Warm autoimmune hemolytic anemia: Clinical features and diagnosis
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Wendell F Rosse, MD
Wendell F Rosse, MD
- Professor Emeritus of Medicine
- Duke University
Autoimmune hemolytic anemia (AIHA) due to the presence of warm agglutinins is almost always due to the presence of IgG antibodies that react with protein antigens on the red blood cell (RBC) surface at body temperature. For this reason, they are called "warm agglutinins" even though they seldom directly agglutinate the RBCs.
This topic review will discuss the clinical features and diagnosis of AIHA due to warm agglutinins [1,2]. Treatment of this disorder is discussed separately. (See "Warm autoimmune hemolytic anemia: Treatment".)
●AIHA is a frequent problem in patients with systemic lupus erythematosus, occurring in up to 10 percent of patients. This subject is discussed separately. (See "Hematologic manifestations of systemic lupus erythematosus in adults", section on 'Autoimmune hemolytic anemia'.)
●The pathogenesis, diagnosis, and treatment of AIHA associated with the presence of cold agglutinins is discussed separately. (See "Pathogenesis of autoimmune hemolytic anemia: Cold agglutinin disease" and "Clinical features and treatment of autoimmune hemolytic anemia: Cold agglutinins" and "Paroxysmal cold hemoglobinuria".)
A variety of factors may initiate the antibody production in warm agglutinin AIHA. This issue is discussed in detail separately. (See "Pathogenesis of autoimmune hemolytic anemia: Warm agglutinins and drugs", section on 'Genesis of antibody production'.) Reviewed briefly, most cases are idiopathic, in that no underlying disorder or direct cause can be found.
- Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol 2002; 69:258.
- Petz LD. Treatment of autoimmune hemolytic anemias. Curr Opin Hematol 2001; 8:411.
- Young PP, Uzieblo A, Trulock E, et al. Autoantibody formation after alloimmunization: are blood transfusions a risk factor for autoimmune hemolytic anemia? Transfusion 2004; 44:67.
- Hoffman PC. Immune hemolytic anemia--selected topics. Hematology Am Soc Hematol Educ Program 2009; :80.
- Ahmed I, Teruya J, Murray-Krezan C, Krance R. The incidence of autoimmune hemolytic anemia in pediatric hematopoietic stem cell recipients post-first and post-second hematopoietic stem cell transplant. Pediatr Transplant 2015; 19:391.
- Gonzalez H, Leblond V, Azar N, et al. Severe autoimmune hemolytic anemia in eight patients treated with fludarabine. Hematol Cell Ther 1998; 40:113.
- Myint H, Copplestone JA, Orchard J, et al. Fludarabine-related autoimmune haemolytic anaemia in patients with chronic lymphocytic leukaemia. Br J Haematol 1995; 91:341.
- Byrd JC, Hertler AA, Weiss RB, et al. Fatal recurrence of autoimmune hemolytic anemia following pentostatin therapy in a patient with a history of fludarabine-associated hemolytic anemia. Ann Oncol 1995; 6:300.
- Fleischman RA, Croy D. Acute onset of severe autoimmune hemolytic anemia after treatment with 2-chlorodeoxyadenosine for chronic lymphocytic leukemia. Am J Hematol 1995; 48:293.
- Tertian G, Cartron J, Bayle C, et al. Fatal intravascular autoimmune hemolytic anemia after fludarabine treatment for chronic lymphocytic leukemia. Hematol Cell Ther 1996; 38:359.
- Juliusson G. Complications in the treatment of CLL with purine analogues. Hematol Cell Ther 1997; 39 Suppl 1:S41.
- Beyer M, Kochanek M, Darabi K, et al. Reduced frequencies and suppressive function of CD4+CD25hi regulatory T cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood 2005; 106:2018.
- Jones J. Transfusion in oligemia. In: Blood Transfusion in Clinical Medicine, 8th ed, Mollison PL, Engelfriet CP, Contreras M (Eds), Blackwell, Oxford 1987. p.41.
