eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Cold Agglutinin Disease

Author: Sharon Georgy Gendi, MD, Intern, Internal Medicine Residency Program, University of South Florida
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; Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems; Harry L Messmore, Jr, MD, Professor, Department of Medicine, Division of Hematology/Oncology, Loyola University Stritch School of Medicine
Contributor Information and Disclosures

Updated: Feb 16, 2009

Introduction

Background

In 1903, Landsteiner was the first to describe the presence of cold agglutinins in the blood, which were capable of agglutinating red blood cells (RBCs).1 He described the finding of a low titer of these agglutinins in healthy individuals. Later, the appearance of the I antigen on human RBCs in the postnatal period due to modification of the fetal i antigen structure (a change occurring over the first 18 mo) was found to lead to the development of low levels of anti-I agglutinins. These antibodies induce hemagglutination mainly at 4°C but not at 37°C and were therefore termed cold agglutinins.

Subsequent observations have led to the understanding that cold agglutinins are usually immunoglobulin (Ig) M antibodies (less commonly, IgA or IgG) that may result in hemolytic anemia due to complement-mediated RBC destruction in the reticuloendothelial system. Slowing of blood flow with occlusion of superficial blood vessels by agglutinated RBCs can cause a Raynaudlike syndrome (acrocyanosis).2,3,4

For excellent patient education resources, visit eMedicine's Bacterial and Viral Infections Center and Sexually Transmitted Diseases Center. Also, see eMedicine's patient education articles Mononucleosis and Syphilis.

Related eMedicine topics:
Cold Agglutinin Disease [in the Pediatrics: General Medicine section]
Dermatologic Manifestations of Hematologic Disease
Hemoglobinuria, Paroxysmal Cold
Paroxysmal Cold Hemoglobinuria [in the Pediatrics: General Medicine section]

Pathophysiology

Cold agglutinin disease usually develops as a result of the production of a specific IgM antibody directed against the I/i antigens (precursors of the ABH and Lewis blood group substances) on RBCs. These cold agglutinins commonly have variable heavy-chain regions encoded by VH,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21 with a distinct idiotype identified by the 9G4 rat murine monoclonal antibody.4

This 9G4 idiotope is localized to the V4-34 encoded portion of the variable region.22 It is found on cold agglutinin-producing malignant lymphoid cells in the bone marrow in persons with lymphoproliferative disorders, on a small proportion of normal lymphoid cells, and in the spleen of a 15-week-old fetus. In contrast, the cold agglutinins found in healthy individuals, those with no clinical symptoms, are often derived from a variable segment other than V4-34 portion.23,24

The VH genes appear to regulate not only the production of cold agglutinins, but also the formation of normal antibodies to other carbohydrate antigens, both sharing the same fundamental mechanism of production. The I/i antigen analogues are present on human lymphocytes, neutrophils, and monocytes and in human saliva, milk, and amniotic fluid. Thus, in disease states, the finding of a clone of B cells producing this antibody may be the result of expansion of a normal clone that is specific for the production of an immunoglobulin with these properties. Autoimmune and lymphoproliferative disorders can also be associated with the production of cold agglutinins.

The hemolytic anemia associated with monoclonal cold agglutinins is typically more serious than that associated with polyclonal cold agglutinins. The monoclonal form is usually chronic, whereas the polyclonal form is often limited.25 Some polyclonal IgM cold agglutinins arise in association with Mycoplasma pneumoniae infections, infectious mononucleosis,  influenza B, human immunodeficiency virus (HIV), and other infections.

