Diagnosis Of Autoimmune Hemolytic Anemia Research Articles

Autoimmune Hemolytic Anemia: A Review

Autoimmune hemolytic anemia (AIHA) is defined as an anemia caused by the destruction of red blood cells by antibodies directed against the patient's own red blood cell surface antigens. Different forms of AIHA are distinguished based on the characteristics of the antibody responsible for the disease. The most common form (70% of cases) is warm antibody autoimmune hemolytic anemia. These antibodies become active at temperatures between 35°C and 40°C. This type of hemolysis occurs mainly within tissues, particularly in the spleen. The diagnosis of AIHA relies on rigorous interpretation of immunohematological parameters, as well as additional tests to exclude associated diseases. In "idiopathic" cases, it is recommended to continue monitoring elderly patients beyond remission to detect the possible occurrence of lymphoma or myelodysplastic syndrome. Corticosteroid therapy is the standard treatment, but it can lead to numerous side effects. The efficacy of rituximab appears particularly promising in "refractory" forms of AIHA, and its use in the early phase of management to spare corticosteroid therapy should be evaluated in a prospective and randomized study.

Refractory autoimmune hemolytic anemia secondary to Babesia

Introduction: Babesia is endemic in the northeast and upper midwestern United States. Two species that cause human infections are Babesia microti and Babesia divergens. The parasite is transmitted by the bite of the tick Ixodes scapularis. Another mode of transmission is blood transfusion producing either an asymptomatic to mild flu-like illness or hemolytic anemia in immunocompromised and asplenic individuals. Hemolysis is usually non-immune and attributed to lysis of infected erythrocytes. Rarely the infection may cause immune dysregulation and lead to the formation of autoantibodies that cause immune mediated hemolytic anemia. Case Report: A previously healthy young adult male with a recent history of multiple blood transfusions, presented with refractory autoimmune hemolytic anemia within two months of transfusion. The anemia was unresponsive to various immunosuppressive medications and blood transfusions. On follow-up, his peripheral smears showed heavy parasitemia consistent with Babesia species. The organism was speciated to Babesia microti by polymerase chain reaction at the Center for Disease Control. The patient was treated with intravenous quinidine and oral clindamycin. Immune hemolytic anemia resolved following the treatment of Babesiosis. Conclusion: In conclusion, Babesiosis should be in the differential diagnosis of autoimmune hemolytic anemia in a patient with a history of blood transfusion and poor response to steroids or immunosuppressive drugs.

Outcomes of therapeutic plasma exchange in severe autoimmune hemolytic anemia hospitalizations: An analysis of the National Inpatient Sample.

Autoimmune hemolytic anemia (AIHA) is characterized by humoral and/or cellular immune-mediated hemolysis of red blood cells. The role of therapeutic plasma exchange (TPE) in AIHA is unclear. We queried the National Inpatient Sample (NIS) for 2002-2019 to identify hospitalizations with the primary diagnosis of AIHA. We included hospitalizations with the highest severity subclass identified by All Patient Refined Disease Related Group (APR-DRG). We used multivariate regression analysis to compare in-hospital mortality and other relevant in-hospital outcomes between hospitalizations that received TPE and those that did not. We identified 255 weighted hospitalizations in the TPE group and 4973 in the control group. Those in the control group were older (median age 67 vs. 48 years, p < .001) and had a higher prevalence of most comorbidities. The TPE group had higher odds of all-cause in-hospital mortality (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.19-2.11). They also had higher rates of many secondary outcomes, including requiring mechanical ventilation, developing circulatory shock, acute stroke, urinary tract infections, intracranial hemorrhage, acute kidney injury, and requiring new hemodialysis. No significant differences were noted in the rates of acute myocardial infarctions, bacterial pneumonia, sepsis/septicemia, thromboembolic events, and other bleeding events. Furthermore, the TPE group had a higher median length of hospital stay (19 vs. 9 days, p < .001). Hospitalizations with severe AIHA that received TPE had higher rates of adverse in-hospital outcomes.

Aspects of laboratory characteristics, analysis of alloimmunization, and searching for predictors related to survival in patients with Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is characterized by hemolysis caused by autoantibodies. However, many patients do not respond to therapies and may have an unfavorable outcome. It has been hypothesized that patients with AIHA and alloantibodies have a lower survival compared to patients with this disease and without alloimmunization. To this end, the clinical and laboratory profile was described and sought to identify features associated with survival in patients with AIHA. This is a single-site retrospective observational study that included patients (children, adolescents, adults and elderly) diagnosed with AIHA from January 2000 to June 2019. Epidemiological data, laboratory tests, treatment response, alloantibody and autoantibody profile, red cell transfusion and clinical course were analyzed. Survival analysis was performed using Kaplan-Meier curves and Cox proportional hazards regression. The study included 138 patients, mostly caucasians and female. The median age at diagnosis was 48.5 years (0.16–88) and 82 (59.4 %) patients had secondary AIHA. In addition, 33 % (25/75) of subjects had alloantibodies at the time of AIHA diagnosis and 40 % (16/40) detected alloantibody emergence later. The overall 10-year survival rate was 51 % (median follow-up was 39 months). Monocytosis, IgM class autoantibody and Direct Antiglobulin Test (DAT) intensity had a significant impact on predicting mortality in this population. On the other hand, alloimmunization at diagnosis and after did not affect survival in this population.