- Weiskopf RB, Viele MK, Feiner J, et al. Human cardiovascular and metabolic response to acute, severe isovolemic anemia. JAMA 1998; 279:217.
- Roumier M, Loustau V, Guillaud C, et al. Characteristics and outcome of warm autoimmune hemolytic anemia in adults: New insights based on a single-center experience with 60 patients. Am J Hematol 2014; 89:E150.
- Liesveld JL, Rowe JM, Lichtman MA. Variability of the erythropoietic response in autoimmune hemolytic anemia: analysis of 109 cases. Blood 1987; 69:820.
- Birgens H, Frederiksen H, Hasselbalch HC, et al. A phase III randomized trial comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in patients with autoimmune haemolytic anaemia. Br J Haematol 2013; 163:393.
- Barcellini W, Fattizzo B, Zaninoni A, et al. Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients. Blood 2014; 124:2930.
- Marchand A, Galen RS, Van Lente F. The predictive value of serum haptoglobin in hemolytic disease. JAMA 1980; 243:1909.
- Galen RS. Application of the predictive value model in the analysis of test effectiveness. Clin Lab Med 1982; 2:685.
- Mantripragada K, Quesenberry PJ. Doublet spherocytes. Blood 2014; 124:12.
- Chaplin H Jr. Clinical usefulness of specific antiglobulin reagents in autoimmune hemolytic anemias. Prog Hematol 1973; 8:25.
- Wheeler CA, Calhoun L, Blackall DP. Warm reactive autoantibodies: clinical and serologic correlations. Am J Clin Pathol 2004; 122:680.
- Sachs UJ, Röder L, Santoso S, Bein G. Does a negative direct antiglobulin test exclude warm autoimmune haemolytic anaemia? A prospective study of 504 cases. Br J Haematol 2006; 132:655.
- Podberezin M, Levina A, Romanova L, et al. Quantitation of red cell-bound immunoglobulins and complement in lymphoma patients. Immunohematology 2000; 16:147.
- Bencomo AA, Diaz M, Alfonso Y, et al. Quantitation of red cell-bound IgG, IgA, and IgM in patients with autoimmune hemolytic anemia and blood donors by enzyme-linked immunosorbent assay. Immunohematology 2003; 19:47.
- Nathalang O, Chuansumrit A, Prayoonwiwat W, et al. Comparison between the conventional tube technique and the gel technique in direct antiglobulin tests. Vox Sang 1997; 72:169.
- Lin JS, Hao TC, Lyou JY, et al. Clinical application of a flow cytometric direct antiglobulin test. Transfusion 2009; 49:1335.
- Garratty G, Arndt P, Domen R, et al. Severe autoimmune hemolytic anemia associated with IgM warm autoantibodies directed against determinants on or associated with glycophorin A. Vox Sang 1997; 72:124.
- Reusser P, Osterwalder B, Burri H, Speck B. Autoimmune hemolytic anemia associated with IgA--diagnostic and therapeutic aspects in a case with long-term follow-up. Acta Haematol 1987; 77:53.
- Janvier D, Sellami F, Missud F, et al. Severe autoimmune hemolytic anemia caused by a warm IgA autoantibody directed against the third loop of band 3 (RBC anion-exchange protein 1). Transfusion 2002; 42:1547.
- Bardill B, Mengis C, Tschopp M, Wuillemin WA. Severe IgA-mediated auto-immune haemolytic anaemia in a 48-yr-old woman. Eur J Haematol 2003; 70:60.
- Arndt PA, Leger RM, Garratty G. Serologic findings in autoimmune hemolytic anemia associated with immunoglobulin M warm autoantibodies. Transfusion 2009; 49:235.
- Bartolmäs T, Salama A. A dual antiglobulin test for the detection of weak or nonagglutinating immunoglobulin M warm autoantibodies. Transfusion 2010; 50:1131.
