Diagnostic algorithm for classification and characterization of direct antiglobulin test-negative autoimmune hemolytic anemia with 1-year clinical follow-up.
Transfusion
BACKGROUND:Approximately 5%-10% of autoimmune hemolytic anemia (AIHA) cases are negative for direct antiglobulin test (DAT). We previously reported a classification system for untreated patients with DAT-negative AIHA by quantifying levels of red blood cell (RBC)-bound IgG. This study investigated the clinical utility of a novel diagnostic algorithm with a comprehensive classification system and characterized each subgroup in DAT-negative AIHA. STUDY DESIGN AND METHODS:We assessed 637 patients with undiagnosed hemolytic anemia using our diagnostic algorithm and classification system, which was based on RBC-bound IgG levels and results of column method-DAT before and after washing RBCs. RESULTS:Patients were diagnosed with DAT-negative AIHA with 97% sensitivity and 84% specificity when the laboratory tests were performed before treatment and classified into the following six categories: tube DAT-negative, low-affinity IgG, double DAT-negative, IgA- or IgM-positive, low-affinity IgM, and s/o non-AIHA. The first three types were major conditions and accounted for 76% of DAT-negative AIHA cases. Based on multivariate analyses of idiopathic DAT-negative AIHA (n = 71), platelet count and albumin concentration were significant factors for survival at 1-year follow-up. The low-affinity IgG group showed the highest platelet count and albumin levels, better response to steroids, and higher 1-year survival rate than those in other groups. DISCUSSION:Our classification included DAT-negative, IgA-driven, and warm-IgM AIHA categories, which were atypical forms of AIHA with the severe onset and increased risk of relapse. When treating a patient with DAT-negative hemolysis, atypical AIHA should be considered and tested in reference laboratories, especially before treatment.
10.1111/trf.16709
[Diagnosis and classification of direct antiglobulin test-negative autoimmune hemolytic anemia].
Kamesaki Toyomi
[Rinsho ketsueki] The Japanese journal of clinical hematology
About 5-10% of patients with autoimmune hemolytic anemia (AIHA) and a negative result on the direct antiglobulin test (DAT) are difficult to diagnose. Most of these patients with AIHA have red blood cell-associated IgG levels below the cut-off value of DAT. Comprehensive diagnosis and classification of DAT-negative AIHA can be made with additional tests of low-affinity IgG and IgA/IgM autoantibodies. However, 17% of patients with DAT-negative AIHA show negative results on all these tests and are diagnosed with "clinically diagnosed DAT-negative AIHA," after excluding other hemolytic anemias and responsiveness to steroids. This percentage can be reduced to 4% if tests are conducted during pretreatment stage. Patients with "clinically diagnosed DAT-negative AIHA" show relatively worse prognosis than patients with low-affinity IgG, and tend to receive treatment in the later stages of the disease. When treating a patient with DAT-negative hemolysis, DAT-negative AIHA should be considered and tested in reference laboratories, especially at pretreatment stage.
10.11406/rinketsu.62.456
Difficult Cases of Autoimmune Hemolytic Anemia: A Challenge for the Internal Medicine Specialist.
Fattizzo Bruno,Giannotta Juri Alessandro,Serpenti Fabio,Barcellini Wilma
Journal of clinical medicine
Autoimmune hemolytic anemia (AIHA) is diagnosed in the presence of anemia, hemolysis, and direct antiglobulin test (DAT) positivity with monospecific antisera. Many confounders of anemia and hemolytic markers should be included in the initial workup (i.e., nutrients deficiencies, chronic liver or kidney diseases, infections, and cancers). Besides classical presentation, there are difficult cases that may challenge the treating physician. These include DAT negative AIHA, diagnosed after the exclusion of other causes of hemolysis, and supported by the response to steroids, and secondary cases (infections, drugs, lymphoproliferative disorders, immunodeficiencies, etc.) that should be suspected and investigated through careful anamnesis physical examination, and specific tests in selected cases. The latter include autoantibody screening in patients with signs/symptoms of systemic autoimmune diseases, immunoglobulins (Ig) levels in case of frequent infections or suspected immunodeficiency, and ultrasound/ computed tomography (CT) studies and bone marrow evaluation to exclude hematologic diseases. AIHA occurring in pregnancy is a specific situation, usually manageable with steroids and intravenous (iv) Ig, although refractory cases have been described. Finally, AIHA may complicate specific clinical settings, including intensive care unit (ICU) admission, reticulocytopenia, treatment with novel anti-cancer drugs, and transplant. These cases are often severe, more frequently DAT negative, and require multiple treatments in a short time.
10.3390/jcm9123858
Cold Agglutinin Disease.
Gabbard Amy P,Booth Garrett S
Clinical hematology international
Cold agglutinin disease (CAD) is an uncommon form of cold autoimmune hemolytic anemia (AIHA). It should be considered in the differential diagnosis of elderly patients with unexplained chronic anemia presenting with or without cold-induced symptoms in the extremities, such as the fingers, ears, and nose. CAD is a complement-mediated process which leads to intravascular and extravascular hemolysis. A stepwise approach to laboratory testing can help confirm the diagnosis. Nearly all cold agglutinins are positive for the C3d direct antiglobulin test (DAT). A negative C3d DAT should prompt investigation of a possible warm AIHA. Ninety percent of cold agglutinins are of the IgM immunoglobulin class and should have a titer of 1:64 or higher at 4°C. Distinction from a warm AIHA is important, as therapy differs for the two entities. Corticosteroids are not effective at treating CAD and should not be used as therapy in these patients. Approximately 45-60% of patients with CAD respond to rituximab monotherapy. Combination therapy of rituximab and fludarabine has been shown to be effective in up to 76% of patients; however, patients experience more mild side effects with this treatment. New anti-complement drugs, such as eculizumab and sutimlimab, are currently in phase-3 trials to determine their efficacy and safety in patients with CAD.
10.2991/chi.k.200706.001
Autoimmune Hemolytic Anemia in the Pediatric Setting.
Voulgaridou Aikaterini,Kalfa Theodosia A
Journal of clinical medicine
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.
10.3390/jcm10020216
DAT-Negative Autoimmune Hemolytic Anemia.
Hematology/oncology clinics of North America
Hematologists often rely on the results of a positive direct antiglobulin test to confirm a diagnosis of autoimmune hemolytic anemia, but immune hemolytic anemia can occur when no immunoglobulin is detectable by routine methods. Negative DATs in these patients may be due to a small quantity of IgG on their red blood cells (RBCs) (below detectable levels), or when low-affinity anti-IgG is present, or when the autoantibodies are IgA or IgM in nature. A panel of tests developed to detect immunoglobulins on these patients' RBCs may be performed in a few specialized laboratories. These tests can be helpful in instances whereby the clinical picture of AIHA seems obvious, but the laboratory values are misleading.
10.1016/j.hoc.2021.11.004