Cold Agglutinin Disease


Practice Essentials

Cold agglutinin disease is a rare form of autoimmune hemolytic anemia caused by cold-reacting autoantibodies. Autoantibodies that bind to the erythrocyte membrane leading to premature erythrocyte destruction (hemolysis) characterize autoimmune hemolytic anemia. (See Pathophysiology and Etiology.) Peripheral blood smears may reveal clumps of red blood cells (RBCs). See the image below.

View Image

Peripheral blood smear showing several clumps of RBCs with the largest in the center. These are typical of aggregates seen in persons with cold agglut....

A common complaint among patients with cold agglutinin disease 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. See Presentation.

Autoimmune hemolytic anemia is classified as primary or secondary and is subclassified according to autoantibody type. Primary cold agglutinin disease is characterized by a clonal lymphoproliferative disorder.[1, 2] Secondary cold agglutinin syndrome results from a systemic disease—infection or malignancy.[3]

In 90% of cases, the autoantibody in cold agglutinin disease is immunoglobulin M (IgM); rarely, it may involve monoclonal immunoglobulin G (IgG), immunoglobulin A (IgA), or λ light chain restriction. In contrast, warm autoimmune hemolytic anemia predominantly involves IgG.[1] Donath-Landsteiner hemolytic anemia is also caused by a cold-reacting immunoglobulin, but most cases are due to polyclonal IgG.[1]  

Another autoimmune hemolytic anemia syndrome associated with cold-reacting autoantibodies is paroxysmal cold hemoglobinuria, which involves the IgG Donath-Landsteiner (D-L) antibody. Unlike cold agglutinin disease, in which affected RBCs are removed via extravascular phagocytosis, paroxysmal cold hemoglobinuria involves intravascular hemolysis. (See DDx.)

Primary and secondary disease

Primary cold agglutinin disease is usually associated with monoclonal cold-reacting autoantibodies. Primary cold agglutinin disease is chronic and occurs after the fifth decade of life, with a peak incidence in the seventh and eighth decades. (See Epidemiology.)

Secondary cold agglutinin disease may be associated with either monoclonal or polyclonal cold-reacting autoantibodies. It predominantly is caused by infection and lymphoproliferative disorders. Monoclonal secondary disease is usually chronic, occurring in adults. Polyclonal secondary cold agglutinin disease, which occurs in children and young adults, is usually transient. (See Etiology and Prognosis.)


Idiopathic cold agglutinin disease is usually benign, and most patients need only take protective measures against cold temperatures. Case studies report benefit from treatment with rituximab or the complement inhibitor eculizumab. RBC transfusion is indicated in severe, acute disease. Glucocorticoids are generally not useful in IgM-induced cold agglutinin disease but may occasionally work in selected patients. The presence of an associated malignancy requires specific therapy. See Treatment and Medication.


Cold agglutinins, or cold autoantibodies, occur naturally in nearly all individuals. These natural cold autoantibodies occur at low titers, less than 1:64 measured at 4°C, and have no activity at higher temperatures. Pathologic cold agglutinins occur at titers over 1:1000 and react at 28-31°C and sometimes at 37°C.

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

Because the I antigen is not activated until after birth, anti-i autoantibodies predominantly agglutinate neonatal RBCs, and anti-I autoantibodies predominantly agglutinate adult RBCs.

VH genes

The 9G4 idiotope is localized to the V4-34 encoded portion of the variable region.[21] 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 the V4-34 portion.[22, 23]

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.

In vitro studies have shown that human monoclonal antibodies encoded by the V4-34 gene segment not only have cold agglutinin properties but also exhibit multireactivity. This is in contrast to the generally monospecific I/i reactivity of sera from patients with cold agglutinin disease.[18]

Associated infections

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.[24]

Some polyclonal IgM cold agglutinins arise in association with infections with Mycoplasma pneumoniae, infectious mononucleosis, influenza B, and human immunodeficiency virus (HIV), as well as with other infections. (Cold agglutinins develop in more than 60% of patients with infectious mononucleosis, but hemolytic anemia is rare.)

Cytomegalovirus (CMV), rubella virus, varicella-zoster virus (VZV), parvovirus B19, and Chlamydia psittaci have also been implicated.[25]

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.[25] Furthermore, increased expression of I/i antigens have been described on hemoglobin SS (HbSS) erythrocytes, which suggests that such patients may have increased susceptibility to cold-mediated hemolysis.[26]

Antigen specificity

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.[27]

In a study of 78 patients, κ light-chain specificity was found in the majority of patients with chronic cold agglutinin disease or Waldenström macroglobulinemia, whereas two thirds of cold agglutinins found in patients with lymphomas had λ 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) was anti-I, but 75% of IgM/λ had other antigen specificities.[11]

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.[7, 10, 13] Exclusive occurrence of κ chains has also been shown with some cold agglutinins.[6] Thus, benign and malignant cold agglutinins exhibit differences in their light chains and their specificities toward membrane antigens.

Association of complement fixation with temperature

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 than 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.

Complement levels in hemolysis

In chronic cold agglutinin disease, complement tends to be depleted. Thus, the hemolysis is self-controlled, and anemia may be only 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.[15] 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.

Idiopathic disease and lymphoma

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.[27, 13] One study of 86 patients in Norway showed clonal light-chain predominance in 90% of patients, evidence of lymphoplasmacytic lymphoma in 50% of patients, and lymphoma of any type in 76% of patients overall.[1]

Warm-cold antibody combinations

Hemolysis due to cold agglutinins can sometimes be accompanied by a warm antibody (IgG), resulting in a mixed autoimmune hemolytic anemia,[27, 12] that is, cold agglutinin syndrome and warm antibody autoimmune hemolysis, with the direct antiglobulin (direct Coombs) test results positive for the presence of 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.[19]

Biphasic hemolysins

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.[28]

Modulation of agglutinin production

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.[17] This inverse correlation was found only in patients with anti-I/i and in the presence of a monoclonal lymphocyte population.

Requirements for induction of active hemolytic anemia

Several factors play a role in determining the ability of a cold agglutinin to induce an active hemolytic anemia.[4, 1] These include the following:


Cold agglutinins develop in more than 60% of patients with infectious mononucleosis, but hemolytic anemia is rare.

Classic chronic cold agglutinin disease is idiopathic, associated with symptoms and signs in relation to cold exposure. Causes of the monoclonal secondary disease include the following:

Causes of polyclonal secondary cold agglutinin disease include the following:

Bacterial and viral infections

Transient acute hemolysis may occur secondary to certain infectious diseases, such as M pneumoniae infection and infectious mononucleosis (eg, EBV). Other viral infections, such as influenza, HIV, CMV, rubella, varicella, and mumps, have also been reported to be associated with a hemolytic anemia due to cold agglutinins. Associated illnesses also 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.

CANOMAD syndrome

Cold agglutinins are seen in CANOMAD syndrome (chronic ataxic neuropathy ophthalmoplegia M-protein agglutination disialosyl antibodies). This 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.[31] The neurologic and hematologic symptoms have been seen to respond to rituximab.[32]


Lymphoproliferative and autoimmune diseases, myeloma, Kaposi sarcoma, and angioimmunoblastic lymphoma may occasionally be associated with the production of cold agglutinins. An idea of associated disease distribution was provided by a study of 78 patients with persistent cold agglutinins. Among these patients, 31 had lymphoma, 13 had Waldenström macroglobulinemia, 6 had chronic lymphoid leukemia, and 28 had chronic idiopathic cold agglutinin disease.[11]

A case of cold agglutinin–induced hemolytic anemia has been described in association with an aggressive natural killer cell (NK-cell) leukemia.[33] Nonhematologic malignancies can occasionally be associated with a high-titer cold agglutinin–induced hemolytic anemia.[9, 34]

Trisomy and translocation

Cytogenetic studies in patients with cold agglutinin disease have revealed the presence of trisomy 3 and trisomy 12. Translocation (8;22) has also been reported in association with cold agglutinin disease.[1, 35, 36]


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, which selectively affect T-cell function and spare B-lymphocytes, may interfere with the deletion of autoreactive T-cell clones, resulting in autoimmune disease.[37, 38, 39]

