Profound autoimmune hemolysis and Evans syndrome in two asplenic patients with babesiosis.

BACKGROUND: Evans syndrome (ES) is characterized by the simultaneous or sequential presence of multiple autoimmune cytopenias. It is often secondary to rheumatologic disorders or lymphoid malignancies, but has not previously been associated with babesiosis. Here we present two cases of severe cytopenias in asplenic patients precipitated by active babesiosis. CASE REPORT: The first patient had a history of Hodgkin's lymphoma in remission and autoimmune hemolytic anemia (AIHA) treated by splenectomy 12 years prior who presented with severe AIHA and thrombocytopenia after Babesia infection. The second patient had a history of ES requiring splenectomy, which relapsed after Babesia infection. RESULTS: The complex presentation and medical histories of both patients made the diagnosis challenging. Both patients' cytopenias responded to therapy, although the use of immunosuppressive agents in patients with active hematologic infections was challenging and required a multidisciplinary approach. CONCLUSION: These two cases illustrate the possibility of babesiosis to not only reactivate ES in asplenic patients, but also precipitate increased levels of immune deregulation, potentially provoking ES, a phenomenon not previously reported.

How we investigate drug-induced immune hemolytic anemia.

Drugs are a rare cause of immune hemolytic anemia, but an investigation for a drug antibody may be warranted if a patient has definitive evidence of immune hemolysis, other more common causes of hemolysis have been excluded, and there is a good temporal relationship between the administration of a drug and the hemolytic event. Drug antibodies are either drug-dependent (require drug to be in the test system) or drug-independent (reactive without drug present in the test). Drug-dependent antibodies are investigated by testing drug-treated red blood cells (RBCs) or by testing RBCs in the presence of a solution of drug. Drug-independent antibodies are serologically indistinct from idiopathic warm autoantibodies and cannot be defined or excluded by serologic testing. Nonimmunologic protein adsorption, caused by some drugs, is independent of antibody production but may also cause immune hemolytic anemia. Serologic methods for testing for drug antibodies are presented, and observations from more than 30 years of this laboratory's experience are discussed.

Drugs that have been shown to cause drug-induced immune hemolytic anemia or positive direct antiglobulin tests: some interesting findings since 2007.

This review updates new findings in drug-induced immune- hemolytic anemia (DIIHA) since the 2007 review in Immunohematology by these authors. Twelve additional drugs have been added to the three tables listing drugs associated with drug-dependent antibodies, drugs associated with drug-independent antibodies, and drugs associated with nonimmunologic protein adsorption. Other updated findings include (1) piperacillin is currently the most commonly encountered cause of DIIHA, (2) new data on blood group specificity of drug-dependent antibodies, (3) drug-dependent antibodies detected in healthy donors, (4) DIIHA associated with transplantation, and(5) DIIHA associated with chemotherapeutic drugs.

Fatal carboplatin-induced immune hemolytic anemia in a child with a brain tumor.

Drug-induced immune hemolytic anemia (DIIHA) is an uncommon side effect of pharmacologic intervention. A rare mediator of DIIHA, carboplatin is an agent used to treat many pediatric cancers. We describe here, the first case of fatal carboplatin induced DIIHA in a pediatric patient and a brief review of the literature. Our patient developed acute onset of multi-organ failure with evidence of complement activation, secondary to a drug induced red cell antibody. Early recognition of the systemic insult associated with carboplatin induced hemolytic anemia may allow for future affected patients to receive plasmapheresis, a potentially effective therapy.

Anti-Ge3 causes late-onset hemolytic disease of the newborn: the fourth case in three Hispanic families.