Autoimmune hemolytic anemia complicated with acute kidney injury and tubulopathy due to hemoglobin casts

A 62-year-old male patient was admitted for close monitoring of anemia (hemoglobin level, 8.2 g/dl). Hemolytic anemia was observed; however, the direct antiglobulin test (DAT) result (standard tube method) was negative. Nevertheless, autoimmune hemolytic anemia (AIHA) was still suspected; therefore, a DAT (Colum method) and quantifying levels of red-blood-cell bound immunoglobulin G were performed, resulting in a definite diagnosis of warm AIHA. The patient also had an acute kidney injury (AKI) from the time of admission, which was poorly improved by supplemental fluids therapy alone. Therefore, renal biopsy was performed. Renal biopsy revealed acute tubular injury due to hemoglobin columns, and a diagnosed AKI caused by hemolysis due to AIHA. Following the definitive diagnosis of AIHA, the patient was treated with prednisolone, and after approximately 2 weeks, the anemia and nephropathy completely improved, which is maintained to this day. We report this case as a rare case of AKI induced by hemolysis of AIHA and a successful case of renal salvage by early administration of steroid.

Hyper IgE syndrome with autoimmune hemolytic anemia in Saudi Arabia

Background: Hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by elevated serum immunoglobulin E (IgE) levels. Autosomal dominant and autosomal recessive forms of HIES have been reported. Autosomal recessive HIES typically includes a history of asthma, atopic dermatitis, food allergy, and recurrent viral infection. HIES diagnosis requires genetic study, which is time-consuming and not always feasible. Case Presentation: We report the case of an 8-year-old female. The patient recently presented to our emergency department with pallor and syncope. Upon examination, the hemoglobin level was 4.9 g/dl. Direct antiglobulin test showed a positive result. The patient had an admitting diagnosis of autoimmune hemolytic anemia, a rare complication of autosomal recessive HIES. The patient is a known case of asthma, herpetiformis dermatitis, nut allergy, and allergic rhinitis. HIES was the first possible diagnosis, which was further confirmed by clinical presentation and a high serum IgE count. The patient was referred to a tertiary care center for genetic counseling and further follow-up. Conclusion: HIES is a rare immune deficiency disorder that can be inherited in either an autosomal dominant or recessive pattern. Although these two types show similar clinical presentations, certain features remain distinct, providing a valuable insight into the final diagnosis even without the gene study results. To the best of our knowledge, no study has evaluated HIES in general, and no case report has evaluated autosomal recessive HIES in Saudi Arabia. This case study will guide the medical community in the early-stage diagnosis and management of HIES.

Autoimmune Hemolytic Anemia and Increased Stroke Risk in the United States: A Population-Based Study

Introduction Autoimmune hemolytic anemia (AIHA) is a clinically heterogeneous collection of disorders characterized by the presence of autoantibodies against the patient's erythrocytes. AHIA has been associated with an increased risk of thromboembolic events, including stroke. A recent nationwide cohort study from Denmark and France showed an increased risk of ischemic stroke compared to the general population. However, no extensive studies have been done in the United States (US); hence, we conducted a study of stroke and AIHA in the US population. Methods This is a retrospective study from 1999 to 2022. We analyzed data from a nationwide commercial database (Explorys, IBM) that aggregates records from 26 healthcare systems spread over 50 states with almost 80 million patients. It is a cloud-based platform in which participating institutions provide de-identified data from electronic health records. Pooled data is then standardized and normalized. Explorys uses Systemized Nomenclature of Medicine - Clinical Terms (SNOMED CT) coding for medical diagnosis. We identified adult patients (over 18 years old) with the diagnosis of AIHA. Patients with stroke were identified with the following SNOMED-CT diagnosis "cerebrovascular accidents''. In addition, we obtained information on risk factors for stroke, including sex, age over 65 years, and comorbidities known to be a risk factor, including hypertension, atrial fibrillation, diabetes mellitus, hyperlipidemia, smoking, and obesity.Multivariable logistic regression adjusting for all covariates was created to test for stroke. Results were presented as odds ratio (OR) with a corresponding 95% confidence interval (CI). All tests were two-sided, and a p-value ≤ 0.01 was considered statistically significant. Results An adult population of 69,339,860 were included. AHIA was diagnosed in 12,800 patients (less than 1 per 100,000) and stroke was diagnosed in 238,860 (0.34%). AIHA population characteristics were; females 7,720 (60%), age over 65 years 7,510 (59%), stroke 260 (2%), hypertension 8,260 (65%), hyperlipidemia 6,580 (51%), diabetes mellitus 4,030 (31%), obesity 3,080 (24%), atrial fibrillation 2,650 (21%), and smoking 1,080 (14%). Baseline characteristics are shown in table 1. Statically significant OR of covariates tested is as follows; hypertension OR 9.35 (95% CI 9.22-9.49), AHIA OR 2.75 (95% CI 2.49 - 3.01), atrial fibrillation OR 2.59 (95% CI 2.57 - 2.62), diabetes mellitus 2.44 (95% CI 2.42, 2.47), hyperlipidemia OR 1.96 (95% CI 1.94, 1.98), smoking OR 1.5 (95% CI 1.94, 1.98), age over 65 years OR 1.19 (95% CI 1.18, 1.20), and male OR 0.85 (95% CI 0.84, 0.85). Multivariable logistic regression of factors associated with stroke is shown in table 2. Discussion and conclusion This is the largest population-based study analyzing the association between AIHA and stroke, and we included the most relevant confounding risk factors in our analysis. As expected, the strongest risk factor associated with stroke was hypertension. What was surprising was that AIHA followed it as the second strongest risk factor, which exceeded atrial fibrillation as a risk factor. Limitations of the retrospective design of the study are numerous. They include lack of patient-level data, the subtype of stroke, the subtype of AIHA, the severity of AIHA, temporality, medications used, and their implications on stroke risk, and inaccuracies in coding. A potential explanation for increased thrombosis includes depletion of nitric oxide as a consequence of intravascular hemolysis with resultant enhanced platelet adhesions, and another possible mechanism is the release of procoagulant microparticles during hemolysis. While there is an ongoing trial looking into long-term apixaban in the primary prevention of venous thromboembolism in AIHA (NCT05089227), no active study is looking into minimizing stroke risk. Prospective studies to affirm association, risk stratifies patients, and ultimately test the utility of prophylactic anticoagulation are most needed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Autoimmune Hemolytic Anemia during Pregnancy or Post-Partum: An International Multi-Center Experience

