Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Pathogenesis of autoimmune hemolytic anemia: Cold agglutinin disease

Stanley L Schrier, MD
Carlo Brugnara, MD
Section Editor
William C Mentzer, MD
Deputy Editor
Jennifer S Tirnauer, MD


One of the most common causes of acquired hemolytic anemia is immunologic destruction of red blood cells (RBCs) mediated by autoantibodies directed against antigens on the patient's RBCs. The clinical manifestations of this group of diseases, called autoimmune hemolytic anemia (AIHA), depend greatly upon the type of antibody that is produced by the abnormal immune reaction.

This topic will review the mechanisms underlying AIHA due to cold agglutinins [1]. The clinical features and treatment of this disorder and issues related to another form of cold-related hemolysis, paroxysmal cold hemoglobinuria, are discussed separately. (See "Cold agglutinin disease" and "Paroxysmal cold hemoglobinuria".)


In general, antibodies of two major types, each with specific characteristics, are produced in AIHA:

IgM antibodies that generally react with polysaccharide antigens on the RBC surface only at temperatures below that of the core temperature of the body. They are therefore called "cold agglutinins." Rarely, IgG antibodies have these reaction characteristics, occurring either alone or with IgM antibodies [2].

IgG antibodies that generally react with protein antigens on the RBC surface at body temperature. For this reason, they are called "warm agglutinins" even though they seldom directly agglutinate the RBCs. Rarely, IgM antibodies have these reaction characteristics and readily agglutinate red cells. (See "Pathogenesis of autoimmune hemolytic anemia: Warm agglutinins and drugs".)