- Kamesaki T, Oyamada T, Omine M, et al. Cut-off value of red-blood-cell-bound IgG for the diagnosis of Coombs-negative autoimmune hemolytic anemia. Am J Hematol 2009; 84:98.
- Kamesaki T, Toyotsuji T, Kajii E. Characterization of direct antiglobulin test-negative autoimmune hemolytic anemia: a study of 154 cases. Am J Hematol 2013; 88:93.
- Conley CL, Lippman SM, Ness P. Autoimmune hemolytic anemia with reticulocytopenia. A medical emergency. JAMA 1980; 244:1688.
- Michel M, Chanet V, Dechartres A, et al. The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases. Blood 2009; 114:3167.
- Savaşan S, Warrier I, Buck S, et al. Increased lymphocyte Fas expression and high incidence of common variable immunodeficiency disorder in childhood Evans' syndrome. Clin Immunol 2007; 125:224.
- Teachey DT, Manno CS, Axsom KM, et al. Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). Blood 2005; 105:2443.
- Seif AE, Manno CS, Sheen C, et al. Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study. Blood 2010; 115:2142.
- Stepensky P, Rensing-Ehl A, Gather R, et al. Early-onset Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency. Blood 2015; 125:753.
- Genty I, Michel M, Hermine O, et al. [Characteristics of autoimmune hemolytic anemia in adults: retrospective analysis of 83 cases]. Rev Med Interne 2002; 23:901.
- Sallah S, Wan JY, Hanrahan LR. Future development of lymphoproliferative disorders in patients with autoimmune hemolytic anemia. Clin Cancer Res 2001; 7:791.
- Allgood JW, Chaplin H Jr. Idiopathic acquired autoimmune hemolytic anemia. A review of forty-seven cases treated from 1955 through 1965. Am J Med 1967; 43:254.
- Hendrick AM. Auto-immune haemolytic anaemia--a high-risk disorder for thromboembolism? Hematology 2003; 8:53.
- Yusuf HR, Hooper WC, Beckman MG, et al. Risk of venous thromboembolism among hospitalizations of adults with selected autoimmune diseases. J Thromb Thrombolysis 2014; 38:306.
- Saif MW, Bona R, Greenberg B. AIDS and thrombosis: retrospective study of 131 HIV-infected patients. AIDS Patient Care STDS 2001; 15:311.
- Pullarkat V, Ngo M, Iqbal S, et al. Detection of lupus anticoagulant identifies patients with autoimmune haemolytic anaemia at increased risk for venous thromboembolism. Br J Haematol 2002; 118:1166.
- Comellas-Kirkerup L, Hernández-Molina G, Cabral AR. Antiphospholipid-associated thrombocytopenia or autoimmune hemolytic anemia in patients with or without definite primary antiphospholipid syndrome according to the Sapporo revised classification criteria: a 6-year follow-up study. Blood 2010; 116:3058.
- Sokol RJ, Hewitt S, Stamps BK. Erythrocyte autoantibodies, autoimmune haemolysis and pregnancy. Vox Sang 1982; 43:169.
- Lawe JE. Successful exchange transfusion of an infant for AIHA developing late in mother's pregnancy. Transfusion 1982; 22:66.
- Williamson TD, Liles LH, Blackall DP. A maternal warm-reactive autoantibody presenting as a positive direct antiglobulin test in a neonate. Immunohematology 1997; 13:6.
- Underlying causes
- CLINICAL MANIFESTATIONS
- LABORATORY FINDINGS
- Hemolytic anemia
- Positive antiglobulin (Coombs) test
- - The direct Coombs test
- - The indirect Coombs test
- - Coombs negative AIHA
- Reticulocyte response
- Other findings
- Evans syndrome
- DIFFERENTIAL DIAGNOSIS
- DISEASE ASSOCIATIONS
- Lymphoproliferative disorder
- Venous thromboembolism
- AIHA in the newborn
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS