Diagnostic Considerations

Conditions to consider in the differential diagnosis of cold agglutinin disease include the following:

Cryoglobulinemia
Warm antibody–mediated autoimmune hemolytic anemia (AIHA) - Some cases of cold agglutinin disease may be confused with this condition, particularly those in which the antibody has a high thermal amplitude
Episodic hemoglobinuria following cold exposure
Neoplasms - Especially of the lymphoid type
Drug-induced immune hemolytic anemia
Rheumatologic diseases manifesting Raynaud syndrome
Heparin-induced thrombocytopenia/thrombosis syndrome - Patients may have painful digits; anemia could be due to bleeding, but other manifestations are different
Systemic vasculitis, sometimes with hemolysis (systemic lupus and scleroderma)
Erythromelalgia in association with primary thrombocythemia and painful fingers and toes
Malaria and certain other infections

Cryoglobulinemia

This condition has almost none of the features of cold agglutinin disease, except for a history of Raynaud syndrome and an elevated IgM level in some cases (but without hemolysis).

Warm antibody–mediated autoimmune hemolytic anemia

This must be differentiated from cold agglutinin disease, especially when no symptoms or findings suggest cold-induced acrocyanosis or Raynaud-type phenomenon. The cold agglutinin titer is a specific differentiating test, and a positive IgG-specific Coombs test result would exclude cold agglutinin disease. Examination of the peripheral blood smear is less specific, but finding typical RBC clumps would be unlikely in AIHA, unless it is a mixed IgG-IgM warm-cold autoimmune hemolytic anemia.^{[12, 15]}

Episodic hemoglobinuria following cold exposure

This can occur in more severe cases of cold agglutinin disease, so confusion may exist as to whether a patient has Donath-Landsteiner hemolytic anemia or cold agglutinin disease. The cold agglutinin titer is less than 1:64 in Donath-Landsteiner, and the result of the Donath-Landsteiner test for cold hemolysis is positive. (Donath-Landsteiner screening tests are warranted only if hemoglobinuria is detected in the patient.) The age of the patient is very important, as a diagnosis of Donath-Landsteiner hemolytic anemia is more probable in a child; in one study, the median age at presentation was 5 years and the peak incidence was in children 4 years and under.^[27]March hemoglobinuria (episodic) is clearly related to exertion.

Neoplasms

Neoplasms may be associated with a cold agglutinin or a cryoglobulin, giving rise to symptoms of Raynaud syndrome. If the cold agglutinin titer is elevated and a complement-specific Coombs test result is positive, the patient may have a neoplastic clone of lymphocytes producing the cold agglutinin disease. This would be important in terms of therapy and prognosis, because the underlying lymphoma may be responsive to treatment. Often, the more severe forms of cold agglutinin disease are associated with lymphoid malignancy.^[47]

Drug-induced immune hemolytic anemia

This condition may also be a source of confusion, particularly when the direct Coombs test result is positive only for complement. However, the specific drug used and low cold-agglutinin titer should help to distinguish drug-induced hemolytic anemia from cold agglutinin disease.

Differential Diagnoses

Workup

Swiecicki PL, Hegerova LT, Gertz MA. Cold agglutinin disease. Blood. 2013 Aug 15. 122 (7):1114-21. [Medline]. [Full Text].
Małecka A, Trøen G, Tierens A, Østlie I, Małecki J, Randen U, et al. Immunoglobulin heavy and light chain gene features are correlated with primary cold agglutinin disease onset and activity. Haematologica. 2016 May 19. [Medline].
Berentsen S, Randen U, Tjønnfjord GE. Cold agglutinin-mediated autoimmune hemolytic anemia. Hematol Oncol Clin North Am. 2015 Jun. 29 (3):455-71. [Medline].
Rosse WF, Adams JP. The variability of hemolysis in the cold agglutinin syndrome. Blood. 1980 Sep. 56(3):409-16. [Medline]. [Full Text].
Dacie J, The auto-immune haemolytic anaemias. The Haemolytic Anaemias. 3rd ed. Edinburgh, United Kingdom: Churchill Livingstone; 1992. Vol 3.: 210-362.
Harboe M, van Furth R, Schubothe H, Lind K, Evans RS. Exclusive occurrence of K chains in isolated cold haemagglutinins. Scand J Haematol. 1965. 2(3):259-66. [Medline].
Angevine CD, Andersen BR, Barnett EV. A cold agglutinin of the IgA class. J Immunol. 1966 Apr. 96(4):578-86. [Medline].
Garratty G, Petz LD, Hoops JK. The correlation of cold agglutinin titrations in saline and albumin with haemolytic anaemia. Br J Haematol. 1977 Apr. 35(4):587-95. [Medline].
Wortman J, Rosse W, Logue G. Cold agglutinin autoimmune hemolytic anemia in nonhematologic malignancies. Am J Hematol. 1979. 6(3):275-83. [Medline].
Roelcke D. The Lud cold agglutinin: a further antibody recognizing N-acetylneuraminic acid-determined antigens not fully expressed at birth. Vox Sang. 1981 Nov-Dec. 41(5-6):316-8. [Medline].
Crisp D, Pruzanski W. B-cell neoplasms with homogeneous cold-reacting antibodies (cold agglutinins). Am J Med. 1982 Jun. 72(6):915-22. [Medline].
Sokol RJ, Hewitt S, Stamps BK. Autoimmune hemolysis: mixed warm and cold antibody type. Acta Haematol. 1983. 69(4):266-74. [Medline].
Roelcke D. Reaction of anti-Gd, anti-Fl and anti-Sa cold agglutinins with p erythrocytes. Vox Sang. 1984. 46(3):161-4. [Medline].
Agarwal SK, Ghosh PK, Gupta D. Cardiac surgery and cold-reactive proteins. Ann Thorac Surg. 1995 Oct. 60(4):1143-50. [Medline].
Packman CH, Leddy JP. Cryopathic hemolytic syndromes. Beutler E, Lichtman M, Coller B, Kippst, eds. Williams Hematology. 5th ed. New York, NY: McGraw-Hill; 1995. 685-91.
Jacobs A. Cold agglutinin hemolysis responding to fludarabine therapy. Am J Hematol. 1996 Dec. 53(4):279-80. [Medline].
Terness P, Kirschfink M, Navolan D, et al. Inverse correlation between IgG-antihinge region and antierythrocyte autoantibody in chronic benign and malignant cold agglutination. J Clin Immunol. 1997 May. 17(3):220-7. [Medline].
Thorpe SJ, Turner CE, Stevenson FK, et al. Human monoclonal antibodies encoded by the V4-34 gene segment show cold agglutinin activity and variable multireactivity which correlates with the predicted charge of the heavy-chain variable region. Immunology. 1998 Jan. 93(1):129-36. [Medline]. [Full Text].
Ciejka JZ, Cook EB, Lawler D, et al. Severe cold agglutinin disease and cryoglobulinemia secondary to a monoclonal anti-Pr2 IgM lambda cryoagglutinin. Clin Exp Rheumatol. 1999 Mar-Apr. 17(2):227-31. [Medline].
De Silva BD, McLaren K, Doherty VR. Equestrian perniosis associated with cold agglutinins: a novel finding. Clin Exp Dermatol. 2000 Jun. 25(4):285-8. [Medline].
Potter KN. Molecular characterization of cold agglutinins. Transfus Sci. 2000 Feb-Apr. 22(1-2):113-9. [Medline].
Jefferies LC, Carchidi CM, Silberstein LE. Naturally occurring anti-i/I cold agglutinins may be encoded by different VH3 genes as well as the VH4.21 gene segment. J Clin Invest. 1993 Dec. 92(6):2821-33. [Medline]. [Full Text].
Berentsen S, Beiske K, Tjonnfjord GE. Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features and therapy. Hematology. 2007 Oct. 12(5):361-70. [Medline]. [Full Text].
Gertz MA. Management of cold haemolytic syndrome. Br J Haematol. 2007 Aug. 138(4):422-9. [Medline].
McNicholl FP. Clinical syndromes associated with cold agglutinins. Transfus Sci. 2000 Feb-Apr. 22(1-2):125-33. [Medline].
Maniatis A, Papayannopoulou T, Bertles JF. Fetal characteristics of erythrocytes in sickle cell anemia: an immunofluorescence study of individual cells. Blood. 1979 Jul. 54(1):159-68. [Medline]. [Full Text].
Sokol RJ, Booker DJ, Stamps R. Erythropoiesis: Paroxysmal Cold Haemoglobinuria: A Clinico-Pathological Study of Patients with a Positive Donath-Landsteiner Test. Hematology. 1999. 4 (2):137-164. [Medline].
Sokol RJ, Booker DJ, Stamps R, Walewska R. Cold haemagglutinin disease: clinical significance of serum haemolysins. Clin Lab Haematol. 2000 Dec. 22(6):337-44. [Medline].
Maura F, Visco C, Falisi E, Reda G, Fabris S, Agnelli L, et al. B-cell receptor configuration and adverse cytogenetics are associated with autoimmune hemolytic anemia in chronic lymphocytic leukemia. Am J Hematol. 2012 Sep 26. [Medline].
Khan FY, A yassin M. Mycoplasma pneumoniae associated with severe autoimmune hemolytic anemia: case report and literature review. Braz J Infect Dis. 2009 Feb. 13(1):77-9. [Medline].
Delval A, Stojkovic T, Vermersch P. Relapsing sensorimotor neuropathy with ophthalmoplegia, antidisialosyl antibodies, and extramembranous glomerulonephritis. Muscle Nerve. 2006 Feb. 33(2):274-7. [Medline].
Siddiqui K, Cahalane E, Keogan M, Hardiman O. Chronic ataxic neuropathy with cold agglutinins: atypical phenotype and response to anti-CD20 antibodies. Neurology. 2003 Nov 11. 61(9):1307-8. [Medline].
Skorupa A, Chaudhary UB, Lazarchick J. Cold agglutinin induced autoimmune hemolytic anemia and NK-cell leukemia: a new association. Am J Hematol. 2007 Jul. 82(7):668-71. [Medline]. [Full Text].
Cao L, Kaiser P, Gustin D, Hoffman R, Feldman L. Cold agglutinin disease in a patient with uterine sarcoma. Am J Med Sci. 2000 Nov. 320(5):352-4. [Medline].
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 May. 76(5):201-4. [Medline].
Chng WJ, Chen J, Lim S, et al. Translocation (8;22) in cold agglutinin disease associated with B-cell lymphoma. Cancer Genet Cytogenet. 2004 Jul 1. 152(1):66-9. [Medline].
Kitamura T, Mizuta K, Kawarasaki H, Sugawara Y, Makuuchi M. Severe hemolytic anemia related to production of cold agglutinins following living donor liver transplantation: a case report. Transplant Proc. 2003 Feb. 35(1):399-400. [Medline].
Tamura T, Kanamori H, Yamazaki E, et al. Cold agglutinin disease following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1994 Mar. 13(3):321-3. [Medline].
Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. 1995 Dec. 17(6):584-91. [Medline].
Oshima M, Maeda H, Morimoto K, Doi M, Kuwabara M. Low-titer cold agglutinin disease with systemic sclerosis. Intern Med. 2004 Feb. 43(2):139-42. [Medline]. [Full Text].
Torres JR, Villegas L, Perez H, et al. Low-grade parasitaemias and cold agglutinins in patients with hyper-reactive malarious splenomegaly and acute haemolysis. Ann Trop Med Parasitol. 2003 Mar. 97(2):125-30. [Medline].
Johnson ST, McFarland JG, Kelly KJ, Casper JT, Gottschall JL. Transfusion support with RBCs from an Mk homozygote in a case of autoimmune hemolytic anemia following diphtheria-pertussis-tetanus vaccination. Transfusion. 2002 May. 42(5):567-71. [Medline].
Gunduz Gedikoglu A, Cantez T. Haemolytic-anaemia relapses after immunisation and pertussis. Lancet. 1967 Oct 21. 2(7521):894-5. [Medline].
Zupanska B, Lawkowicz W, Gorska B, et al. Autoimmune haemolytic anaemia in children. Br J Haematol. 1976 Nov. 34(3):511-20. [Medline].
Haneberg B, Matre R, Winsnes R, et al. Acute hemolytic anemia related to diphtheria-pertussis-tetanus vaccination. Acta Paediatr Scand. 1978 May. 67(3):345-50. [Medline].
Kamesaki T, Toyotsuji T, Kajii E. Characterization of direct antiglobulin test-negative autoimmune hemolytic anemia: A study of 154 cases. Am J Hematol. 2012 Oct 25. [Medline].
Berentsen S. How I manage patients with cold agglutinin disease. Br J Haematol. 2018 May. 181 (3):320-330. [Medline].