Autoimmune hemolytic anemia (AIHA) developing or relapsing during pregnancy or postpartum is a rare finding, and few is known about maternal and fetal outcomes. Furthermore, AIHA management during pregnancy and lactation is not standardized and drug use is often limited by safety concerns. Here, we report the results of a multi-center retrospective cohort study evaluating AIHA impact on pregnancy focusing on disease severity, treatment need and maternal and fetal outcome. Forty-one pregnancies occurring in 31 women were registered from 1997 to 2022 at 11 European centers in Italy, Denmark, France, the Netherlands, USA, and Spain. AIHA was classified according to the direct antiglobulin test as warm, cold, mixed or atypical. Outcomes were compared with a control group of 56 healthy women matched for age at pregnancy and decade of pregnancy. Overall, we observed 21 warm AIHA (13 IgG; 8 IgG+C3d), 2 cold agglutinin diseases, 3 mixed and 5 atypical forms (Table 1). Evans syndrome (i.e., association of AIHA and immune thrombocytopenia or neutropenia) was present in 5 women. Mean age at AIHA diagnosis was 27 (3-39) years and at pregnancy 32 (21-41) years. AIHA diagnosis predated pregnancy in 16 women and had required at least 1 therapy line in all of them, and ≥2 lines in 13 (rituximab, N=8; cytotoxic immunosuppressants, N=6; splenectomy, N=5). Among these 16 patients, 7 had a relapse during pregnancy, 3 during postpartum and 9 were on active treatment at the time of pregnancy (steroids, N=7; cyclosporine, N=1; steroids plus azathioprine, N=1; the latter stopped after positive pregnancy test). A patient with a previous AIHA, relapsed as immune thrombocytopenia during pregnancy. Further 9 patients developed AIHA during gestation and 2 in the postpartum. A patient had AIHA onset during the postpartum of the 1st pregnancy and relapsed during the 2nd one. In total, we observed 22 hemolytic events in 21 women during pregnancy/postpartum. Median Hb and LDH levels were 6.4 g/dL (3.1 - 8.7) and 599 IU/L (269-1631), respectively. Management consisted in blood transfusions (N=11, 50%) and prompt establishment of steroid therapy +/- intravenous immunoglobulins (N=22, 100%), all with response (complete N=15, partial N=7). After delivery, rituximab was necessary in 4 patients and cyclosporine was added in one. Anti-thrombotic prophylaxis was given in 7 patients. Overall, we registered 10 maternal complications (10/41, 24%), including 4 early miscarriages, a premature rupture of membranes, a placental detachment, 2 preeclampsia, a postpartum infection and a biliary colic. Notably, 8/10 complications occurred during active hemolysis and treatment for AIHA. Ten fetal adverse events (10/41, 24%) were reported: a transitory respiratory distress of the newborn in a mother with active AIHA; 4 cases of fetal growth restriction; a preterm birth; an infant reporting neurologic sequelae; a case of AIHA of the new-born requiring intravenous immunoglobulins, blood transfusions and plasma exchange; and 2 perinatal deaths. The latter two occurred in women on active AIHA therapy and were secondary to a massive placental detachment and a symptomatic SARS-CoV-2 infection. Finally, the comparison between AIHA women and the control group showed a similar prevalence of maternal complications (24% in AIHA versus 18% in controls). At variance, AIHA was marked by a significant increase of fetal adverse events versus control group (24% versus 5%, p=0.008), with more severe complications in the former. In conclusion, AIHA developing/reactivating during pregnancy or postpartum is rare but mainly severe, requiring red cell transfusions in half of cases and steroid therapy in all patients. Notably, severe maternal and fetal complications may occur in up to a quarter of cases mostly associated with active hemolysis. Finally, AIHA was significantly associated with severe fetal complications compared with healthy population, further pinpointing the importance of maintaining a high level of awareness. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune Hemolytic Anemia

The diagnosis of autoimmune haemolytic anaemia (AIHA) is a challenge for both the immune-haematology laboratory and the clinician as the laboratory investigation can be troublesome and often requires extensive time-consuming serological testing, especially when a blood transfusion is needed. Frequently, there is a need to start therapy rapidly. Autoantibodies directed to epitopes on red blood cell (RBC) consisting in sugar and/or protein structures are crucial in the pathogenesis of AIHA. The isotype is important for the clinical significance of an autoantibody. Frequently, patients are icteric and suffer from clinical signs of anaemia, such as pallor, fatigue, shortness of breath and palpitations, on examination hepatosplenomegaly can be present. If there is no vital indication for a transfusion it is prudent to wait for the results of the immune-haematological tests and the ensuing transfusion advice based on this. Focus of treatment should be stoppage of hemolysis or at least be attenuated via an inhibition of autoantibody production and/or inhibition of premature RBC destruction. Successful treatment of secondary AIHA is only possible when the underlying disease is treated.

A Study of Clinical and Serological Correlation of Positive Direct Antiglobulin Test in Blood Bank at a Tertiary Care Center.

Objectives Detection of red cell bound immunoglobulins and/or complement by direct antiglobulin test (DAT) is a crucial serological assay in the diagnosis of autoimmune hemolytic anemia (AIHA). However, DAT may be positive in a variety of clinical conditions with or without hemolysis. We aimed at evaluating the clinical and serological correlation of positive DAT by categorizing the clinical conditions associated with positive DAT, estimating the presence of in vivo hemolysis in case of positive DAT with polyspecific and monospecific antisera and correlating the strength of positive DAT with the presence of hemolysis. Materials and Methods The prospective observational study was performed on 200 samples that were positive for DAT with polyspecific antiglobulin reagent as the baseline investigation. These samples were further tested with anti-immunoglobulin G and anti-C3 monospecific DAT reagents to evaluate the type of protein responsible for positive DAT. The antiglobulin tests were performed by tube technique. DAT positivity was graded (1+ to 4 + ) in each patient. Autocontrol test was included. The patients with positive polyspecific DAT were categorized into different clinical conditions. The presence or absence of in vivo hemolysis was evaluated in all clinical categories and also for each grade of positivity with polyspecific and monospecific antiglobulin reagents. Statistical Analysis Binomial logistic regression and Mann–Whitney U test were applied to between the group analyses. For categorical variables, Fisher's exact test and relative risk were used. The qualitative data were expressed in numbers and percentages. Results The highest number of patients (75/200, 37.5%) belonged to the autoimmune diseases group. Tuberculosis and hepatitis C were the main infectious diseases associated with positive DAT. Out of 200 DAT-positive patients, 98 (49%) had in vivo hemolysis and 102 (51%) did not have hemolysis. AIHA (22) and systemic lupus erythematosus (18) were the commonest clinical conditions associated with in vivo hemolysis. All the 11 samples that showed positivity with only anti-C3 reagent did not show any hemolysis. There was statistically significant increase in the incidence of in vivo hemolysis with increasing grades of DAT positivity with all the three antihuman globulin reagents. Conclusion There are different disease conditions which show positive DAT with or without hemolysis. So, it is important to clinically and serologically correlate positive DAT results.

Transfusion challenges and use of best match blood transfusion in autoimmune hemolytic anemia patients: Experience from a Tertiary Care Hospital of South India

Background and Objectives: In autoimmune hemolytic anemia (AIHA) patients, there is decreased survival of red blood cells (RBCs) because of increased destruction by patients' autoantibodies. Due to decreased survival of RBCs, there is an increase in erythropoiesis and other biochemical parameters of hemolysis. One of the vital tests in AIHA is direct Coombs test (DCT). In this study, we share our experience on the difficulties faced by us during the compatibility testing and providing transfusion support to these patients. Methods: This is a retrospective study done in the department of transfusion medicine in a tertiary care hospital of South India. Patients from January 2020 to March 2021 with the diagnosis of AIHA requiring transfusion were included in this study. A total of 136 patients with positive DCT with AIHA diagnosis requiring transfusion support were included in our study. Results: Out of 136 cases, 58% (n=79) of patients had incompatibility during cross matching while in 42% (n=57) had cross matched compatible unit. In all incompatible cases best match blood was transfused. Most transfusions were done for patients with DCT Grade 4+. Out of 45 patients with mixed AIHA, 40 (88.8%) patients required a transfusion (P < 0.05). Of that 104 patients with transfusion support, 66 (63%) were with primary AIHA and 38 (36.04%) with secondary AIHA. Conclusion: It is tough and challenging to get compatible units in AIHA patients. Best-matched blood is useful when transfusion becomes essential during life-threatening anemia.

COVID-19 and Immune-Mediated RBC Destruction.

