UpToDate
Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Cold agglutinin disease

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

INTRODUCTION

Cold agglutinin disease (ie, cold agglutinin associated autoimmune hemolytic anemia [AIHA]) is typically characterized by the presence of clinical symptoms related to exposure to cold, hemolytic anemia, and antibodies (most commonly IgM, rarely IgA or IgG) directed against polysaccharide antigens on the red blood cell surface that are responsible for the agglutination of red cells at low temperatures [1]. (See "Pathogenesis of autoimmune hemolytic anemia: Cold agglutinin disease".)

This topic will review the clinical manifestations, diagnosis, and treatment of AIHA due to cold agglutinins [2]. Paroxysmal cold hemoglobinuria, another form of cold-related hemolysis, as well as the clinical features and treatment of AIHA due to warm agglutinins, are discussed separately. (See "Paroxysmal cold hemoglobinuria" and "Warm autoimmune hemolytic anemia: Clinical features and diagnosis" and "Warm autoimmune hemolytic anemia: Treatment".)

EPIDEMIOLOGY

Cold agglutinin disease is rare, most often affecting females in the seventh decade of life, with an incidence of one case per million people per year [3]. As an example, in a single institutional experience with 43,000 patients having a monoclonal gammopathy, less than 1 percent had cold-reactive autoantibodies [4].

In the largest reported series to date, covering 89 patients, the median age at diagnosis was 72 years (range: 43 to 91), while the median age at the onset of symptoms was 65 years (range: 41 to 83). Sixty-one percent of the affected individuals were female [4]. In two series, the median survival following diagnosis was 10.6 and 12.5 years, being similar to that of an age- and sex-matched normal population [3,4].

CLINICAL MANIFESTATIONS

Pathologic cold agglutinins are produced either in response to infection or by paraneoplastic or neoplastic growth of a single lymphocyte clone. In either case, they generally share the same immunochemical characteristics and polysaccharide specificities, and result in the same clinical manifestations.

                             

