin, and the biggest concern is that they mask the presence of alloantibodies. It is important to rule out, or identify, alloantibodies in the plasma/serum, and identification of the autoantibody specificity is rarely useful. The serologic work required to detect and identify underlying alloantibodies may include multiple autologous adsorptions and elutions, and once a patient is transfused, alloantibody identification becomes more difficult, requiring allogeneic adsorptions. Molecular testing is also being used as a valuable method to predict the extended red cell antigen profile in order to select antigen‐negative red‐blood‐cells for adsorption of autoantibodies when searching for underlying alloantibodies and to provide extended matched units to the patients. Considering that patients with AIHA become alloimmunized much more commonly than other patients, it is very important that efficient procedures for detecting underlying alloantibodies, although labour‐intensive, must be used in pretransfusion testing.

High Prevalence of Monoclonal Gammopathy among Patients with Warm Autoimmune Hemolytic Anemia

High Prevalence of Monoclonal Gammopathy among Patients with Warm Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia presenting concurrently with thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is an acute, life-threatening syndrome typically characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA). Both genetic and idiopathic TTP are caused by deficient activity of the serine protease ADAMTS-13, allowing its normal substrate, von Willebrand factor, to polymerize and bind platelets under high sheer conditions. Autoimmune TTP is typically treated by plasmapheresis and corticosteroids. Here, we describe a 69-year-old patient presenting with thrombopenia comorbid with "warm" autoimmune hemolytic anemia (WAIHA). Treatment with steroids and plasma exchange initiated at the beginning and patient acquired a clinical as well as biological response. Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition typically (but not always) associated with autoimmune or genetic inactivation of the protease ADAMTS-13, for which consistently effective therapeutic interventions remain elusive.

Disseminated necrotizing leukoencephalopathy eight months after alemtuzumab treatment for multiple sclerosis

To the editor We report a case of disseminated necrotizing leukoencephalopathy (DNL) occurring after alemtuzumab treatment for multiple sclerosis (MS). A 33 year-old female patient with a 14-year history of highly active, relapsingremitting MS despite treatment with interferons, natalizumab and fingolimod was administered 12 mg of alemtuzumab for five consecutive days. Alemtuzumab is a humanized monoclonal antibody directed against the CD52 antigen that significantly reduces relapses, MRI activity and the rate of sustained accumulation of disability [1]. Autoimmune disorders such as autoimmune thyroid disease occur in up to 28 % of patients after alemtuzumab therapy and are associated with the phase of immune reconstitution [2, 3]. In addition, respiratory infections are well known side effects observed in 60 % of patients [2]. Eight months after treatment, during a phase of clinically stable MS, the patient was admitted to the hospital due to anemia with low hemoglobin which was observed in her for the first time, and warm autoimmune hemolytic anemia was diagnosed. The hemoglobin dropped as low as 2.4 g/dl, requiring therapy with corticosteroids, intravenous immunoglobulins, plasma separation, cyclophosphamide and erythrocyte substitution. The anemia could not be stabilized. A lower respiratory tract infection with consecutive septic shock developed. The patient lost consciousness and required intubation. No focal neurological deficits were documented, and due to the fulminant disease course no MRI was performed. The patient died six days after admission and a brain autopsy was performed. Autopsy revealed, besides characteristic inactive MS lesions, numerous small, round, disseminated and necrotizing lesions in the supratentorial white matter, the cerebellum and the brain stem including the pons. These lesions were characterized by numerous axonal spheroids and a pronounced macrophage infiltrate in the absence of lymphocytes, consistent with DNL (Fig. 1) [4, 5]. Severe autoimmune hemolytic anemia has been reported after alemtuzumab therapy, and may be caused by an immune dysregulation with the development of autoimmunity following drug application [6, 7]. Paradoxically, alemtuzumab is also used to treat autoimmune hemolytic anemia [6, 8]. The etiology of DNL is still unknown. It was first described in patients with brain tumors treated with highdose, methotrexate-based chemotherapy and whole brain irradiation [4, 5]. DNL has been found in immunosuppressed patients, including HIV patients [1]. Single case reports described DNL occurring with infectious diseases and sepsis, suggesting an excessive inflammatory response as etiologic factor [9]. Symptoms occur directly after therapy or many months later [4]. Thus, DNL in our patient may be related to the direct effects of alemtuzumab, e.g. immunosuppression, or it could be linked to side effects of alemtuzumab infusions such as the respiratory tract infection with sepsis or the warm hemolytic anemia and its immunosuppressive treatment. The autopsy showed acute necrotizing lesions, suggesting they developed simultaneously with the sepsis and hemolytic anemia. Clinical symptoms of DNL include irritability, somnolence, rapidly progressive subcortical dementia and coma with fatal outcome. Neuroimaging may be normal * Correspondence: imetz@gwdg.de Department of Neuropathology, University Medical Center Gottingen, Georg-August-University, Robert-Koch-Str. 40, 37075 Gottingen, Germany Full list of author information is available at the end of the article

Acquired and Congenital Hemolytic Anemia.