ObjectivesTo summarize the epidemiologic, clinical, and laboratory characteristics of autoimmune hemolytic anemia (AIHA) secondary to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or vaccination.MethodsWe conducted a systematic review using standardized keyword search to identify all reports of SARS-CoV-2 infection or vaccination and AIHA across PubMed, Web of Science, Scopus, and Google Scholar through September 24, 2021.ResultsFifty patients (mean [SD] age, 50.8 [21.6] years) diagnosed with coronavirus disease 2019 (COVID-19) and AIHA were identified. AIHA subtypes and number of patients were as follows: cold AIHA (n = 18), warm AIHA (n = 14), mixed-type AIHA (n = 3), direct antiglobulin test (DAT)–negative AIHA (n = 1), DAT-negative Evans syndrome (n = 1), Evans syndrome (n = 3), and subtype not reported (n = 10). Mean (SD) hemoglobin at AIHA diagnosis was 6.5 [2.8] g/dL (95% confidence interval, 5.7-7.3 g/dL). Median time from COVID-19 symptom onset to AIHA diagnosis was 7 days. In total, 19% (8/42) of patients with COVID-19–associated AIHA with reported outcomes were deceased. Four patients (mean [SD] age, 73.5 [16.9] years) developed AIHA following SARS-CoV-2 vaccination: Pfizer-BioNTech BNT162b2 vaccine (n = 2); Moderna mRNA-1273 vaccine (n = 1); undisclosed mRNA vaccine (n = 1). AIHA occurred after 1 dose in 3 patients (median, 5 days).ConclusionsSARS-CoV-2 infection and vaccination are associated with multiple AIHA subtypes, beginning approximately 7 days after infectious symptoms and 5 days after vaccination.

Graves Disease (Thyroid Storm) with Polyautoimmune Disorders (Autoimmune Hemolytic Anemia and Probable Autoimmune Hepatitis)

Graves' disease is caused by IgG antibodies that bind to the Thyroid Stimulating Hormone (TSH) receptor on the surfaceof the thyroid gland. These bonds drive the growth of stimulated thyroid follicular cells causing the glands to enlarge andincrease the production of thyroid hormones. Previous studies mention the association of HLA-B8 and HLA-DR3 withGraves' disease and the Cytotoxic T-lymphocyte-associated-4 (CTLA-4) gene on chromosome 2q33 as a result of reducingT-cell regulation, resulting in autoimmune disease. Autoimmune thyroid disease is often found together with otherautoimmune disorders (polyautoimmune). A 51-year-old male complained of dyspnea, yellowing of the body, and a lumpon the neck. One year ago, he was diagnosed with hyperthyroidism. Graves' disease was suspected due to a score of 22 forthe Wayne index, FT4 96.9 pmol/L, TSHs &lt;0.01 μIU/mL, TRAb 10.8 IU/L, thyroid uptake test for toxic diffuse struma. Inaddition, the patient had atrial fibrillation and a thyroid storm with a Bruch Wartofsky index score of 65. Laboratoryexamination found normocytic normochromic anemia, thrombocytopenia, reticulocytosis, direct coomb test and autocontrol results positive one, SGOT 87 U/L, SGPT 59 U/L, alkali phosphatase 166 U/L, total bilirubin 38.13 mg/dL, directbilirubin 16.59 mg/dL, indirect bilirubin 21.54, LDH 318 U/L, establishing the diagnosis of Autoimmune Hemolytic Anemia(AIHA). Autoimmune hepatitis score: 15, so a diagnosis of probable autoimmune hepatitis was made.

Increased Risk of Ischemic Stroke Amongst Patients with Primary Autoimmune Hemolytic Anemia in Denmark and France