BACKGROUND: The Gerbich (Ge) blood group system consists of 11 antigens carried on red blood cell (RBC) membrane glycophorins C and D; of these, Ge:3 antigen is of high prevalence, and the anti-Ge3 is found to be clinically significant. CASE REPORT: A 34-week neonate born to a Hispanic mother with anti-Ge3 developed late-onset hemolysis with hyperbilirubinemia and was successfully treated with transfusions from her mother. Relevant clinical findings and laboratory results for this case are summarized and compared to three other previously reported cases; all babies were born from a mother of Hispanic ethnicity. CONCLUSION: Hemolytic disease of the fetus and new born associated with anti-Ge3 is rare but should be considered when working up a broadly reactive RBC antibody screen in women of Hispanic ethnicity. Early identification of pregnant women with anti-Ge3 is recommended for prenatal transfusion planning and close monitoring of the newborn infant for evidence of late-onset anemia.

Antibodies against polyethylene glycol in healthy subjects and in patients treated with PEG-conjugated agents.

In contrast to the accepted general assumption that polyethylene glycol (PEG) is non-immunogenic and non-antigenic, animal studies clearly showed that uricase, ovalbumin and some other PEGylated agents can elicit antibody formation against PEG (anti-PEG). In humans, anti-PEG may limit therapeutic efficacy and/or reduce tolerance of PEG-asparaginase (PEG-ASNase) in patients with acute lymphoblastic leukemia and of pegloticase in patients with chronic gout, but did not impair hyposensitization of allergic patients with mPEG-modified ragweed extract or honeybee venom or the response to PEG-IFN in patients with hepatitis C. Of major importance is the recent finding of a 22 - 25% occurrence of anti-PEG in healthy blood donors, compared with a very low 0.2% occurrence two decades earlier. This increase may be due to an improvement of the limit of detection of antibodies during the years and to greater exposure to PEG and PEG-containing compounds in cosmetics, pharmaceuticals and processed food products. These results raise obvious concerns regarding the efficacy of PEG-conjugated drugs for a subset of patients. To address these concerns, the immunogenicity and antigenicity of approved PEGylated compounds should be carefully examined in humans. With all these data in hand, patients should be pre-screened and monitored for anti-PEG prior to and throughout a course of treatment with a PEGylated compound. Finally, protein conjugates with the poorly immunogenic hydroxy-PEG sequence or other hydrophilic polymers are in early phases of development and may represent an alternative to immunogenic PEGylated proteins.

Immune hemolytic anemia caused by drugs.

INTRODUCTION: Drug-induced immune hemolytic anemia (DIIHA) is a rare cytopenia; about 130 drugs have been incriminated. The antibodies causing DIIHA can be i) drug-independent (drug not needed to be present to detect antibodies in vitro)-DIIHA caused by this type of antibody presents clinically and serologically as an autoimmune hemolytic anemia (AIHA) with red cell (RBC) autoantibodies in patients' sera and in eluates from their RBCs; or (2) drug-dependent (antibodies react in vitro with RBCs only in the presence of drug, on the RBC membrane or when added to the patient's plasma and RBCs). AREAS COVERED: Literature is reviewed regarding pathophysiology of DIIHA (mechanisms; incidence of drugs involved; the clinical, hematological, and serological characteristics of the most common antibodies causing DIIHA). EXPERT OPINION: DIIHA is often poorly investigated and many reports do not provide data to support the diagnosis (i.e., no serology to support an immune etiology). The three most common drugs currently causing DIIHA are piperacillin, cefotetan, and ceftriaxone. All three (especially piperacillin) can cause in vitro and in vivo effects mimicking AIHA, and in transfused patients, hemolytic transfusion reactions. It is important to exclude DIIHA in such patients as the only treatment needed is to discontinue the drug.

Serologic characteristics of ceftriaxone antibodies in 25 patients with drug-induced immune hemolytic anemia.

BACKGROUND: Ceftriaxone, a third-generation cephalosporin, is commonly used to prevent and treat infections. Since 1987, it has been the second most common cause of drug-induced immune hemolytic anemia (DIIHA) investigated in our laboratory. STUDY DESIGN AND METHODS: Samples from 79 patients (1987-2010), suspected of having DIIHA caused by ceftriaxone, were studied for the presence of ceftriaxone antibodies. Direct antiglobulin tests (DATs) and tests with ceftriaxone-treated red blood cells (RBCs) or untreated and enzyme-treated RBCs in the presence of ceftriaxone were performed. RESULTS: Twenty-five (32%) of the 79 patients had antibodies to ceftriaxone detected. Seventeen (68%) of the 25 patients were children; reactions in children were usually dramatic and severe. Nine (36%) of the 25 patients had fatal DIIHA. Nineteen of the 25 samples had DATs performed by our laboratory; 100% of samples were reactive with anti-C3 and 47% were reactive with anti-IgG. All 25 sera had ceftriaxone antibodies detected when testing untreated or ficin-treated RBCs in the presence of ceftriaxone (resulting in agglutination, hemolysis or sensitization of test RBCs). These antibodies were primarily IgM and reactivity was enhanced by testing ficin-treated RBCs. Sixteen (64%) of the 25 sera reacted with test RBCs when no ceftriaxone was added in vitro; this was most likely due to the transient presence of drug or drug-immune complexes in the patient's circulation at the time that the blood samples were drawn. CONCLUSION: Ceftriaxone antibodies can cause severe intravascular hemolysis. Complement can usually be detected on the patient's RBCs and IgM antibodies are usually detected in the patient's serum.

Antibodies to oxaliplatin, a chemotherapeutic, are found in plasma of healthy blood donors.

BACKGROUND: Oxaliplatin is one of the platinum chemotherapeutics that includes cisplatin and carboplatin. Antibodies to all three drugs have caused immune hemolytic anemia (IHA). In an investigation of oxaliplatin-induced IHA, the negative plasma control agglutinated oxaliplatin-coated red blood cells (RBCs). Previous preparations of this control had not agglutinated oxaliplatin- or cisplatin-coated RBCs. STUDY DESIGN AND METHODS: Drug-coated RBCs, prepared by incubating 1/10th volume of RBCs with 1 mg/mL drug in phosphate-buffered saline for 1 hour at 37°C, were incubated with plasma from random blood donors and patients. Plasma was treated with dithiothreitol to determine the immunoglobulin class. Hapten inhibition was performed by incubating plasma with solutions of oxaliplatin or cisplatin. RESULTS: Nineteen of 121 (16%) donors' plasma samples agglutinated oxaliplatin-coated RBCs; 7 of 102 (7%) donors' plasma samples agglutinated cisplatin-coated RBCs. Two of 50 (4%) patients' samples agglutinated oxaliplatin-coated RBCs. The agglutinin was immunoglobulin M and inhibited by oxaliplatin and cisplatin. CONCLUSION: An agglutinin reactive with oxaliplatin-coated RBCs was found in 16% of donors' and 4% of patients' samples. Inhibition by oxaliplatin and cisplatin indicates the antibody may be directed to platinum. The presence of this antibody in healthy individuals may be related to the increasing environmental presence of platinum in air and soil as a byproduct of automobile catalytic converters and pharmaceuticals in our water and food chain. This antibody in individuals without IHA suggests that testing untreated and enzyme-treated RBCs in the presence of a solution of drug may be the best method to investigate IHA caused by drugs in the platinum family.

A severe case of cefoxitin-induced immune hemolytic anemia.

Drug-induced immune hemolytic anemia is a rare but underdiagnosed and potentially fatal condition. We report a case of severe hemolytic anemia induced by cefoxitin in a 45-year-old woman admitted with menometrorrhagia. Hemoglobin levels reached a nadir of 4.7 g/dl approximately 72 h after cefoxitin initiation, and hemolysis resolved when cefoxitin was discontinued and prednisone 1 mg/kg was initiated. A transfusion reaction workup revealed no abnormalities. Direct antiglobulin testing was weakly positive with anti-C3. The patient's plasma and RBC eluate reacted with cefoxitin-treated RBCs but not with untreated RBCs in the presence or absence of cefoxitin.

Immune hemolytic anemia associated with drug therapy.

Drug-induced immune hemolytic anemia (DIIHA) is rare; it can be mild or associated with acute severe hemolytic anemia (HA) and death. About 125 drugs have been implicated as the cause. The HA can be caused by drug-independent antibodies that are indistinguishable, in vitro and in vivo, from autoantibodies causing idiopathic warm type autoimmune hemolytic anemia (AIHA). More commonly, the antibodies are drug-dependent (i.e., will only react in vitro in the presence of the drug). The most common drugs to cause DIIHA are anti-microbials (e.g., cefotetan, ceftriaxone and piperacillin), which are associated with drug-dependent antibodies. The most common drug to cause AIHA is fludarabine. Finding out which drug is causing the problem and stopping that drug is the first approach to therapy. It is not easy to identify the drug interactions accurately in vitro; laboratories specializing in this area can be of great help.

A critical review of published methods for analysis of red cell antigen-antibody reactions by flow cytometry, and approaches for resolving problems with red cell agglutination.

Flow cytometry operators often apply familiar white blood cell (WBC) methods when studying red blood cell (RBC) antigens and antibodies. Some WBC methods are not appropriate for RBCs, as the analysis of RBCs requires special considerations, for example, avoidance of agglutination. One hundred seventy-six published articles from 88 groups studying RBC interactions were reviewed. Three fourths of groups used at least one unnecessary WBC procedure for RBCs, and about one fourth did not use any method to prevent/disperse RBC agglutination. Flow cytometric studies were performed to determine the effect of RBC agglutination on results and compare different methods of preventing and/or dispersing agglutination. The presence of RBC agglutinates have been shown to be affected by the type of pipette tip used for mixing RBC suspensions, the number of antigen sites/RBC, the type and concentration of primary antibody, and the type of secondary antibody. For quantitation methods, for example, fetal maternal hemorrhage, the presence of agglutinates have been shown to adversely affect results (fewer fetal D+ RBCs detected).

Piperacillin-induced immune hemolytic anemia in an adult with cystic fibrosis.

We report a case of drug-induced immune hemolytic anemia (DIIHA) in an adult female with cystic fibrosis (CF), complicating routine treatment of a pulmonary exacerbation with intravenous piperacillin-tazobactam. Workup revealed a positive direct antiglobulin test (DAT) due to red blood cell (RBC)-bound IgG and C3 and piperacillin antibodies detectable in the patient's serum. The potential influence of CF transmembrane conductance regulator mutations on the severity of DIIHA is discussed. This report illustrates the importance of early identification of DIIHA, a rare complication of a commonly utilized medication in CF.

Increased all-cause and cancer mortality in HTLV-II infection.

BACKGROUND: Human T-lymphotropic virus (HTLV)-I and HTLV-II cause chronic human retroviral infections, but few studies have examined the impact of either virus on survival among otherwise healthy individuals. The authors analyzed all-cause and cancer mortality in a prospective cohort of 155 HTLV-I, 387 HTLV-II, and 799 seronegative subjects. METHODS: Vital status was ascertained using death certificates, the US Social Security Death Index or family report, and causes of death were grouped into 9 categories. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models. RESULTS: After a median follow-up of 15.9 years, there were 105 deaths: 22 HTLV-I, 41 HTLV-II, and 42 HTLV-seronegative. Cancer was the predominant cause of death, resulting in 8 HTLV-I, 17 HTLV-II, and 15 HTLV-seronegative deaths. After adjustment for confounding, HTLV-I status was not significantly associated with increased all-cause mortality, though there was a positive trend (HR: 1.6, 95% CI: 0.8 to 3.1). HTLV-II status was strongly associated with increased all-cause (HR: 2.4, 95% CI: 1.4 to 4.4) and cancer mortality (HR: 3.8, 95% CI: 1.6 to 9.2). CONCLUSIONS: The observed associations of HTLV-II with all-cause and cancer mortality could reflect biological effects of HTLV-II infection, residual confounding by socioeconomic status or other factors, or differential access to health care and cancer screening.