Cytomegalovirus (CMV), rubella virus, varicella-zoster virus (VZV), parvovirus B19, and Chlamydia psittaci have also been implicated.26 In the case of infectious mononucleosis, hemolysis tends to develop 1-2 weeks after the onset of illness, but it may occur simultaneously for up to 2 months after onset.26 Furthermore, increased expression of both I/i antigens have been described on hemoglobin SS (HbSS) erythrocytes, which suggests that such patients may have increased susceptibility to cold-mediated hemolysis.27

In its classic presentation, with hemolytic anemia and Raynaud syndrome, cold agglutinin disease is usually idiopathic. As with most autoimmune diseases of a chronic nature, stimulated B lymphocytes begin to produce pathogenic antibodies against an antigen that is normally present in human tissue. In cold agglutinin disease, the antibody is an IgM, usually monoclonal, with kappa (κ) or lambda (λ) light chains. In chronic cold agglutinin disease, the antibody is usually directed against the I antigen on the membrane of normal adult RBCs.

Uncommonly, the antibody may be directed against only the i antigen found on fetal cord blood RBCs, which lack the mature I antigen; this has been reported in association with infectious mononucleosis.9 In a study of 78 patients, κ light-chain specificity was found in the majority of patients with chronic cold agglutinin disease or Waldenstrom macroglobulinemia, whereas two thirds of cold agglutinins found in patients with lymphomas had light-chain specificity. The type of light chain appears to correlate with the antigen specificity of the cold agglutinin.

Fifty-eight percent of IgM/κ (usually κIII variable region subgroup) were anti-I, but 75% of IgM/λ had other antigen specificities.12 Antigen specificities of cold agglutinins other than the I/i system that have been described include those against Pr, M, P, and Lud and anti-Gd, anti-Fl, and anti-Sa.6,11,14 Exclusive occurrence of κ chains has also been shown with some cold agglutinins.5 Thus, benign and malignant cold agglutinins exhibit differences in their light chains and their specificities toward membrane antigens.

In vivo, the IgM antibody attaches to RBCs and causes them to agglutinate at temperatures below 37°C and maximally at 0-5°C, resulting in impaired blood flow to the digits, nose, and ears (ie, areas more likely to have colder temperatures [in the 30°C range]) when exposed to the cold. Fixation of the C3 component of complement to the RBC by the cold agglutinin usually occurs in vivo at higher temperatures compared with those required by the IgM cold agglutinin to attach to the RBC, but it is generally less than 31°C. When the IgM/C3b-coated RBC circulates to warmer tissues, the IgM dissociates, leaving complement C3b on the original RBC.

The dissociated IgM cold agglutinin can then bind to another RBC at lower temperatures. Fixation of complement results in C3b and/or C4b components on the RBC membrane, which may lead to phagocytosis by macrophages in the reticuloendothelial system, particularly in the liver, where the macrophages have specific complement receptors. With time, the C3b components are converted enzymatically to C3dg, which is not recognized by macrophage receptors.

In chronic cold agglutinin disease, complement tends to be depleted. Thus, the hemolysis is self-controlled, and anemia may only be mild or moderate, because these C3dg-coated RBCs are no longer capable of reacting with the IgM antibody in the cold, the C3dg-coated RBCs are not recognized by the macrophages, and low complement levels become rate limiting.

Temporary increases in complement levels, as can occur with intercurrent febrile illnesses, can increase hemolysis. Lytic components of complement C5-C9 generally do not form on these cells, and intravascular hemolysis by complement is less likely to occur.16 Hemolysis develops acutely following M pneumoniae infections and lasts approximately 1-3 weeks. Subclinical mild hemolysis with reticulocytosis may also occur, and the results of a direct Coombs test may be weakly positive, especially with M pneumoniae infections.

Monoclonal cold agglutinin IgM antibodies found in patients with lymphoma are the product of the abnormal clone. Progression of an idiopathic cold agglutinin disease to malignant lymphoma may occur in some cases; thus, affected patients require close long-term follow-up, with obvious therapeutic implications.9,14  One study of 86 patients in Norway showed clonal light chain predominance in 90% of patients, evidence of lymphoplasmacytic lymphoma in 50%, and lymphoma of any type in 76% overall.28

Hemolysis due to cold agglutinins can sometimes be accompanied by a warm antibody (IgG), resulting in a mixed autoimmune hemolytic anemia,9,13  that is, cold agglutinin syndrome and warm antibody autoimmune hemolysis, with the direct antiglobulin (direct Coombs) test results positive for the presence of both IgG and complement on the surface of the sensitized RBC. In mixed antibody syndromes, the IgG and IgM antibody components can be separated. The cold autoantibodies reactive at temperatures of 30°C or higher often show blood group specificity to the adult I antigen, whereas the warm autoantibodies are not directed against this system. A combination of cold agglutinins and cryoglobulins has also been reported with an IgM κ monoclonal antibody, with specificity to the Pr2 antigen system.20

Several factors play a role in determining the ability of a cold agglutinin to induce an active hemolytic anemia. These factors include the ability to initiate; the extent of antibody-induced complement activation; the concentration of the antibody; the range of temperatures, including the highest temperature at which the antibody interacts with the RBC (its thermal amplitude); the qualitative binding of IgM to the RBC; and modification of the antibody's ability to fix complement components onto the RBCs.10,28  In addition, the presence of biphasic hemolysins implicates more severe disease. Biphasic hemolysins bind to RBCs at low temperatures and activate complement to produce in vitro hemolysis at warmer temperatures (37°C), whereas monophasic hemolysins bind to RBCs and activate complement at the same temperature.29

In vitro studies have shown that human monoclonal antibodies encoded by the V4-34 gene segment not only have cold agglutinin properties, but they also exhibit multireactivity. This is in contrast to the generally monospecific I/i reactivity of sera from patients with cold agglutinin disease.19 Data have confirmed an immunomodulatory/immunosuppressive role of the naturally occurring anti-F(ab')2 antibodies in the production of cold agglutinins, with an inverse correlation between the titers of IgG-anti-F(ab')2 and cold agglutinins.18 This inverse correlation was found only in patients with anti-I/i and in the presence of a monoclonal lymphocyte population.

Frequency

United States

Low titers of cold agglutinins (1:64 or less) reactive at low temperatures are commonly found in the sera of healthy persons. Postinfectious elevations in the cold agglutinin titers (eg, M pneumoniae, Epstein-Barr virus [EBV], CMV) are transient. Cold agglutinins develop in more than 60% of patients with infectious mononucleosis, but hemolytic anemia is rare.

Development of the cold agglutinin syndrome is relatively uncommon, at least in the classic chronic form. Various reports state that 7-25% of cases of autoimmune hemolytic anemia are cold agglutinin mediated. Incidence of both cold and warm autoimmune hemolytic anemia (combined) is approximately 1 in 80,000; the incidence of cold agglutinin disease, which is approximately one fourth of the total, is approximately 1 in 300,000. Among autoimmune hemolytic anemias, cold agglutinin disease is the second most common cause, after warm autoantibody–induced immune hemolysis.

International

Data regarding incidence of cold agglutinin disease are lacking. Frequency figures listed for the United States probably also apply to Canada and the United Kingdom.

Mortality/Morbidity

Morbidity in chronic cold agglutinin disease is usually limited to symptoms precipitated by exposure to the cold. Transfusions for life-threatening symptoms due to severe anemia require prewarming and the use of washed RBCs (not cold). Occasionally, peripheral gangrene and, rarely, fatalities, have occurred after inadvertent and perhaps prolonged exposure to the cold.

Race

A racial predilection has not been reported for cold agglutinin disease.

Sex

Women are affected more commonly than men.4,9 The incidence of mixed autoimmune hemolysis has a male-to-female ratio of 1:1.5.

Age

Infants and children are rarely affected with chronic cold agglutinin disease, although M pneumoniae and infectious mononucleosis are diseases of young persons. Chronic cold agglutinin disease appears to affect adults who are of middle age and older, with an average age more commonly older than 60 years (peaking in the seventh and eighth decades of life). Although found in persons of all age groups, mixed autoimmune hemolysis is also more frequent in later life.