▪IntroductionAn increased risk of thromboses has been described in patients with autoimmune hemolytic anemia (AIHA), including stroke. Previous studies focused on a broad variety of autoimmune disorders and only adjusted to a limited extent for potential confounders. Further, these studies could not robustly address the relationship of stroke risk with time since AIHA diagnosis. To overcome these shortcomings, we conducted a study of the risk of ischemic stroke amongst patients with primary AIHA in two nationwide cohorts in Denmark and France.MethodWe identified all patients 15+ years of age diagnosed with primary AIHA in the Danish National Patient Register (1996-2016) and the French health insurance database, Système National des Données de Santé (2012 - 2017). At AIHA diagnosis, patients were age- and sex-matched to comparison cohorts from the general populations in Denmark (1:50) and France (1:5), respectively. Each patient's date of diagnosis was allotted to their corresponding comparisons and marked the start of a 5-year follow-up of the cohorts. We linked data on the cohorts to information from national registers concerning (co)morbidity, vital status and outcomes. Based on this data, we identified comorbidities at baseline (including preexisting cardiovascular and cerebrovascular events (CVD) at diagnosis) and ischemic stroke events during follow-up.We evaluated the absolute risk of ischemic stroke using cumulative incidences, treating death and migration as competing events. Further, the relative risk of ischemic stroke was evaluated using unadjusted cause-specific proportional hazard regression (csHR) and Fine-Gray subdistribution HR (subHR), and subsequently adjusting for CVD event history, atrial fibrillation, diabetes, hypertension, dyslipidemia, history of venous thromboembolism, cancer, and time-varying exposure to antiplatelet, anticoagulant, lipid lowering, and antihypertensive drugs. HRs were estimated both overall for all five years and for the first year after diagnosis for the two countries separately. Hazard ratios for the data from both countries combined were also computed using meta-analysis techniques.ResultsWe included 1,171 (Denmark) and 4,823 (France) patients with primary AIHA and 57,773 (Denmark) and 23,752 (France) comparisons from the general population. During follow-up, 35.1% (Denmark) and 38.3% (France) of patients with AIHA died.Age, gender, and comorbidity distribution as well as mortality was similar in the two countries. Similar differences in the prevalence of previous CVD events were observed between AIHA patients (higher prevalence of CVD) and comparison cohorts in both countries.We identified 29 (Denmark) and 92 (France) ischemic stroke events amongst patients with AIHA, of whom 12 (Denmark) and 57 (France) occurred during the first year after AIHA diagnosis.The cumulative stroke incidences are depicted in the Figure (Panel A: French cohort. Panel B: Danish cohort).Overall, the combined adjusted csHR was 1.3 [1.1; 1.6], and the subHR was 1.0 [0.9; 1.2].Within the first year from diagnosis, the combined adjusted csHR was 2.3 [1.8; 2.9], and the subHR was 1.7 [1.3; 2.2].Discussion and conclusionIn a combined Danish-French cohort of 5.994 patients with primary AIHA and 81.525 comparisons, we confirm that the risk of ischemic stroke amongst patients with primary AIHA is increased.The risk is highest within the first year after diagnosis with a csHR of 2.3 and a subHR of 1.7. This indicates that although the risk of ischemic stroke is high among patients with primary AIHA compared to the general population, the effect on the cumulative incidence of ischemic stroke is diminished by competing events - especially death.Granular data on treatment was not generally available and our data does not allow us to infer whether the increased risk of ischemic stroke in AIHA derives from the hemolytic process, the treatment or other factors. However, as the risk was highest within the first year and as prior thromboembolic and vascular events were more prevalent amongst patients this could support the hypothesis that free hemoglobin leads to endothelial dysfunction and a procoagulant state that also increases the risk of stroke. [Display omitted] DisclosuresHansen: Novartis: Research Funding; Alexion: Research Funding. Berentsen: True North Therapeutics: Consultancy; Sanofi: Consultancy, Honoraria; Janssen-Cilag: Honoraria; Bioverativ: Consultancy, Honoraria; Mundipharma: Research Funding; Apellis Pharmaceuticals: Consultancy, Honoraria; Alexion Pharmaceuticals, Inc: Honoraria. Frederiksen: Novartis: Research Funding; Alexion: Research Funding; Gilead: Research Funding; Abbvie: Research Funding; Janssen Pharmaceuticals: Research Funding. Moulis: Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Argenix: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sobi: Membership on an entity's Board of Directors or advisory committees.

Epidemiology of Hospitalizations Due to Autoimmune Hemolytic Anemia in the United States

Introduction:Autoimmune hemolytic anemia (AIHA) is an acquired immune disorder resulting in the production of cold and warm autoantibodies directed against red blood cell antigens; characterized by shortened red blood cell survival and a positive Coombs test. Types include primary disease (idiopathic) or secondary to other autoimmune disorders, malignancies, or infections. Treatment involves immunosuppression with corticosteroids and other agents, Transfusion. There is not much recent data available on epidemiology of AIHA. We aim to estimate epidemiological trends and outcomes of AIHA as well as factors associated with poor outcomes by using the largest available national database from the United States.Methods:We derived a study cohort from the National Inpatient Sample (NIS) for the years 2007-2018 for hospitalizations due to AIHA by using International Classification of Diseases (9th/10th Editions) Clinical Modification diagnosis codes ICD-9-CM/ICD-10-CM). Other diagnosis and comorbidities were also identified by ICD-9/10-CM codes and Elixhauser comorbidity software. Our primary outcome was discharge disposition following AIHA hospitalization. We utilized multivariable survey logistic regression models to analyze and identify predictors of poor outcomes.Results:Between 2007-2018, a total of 52,814 hospitalizations occurred due to primary diagnosis of AIHA. Burden of hospitalizations remained stable from 4,254 (8.1%) in 2007 to 4,405 (8.3%) in 2018. AIHA patients in the study cohort were mostly above 65 years of age (48.6%) followed by 35-65 years of age (33.7%), females (58.3%) and Caucasians (69.1%). Overall in-hospital mortality of AIHA hospitalizations was 3.1%, and discharge to facility was 11.86%. Median length of stay for AIHA hospitalization was 4-days (interquartile range: 2-days to 6-days). Furthermore, in multivariable logistic regression analysis, increasing age (OR 1.2; 95%CI 1.1-1.3; p<0.001), male gender (OR 1.5; 95%CI 1.2-1.3; p:0.0024), vascular events (OR 1.5 ; 95%CI 1.1-2.0; p:0.0156), teaching hospitals (OR 3.1; 95%CI 1.5-6.5; p:0.002), plasmapheresis (OR 5.5; 95%CI 2.8-10.8; p:0.001) and intravenous immunoglobulins (OR 1.9; 95%CI 1.3-3.0; p:0.001) were associated with higher in-hospital mortality.Conclusion:Our study describes the epidemiology of hospitalizations due to AIHA in the United States from a nationally representative database. We observed that hospitalization burden due to AIHA have remained stable from 2007 to 2018. We also identified factors associated with higher in-hospital mortality and some of which are modifiable. Further studies are required to establish the causal association of these factors to poor outcomes and develop better risk stratification strategies to improve overall outcomes of AIHA. DisclosuresNo relevant conflicts of interest to declare.