Hoppe B, Gaedicke G, Kiesewetter H, Salama AR. Response to intravenous immunoglobulin G in an infant with immunoglobulin A-associated autoimmune haemolytic anaemia. Vox Sang. 2004 Feb. 86(2):151-3. [Medline].
Roy-Burman A, Glader BE. Resolution of severe Donath-Landsteiner autoimmune hemolytic anemia temporally associated with institution of plasmapheresis. Crit Care Med. 2002 Apr. 30(4):931-4. [Medline].
Teachey DT, Felix CA. Development of cold agglutinin autoimmune hemolytic anemia during treatment for pediatric acute lymphoblastic leukemia. J Pediatr Hematol Oncol. 2005 Jul. 27(7):397-9. [Medline].
Giulino LB, Bussel JB, Neufeld EJ. Treatment with rituximab in benign and malignant hematologic disorders in children. J Pediatr. 2007 Apr. 150(4):338-44, 344.e1. [Medline]. [Full Text].
Webster D, Ritchie B, Mant MJ. Prompt response to rituximab of severe hemolytic anemia with both cold and warm autoantibodies. Am J Hematol. 2004 Apr. 75(4):258-9. [Medline]. [Full Text].
Berentsen S, Ulvestad E, Tjonnfjord GE. B-lymphocytes as targets for therapy in chronic cold agglutinin disease. Cardiovasc Hematol Disord Drug Targets. 2007 Sep. 7(3):219-27. [Medline].
Berentsen S, Randen U, Vagan AM, Hjorth-Hansen H, Vik A, Dalgaard J. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease. Blood. 2010 Oct 28. 116(17):3180-4. [Medline].
Shapiro R, Chin-Yee I, Lam S. Eculizumab as a bridge to immunosuppressive therapy in severe cold agglutinin disease of anti-Pr specificity. Clin Case Rep. 2015 Nov. 3 (11):942-4. [Medline].
Alexander Röth, Martin Bommer, Andreas Hüttmann, et al. Complement Inhibition with Eculizumab in Patients with Cold Agglutinin Disease (CAD): Results from a Prospective Phase II Trial (DECADE Trial). Blood. 2015 Dec 06. 126:274.
Sandip Panicker, Graham C. Parry, Michael Fillitz, et al. TNT009, a monoclonal antibody inhibitor of C1s, induces a rapid and complete remission of anemia in primary cold agglutinin disease patients. Immunobiology. 2016 Oct 01. 221:1170-1171.
Inaba H, Geiger TL, Lasater OE, Wang WC. A case of hemoglobin SC disease with cold agglutinin-induced hemolysis. Am J Hematol. 2005 Jan. 78(1):37-40. [Medline]. [Full Text].
Batalias L, Trakakis E, Loghis C, et al. Autoimmune hemolytic anemia caused by cold agglutinins in a young pregnant woman. J Matern Fetal Neonatal Med. 2006 Apr. 19(4):251-3. [Medline].
Atkinson VP, Soeding P, Horne G, Tatoulis J. Cold agglutinins in cardiac surgery: management of myocardial protection and cardiopulmonary bypass. Ann Thorac Surg. 2008 Jan. 85(1):310-1. [Medline].
Aoki A, Kay GL, Zubiate P, Ruggio J, Kay JH. Cardiac operation without hypothermia for the patient with cold agglutinin. Chest. 1993 Nov. 104(5):1627-9. [Medline].
Barbara DW, Mauermann WJ, Neal JR, Abel MD, Schaff HV, Winters JL. Cold agglutinins in patients undergoing cardiac surgery requiring cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2013 Sep. 146(3):668-80. [Medline].
Hippe E, Jensen KB, Olesen H, Lind K, Thomsen PE. Chlorambucil treatment of patients with cold agglutinin syndrome. Blood. 1970 Jan. 35(1):68-72. [Medline]. [Full Text].
O'Connor BM, Clifford JS, Lawrence WD, Logue GL. Alpha-interferon for severe cold agglutinin disease. Ann Intern Med. 1989 Aug 1. 111(3):255-6. [Medline].
Shi J, Rose EL, Singh A, Hussain S, Stagliano NE, Parry GC, et al. TNT003, an inhibitor of the serine protease C1s, prevents complement activation induced by cold agglutinins. Blood. 2014 Jun 26. 123 (26):4015-22. [Medline].
Risitano AM, Marotta S. Therapeutic complement inhibition in complement-mediated hemolytic anemias: Past, present and future. Semin Immunol. 2016 Jun. 28 (3):223-40. [Medline].
Bartko J, Schoergenhofer C, Schwameis M, Firbas C, Beliveau M, Chang C, et al. A Randomized, First-in-Human, Healthy Volunteer Trial of sutimlimab, a Humanized Antibody for the Specific Inhibition of the Classical Complement Pathway. Clin Pharmacol Ther. 2018 May 8. 88 (12):1715, 1722-3. [Medline].

