Durable response to combination therapy including staphylococcal protein A immunoadsorption in life-threatening refractory autoimmune hemolysis

BACKGROUND: Few therapeutic options are available for severe, life-threatening, refractory autoimmune hemolytic anemia. CASE REPORT: A 53-year-old 110-kg man was seen with acute onset of symptomatic severe anemia with syncope, unstable angina, and jaundice. His nadir Hct was 8.3 percent with a peak total bilirubin of 44 mg per dL. The DAT was positive but the IAT was negative. Elution studies demonstrated an IgG pan-agglutinin antibody reactive at 37 degrees C. Treatment with high-dose corticosteroids and IVIG was instituted. An accessory spleen measuring 2 cm was identified and surgically removed, but the patient continued to have intense hemolysis. Cyclophosphamide at 200 mg per day was started. Apheresis with a staphylococcal protein A immunoadsorption column (Prosorba, Cypress Bioscience, Inc.) was initiated on Day 18 and was performed twice weekly for a total of six treatments. Cyclophosphamide was continued for a total of 14 days. His transfusion requirement ceased by the third immunoadsorption treatment. Forty units of RBCs were required over 23 days in an attempt to maintain a Hct greater than or equal to 15 percent. CONCLUSION: Refractory autoimmune hemolysis can be a life-threatening event. The patient did not achieve a response until after several different therapeutic modalities were instituted, including plasmapheresis with a staphylococcal protein A column (Prosorba). A complete response continues to be durable for more than 1 year after therapy.     

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.     

Hemolytic anemia

Hemolysis presents as acute or chronic anemia, reticulocytosis, or jaundice. The diagnosis is established by reticulocytosis, increased unconjugated bilirubin and lactate dehydrogenase, decreased haptoglobin, and peripheral blood smear findings. Premature destruction of erythrocytes occurs intravascularly or extravascularly. The etiologies of hemolysis often are categorized as acquired or hereditary. Common acquired causes of hemolytic anemia are autoimmunity, microangiopathy, and infection. Immune-mediated hemolysis, caused by antierythrocyte antibodies, can be secondary to malignancies, autoimmune disorders, drugs, and transfusion reactions. Microangiopathic hemolytic anemia occurs when the red cell membrane is damaged in circulation, leading to intravascular hemolysis and the appearance of schistocytes. Infectious agents such as malaria and babesiosis invade red blood cells. Disorders of red blood cell enzymes, membranes, and hemoglobin cause hereditary hemolytic anemias. Glucose-6-phosphate dehydrogenase deficiency leads to hemolysis in the presence of oxidative stress. Hereditary spherocytosis is characterized by spherocytes, a family history, and a negative direct antiglobulin test. Sickle cell anemia and thalassemia are hemoglobinopathies characterized by chronic hemolysis.     

Posttransplant immune-mediated hemolysis

BACKGROUND: Immune-mediated hemolysis is a well-recognized complication of transplantation, but few reports have drawn together the different mechanisms that could be involved. STUDY DESIGN AND METHODS: The clinical and laboratory records of three patients are used to illustrate different types and complexities of posttransplant immune-mediated RBC destruction. RESULTS: Patient 1 received bone marrow from an HLA-matched, unrelated donor. At 7 months after transplant, his Hb level fell to 50 g per L. The serum contained warm autoantibodies, and the DAT was strongly positive for IgG, IgM, and C3d; an eluate yielded IgG and IgM autoantibodies. Autoimmune hemolytic anemia was diagnosed. Patient 2, blood group A, experienced severe hemolysis 14 days after receiving a lung from a group O donor. The DAT was positive for IgG. Serum and RBC eluate contained anti-A produced by immunocompetent B cells in the transplanted lung-this was the passenger lymphocyte syndrome. Patient 3 experienced posttransplant hemolysis caused by two different immune mechanisms. Originally group A, D- with anti-C, -D, -E, she received a peripheral blood progenitor cell (PBPC) transplant from her HLA-identical group A, D+ son. Six months later, chimerism was evident; the remaining recipient marrow was still producing antibodies that destroyed D+ RBCs made by the transplant. Later, autoimmune hemolytic anemia also developed; the DAT became positive for IgG, and warm autoantibodies were eluted from D- RBCs. CONCLUSION: An understanding of the causes and circumstances under which posttransplant immune hemolysis arises is required for proper management. As more patients become long-term survivors of unrelated bone marrow and/or PBPC transplants, chimerism and complex serologic problems will become more common.     

Evans' syndrome: possible benefit from plasma exchange

Because of previous reports of benefit of plasma exchange in immunologic disorders, we plasmapheresed a 45-year-old woman with immune thrombocytopenia and autoimmune hemolytic anemia (Evans' syndrome) who appeared to be dying despite splenectomy, prednisone, immunosuppressives and transfusions. Nine liters of plasma were removed over a 12-day period. Prior to plasma exchange, the patient's hematocrit remained below 16 per cent despite six units of red blood cells over a three-day period. Following plasma exchange, the hematocrit rose to 29 per cent; the platelet count gradually rose from 14,500/microliter to 272,000/microliter; and the transfusion requirements declined to only two units of red blood cells over the next 37 days. We conclude that plasmapheresis should be considered in the management of patients with refractory immune thrombocytopenia and autoimmune hemolytic anemia.     

Apparent hemolysis following intravenous antithymocyte globulin treatment in a patient with marrow failure and a paroxysmal nocturnal hemoglobinuria clone

BACKGROUND: Antithymocyte globulin (ATG) is a commonly used medication in the treatment of aplastic anemia. Although serum sickness has been described with the use of ATG, few cases of acute intravascular hemolysis have been reported. We report a case of apparent ATG-related hemolysis in a patient with aplastic anemia and a paroxysmal nocturnal hemoglobinuria (PNH) clone. CASE REPORT: A 62-year-old, group A, RhoD+ man with aplastic anemia and an 11.6 percent glycosylphosphatidylinositol (GPI)-anchored protein-negative population of red cells (RBCs), representing approximately 190 mL of his RBC volume, and 90 percent GPI-negative neutrophils were scheduled to receive equine ATG at 40 mg per kg per day for 4 days. After the first infusion, he developed a 1.6 g per dL decline in hemoglobin concentration and an increase in serum lactate dehydrogenase (normal, 113-226 U/L) from 284 to 1127 U per L. The hemolytic process was complicated by acute renal failure characterized by an increase in serum creatinine from 0.9 to 4.2 mg per dL and the appearance of dark-colored urine. Pre- and post-ATG direct antiglobulin tests were negative. CONCLUSION: The temporal association of intravenous ATG to lysis of complement-sensitive RBCs suggests a causal relationship. Although intravascular hemolysis after ATG administration appears to be uncommon, the clinical consequences may be severe, and determining the pathophysiology may yield clues to the mechanism of intravascular hemolysis.     

A simple model for estimating the hemolytic rate in patients with sickle cell anemia

The pathophysiologic processes of hemolysis in sickle cell anemia were formulated by a simple mathematical model that assumed a unimodal bone marrow erythrocyte population and a finite probability of random destruction of red blood cells (RBCs) in the circulation. Recognizing that the hemolytic rate of marrow RBCs is likely to be distributed normally around a mean hemolytic rate, we simplified the model by using the mean hemolytic rate as representative of the entire marrow RBC population. The model thus constructed allows an easy estimation of the mean steady-state hemolytic rate simply by measurement of reticulocyte counts and hematocrit levels. When the model was applied to data from 43 patients with sickle cell anemia, the estimated mean hemolytic rates based on the model correlated significantly with the published hemolytic rates obtained by diisopropylphosphofluoridate-RBC survival studies of the peripheral blood, but were generally greater than the published rates. This discrepancy was postulated to be the result of an enrichment of RBCs with smaller hemolytic rate in the circulation. The results of computer simulation studies were consistent with this hypothesis and suggest that the variation in the hemolytic rate for marrow RBCs is on the order of 10%. This simplified model may serve as a close approximation of this pathophysiologic system. The estimates of the steady-state hemolytic rate provided by the model should be clinically useful, especially when repeated estimations are required. The method of calculation is illustrated.     

A clinically significant anti-N in a patient whose red cells were negative for N and U antigens

A patient with sickle cell anemia had M+N-S-s-U-phenotype and developed anti-E, anti-U, and anti-N after multiple transfusions. The anti-N was IgG, showed positive red cell mononuclear phagocyte assay, caused shortened survival of 51Cr-labeled N+ red cells, and incited a delayed hemolytic transfusion reaction. The anti-U also caused decreased survival of U+ cells. The serological findings indicated that the anti-N recognized both N and 'N' antigens.     

RBC autoantibodies in autoimmune lymphoproliferative syndrome

BACKGROUND: Patients with autoimmune lymphoproliferative syndrome (ALPS) have an autosomal dominant genetic defect that affects lymphocyte apoptosis and is associated with chronic nonmalignant lymphadenopathy, splenomegaly, and autoimmunity, particularly affecting RBCs, WBCs, and platelets. STUDY DESIGN AND METHODS: DATs were performed on 34 consecutive patients with ALPS and 37 of their clinically unaffected relatives. The effects of age, sex, race, and immunoglobulin levels on the incidence of autoantibodies and clinical hemolysis were assessed. RESULTS: The DAT was positive in 21 (62%) of ALPS patients but in only 1 (3%) of their relatives (p = 0.001). The DAT reacted because of IgG alone in 43 percent, complement alone in 5 percent, and IgG plus complement in 19 percent; 33 percent of the patients' cells had a positive reaction with polyspecific reagent only. All 10 ALPS patients with a history of hemolytic anemia had a positive DAT. Sixty percent of them had only IgG on their cells, 30 percent had IgG and complement, and 10 percent reacted only with polyspecific reagent. Of the 11 patients with a positive DAT and no history of hemolytic anemia, IgG alone was present in 27 percent, complement alone in 9%, and IgG plus complement in 9 percent; 55 percent had positive DATs only with polyspecific reagent. Among ALPS patients, those with a positive DAT had greater quantities of cells with increased alpha and ss T-cell receptors that phenotyped as CD4-CD8- and higher IgG levels. CONCLUSIONS: The DAT results in ALPS patients are most similar to those found in warm autoimmune hemolytic anemia. The DAT is useful to distinguish affected and unaffected persons within an ALPS family.     

Autoimmune hemolytic anemia in Kawasaki disease: a case report

A 3-year-old boy presented with the fever, conjunctivitis, rash, and lymphadenopathy diagnostic of Kawasaki disease. Treatment with antibiotics, aspirin, and intravenous immunoglobulin was instituted. The hematocrit decreased from 35 percent on admission to 11 percent by hospital Day 10, and the white cell count had increased from 13.7 to 42 × 10(3) per microL, and the patient had a leukoerythroblastic blood smear. The direct antiglobulin test demonstrated IgG but not complement on the red cell (RBC) surface. An acid eluate reacted (titer of 4) with all panel cells in the antiglobulin phase. Intravenous immunoglobulin from the same lot used for treatment did not contain antibody that reacted with the patient's group O RBCs or a panel of group O RBCs, but did contain IgG anti-A and -B (titer of 4). The patient received a transfusion and was given methylprednisone. The direct antiglobulin test and acid eluate were negative 4 days later. The patient had an uneventful recovery. The distinction between antibody-mediated hemolytic anemia and autoimmune hemolytic anemia is important in the treatment of this disease.     

pH-dependent anti-U in autoimmune hemolytic anemia

Auto anti-U of unusual serologic characteristics is described in a Caucasian patient with autoimmune hemolytic anemia associated with chronic lymphocytic leukemia. The direct antiglobulin test was strongly positive (3+) with broad spectrum and anticomplement reagents. Auto anti-U was demonstrated only when the serum was acidified to pH 6.5 and anticomplement reagent was used in the antiglobulin test. Multiple transfusions of U positive red blood cells had clinically decreased survival manifested by jaundice and return of hemoglobin to pretransfusion levels within days. The autoantibody reacted weakly with U positive cord red blood cells interpreted as mosaicism of the U antigen possibly on a developmental basis.     