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Nov 2017. | This topic last updated: Sep 26, 2017.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Berentsen S. Complement, cold agglutinins, and therapy. Blood 2014; 123:4010.
  2. Silberstein LE, Berkman EM, Schreiber AD. Cold hemagglutinin disease associated with IgG cold-reactive antibody. Ann Intern Med 1987; 106:238.
  3. Göttsche B, Salama A, Mueller-Eckhardt C. Autoimmune hemolytic anemia associated with an IgA autoanti-Gerbich. Vox Sang 1990; 58:211.
  4. 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.
  5. Pereira A, Mazzara R, Escoda L, et al. Anti-Sa cold agglutinin of IgA class requiring plasma-exchange therapy as early manifestation of multiple myeloma. Ann Hematol 1993; 66:315.
  6. Amzel R, Hirszfeld L. Ueber die Kälteagglutination der roten Blutkörperchen. Z Immun-Forsch 1925; 43:526.
  7. Rosenthal F, Corten M. Uber das phänomenon der autohämagglutination und über die eigenschaften der kältehämagglutinine. Folia Haematol 1937; 58:64.
  9. Rosse WF. The detection of small amounts of antibody on the red cell in autoimmune hemolytic anemia. Ser Haematol 1974; 7:358.
  10. Pascual V, Victor K, Spellerberg M, et al. VH restriction among human cold agglutinins. The VH4-21 gene segment is required to encode anti-I and anti-i specificities. J Immunol 1992; 149:2337.
  11. Smith G, Spellerberg M, Boulton F, et al. The immunoglobulin VH gene, VH4-21, specifically encodes autoanti-red cell antibodies against the I or i antigens. Vox Sang 1995; 68:231.
  12. Silberstein LE, Jefferies LC, Goldman J, et al. Variable region gene analysis of pathologic human autoantibodies to the related i and I red blood cell antigens. Blood 1991; 78:2372.
  13. Potter KN. Molecular characterization of cold agglutinins. Transfus Sci 2000; 22:113.
  14. Pascual V, Victor K, Lelsz D, et al. Nucleotide sequence analysis of the V regions of two IgM cold agglutinins. Evidence that the VH4-21 gene segment is responsible for the major cross-reactive idiotype. J Immunol 1991; 146:4385.
  15. Thorpe SJ, Boult CE, Stevenson FK, et al. Cold agglutinin activity is common among human monoclonal IgM Rh system antibodies using the V4-34 heavy chain variable gene segment. Transfusion 1997; 37:1111.
  16. Potter KN, Hobby P, Klijn S, et al. Evidence for involvement of a hydrophobic patch in framework region 1 of human V4-34-encoded Igs in recognition of the red blood cell I antigen. J Immunol 2002; 169:3777.
  17. Cauerhff A, Braden BC, Carvalho JG, et al. Three-dimensional structure of the Fab from a human IgM cold agglutinin. J Immunol 2000; 165:6422.
  18. Thompson KM, Sutherland J, Barden G, et al. Human monoclonal antibodies against blood group antigens preferentially express a VH4-21 variable region gene-associated epitope. Scand J Immunol 1991; 34:509.
  19. Stevenson FK, Longhurst C, Chapman CJ, et al. Utilization of the VH4-21 gene segment by anti-DNA antibodies from patients with systemic lupus erythematosus. J Autoimmun 1993; 6:809.
  20. Bieber MM, Bhat NM, Teng NN. Anti-endotoxin human monoclonal antibody A6H4C5 (HA-1A) utilizes the VH4.21 gene. Clin Infect Dis 1995; 21 Suppl 2:S186.
  21. Rosse WF, Adams JP. The variability of hemolysis in the cold agglutinin syndrome. Blood 1980; 56:409.
  22. Bendix BJ, Tauscher CD, Bryant SC, et al. Defining a reference range for cold agglutinin titers. Transfusion 2014; 54:1294.
  23. Jenkins W, Marsh WL, Noades J, et al. The I antigen and antibody. Vox Sang 1960; 17:217.
  24. MARSH WL. Anti-i: a cold antibody defining the Ii relationship in human red cells. Br J Haematol 1961; 7:200.
  25. Roelcke D. A new serological specificity in cold antibodies of high titre: anti-HD. Vox Sang 1969; 16:76.
  26. Feizi T. Monotypic cold agglutinins in infection by mycoplasma pneumoniae. Nature 1967; 215:540.
  27. Horwitz CA, Moulds J, Henle W, et al. Cold agglutinins in infectious mononucleosis and heterophil-antibody-negative mononucleosis-like syndromes. Blood 1977; 50:195.
  28. Ulvestad E, Berentsen S, Bø K, Shammas FV. Clinical immunology of chronic cold agglutinin disease. Eur J Haematol 1999; 63:259.
  29. Crisp D, Pruzanski W. B-cell neoplasms with homogeneous cold-reacting antibodies (cold agglutinins). Am J Med 1982; 72:915.
  30. Silberstein LE, Litwin S, Carmack CE. Relationship of variable region genes expressed by a human B cell lymphoma secreting pathologic anti-Pr2 erythrocyte autoantibodies. J Exp Med 1989; 169:1631.
  31. Williams DM, Clement JR. Malignant histiocytosis appearing as cold-agglutinin disease. South Med J 1985; 78:1373.
  32. Richard JL, Vives JF, Bizot M, et al. [Lymphoproliferative syndrome with cold hemagglutinating, cryoprecipitating monoclonal IgM. Anti-Pr1d specificity]. Rev Fr Transfus Immunohematol 1980; 23:69.
  33. Isbister JP, Cooper DA, Blake HM, et al. Lymphoproliferative disease with IgM lambda monoclonal protein and autoimmune hemolytic anemia. A report of four cases and a review of the literature. Am J Med 1978; 64:434.
  34. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood 2013; 122:1114.
  35. Randen U, Troen G, Tierens A, et al. Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Blood 2014.
  36. Randen U, Trøen G, Tierens A, et al. Primary cold agglutinin-associated lymphoproliferative disease: a B-cell lymphoma of the bone marrow distinct from lymphoplasmacytic lymphoma. Haematologica 2014; 99:497.
  37. http://www.bloodjournal.org/content/128/22/2934 (Accessed on September 26, 2017).
  38. Michaux L, Dierlamm J, Wlodarska L, et al. Trisomy 3q11-q29 is recurrently observed in B-cell non-Hodgkin's lymphomas associated with cold agglutinin syndrome. Ann Hematol 1998; 76:201.
  39. Michaux L, Dierlamm J, Wlodarska I, et al. Trisomy 3 is a consistent chromosome change in malignant lymphoproliferative disorders preceded by cold agglutinin disease. Br J Haematol 1995; 91:421.
  40. Chng WJ, Chen J, Lim S, et al. Translocation (8;22) in cold agglutinin disease associated with B-cell lymphoma. Cancer Genet Cytogenet 2004; 152:66.
  41. Wortman J, Rosse W, Logue G. Cold agglutinin autoimmune hemolytic anemia in nonhematologic malignancies. Am J Hematol 1979; 6:275.
  42. Evans RS, Turner E, Bingham M, Woods R. Chronic hemolytic anemia due to cold agglutinins. II. The role of C' in red cell destruction. J Clin Invest 1968; 47:691.
  43. Logue GL, Rosse WF, Gockerman JP. Measurement of the third component of complement bound to red blood cells in patients with the cold agglutinin syndrome. J Clin Invest 1973; 52:493.
  44. Kirschfink M, Knoblauch K, Roelcke D. Activation of complement by cold agglutinins. Infusionsther Transfusionsmed 1994; 21:405.
  45. Schreiber AD, Herskovitz BS, Goldwein M. Low-titer cold-hemagglutinin disease. Mechanism of hemolysis and response to corticosteroids. N Engl J Med 1977; 296:1490.
  46. Shi J, Rose EL, Singh A, et al. TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood 2014; 123:4015.