Media Gallery

Peripheral blood smear showing several clumps of RBCs with the largest in the center. These are typical of aggregates seen in persons with cold agglutinin disease.
Blood smear showing spherocytic and agglutinated red blood cells.

of 2

Author

Salman Abdullah Aljubran, MD Allergist and Immunologist, Associate Director of FARE Center of Excellence, Children's Mercy Hospitals and Clinics; Assistant Professor of Medicine and Pediatrics, Division of Allergy, Asthma and Immunology, University of Missouri-Kansas City School of Medicine

Salman Abdullah Aljubran, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American Medical Association, Clinical Immunology Society

Disclosure: Nothing to disclose.

Coauthor(s)

Richard F Lockey, MD University Distinguished Health Professor, Professor of Medicine, Pediatrics and Public Health, Joy McCann Culverhouse Chair in Allergy and Immunology, University of South Florida College of Medicine; Director, Division of Allergy and Immunology, James A Haley Veterans’ Hospital

Richard F Lockey, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Association for the Advancement of Science, American College of Occupational and Environmental Medicine, American College of Chest Physicians, American College of Physicians, American Medical Association, Florida Medical Association

Disclosure: Nothing to disclose.

Chief Editor

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; Medical Director, Institute for Asthma and Allergy

Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, Association of American Physicians

Disclosure: Nothing to disclose.

Acknowledgements

Nicolas A Camilo, MD Consulting Staff, Mountain States Tumor Institute, Division of Pediatric Hematology-Oncology, St Luke's Regional Medical Center