Hemolytic disease of the newborn due to the Scianna antibody, anti-Sc2

BACKGROUND: Alloantibodies to the low-frequency antigen Scianna 2 (Sc2) are uncommon and not previously reported to cause immune hemolysis. CASE REPORT: A group B, Rh-negative infant born to a group B, Rh- positive mother had a 2+ direct antiglobulin test, as well as modest hyperbilirubinemia and a hematocrit of 45 percent. Ongoing immune hemolysis led to a hematocrit of 17.3 percent on Day 20 of life, and the infant required hospitalization and red cell transfusions. The routine maternal antibody screen was negative, but anti-Sc2 was detected during work-up for a low-frequency red cell antigen, and the father's red cells typed as Sc:1,2. CONCLUSION: Anti-Sc2 can cause clinically significant hemolytic disease of the newborn. Although the antibody is uncommon, its frequency and hemolytic potential may be underappreciated, in part because investigations often are not carried out in the infant whose red cells are ABO-incompatible with maternal blood.     

Severe immune-mediated hemolytic anemia secondary to treatment with cefotetan

Severe acute hemolytic anemia developed in a woman following treatment with multiple antibiotics for possible postpartum uterine infection. On admission, the hemoglobin was 5 g per dL (50 g/L), the reticulocytes were 35 percent (0.350), the direct antiglobulin test was strongly positive for IgG and C3d (mixed fields), and the indirect antiglobulin test was negative. Serologic studies revealed antibody to cefotetan that reacted by both the immune complex and the drug adsorption mechanisms. Before the diagnosis of cefotetan-related immune hemolysis was made, all medications had been discontinued, and the patient received 4 units of red cells and a short course of adrenocorticosteroids. Recovery was prompt and complete.     

Therapeutic apheresis for babesiosis

Infection with the tick-borne protozoa Babesia is becoming more common. Babesiosis is usually successfully treated with antibiotics but, in some cases, apheresis may also be indicated. We report two patients with babesiosis and hemolysis treated by apheresis and antibiotics. One case had traditional indications for red blood cell (RBC) exchange, and a second patient was treated with RBC exchange, and plasmapheresis for hemolysis, probably secondary to Babesia parasitemia. Case 1 involved a 44-year-old man with chronic relapsing pancreatitis who had become infected with Babesia from a unit of RBCs transfused during surgery. At 5 weeks after surgery, fever and severe hemolysis developed, along with a hemoglobin of 69 g/L; 30% of his RBCs were found to be infected with Babesia. This patient had several postoperative complications; the babesiosis was treated with clindamycin, quinine, and three RBC exchanges. Parasitemia fell to less then 1% of RBCs, but the patient died of pancreatitis. Case 2 was a 47-year-old man with a renal transplant who had been receiving immunosuppressive therapy for 8 years. He had a history of tick bites, fever, and hemolytic anemia. Analysis of a peripheral blood smear detected Babesia. He was initially treated with antibiotic therapy and two RBC exchanges. Hemolysis improved transiently but worsening parasitemia developed later, as well as an IgG RBC autoantibody. He was then treated by plasmapheresis and RBC exchange. Although his condition improved, he had a third hemolytic episode, which was treated with plasmapheresis and RBC exchange before the parasitemia and autoimmune hemolytic anemia disappeared. In conclusion, immunosuppressed or severely ill people who become infected with Babesia may benefit from RBC exchange or plasmapheresis, or both. J. Clin. Apheresis 13:32–36, 1998. © 1998 Wiley-Liss, Inc.     

自身免疫性溶血性贫血的分型及临床意义

目的 对自身免疫性贫血（AIHA）患者红细胞膜上结合的不完全抗体进行免疫分型,为临床诊断治疗提供依据。方法 采用天津协和干细胞基因工程有限公司生产的4种抗人免疫球蛋白（IgG、IgA、IgM 和 C3）单价兔抗人球蛋白血清,进行抗人球蛋白分型实验,并对结果 进行分析。结果 931例患者中共检出阳性61例（占6．6％）,其中男性16例,女性45例,男、女性比例为1∶3．6,均以青壮年为主;免疫分型以IgG型最多（32例）,其次为IgG＋C3型（23例）、C3型（5例）,IgM型（1例）。结论 抗人球蛋白分型实验诊断价值优于广谱抗人球蛋白实验,运用抗人球蛋白分型实验对AIHA进行免疫分型,可以更有效地判断溶血程度,为临床诊断治疗提供可靠的依据。     