1. Suzie A. Noronha, MD* 1. *Division of Pediatric Hematology/Oncology, University of Rochester, Golisano Children’s Hospital, Rochester, NY. 1. Pediatricians and other general practitioners may not be aware of the significance of central nervous system disease in children who have sickle cell disease, particularly the more subtle silent infarct. 2. Pediatricians frequently fail to order a reticulocyte count or detect splenomegaly on physical examination before referring a patient with anemia. These findings are critical to diagnosing hemolytic anemia. After completing this article, the reader should be able to: 1. Recognize clinical features of hemolysis, including reticulocytosis and splenomegaly. 2. List the different types of acquired autoimmune hemolytic anemias that can manifest throughout childhood. 3. Understand the role of transfusion in the management of neurologic disease in patients who have sickle cell disease. 4. Review the spectrum of disease of α- and β-thalassemias. 5. Recognize clinical findings associated with hereditary spherocytosis. 6. Determine when to suspect glucose-6-phosphate dehydrogenase deficiency and how to counsel families on triggers to avoid. Hemolytic anemia (HA) affects a substantial proportion of the pediatric population globally. Many children are hospitalized every year due to sequelae of this heterogeneous disease. Clinicians should be facile in recognizing its presentation. HA may be defined as increased destruction of red blood cells (RBCs). RBCs are cleared from the circulation via extravascular or intravascular mechanisms (Figure). HA can be caused by congenital or acquired RBC abnormalities (Table 1). Figure. Mechanism of extravascular versus intravascular hemolysis. RBC=red blood cell. Courtesy of Jessica Shand, MD. View this table: Table 1. Classification of Common Hemolytic Anemias Extravascular hemolysis is mediated by the reticuloendothelial system (RES) of the spleen and liver. Most HAs, such as warm autoimmune hemolytic anemia (AIHA), sickle cell disease (SCD), and hereditary spherocytosis (HS), are characterized by extravascular hemolysis. The hallmark of extravascular hemolysis is …

Clinical profile of autoimmune hemolytic anemia with monoclonal gammopathy IgMκ

目的探讨伴单克隆免疫球蛋白Mκ（IgMκ）血症的自身免疫性溶血性贫血（AIHA）临床特征。方法回顾性分析85例AIHA患者临床资料，观察伴单克隆IgMκ的AIHA患者一般临床特征、实验室检查特点及转归。结果85例AIHA患者中12例（14.1%）单克隆IgM κ阳性，其中4例温抗体型AIHA, 8例冷凝集素综合征（CAS）。4例温抗体型AIHA患者均为原发病例，免疫表型未见异常；8例CAS患者中，4例继发于小B细胞淋巴瘤，4例为原发CAS，免疫表型未见异常。4例温抗体型AIHA患者中2例TCR重排阳性；8例CAS患者中6例IgH重排阳性，1例TCR/IgH重排均阳性。4例温抗体型AIHA患者均给予糖皮质激素治疗，3例达完全缓解，1例部分缓解。8例CAS患者中3例给予小剂量利妥昔单抗治疗，2例部分缓解，1例无效；2例给予COP（环磷酰胺、长春新碱、甲泼尼龙）方案化疗，1例部分缓解，1例无效；2例HGB正常患者给予保暖对症治疗；1例院外行脾脏切除术，术后死于感染。结论CAS常伴有单克隆IgMκ，而温抗体型AIHA伴单克隆IgMκ较少见。

Rituximab is an effective and safe treatment of relapse in elderly patients with resistant warm AIHA.

We evaluated the efficacy and safety of rituximab for the treatment of 23 elderly patients (median age 78 years) with warm autoimmune haemolytic anaemia (AIHA). The median follow-up was 31 months. Patients had received one to five previous treatments. Rituximab was administered by intravenous infusion at a dose of 375 mg/m(2) once weekly for 4 weeks. The OR rate was 86.9 % (CR = 39.1 %, PR = 47.8 %). Median OS was 87 months. The median OS of patients who reached CR could not be calculated, and that of patients with PR was 67 months. At last follow-up, eight of the 20 responding patients, including one patient in CR and seven in PR, had relapsed after a median of 6 months. Failure to achieve CR was a risk factor for relapse (p = 0.028). We did not identify any pretreatment characteristics predictive of response to rituximab. In conclusion, rituximab is an effective treatment for elderly patients with refractory warm AIHA.