Comparison of Polybrene DAT and Conventional DAT in Cases of Suspected DAT Negative Autoimmune Hemolytic Anemia (AIHA)

Abstract Introduction/Objective A negative Direct Antiglobulin Test (DAT) is seen in approximately 1-5% of patients presenting with signs and symptoms of immune hemolysis. A well-performed ‘standard’ DAT detects ~100-500 molecules of bound IgG per red cell. A more sensitive polybrene DAT may be helpful in order to confirm a diagnosis of AIHA in patients whose samples have tested negative via standard DAT. However, there has been little reported on utility of the polybrene DAT in evaluating such cases with modern DAT reagents. We hypothesized that the polybrene DAT would not contribute substantially to the analysis of Coombs-negative hemolytic anemia (C-NHA), based primarily on our anecdotal observation. As such, we undertook a study to assess results of polybrene DAT in cases evaluated for possible (C-NHA). Methods/Case Report Two study sites were used for data analysis (Yale-New Haven Hospital, Site A, and VA Connecticut, Site B) over a five year period (2016-2021). During this time, standard DATs were performed at both study sites by the tube method using polyspecific antiglobulin and, if positive, reflex to anti-IgG and -C3. For cases of suspected C-NHA (which are reported to Blood Bank via a consult mechanism), conventioned DAT- samples are referred to our regional immunohematology laboratory (American Red Cross, Farmington, CT) for manual hexadimethrine bromide (Polybrene) DAT. Polybrene DAT is reported as negative with two sources of polyspecific AHG. Subsets of patients also underwent acid elution studies (Gamma ELU-KITII) as part of a C-NHA algorithm developed during the study period. Results of standard DAT, acId elution, and polybrene DAT were extracted from Blood Bank electronic records at both study sites. Results (if a Case Study enter NA) Evaluation for C-NHA was performed in 32 patients/cases over the study period. Amongst these individuals, 96.8% (31/32) underwent polybrene DAT assessment and none (0%; 0/31) demonstrated a positive polybrene DAT result. Notably, acid elution studies were performed in 90.6% (29/32) of traditional DAT negative cases. Of these, 10.3% (3/29) had reactive eluates. Conclusion Performance of the polybrene DAT appeared to be of no value in the assessment of suspected C-NHA. Given that nearly 10% of individuals with a negative conventional DAT had a positive acid elution, this testing step appears to be of greater value in potentially identifying an autoantibody in suspected cases of C-NHA.

Autoimmune Hemolytic Anemia as a Complication of Congenital Anemias. A Case Series and Review of the Literature.

Congenital anemias may be complicated by immune-mediated hemolytic crisis. Alloantibodies are usually seen in chronically transfused patients, and autoantibodies have also been described, although they are rarely associated with overt autoimmune hemolytic anemia (AIHA), a serious and potentially life-threatening complication. Given the lack of data on the AIHA diagnosis and management in congenital anemias, we retrospectively evaluated all clinically relevant AIHA cases occurring at a referral center for AIHA, hemoglobinopathies, and chronic hemolytic anemias, focusing on clinical management and outcome. In our cohort, AIHA had a prevalence of 1% (14/1410 patients). The majority were warm AIHA. Possible triggers were recent transfusion, infection, pregnancy, and surgery. All the patients received steroid therapy as the first line, and about 25% required further treatment, including rituximab, azathioprine, intravenous immunoglobulins, and cyclophosphamide. Transfusion support was required in 57% of the patients with non-transfusion-dependent anemia, and recombinant human erythropoietin was safely administered in one third of the patients. AIHA in congenital anemias may be challenging both from a diagnostic and a therapeutic point of view. A proper evaluation of hemolytic markers, bone marrow compensation, and assessment of the direct antiglobulin test is mandatory.

Autoimmune Hemolytic Anemia in the Pediatric Setting.

Autoimmune hemolytic anemia (AIHA) is a rare disease in children, presenting with variable severity. Most commonly, warm-reactive IgG antibodies bind erythrocytes at 37 °C and induce opsonization and phagocytosis mainly by the splenic macrophages, causing warm AIHA (w-AIHA). Post-infectious cold-reactive antibodies can also lead to hemolysis following the patient’s exposure to cold temperatures, causing cold agglutinin syndrome (CAS) due to IgM autoantibodies, or paroxysmal cold hemoglobinuria (PCH) due to atypical IgG autoantibodies which bind their target RBC antigen and fix complement at 4 °C. Cold-reactive antibodies mainly induce intravascular hemolysis after complement activation. Direct antiglobulin test (DAT) is the gold standard for AIHA diagnosis; however, DAT negative results are seen in up to 11% of warm AIHA, highlighting the need to pursue further evaluation in cases with a phenotype compatible with immune-mediated hemolytic anemia despite negative DAT. Prompt supportive care, initiation of treatment with steroids for w-AIHA, and transfusion if necessary for symptomatic or fast-evolving anemia is crucial for a positive outcome. w-AIHA in children is often secondary to underlying immune dysregulation syndromes and thus, screening for such disorders is recommended at presentation, before initiating treatment with immunosuppressants, to determine prognosis and optimize long-term management potentially with novel targeted medications.