Clinical

History

  • A common complaint is painful fingers and toes with purplish discoloration associated with cold exposure. In chronic cold agglutinin disease, the patient is more symptomatic during the colder months.
  • Cold agglutinin – mediated acrocyanosis differs from Raynaud phenomenon. In Raynaud phenomena, caused by vasospasm, a triphasic color change occurs from white to blue to red based on vasculature response; no evidence of such a response exists in cold agglutinin disease.26
  • Chronic fatigue may also be a complaint, due to the anemia during those periods.
  • Respiratory symptoms may be present in patients with M pneumoniae infection.
  • Hemoglobinuria (the passage of dark urine that contains hemoglobin) may be rarely reported following prolonged exposure to cold; this is a result of hemolysis. This is more commonly seen in paroxysmal cold hemoglobinuria.
  • Other symptoms are related to the underlying disease state associated with the production of cold agglutinins. The severity of the clinical manifestations of the cold agglutinins themselves varies from an inconsequential laboratory finding in the benign variety to serious manifestations, such as acute hemolytic crises and Raynaud-type phenomena, with the more malignant variety.
  • History of weight loss, adenopathy, and other symptoms relate to the associated disease state.

Physical

  • Physical examination may reveal nothing unusual or only pallor, unless the patient is observed during or shortly after cold exposure. Purplish discoloration of the ears, forehead, tip of the nose, and digits may then be observed. Livedo reticularis has been observed as well.
  • Ischemic necrosis can lead to pain, but skin ulceration secondary to ischemia is uncommon.
  • Splenomegaly and jaundice, characteristic of lymphoproliferative disorders or infectious mononucleosis, may sometimes be observed in those with chronic cold agglutinin disease but are usually absent.
  • Lymphadenopathy, fever, or both may be present in patients with lymphoma, infectious mononucleosis, or other infections.
  • Pulmonary signs such as rales and fever may be found in patients with mycoplasma pneumonia.3,9,16 Other findings, including hepatomegaly, relate to the presence of underlying or associated disease states.

Causes

  • Classic chronic cold agglutinin is idiopathic, associated with symptoms and signs in relation to cold exposure.
  • Rarely, the first manifestations develop when the patient is subjected to hypothermia for cardiopulmonary bypass surgery.15
  • Transient acute hemolysis may occur secondary to certain infectious diseases, such as M pneumoniae infection and infectious mononucleosis (eg, EBV) infections. Other viral infections, such as influenza, HIV, CMV, rubella, varicella, and mumps, have been reported to be associated with a hemolytic anemia due to cold agglutinins. Other associated illnesses include subacute bacterial endocarditis, syphilis, and malaria. The development of a febrile illness in a patient with chronic cold agglutinin disease may also accelerate hemolysis.
  • Cold agglutinins are seen in CANOMAD syndrome (chronic ataxic neuropathy ophthalmoplegia M-protein agglutination disialosyl antibodies). CANOMAD syndrome is described by gait and upper-limb ataxia; cranial nerve involvement with external ophthalmoplegia; and the presence of cold agglutinins, IgM paraprotein, and anti-disialosyl antibodies.30 Both the neurologic and hematologic symptoms have been seen to respond to rituximab.31
  • Equestrian perniosis is a rare cause of persistent elevated titers of cold agglutinins.21
  • An idea of associated disease distribution is provided by a study of 78 patients with persistent cold agglutinins. Of these, 31 had lymphoma, 13 had Waldenstrom syndrome, 6 had chronic lymphocytic leukemia, and 24 had chronic idiopathic cold agglutinin disease.12 Thus, lymphoproliferative and autoimmune diseases, myeloma, Kaposi sarcoma, and angioimmunoblastic lymphoma may occasionally be associated with the production of cold agglutinins. A case of cold agglutinin – induced hemolytic anemia has been described in association with an aggressive natural killer-cell (NK-cell) leukemia.32 Nonhematologic malignancies can occasionally be associated with a high-titer cold agglutinin–induced hemolytic anemia.8,33
  • Cytogenetic studies in patients with cold agglutinin disease have revealed the presence of trisomy 3 and trisomy 12. Translocation (8;22) is also reported in association with cold agglutinin disease.28,34,35
  • Cold agglutinin–mediated hemolytic anemia has been described in patients after living-donor liver transplantation treated with tacrolimus and after bone marrow transplantation with cyclosporine treatments. It is postulated that such calcineurin inhibitors, that selectively affect T-cell function and spare B-lymphocytes, may interfere with the deletion of autoreactive T-cell clones, resulting in autoimmune disease.36,37,38
  • Cold agglutinin disease has been described in patients with sclerodermic features in which the degree of anemia is associated with increasing disease activity of the patient’s systemic sclerosis. This may suggest a close association between systemic rheumatic disease and autoimmune hematologic abnormalities.39
  • Hyperreactive malarial splenomegaly (HMS) is an immunopathologic complication of recurrent malarial infection. Patients with HMS develop splenomegaly, acquired clinical immunity to malaria, high serum concentrations of anti-Plasmodium antibodies, and high titers of IgM, with a complement-fixing IgM that acts as a cold agglutinin.40
  • Vaccination with diphtheria-pertussis-tetanus (DPT) vaccination has been implicated in the development of autoimmune hemolytic anemia caused by IgM autoantibody with a high thermal range. A total of 6 cases have been reported; 2 followed the initial vaccination and 4 followed the second or third vaccinations.24,41,42,43,44

More on Cold Agglutinin Disease

Overview: Cold Agglutinin Disease
Differential Diagnoses & Workup: Cold Agglutinin Disease
Treatment & Medication: Cold Agglutinin Disease
Follow-up: Cold Agglutinin Disease
Multimedia: Cold Agglutinin Disease
References
[ CLOSE WINDOW ]

References

  1. Landsteiner K. [Uber beziehunger dem Blutserum und den Korperzellen] [German]. Munch med Wochenschr. 1903;50:1812.

  2. Schobuthe H. Antikorperbedingte hamolytische anamian. Vehr Dtsch Ges Inn Med. 1952;50:679.

  3. Schubothe H. The cold hemagglutinin disease. Semin Hematol. Jan 1966;3(1):27-47. [Medline].

  4. Dacie J, The auto-immune haemolytic anaemias. The Haemolytic Anaemias. Vol 3. 3rd ed. Edinburgh, United Kingdom: Churchill Livingstone; 1992:210-362.

  5. 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].

  6. Angevine CD, Andersen BR, Barnett EV. A cold agglutinin of the IgA class. J Immunol. Apr 1966;96(4):578-86. [Medline].

  7. Garratty G, Petz LD, Hoops JK. The correlation of cold agglutinin titrations in saline and albumin with haemolytic anaemia. Br J Haematol. Apr 1977;35(4):587-95. [Medline].

  8. Wortman J, Rosse W, Logue G. Cold agglutinin autoimmune hemolytic anemia in nonhematologic malignancies. Am J Hematol. 1979;6(3):275-83. [Medline].

  9. Petz LD, Garratty G, eds. Acquired Immune Hemolytic Anemias. New York, NY: Churchill Livingstone; 1980:37-50.

  10. Rosse WF, Adams JP. The variability of hemolysis in the cold agglutinin syndrome. Blood. Sep 1980;56(3):409-16. [Medline]. [Full Text].

  11. Roelcke D. The Lud cold agglutinin: a further antibody recognizing N-acetylneuraminic acid-determined antigens not fully expressed at birth. Vox Sang. Nov-Dec 1981;41(5-6):316-8. [Medline].

  12. Crisp D, Pruzanski W. B-cell neoplasms with homogeneous cold-reacting antibodies (cold agglutinins). Am J Med. Jun 1982;72(6):915-22. [Medline].

  13. Sokol RJ, Hewitt S, Stamps BK. Autoimmune hemolysis: mixed warm and cold antibody type. Acta Haematol. 1983;69(4):266-74. [Medline].

  14. Roelcke D. Reaction of anti-Gd, anti-Fl and anti-Sa cold agglutinins with p erythrocytes. Vox Sang. 1984;46(3):161-4. [Medline].

  15. Agarwal SK, Ghosh PK, Gupta D. Cardiac surgery and cold-reactive proteins. Ann Thorac Surg. Oct 1995;60(4):1143-50. [Medline].

  16. Packman CH, Leddy JP. Cryopathic hemolytic syndromes. In: Beutler E, Lichtman M, Coller B, Kippst, eds. Williams Hematology. 5th ed. New York, NY: McGraw-Hill; 1995:685-91.

  17. Jacobs A. Cold agglutinin hemolysis responding to fludarabine therapy. Am J Hematol. Dec 1996;53(4):279-80. [Medline].

  18. 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. May 1997;17(3):220-7. [Medline].

  19. 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. Jan 1998;93(1):129-36. [Medline]. [Full Text].

  20. 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. Mar-Apr 1999;17(2):227-31. [Medline].

  21. De Silva BD, McLaren K, Doherty VR. Equestrian perniosis associated with cold agglutinins: a novel finding. Clin Exp Dermatol. Jun 2000;25(4):285-8. [Medline].

  22. Potter KN. Molecular characterization of cold agglutinins. Transfus Sci. Feb-Apr 2000;22(1-2):113-9. [Medline].

  23. 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. Dec 1993;92(6):2821-33. [Medline]. [Full Text].

  24. Berentsen S, Beiske K, Tjonnfjord GE. Primary chronic cold agglutinin disease: an update on pathogenesis, clinical features and therapy. Hematology. Oct 2007;12(5):361-70. [Medline]. [Full Text].

  25. Gertz MA. Management of cold haemolytic syndrome. Br J Haematol. Aug 2007;138(4):422-9. [Medline].

  26. McNicholl FP. Clinical syndromes associated with cold agglutinins. Transfus Sci. Feb-Apr 2000;22(1-2):125-33. [Medline].

  27. Maniatis A, Papayannopoulou T, Bertles JF. Fetal characteristics of erythrocytes in sickle cell anemia: an immunofluorescence study of individual cells. Blood. Jul 1979;54(1):159-68. [Medline]. [Full Text].

  28. Gertz MA. Cold agglutinin disease. Haematologica. Apr 2006;91(4):439-41. [Medline]. [Full Text].

  29. Sokol RJ, Booker DJ, Stamps R, Walewska R. Cold haemagglutinin disease: clinical significance of serum haemolysins. Clin Lab Haematol. Dec 2000;22(6):337-44. [Medline].

  30. Delval A, Stojkovic T, Vermersch P. Relapsing sensorimotor neuropathy with ophthalmoplegia, antidisialosyl antibodies, and extramembranous glomerulonephritis. Muscle Nerve. Feb 2006;33(2):274-7. [Medline].

  31. Siddiqui K, Cahalane E, Keogan M, Hardiman O. Chronic ataxic neuropathy with cold agglutinins: atypical phenotype and response to anti-CD20 antibodies. Neurology. Nov 11 2003;61(9):1307-8. [Medline].

  32. Skorupa A, Chaudhary UB, Lazarchick J. Cold agglutinin induced autoimmune hemolytic anemia and NK-cell leukemia: a new association. Am J Hematol. Jul 2007;82(7):668-71. [Medline]. [Full Text].