Diagnosis and treatment of autoimmune hemolytic anemia: classic approach and recent advances.

Diagnosis and treatment of autoimmune hemolytic anemia: classic approach and recent advances.

Pure red cell aplasia in chronic lymphocytic leukemia: Case report and review of literature

Despite being immune deficient, chronic lymphocytic leukemia (CLL) patients have an increased incidence of autoimmune cytopenias secondary to autoantibody formation. These are: warm autoimmune hemolytic anemia; idiopathic thrombocytopenia; pure red cell aplasia (PRCA), and In this case report, we describe a patient with CLL who developed severe anemia requiring frequent red cell transfusion after the third cycle of chemotherapy. Blood film showed no evidence of hemolysis and absolute reticulocytopenia. Bone marrow showed erythroid hypoplasia and residual interstitial infiltrate of CLL. The diagnosis of CLL-induced PRCA was made, and the patient showed a prompt and dramatic response to treatment with cyclosporine.

Clinical characteristics and treatment outcomes of primary autoimmune hemolytic anemia: a single center study from South India.

BackgroundAutoimmune hemolytic anemia (AIHA) is a less recognized, potentially fatal condition. There is a scarcity of data on clinicoserological characteristics and response to therapy concerning this disease from South India.MethodsData for 33 patients with primary AIHA recorded from July 2009 to June 2015 were retrospectively analyzed for clinical presentation, response to frontline therapy, durability of response, time to next treatment (TTNT), and response to second-line agents.ResultsThe median follow-up period was 50 months. Among 33 patients, 48% of the cases were warm autoimmune hemolytic anemia (WAIHA), 46% were cold agglutinin disease (CAD), and 6% were atypical. Three-fourth of patients had severe anemia (<8 g/dL hemoglobin [Hb]) at onset; younger patients (age <40 yr) had more severe anemia. All of the patients who required treatment received oral prednisolone at 1.5 mg/kg/d as a frontline therapy, and the response rate was 90% (62% complete response [CR] and 28% partial response [PR]). The overall response to corticosteroids in WAIHA and CAD was 87% and 92%, respectively. The median corticosteroid duration was 14 months, and 50% of the patients required second-line agents. Fourteen patients received azathioprine as a second-line agent, and 11 of these patients responded well, with half of them not requiring a third agent. Four patients developed severe infections (pneumonia, sepsis, and soft tissue abscess) and two had life-threatening venous thrombosis. One case of death was recorded.ConclusionAIHA is a heterogeneous disease that requires care by physicians experienced in treating these patients.

Autoimmune hemolytic anemia presenting concurrently with thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is an acute, life-threatening syndrome typically characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA). Both genetic and idiopathic TTP are caused by deficient activity of the serine protease ADAMTS-13, allowing its normal substrate, von Willebrand factor, to polymerize and bind platelets under high sheer conditions. Autoimmune TTP is typically treated by plasmapheresis and corticosteroids. Here, we describe a 69-year-old patient presenting with thrombopenia comorbid with "warm" autoimmune hemolytic anemia (WAIHA). Treatment with steroids and plasma exchange initiated at the beginning and patient acquired a clinical as well as biological response. Thrombotic thrombocytopenic purpura (TTP) is a life-threatening condition typically (but not always) associated with autoimmune or genetic inactivation of the protease ADAMTS-13, for which consistently effective therapeutic interventions remain elusive.

Refractory IgG Warm Autoimmune Hemolytic Anemia Treated with Eculizumab: A Novel Application of Anticomplement Therapy.

Warm autoimmune hemolytic anemia (wAIHA) is the most common form of AIHA, with corticosteroids in first-line treatment resulting in a 60–80% response rate. Atypical wAIHA and IgG plus complement mediated disease have a higher treatment failure rate and higher recurrence rate. We report a case of severe wAIHA secondary to Waldenström macroglobulinemia with life threatening intravascular hemolysis refractory to prednisone, rituximab, splenectomy, and plasmapheresis. A four-week treatment of eculizumab in this heavily pretreated patient resulted in a sustained increase in hemoglobin and transfusion independence, suggesting a role for complement inhibition in refractory wAIHA.