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Wed Oct 05 00:00:00 GMT 2016.
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 ©2016 UpToDate, Inc.
References
Top
  1. Silberstein LE, Berkman EM, Schreiber AD. Cold hemagglutinin disease associated with IgG cold-reactive antibody. Ann Intern Med 1987; 106:238.
  2. Berentsen S. How I manage cold agglutinin disease. Br J Haematol 2011; 153:309.
  3. Berentsen S, Ulvestad E, Langholm R, et al. Primary chronic cold agglutinin disease: a population based clinical study of 86 patients. Haematologica 2006; 91:460.
  4. Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood 2013; 122:1114.
  5. Lyckholm LJ, Edmond MB. Images in clinical medicine. Seasonal hemolysis due to cold-agglutinin syndrome. N Engl J Med 1996; 334:437.
  6. Poldre P, Pruzanski W, Chiu HM, Dotten DA. Fulminant gangrene in transient cold agglutinemia associated with Escherichia coli infection. Can Med Assoc J 1985; 132:261.
  7. Oh SH, Kim DS, Ryu DJ, Lee KH. Extensive cutaneous necrosis associated with low titres of cold agglutinins. Clin Exp Dermatol 2009; 34:e229.
  8. de Witte MA, Determann RM, Zeerleder SS. A man with "black fingers". Cold agglutinin disease (CAD). Neth J Med 2014; 72:35, 39.
  9. Iwasaki H. Acronecrosis with cold agglutinin disease mimics diabetic gangrene. Intern Med 2013; 52:837.
  10. Gertz MA. Management of cold haemolytic syndrome. Br J Haematol 2007; 138:422.
  11. 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.
  12. Crisp D, Pruzanski W. B-cell neoplasms with homogeneous cold-reacting antibodies (cold agglutinins). Am J Med 1982; 72:915.
  13. 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.
  14. Williams DM, Clement JR. Malignant histiocytosis appearing as cold-agglutinin disease. South Med J 1985; 78:1373.
  15. 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.
  16. 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.
  17. Cesana C, Barbarano L, Miqueleiz S, et al. Clinical characteristics and outcome of immunoglobulin M-related disorders. Clin Lymphoma 2005; 5:261.
  18. 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.
  19. Feizi T. Monotypic cold agglutinins in infection by mycoplasma pneumoniae. Nature 1967; 215:540.
  20. Horwitz CA, Moulds J, Henle W, et al. Cold agglutinins in infectious mononucleosis and heterophil-antibody-negative mononucleosis-like syndromes. Blood 1977; 50:195.
  21. Terada K, Tanaka H, Mori R, et al. Hemolytic anemia associated with cold agglutinin during chickenpox and a review of the literature. J Pediatr Hematol Oncol 1998; 20:149.
  22. 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.
  23. 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.
  24. Wortman J, Rosse W, Logue G. Cold agglutinin autoimmune hemolytic anemia in nonhematologic malignancies. Am J Hematol 1979; 6:275.
  25. Mickley H, Sørensen PG. Immune haemolytic anaemia associated with ampicillin dependent warm antibodies and high titre cold agglutinins in a patient with Mycoplasma pneumonia. Scand J Haematol 1984; 32:323.
  26. Bessman JD, Banks D. Spurious macrocytosis, a common clue to erythrocyte cold agglutinins. Am J Clin Pathol 1980; 74:797.
  27. Hinchliffe RF, Bellamy GJ, Lilleyman JS. Use of the Technicon H1 hypochromia flag in detecting spurious macrocytosis induced by excessive K2-EDTA concentration. Clin Lab Haematol 1992; 14:268.
  28. Van De Loosdrecht AA, Hendriks DW, Blom NR, et al. Excessive apoptosis of bone marrow erythroblasts in a patient with autoimmune haemolytic anaemia with reticulocytopenia. Br J Haematol 2000; 108:313.
  29. Conley CL, Lippman SM, Ness P. Autoimmune hemolytic anemia with reticulocytopenia. A medical emergency. JAMA 1980; 244:1688.
  30. Arbach O, Funck R, Seibt F, Salama A. Erythropoietin May Improve Anemia in Patients with Autoimmune Hemolytic Anemia Associated with Reticulocytopenia. Transfus Med Hemother 2012; 39:221.
  31. Bendix BJ, Tauscher CD, Bryant SC, et al. Defining a reference range for cold agglutinin titers. Transfusion 2014; 54:1294.
  32. Ulvestad E, Berentsen S, Mollnes TE. Acute phase haemolysis in chronic cold agglutinin disease. Scand J Immunol 2001; 54:239.
  33. Berentsen S, Tjønnfjord GE. Diagnosis and treatment of cold agglutinin mediated autoimmune hemolytic anemia. Blood Rev 2012; 26:107.
  34. Lee EJ, Kueck B. Rituxan in the treatment of cold agglutinin disease. Blood 1998; 92:3490.
  35. Bauduer F. Rituximab: a very efficient therapy in cold agglutinins and refractory autoimmune haemolytic anaemia associated with CD20-positive, low-grade non-Hodgkin's lymphoma. Br J Haematol 2001; 112:1085.