  33. Cao L, Kaiser P, Gustin D, Hoffman R, Feldman L. Cold agglutinin disease in a patient with uterine sarcoma. Am J Med Sci. Nov 2000;320(5):352-4. [Medline].

  34. 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. May 1998;76(5):201-4. [Medline].

  35. Chng WJ, Chen J, Lim S, et al. Translocation (8;22) in cold agglutinin disease associated with B-cell lymphoma. Cancer Genet Cytogenet. Jul 1 2004;152(1):66-9. [Medline].

  36. 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. Feb 2003;35(1):399-400. [Medline].

  37. Tamura T, Kanamori H, Yamazaki E, et al. Cold agglutinin disease following allogeneic bone marrow transplantation. Bone Marrow Transplant. Mar 1994;13(3):321-3. [Medline].

  38. Thomson AW, Bonham CA, Zeevi A. Mode of action of tacrolimus (FK506): molecular and cellular mechanisms. Ther Drug Monit. Dec 1995;17(6):584-91. [Medline].

  39. Oshima M, Maeda H, Morimoto K, Doi M, Kuwabara M. Low-titer cold agglutinin disease with systemic sclerosis. Intern Med. Feb 2004;43(2):139-42. [Medline]. [Full Text].

  40. 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. Mar 2003;97(2):125-30. [Medline].

  41. 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. May 2002;42(5):567-71. [Medline].

  42. Gunduz Gedikoglu A, Cantez T. Haemolytic-anaemia relapses after immunisation and pertussis. Lancet. Oct 21 1967;2(7521):894-5. [Medline].

  43. Zupanska B, Lawkowicz W, Gorska B, et al. Autoimmune haemolytic anaemia in children. Br J Haematol. Nov 1976;34(3):511-20. [Medline].

  44. Haneberg B, Matre R, Winsnes R, et al. Acute hemolytic anemia related to diphtheria-pertussis-tetanus vaccination. Acta Paediatr Scand. May 1978;67(3):345-50. [Medline].

  45. Hamblin T. Management of cold agglutination syndrome. Transfus Sci. Feb-Apr 2000;22(1-2):121-4. [Medline].

  46. Teachey DT, Felix CA. Development of cold agglutinin autoimmune hemolytic anemia during treatment for pediatric acute lymphoblastic leukemia. J Pediatr Hematol Oncol. Jul 2005;27(7):397-9. [Medline].

  47. Webster D, Ritchie B, Mant MJ. Prompt response to rituximab of severe hemolytic anemia with both cold and warm autoantibodies. Am J Hematol. Apr 2004;75(4):258-9. [Medline]. [Full Text].

  48. Berentsen S, Ulvestad E, Tjonnfjord GE. B-lymphocytes as targets for therapy in chronic cold agglutinin disease. Cardiovasc Hematol Disord Drug Targets. Sep 2007;7(3):219-27. [Medline].

  49. 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. Feb 2004;86(2):151-3. [Medline].

  50. Atkinson VP, Soeding P, Horne G, Tatoulis J. Cold agglutinins in cardiac surgery: management of myocardial protection and cardiopulmonary bypass. Ann Thorac Surg. Jan 2008;85(1):310-1. [Medline].

  51. Inaba H, Geiger TL, Lasater OE, Wang WC. A case of hemoglobin SC disease with cold agglutinin-induced hemolysis. Am J Hematol. Jan 2005;78(1):37-40. [Medline]. [Full Text].

  52. O'Connor BM, Clifford JS, Lawrence WD, Logue GL. Alpha-interferon for severe cold agglutinin disease. Ann Intern Med. Aug 1 1989;111(3):255-6. [Medline].

  53. Hippe E, Jensen KB, Olesen H, Lind K, Thomsen PE. Chlorambucil treatment of patients with cold agglutinin syndrome. Blood. Jan 1970;35(1):68-72. [Medline]. [Full Text].