Erythrocyte depletion of ABO-incompatible bone marrow

Bone marrow transplantation results in the infusion of 150 to 360 ml of erythrocytes. While this poses no problem to a recipient of marrow from an ABO-compatible donor, it clearly represents a serious risk of intravascular hemolysis for the recipient of an ABO-incompatible marrow. Thus, there is a need for removing incompatible erythrocytes from the marrow preparation. We removed erythrocytes from the marrow preparations by automated centrifugation. The erythrocyte-depleted marrow (EDM) contained a mean of 5 ml erythrocytes, representing an average reduction of 98%. The mean mononuclear cell recovery was 88%, resulting in a mean infusion of 0.6 X 10(8) cells/Kg of recipient's body weight in a final average volume of 155 ml. EDM was infused into 22 ABO-incompatible marrow recipients (21 patients with hematologic malignancies and one patient with aplastic anemia) without clinical evidence of hemolysis. The isohemagglutinin titers of recipients ranged from 4 to 4096 and were not lowered prior to infusion. Engraftment (i.e., recovery of peripheral leukocyte and platelet counts) and incidence of graft versus host disease were similar to those observed in recipients of ABO-compatible marrow transplantation. Erythrocyte engraftment was significantly delayed in only one patient who had a high isohemagglutinin titer. The post-transplantation red cell requirement was increased in EDM recipients: 9 units compared to 6 units in ABO-compatible bone marrow transplanted patients with neither hemolysis nor interference with successful engraftment.     

Autoimmune hemolytic anemia associated with IgG auto anti-N

A second case of autoimmune hemolytic anemia mediated by an IgG auto Anti-N is described. The patient's red blood cells were sensitized with both IgG and complement. The serum antibody was not inactivated by 2- mercaptoethanol treatment, and reacted by indirect antiglobulin test at 37 C with monospecific anti-IgG. The IgG antibody eluted from the red blood cells and in the serum showed anti-N specificity. The patient was thought to have systemic lupus erythematosus. Following steroid therapy, the hemolytic anemia resolved with disappearance of the anti-N.     

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.     

Arsine toxicity treated with red blood cell and plasma exchanges

BACKGROUND: Acute toxicity due to inhalation of arsine gas (AsH(3)) has no known antidote. Exchange transfusion may be beneficial, and dialysis is often required because arsine may cause acute intravascular hemolysis and renal failure. A patient with arsine toxicity has recently been treated by both red blood cell exchange (RBC-E) and plasma exchange (PE) therapy and our experience is reported. CASE REPORT: A 46-year-old man was accidentally and unknowingly exposed to arsine gas while observing an industrial procedure. Within 6 hours he developed fatigue, nausea, vomiting, and tingling in his extremities and voided dark urine. He quickly developed renal failure secondary to acute arsine toxicity (arsenic level, 1250 microg/L). Laboratory findings were a hematocrit level of 24 percent; blood urea nitrogen and creatinine, 84 and 5.5 mg per dL, respectively; bilirubin, 9.1 mg per dL; indirect bilirubin, 6.8 mg per dL; haptoglobin, less than 6 (normal, 30-200); and lactic dehydrogenase, 10,413 units per L (normal, 265-580). An emergent 1-vol RBC-E transfusion by continuous-flow method revealed dramatic black, grossly hemolyzed plasma. After two additional RBC-E and two PE and daily hemodialysis, he completely recovered over the course of 1 month. CONCLUSION: Patients with arsine toxicity resulting in intravascular hemolysis should receive RBC-E as soon as possible. In addition, PE may be beneficial in removing the components of RBC lysis and further reducing arsenic levels.     

Coombs'-positive hemolytic anemia and ibuprofen.

A patient who developed an autoimmune hemolytic anemia during treatment with ibuprofen (Motrin) is described. Positive indirect Coombs' reaction was demonstrated with the patient's red blood cell eluate in the presence of the drug, supporting a drug-related immune hemolysis. The positive direct Coombs' reaction to anti-C3 antiserum strongly suggested that the immune hemolysis in this patient is probably mediated through complement alone; however, the presence of a small amount of IgG antibodies on the surface of the red blood cells which cannot be detected under conventional screening procedures cannot be completely excluded. Further studies, both clinical and laboratory, disclosed that the responsible ingredient in this particular instance appeared to be the orange dye coating of the Motrin-400 tablet rather than the ibuprofen itself.