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.     

Rituximab as successful therapy in a patient with refractory paroxysmal cold hemoglobinuria

BACKGROUND: Paroxysmal cold hemoglobinuria (PCH) is a rare autoimmune hemolytic anemia (AIHA) attributed to a biphasic hemolysin known as the Donath-Landsteiner (DL) antibody. It is most commonly encountered as an acute transient AIHA after a viral infection in children; the disease resolves after cessation of the infection. The rarest form of PCH is a chronic form in adults that is not (nowadays) associated with infection and is not responsive to conventional therapies. Rituximab has been found to be effective therapy in other forms of AIHA, such as cold agglutinin syndrome, that are refractory to conventional therapies. We describe a case of PCH refractory to steroids that responded to rituximab therapy on two separate occasions. CASE REPORT: A 64-year-old woman with fatigue was found to be profoundly anemic with laboratory findings consistent with AIHA. She was admitted for the workup and management of her disease after she failed to respond to a course of oral steroids. Laboratory evaluation demonstrated a positive DL test suggesting PCH. She was given a course of rituximab that resulted in normalization of her hemoglobin concentration. She presented 9 months later with recurrent hemolysis. She was given another course of rituximab that again resulted in termination of hemolysis. The patient remained in remission since her last dose of rituximab 19 months previously. CONCLUSION: To our knowledge, this is the first report of an adult case of refractory PCH successfully treated with rituximab.     

Aquired immune hemolytic anemias

Aquired immune hemolytic anemias are classified in autoimmune hemolytic anemia (AIHA) of warm type, cold agglutinine disease, paroxysmal cold hemoglobinuria, drug-induced immune hemolytic anemia, and paroxysmal nocturnal hemoglobinuria. The autoantibodies in AIHA of warm type react most strongly at 37 degrees C (warm autoantibodies). They are of the IgG, less commonly of the IgM and IgA classes. The cause of autoimmunization remains obscure in 50% of the patients (idiopathic AIHA). In the remaining cases, the AIHA is associated with other diseases. Corticosteroids are the mainstay of therapy, but most patients with AIHA of warm type require additional treatment with azathioprine or other drugs. Cold agglutinins are the cause of hemolysis in about 10% of patients with AIHA. Paroxysmal cold hemoglobinuria (Donath-Landsteiner) is less common and occur in children following infections. Drugs are the cause of hemolysis in about 10% of all cases with AIHA. The true incidence of alloimmune hemolytic anemias including neonatal immune hemolytic anemias is unknown. The paroxysmal nocturnal hemoglobinuria is rare. It is caused by complement activation due to aquired membrane defects.     

A dual antiglobulin test for the detection of weak or nonagglutinating immunoglobulin M warm autoantibodies

BACKGROUND: Immunoglobulin (Ig)M warm autoantibodies (AABs) usually cause severe autoimmune hemolytic anemia (AIHA) and, in some cases, red blood cell (RBC)‐bound IgM cannot be detected. We describe a simple dual antiglobulin test (DDAT) for diagnosing such cases. STUDY DESIGN AND METHODS: A patient with erroneously suspected cold agglutinin syndrome was investigated. The direct antiglobulin test (DAT) was performed using standard techniques and dual (two stages) antiglobulin reagents (IgG rabbit anti‐human IgM, IgG goat anti‐rabbit IgG). RESULTS: A cold agglutinin syndrome was diagnosed initially, as the patient's serum was reactive with RBCs at a temperature of 28°C or less, and the DAT was strongly positive with anti‐C₃d. Six months later, the patient was reexamined at this hospital due to progressive hemolysis. His RBCs were found to be coated with IgM warm AABs that only became detectable using a DDAT, and his serum contained only a weak cold agglutinin. The hemolysis remained refractory to treatment with prednisolone and also prednisolone plus azathioprine, but gradually improved after treatment with prednisolone plus cyclophosphamide. CONCLUSION: Weak or nonagglutinating RBC‐bound IgM warm antibodies can be identified by the presented DDAT.     

Eculizumab as a bridge to immunosuppressive therapy in severe cold agglutinin disease of anti‐Pr specificity

Severe cold agglutinin disease with hemodynamic compromise requires rapid stabilization of the autoimmune hemolytic anemia as a bridge to the immunosuppressive effect of rituximab. Herein, we describe eculizumab treatment of severe complement‐mediated hemolysis in a patient whose hemodynamic status deteriorated in spite of supportive blood transfusions and therapeutic plasma exchange.     

Resolution of serologic problems due to cold agglutinin mediated autoimmune hemolytic anemia and its transfusion decision

BackgroundAutoimmune hemolytic anemia (AIHA) is a rare disease characterized by hemolysis caused by autoantibodies against erythrocyte surface antigen. These antibodies can be classified as warm, cold, or mixed types.MethodsWe report two cases of cold agglutinin disease (CAD), which were eventually diagnosed owing to blood group discrepancy. Resolution was achieved after washing the red blood cells (RBCs) with warm saline and absorbing the autoantibodies at 4°C with the washed RBCs. We also assessed the patient''s condition and discussed the strategy of blood transfusion.ResultsThe first case occurred after postoperative chemotherapy for rectal cancer, and the other manifested with anemia from the outset. Direct antiglobulin tests were positive and revealed autoantibodies against C3d only. Cold agglutinin titration was performed, and the titers of both were 1:1024. Eventually, the patient''s condition stabilized without blood transfusion.ConclusionThe serological discrepancies observed in the blood transfusion department can successfully guide blood transfusion decisions in cases of CAD.     

Plasma exchange in autoimmune hemolytic anemia (AIHA)

Plasma exchange therapy in autoimmune hemolytic anemia (AIHA) was used in four patients (two with warm hemolytic anemia and two with cold hemolytic anemia). The size of each plasma exchange approximated 1 plasma volume; three consecutive daily exchanges removed 80–90% of the immunoglobulins—immunoglobulin G (IgG) and immunoglobulin M (IgM)—. complement (C₃, C₄), and reduced antibody titers. Transfusion requirements dramatically decreased after plasma exchange in each case. In two patients, red blood cell (RBC) survival studies were performed to more accurately assess the effect of plasma exchange therapy, since steroid and/or immunosuppressive therapy was given concomitantly. In one case of cold AIHA, homologous ⁵¹Cr-RBC were injected 4 days prior to plasma exchange and repeat injection (same donor) following completion of plasma exchange. The survival curve prior to plasma exchange therapy had a T 1/2 = 7.8 days (r = ?0.988) and after plasma exchange therapy had a T 1/2 = 20.4 days (r = ?0.925). RBC survival studies using homologous ⁵¹Cr-RBC were also performed in a patient with warm AIHA. The survival curve before plasma exchange had a T 1/2 = 2 days (r = ?0.95), and postplasma exchange a T 1/2 = 1.8 days (r = ?0.91). Plasma exchange therapy seems to have a beneficial effect in cold rather than warm autoimmune hemolytic anemia.     

Ham′s试验阳性的宽热幅异常冷凝集素型自身免疫性溶血性贫血

报告一例误诊为阵发性睡眠性血红蛋白尿症的宽热幅异常冷凝集素型自身免疫性溶血性贫血。患者冷凝素试验４℃效价＞４０９６，积分１０４；２５℃效价１２８，积分３８；３７℃效价６４，积分２２。讨论了两者在临床与溶血机制方面的鉴别诊断。     

Mixed-type autoimmune hemolytic anemia: differential diagnosis and a critical review of reported cases

BACKGROUND: Autoimmune hemolytic anemia (AIHA) is usually classified as either warm or cold type. During the past few decades, mixed types (Mxs) have also been described in a number of cases (6%‐8% of AIHA), often without serologic data to support the diagnosis. In this study, we demonstrate that the incidence of Mx AIHA in our institution is extremely rare. STUDY DESIGN AND METHODS: Between August 1998 and August 2007, all in‐ and outpatients with detectable warm autoantibodies (WABs) were included in this study. Serologic testing was performed using standard techniques for the detection of red blood cell antibodies. RESULTS: From a total of 2194 patients with detectable WABs, only 2 patients (<0.1%) developed both WABs and cold agglutinins (CAs), which in the presence of clinical evidence of hemolytic anemia, satisfies the criteria for Mx AIHA. Only 1 of these patients, however, showed cold and warm hemolysis. Insignificant CAs at temperatures of not more than 24°C were found in 242 patients. CONCLUSION: There is evidence that the presence of CAs with high thermal amplitude and WABs may lead to confusion and misdiagnosis in some patients with AIHA. This study demonstrates that Mx AIHA is less common than previously reported.     

Chronic Hemolytic Anemia due to Cold Agglutinins: the Mechanism of Resistance of Red Cells to C′ Hemolysis by Cold Agglutinins

The red cells of patients with chronic hemolytic anemia due to cold agglutinins are agglutinated by antiglobulin serum in a nongamma reaction due to the coating of beta-globulins, C'4 and C'3. The red cells of such patients are abnormally resistant to C' hemolysis by cold agglutinin.Normal red cells can be made equally resistant to C' hemolysis by incubation with cold agglutinin and normal serum at temperatures which allow transient reactions between the red cells and cold agglutinins. The development of resistance to C' hemolysis was related to increasing susceptibility to agglutination in anti-beta(1c)- and anti-beta(1e)-sera and by increasing uptake of (131)I activity from labeled anti-beta-globulin serum containing antibodies for both globulins. There was decrease in the adsorption of (131)I-labeled cold agglutinin during the development of resistance to C' hemolysis and reduced susceptibility to agglutination by cold agglutinins.Since cold agglutinins have been demonstrated to dissociate from the red cell, leaving fractions of C' globulin attached, it is postulated that repeated transient reactions produce the accumulation of incomplete C' complexes. Steric hindrance by the adsorbed C' complexes is probably responsible for the inhibition of the reaction with cold agglutinin. There is evidence that the adsorbed C' complexes also interfere with the hemolytic action of C' even when cold agglutinin has become reattached to the red cells.The accumulation of C' complexes by cold agglutinins appears to be the most important factor in the abnormal resistance to C' hemolysis exhibited by the patient's red cells. Other factors, such as the heterogeneity within a population of normal cells, appear to be of minor significance.     

23例温冷双抗体型自身免疫性溶血性贫血的临床特征

目的 了解近十年温冷双抗体型自身免疫性溶血性贫血（AIHA）患者的临床特征，以加深对该病的认识。方法 对1994年1月至2004年4月诊断的23例温冷双抗体型AIHA的临床表现、实验室特征及治疗反应进行回顾性分析。结果 近十年温冷双抗体型AIHA在同期AIHA中占22．1％，较20世纪80年代的17．6％有所增加；原发性病例占73．9％；女性多见；自身抗体的类型以复合型为主，含IgM抗体者多见（56．5％），抗体温幅及补体水平与溶血程度相关；对肾上腺皮质激素合并其它免疫抑制剂反应较好；中位随访时间4个月，复发率为77．8％。结论 温冷双抗体型AIHA是一种女性多见、原发性为主、与抗体种类和温幅及补体激活相关、复发率较高的溶血性疾病，联合免疫抑制治疗效果较好。     

IgM cold-warm hemolysins in infectious mononucleosis

A patient with infectious mononucleosis and immune hemolytic anemia is described. The hemolysis was mediated by the temporary appearance of both a serum IgM anti-i cold agglutinin and an increase of red blood cell i antigen. The cold agglutinin had a high titer, low thermal amplitude and cold-warm hemolytic activity.     

Early-onset autoimmune hemolytic anemia after cladribine therapy for Waldenström's macroglobulinemia

BACKGROUND: Purine nucleoside analogs are a class of antineoplastic drugs with potent lymphotoxicity against T and B lymphocytes, causing prolonged lymphopenia and linked to delayed immune complications such as opportunistic infections and more recently autoimmune hemolytic anemia (AIHA), seen mostly in patients with chronic lymphocytic leukemia (CLL). A characteristic temporal relation between fludarabine therapy and the appearance of a warm‐reactive immunoglobulin G (IgG)‐mediated AIHA in patients with CLL has been observed and, in some, the AIHA has been fatal. Whether both fludarabine and cladribine cause AIHA is uncertain because AIHA is commonly seen in patients with CLL without the use of these drugs. In contrast, AIHA is encountered in Waldenström's macroglobulinemia (WM) much less frequently, and the autoantibody is usually cold‐reactive and IgM‐mediated. In a few reported cases of AIHA arising in patients with WM after cladribine therapy, there was a latency of 24 to 60 months between therapy and the onset of AIHA, three of which were warm‐reactive and IgG‐mediated. CASE REPORT: A warm‐reacting IgG red cell autoantibody and evidence of hemolysis detected 1 month after completing cladribine therapy for WM, with warm antibody AIHA developing 4 months later, are described. CONCLUSIONS: Cladribine, like fludarabine, is possibly able to produce this complication during or early after therapy. Because the use of purine analogs is becoming increasingly common, it is important to have an awareness of the complications that can arise during and after treatment. Further observations of warm AIHA during cladribine therapy are needed to establish it as a distinct complication.     

Benefit of a 37 degree C extracorporeal circuit in plasma exchange therapy for selected cases with cold agglutinin disease

Plasmapheresis is commonly advocated in cold agglutinin disease with life-threatening hemolysis. Some clinicians, however, are reluctant to use this therapy because of perceived technical problems and risks attendant with the temperature of the extracorporeal circulation. In this study we report our experience of two patients with severe life-threatening hemolysis and in whom plasma exchange was not feasible due to red blood cell autoagglutination in the extracorporeal circuit. A method is described involving the use of blood warmers and the Fenwal CS-3000 blood cell separator with its 37 degrees C centrifuge compartment. The use of plasma exchange in this manner is a safe and beneficial form of adjunctive therapy and should be considered for patients with cold agglutinin disease at risk for extracorporeal agglutination or hemolysis.     

Chronic hemolytic anemia due to cold agglutinins: II. The role of C′ in red cell destruction

The sera of four patients with chronic hemolytic anemia due to cold agglutinins deposited C' globulins on normal red cells at 37 degrees C. The circulating cells of the patients were heavily coated with C' complex and were relatively resistant to C' hemolysis by cold agglutinin. Such red cells were removed from the patients' circulation at an exponential rate with (51)Cr t((1/2)) that varied from 7 to 19 days. Normal red cells were removed rapidly by hepatic sequestration during the first hours in the patients' circulation. Thereafter, a slower rate of abnormal destruction occurred which was associated with the accumulation of C' complexes on the red cell and the development of resistance to C' hemolysis by cold agglutinin. Normal red cells coated with sufficient C' complex by action of cold agglutinins in vitro to produce resistance to C' hemolysis by cold agglutinins demonstrated varying degrees of improved survival during the first hours in the circulation of three of the patients.The levels of serum C' were reduced in all four patients with chronic hemolytic anemia due to cold agglutinins. Transfusion of large volumes of normal red cells into two patients further reduced serum C'. (51)Cr-labeled normal red cells survived longer after red cell transfusions than before, because of less rapid destruction during the first hours in the circulation. The reduction in serum C' levels appeared responsible for the improved survival.In subjects without cold agglutinins, the presence of the spleen decreased the survival of red cells from a patient who had previously undergone splenectomy. Splenic removal also predominated in the reduced survival of autologous red cells in one patient. Neither hepatic nor splenic mechanisms predominated in removing autologous C'-coated cells in the other two patients.     

33例获得性免疫性溶血性贫血的实验室结果分析

目的探讨实验室检测结果分析对获得性免疫性溶血性贫血诊断价值。方法33例获得性溶血性贫血,应用常规的实验方法。结果24例温抗体型自身免疫性溶贫(WAIHA),直接抗人球蛋白试验(Coombs试验)阳性。3例阵发性睡眠性血红蛋白尿(PNH),酸化血清溶血试验(Hams试验)阳性。1例冷凝集素综合征(CAS),冷凝集素滴度明显增高。结论应用最常规实验方法来诊断鉴别获得性免疫性溶血性贫血,是非常重要的,其特点快速,简便,成本低,便于实验室推广应用。     

Successful renal transplantation in a patient with cold agglutinin disease

Cold agglutinin disease is a rare cause of acute graft loss after renal transplantation. A 71‐year‐old female with end stage renal failure was diagnosed to have cold agglutinin disease when investigated for recurrent clotting of hemodialysis circuits. Kidney transplantation was a major challenge due to unavoidable exposure of the transplant kidney to cold temperatures. Large volume plasma exchange given pre‐transplant and infusion of warm saline prior to anastomosis resulted in successful renal transplantation with good graft function despite initial delayed graft function. This challenging case illustrates the complete removal of cold agglutinin antibodies with therapeutic large volume plasma exchange. J. Clin. Apheresis 32:56–58, 2017. © 2016 Wiley Periodicals, Inc.     

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.     

自身免疫性溶血性贫血的免疫分型及临床分析

目的 对64例自身免疫性溶血性贫血(AIHA)患者血液中红细胞上结合的抗体进行免疫分型,进一步指导临床治疗.方法 采用免疫分型技术及相关溶血性贫血系列检测法.结果 发病较多的是青壮年,女性多于男性,类型分布以IgG C3型多见,且贫血、溶血程度重,余依次为C3型、IgG型.结论 AIHA免疫分型可判定疾病的严重程度以及为临床治疗提供依据.     

Vaccination-associated immune hemolytic anemia in two children

BACKGROUND: Two children in whom acute autoimmune hemolytic anemia (AIHA) developed after vaccination were studied. CASE REPORTS: The children were a 20-month-old girl and a 21-month-old boy. The diagnosis of AIHA was made in accordance with established criteria (hemolysis, positive DAT, and lack of other reasons for the hemolysis). Serologic tests were performed according to standard technique. RESULTS: The girl experienced two attacks of hemolysis. The first episode occurred 2 weeks after oral polio vaccination, and the second episode was observed 7 months later, when she received a simultaneous vaccination against mumps, rubella, and measles. The DAT was strongly positive with anti-C3d. No autoantibodies were detectable in either episode. The boy experienced acute hemolysis a few days after a simultaneous revaccination against diphtheria-pertussis-tetanus, Haemophilus influenzae, hepatitis B, and polio. The DAT using anti-IgG was strongly positive, and the DAT performed with anti-C3d was weakly positive. CONCLUSION: Vaccination-induced AIHA resembles those forms of AIHA related to infectious diseases, and it may occur more frequently than has been reported.