  54. Aoki A, Kay GL, Zubiate P, Ruggio J, Kay JH. Cardiac operation without hypothermia for the patient with cold agglutinin. Chest. Nov 1993;104(5):1627-9. [Medline].

  55. Robinson KL, Marasco SF, Street AM. Practical management of anticoagulation, bleeding and blood product support for cardiac surgery. Part two: transfusion issues. Heart Lung Circ. 2002;11(1):42-51. [Medline].

  56. 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. Apr 2006;19(4):251-3. [Medline].

  57. Bossi E, Wagner HP. Autoimmune hemolytic anemia and cytomegalovirus infection in a six-months-old child, treated with azathioprine. Helv Paediatr Acta. Jun 1972;27(2):155-62. [Medline].

  58. Fest T, de Wazieres B, Lamy B, et al. Successful response to alpha-interferon 2b in a refractory IgM autoagglutinin-mediated hemolytic anemia. Ann Hematol. Sep 1994;69(3):147-9. [Medline].

  59. Geffray E, Najman A. [Efficacy of danazol in autoimmune hemolytic anemia with cold agglutinins. 4 cases] [French]. Presse Med. Sep 26 1992;21(31):1472-5. [Medline].

  60. Jefferies LC. Transfusion therapy in autoimmune hemolytic anemia. Hematol Oncol Clin North Am. Dec 1994;8(6):1087-104. [Medline].

  61. Mainwaring CJ, Walewska R, Snowden J, et al. Fatal cold anti-i autoimmune haemolytic anaemia complicating hairy cell leukaemia. Br J Haematol. Jun 2000;109(3):641-3. [Medline].

  62. 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. Oct 1 1992;149(7):2337-44. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

cold agglutinin disease, cold agglutinin hemolytic anemia, idiopathic acquired hemolytic anemia, autoimmune hemolytic anemia, hemolytic anemia, CAD, acrocyanosis, cold-induced immune hemolytic anemia, mixed autoimmune hemolysis,
Mycoplasma pneumoniae, M pneumoniae, infectious mononucleosis, Epstein-Barr virus, EBV, influenza, human immunodeficiency virus, HIV, cytomegalovirus, CMV, rubella, varicella, varicella zoster virus, mumps, subacute bacterial endocarditis, syphilis, malaria, equestrian perniosis,

lymphoma, Waldenstrom syndrome, chronic lymphocytic leukemia, CLL, lymphoproliferative disease, autoimmune disease, myeloma, Kaposi sarcoma, Kaposi's sarcoma, angioimmunoblastic lymphoma

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Sharon Georgy Gendi, MD, Intern, Internal Medicine Residency Program, University of South Florida
Sharon Georgy Gendi, MD is a member of the following medical societies: Phi Beta Kappa
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 Chest Physicians, American College of Occupational and Environmental Medicine, American College of Physicians, American Medical Association, and Florida Medical Association
Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Harry L Messmore, Jr, MD, Professor, Department of Medicine, Division of Hematology/Oncology, Loyola University Stritch School of Medicine
Harry L Messmore, Jr, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Angiology, American College of Physicians, American Heart Association, American Society of Hematology, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Medical Editor

Jeffrey Lee Kishiyama, MD, Assistant Clinical Professor of Medicine, University of California at San Francisco School of Medicine; Consulting Staff, Allergy and Asthma Associates of Santa Clara Valley Research Center
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Samuel R Marney, Jr, MD, Director, Associate Professor, Department of Internal Medicine, Division of Allergy and Immunology, Vanderbilt University School of Medicine
Samuel R Marney, Jr, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians, and Tennessee Medical Association
Disclosure: Nothing to disclose.

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Chief, Section of Allergy and Immunology, Washington Hospital Center; 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, and Association of American Physicians
Disclosure: Abbott Consulting fee Consulting; Alcon Consulting fee Consulting; Glaxo Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting; Schering Consulting fee Consulting; Teva  Consulting; Meda Honoraria Speaking and teaching

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.