  36. Zaja F, Russo D, Fuga G, et al. Rituximab in a case of cold agglutinin disease. Br J Haematol 2001; 115:232.
  37. Engelhardt M, Jakob A, Ruter B, et al. Severe cold hemagglutinin disease (CHD) successfully treated with rituximab. Blood 2002; 100:1922.
  38. Schöllkopf C, Kjeldsen L, Bjerrum OW, et al. Rituximab in chronic cold agglutinin disease: a prospective study of 20 patients. Leuk Lymphoma 2006; 47:253.
  39. Berentsen S, Ulvestad E, Gjertsen BT, et al. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood 2004; 103:2925.
  40. Berentsen S, Randen U, Vågan AM, et al. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood 2010; 116:3180.
  41. Barcellini W, Zaja F, Zaninoni A, et al. Low-dose rituximab in adult patients with idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies. Blood 2012; 119:3691.
  42. Barcellini W, Zaja F, Zaninoni A, et al. Sustained response to low-dose rituximab in idiopathic autoimmune hemolytic anemia. Eur J Haematol 2013; 91:546.
  43. Budmiger H, Rhyner K, Siegenthaler-Zuber G, Bollinger A. [Idiopathic cold agglutinin disease. Clinical aspects, therapy and course in 6 patients]. Schweiz Med Wochenschr 1988; 118:52.
  44. Treon SP. How I treat Waldenström macroglobulinemia. Blood 2009; 114:2375.
  45. Gueli A, Gottardi D, Hu H, et al. Efficacy of rituximab-bendamustine in cold agglutinin haemolytic anaemia refractory to previous chemo-immunotherapy: a case report. Blood Transfus 2013; 11:311.
  46. Carson KR, Beckwith LG, Mehta J. Successful treatment of IgM-mediated autoimmune hemolytic anemia with bortezomib. Blood 2010; 115:915.
  47. 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.
  48. Lahav M, Rosenberg I, Wysenbeek AJ. Steroid-responsive idiopathic cold agglutinin disease: a case report. Acta Haematol 1989; 81:166.
  49. Gertz MA. Cold hemolytic syndrome. Hematology Am Soc Hematol Educ Program 2006; :19.
  50. Rordorf R, Barth A, Nydegger U, Tobler A. [Treatment of severe idiopathic cold-agglutinin diseases using interferon-alpha 2b]. Schweiz Med Wochenschr 1994; 124:56.
  51. Fest T, de Wazières B, Lamy B, et al. Successful response to alpha-interferon 2b in a refractory IgM autoagglutinin-mediated hemolytic anemia. Ann Hematol 1994; 69:147.
  52. Röth A, Hüttmann A, Rother RP, et al. Long-term efficacy of the complement inhibitor eculizumab in cold agglutinin disease. Blood 2009; 113:3885.
  53. Bommer M, Hochsmann B, Flegel WA, et al. Successful treatment of complement mediated refractory haemolysis associated with cold and warm autoantibodies using eculizumab (abstract). Haematologica 2009; 94 (Suppl 2):241.
  54. Gupta N, Wang ES. Long-term response of refractory primary cold agglutinin disease to eculizumab therapy. Ann Hematol 2014; 93:343.
  55. 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.
  56. Sharp JA, Whitley PH, Cunnion KM, Krishna NK. Peptide inhibitor of complement c1, a novel suppressor of classical pathway activation: mechanistic studies and clinical potential. Front Immunol 2014; 5:406.
  57. Siami FS, Siami GA. A last resort modality using cryofiltration apheresis for the treatment of cold hemagglutinin disease in a Veterans Administration hospital. Ther Apher Dial 2004; 8:398.
  58. Geurs F, Ritter K, Mast A, Van Maele V. Successful plasmapheresis in corticosteroid-resistant hemolysis in infectious mononucleosis: role of autoantibodies against triosephosphate isomerase. Acta Haematol 1992; 88:142.
  59. Zoppi M, Oppliger R, Althaus U, Nydegger U. Reduction of plasma cold agglutinin titers by means of plasmapheresis to prepare a patient for coronary bypass surgery. Infusionsther Transfusionsmed 1993; 20:19.
  60. 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.
  61. Valbonesi M, Guzzini F, Zerbi D, et al. Successful plasma exchange for a patient with chronic demyelinating polyneuropathy and cold agglutinin disease due to anti-Pra. J Clin Apher 1986; 3:109.
  62. Bedrosian CL, Simel DL. Cold hemagglutinin disease in the operating room. South Med J 1987; 80:466.
  63. Agarwal SK, Ghosh PK, Gupta D. Cardiac surgery and cold-reactive proteins. Ann Thorac Surg 1995; 60:1143.
  64. Beebe DS, Bergen L, Palahniuk RJ. Anesthetic management of a patient with severe cold agglutinin hemolytic anemia utilizing forced air warming. Anesth Analg 1993; 76:1144.
  65. Talisman R, Lin JT, Soroff HS, Galanakis D. Gangrene of the back, buttocks, fingers, and toes caused by transient cold agglutinemia induced by a cooling blanket in a patient with sepsis. Surgery 1998; 123:592.
  66. Barbara DW, Mauermann WJ, Neal JR, et al. Cold agglutinins in patients undergoing cardiac surgery requiring cardiopulmonary bypass. J Thorac Cardiovasc Surg 2013; 146:668.