Perfil clínico-epidemiológico dos pacientes pediátricos portadores de anemia hemolítica autoimune em um serviço de referência

OBJECTIVES: The autoimmune hemolytic anemia (AIHA) is a group of diseases characterized by the presence of autoantibodies that bind to erythrocytes reducing the half-life of these cells. It is a rare condition that occurs in about 1-3 cases per 100,000 children per year, more common in males in ratio of 2:1 cases. This study aimed to obtain the clinical and epidemiological profile of pediatric patients diagnosed with autoimmune hemolytic anemia (AIHA), treated at the reference outpatient clinic. METHODS: Participated in the study through analysis of medical records and completion of the research protocol 24 children with AIHA attended at the reference outpatient clinic between 2009 and 2019, age from 0 to 18 years. Clinical, laboratory and outcome data were obtained from patients records. RESULTS: The results showed that most of the children are female (58%), receive early diagnosis until 2 years of age (58%). The direct antiglobulin test was positive in over 95% of cases. The patients presented cutaneous-mucous pallor (50%) as the initial symptom. However, the limitations inherent in the study, which had a small sample due to the rarity of the disease, should be evaluated. CONCLUSION: The diagnosis of AIHA must be made early, based on a detailed clinical history, suspected by the pediatrician through the characteristic signs of hemolysis and initiated treatment with corticotherapy, which shows high rates of remission and cure of the pathology.

Incidence of False-Positive Direct Anti Globulin Tests (DAT): A Single-Center Retrospective Analysis.

Background The direct antiglobulin test (DAT) is frequently ordered by both hematologists and non-hematology medical professionals in the workup of possible allo- or autoimmune hemolytic anemias. Frustratingly, positive DAT results in the absence of other abnormal blood hemolysis biomarkers can be challenging to interpret, as published data on the frequency of these "false-positive" DATs is limited. We sought to characterize the frequency of "false-positive" DATs and describe potential associations with co-morbid diseases, in order to better define the diagnostic accuracy of the DAT for allo- or autoimmune hemolysis. Methods After obtaining appropriate Institutional Review Board approval, we identified all positive DAT results from Oregon Health &amp; Science University during the calendar year between January and December 2019. Electronic medical records of the patients associated with these positive DAT results were individually reviewed, with collected data including patient demographics, specific pattern of DAT positivity (IgG, C3 or both), reason for obtaining DAT (suspicion for autoimmune hemolysis or transfusion, or as part of preparatory workup for possible blood product transfusion), hemolysis biomarkers (CBC, reticulocytes, LDH, haptoglobin, total and direct bilirubin), recent blood product transfusion or IVIG administration within the preceding 6 months, and co-morbid illnesses. True positive DAT results were considered those concurrent with at least one other positive blood hemolysis biomarker, or those in patients with a pre-existing diagnosis of autoimmune hemolytic anemia or Evans syndrome. Results 182 positive DAT tests among 134 individual patients were identified within the specified time period. 65 of these were obtained in the ambulatory setting, and 117 as inpatient. The majority of DAT results were positive for IgG only (165 of 182, 90.7%), with 17 of 182 (9.3%) positive for both IgG and C3, and no instances of isolated C3 positivity. The median values for hemolysis biomarkers were as follows: LDH 307, total bilirubin 0.9, and haptoglobin 80. Of the 134 patients with positive DAT results, 48 (36%) had at least one other positive or elevated blood biomarker of hemolysis, and 31 (23%) had two or more positive biomarkers. 55 records (41%) had no other associated findings of hemolysis, and 31 patients had not had hemolysis biomarkers drawn. 53 of 134 patients (40%) had DATs checked as part of alloantibody workup prior to potential blood product transfusion. The calculated rate of DAT positivity concurrent with other positive hemolysis biomarkers was 79 of 134 (59%), and DATs without other signs of hemolysis were seen in 55 of 134 (41%). Among patients with DAT results without signs of hemolysis, common co-morbid illnesses/conditions included recent blood product transfusion, multiple myeloma, acute myeloid leukemia, chronic lymphocytic leukemia, myelodysplastic syndrome, hypothyroidism, and cirrhosis. The majority of patients had received blood product transfusion or IVIG within the preceding 6 months (94 out of 134 [70%]). Discussion In this single-center retrospective analysis, we found a substantial rate of DAT positivity for IgG, or combined IgG and C3, without other laboratory biomarkers of hemolysis. While many of these non-hemolysis-related positive DAT results could be considered false positives, a substantial proportion of patients had also received blood product transfusion or IVIG within the previous 6 months, and thus a large fraction of included patients may have had positive DATs related to previous alloimmunization and lingering "bystander" hemolysis or agglutination of autologous red blood cells. In addition, co-morbid hepatic, autoimmune or hematologic diseases were common among this cohort, corroborating findings in previously published analyses. In summary, we found a clinically meaningful rate of false-positive DAT results in both ambulatory and inpatient settings. We posit that a positive DAT result, in isolation, need not drive extensive hemolysis workup, given the frequent association with prior blood product transfusions and numerous co-morbid illnesses. Disclosures No relevant conflicts of interest to declare.