Systemic sclerosis

Cold agglutinin disease has been described in patients with sclerodermic features, with the degree of anemia being 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.[40]

Hyperreactive malarial splenomegaly

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.[41]

DPT vaccination

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.[23, 42, 43, 44, 45]


Equestrian perniosis is a rare cause of persistent elevated titers of cold agglutinins.[20] Also rarely, the first manifestations of cold agglutinin disease can develop when a patient is subjected to hypothermia for cardiopulmonary bypass surgery.[14]


Occurrence in the United States

The development of 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. Thus, while the incidence of cold and warm autoimmune hemolytic anemia (combined) is approximately 1 in 80,000, the incidence of cold agglutinin disease 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 occurrence

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

Sex- and age-related demographics

In general, no predilection for either sex is noted, although some report a female predilection in older populations. Autoimmune hemolytic anemia appears to be more common in male children and female adolescents.[5, 27]

Only rarely do Infants and children develop chronic cold agglutinin disease, although Mycoplasma pneumoniae and infectious mononucleosis are diseases of young persons. Chronic cold agglutinin disease typically affects adults who are of middle age and older, with an average age of older than 60 years and 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.


Cold agglutinin disease may be associated with an excellent long-term prognosis if it is secondary to M pneumonia or viral infections that are, in themselves, self-limited. In children and young adults, acute hemolysis lasts 1-3 weeks; evidence of cold agglutinins disappears within 6 months.

Patients with the mildly to moderately severe primary (idiopathic) variety of cold agglutinin disease are expected to have a good long-term prognosis if excessive exposure to cold is avoided and with close medical surveillance for complications or progression to lymphoma.

The nature of the antigenic specificity of the cold agglutinin, as when it is directed against the Pr antigen system, may be associated with greater severity of disease.

Cold agglutinin disease associated with HIV infection may have a relatively poor prognosis due to the nature of the underlying disease. The same applies to cases associated with lymphoma, with the prognosis dependent on remission of the underlying malignancy.

Morbidity and mortality

Complications of cold agglutinin disease include the following:

Transfusions for life-threatening symptoms due to severe anemia require prewarming and the use of washed RBCs (not cold). In general, autoimmune hemolytic anemia has a mortality rate of 10%.

A study by Kamesaki et al indicated that the clinical characteristics of patients with autoimmune hemolytic anemia who have a positive direct Coombs test (direct antiglobulin test [DAT]) differ from those of patients with this type of anemia and a negative DAT. The report used data from 216 patients with autoimmune hemolytic anemia, including 154 who were DAT negative and 62 who were DAT positive.[46]

The investigators found that patients who were DAT negative tended to have milder anemia and hemolysis than did patients who were DAT positive and that they needed significantly lower steroid doses during maintenance treatment. The 2 groups of patients were found to have an equally good response to steroids. Survival at 1-year follow-up for each group was comparable to that of the other.

Patient Education

It is essential to educate patients with chronic cold agglutinin disease about the importance of keeping all body parts warm at all times and avoiding cooling of body parts. Appropriate clothing is necessary in cold environments, and avoidance of cold foods and working in cold storage areas is also important.

Patients must comprehend the importance of their daily folic acid intake, which supplies a needed hematinic. Folic acid could easily become a rate-limiting hematinic in a patient with a chronic hemolytic process.

Teach patients to watch for signs of anemia, such as dyspnea, palpitations, and pallor, and to observe for signs of hemolysis, such as jaundice and dark urine.

For patient education information, see Anemia.


A common complaint among patients with cold agglutinin disease 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.[25]

Other symptoms of cold agglutinin disease include the following:

Anemia in patients with cold agglutinin disease may be mild, moderate, or severe. Along with fatigue, symptoms of anemia include pallor, dyspnea, and poor feeding.

Other symptoms of cold agglutinin disease, such as a history of weight loss and adenopathy, can be 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 cases of the benign variety, to serious manifestations, such as acute hemolytic crises and Raynaud-type phenomena, in cases of the more malignant variety.

Physical Examination

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 seen. 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, are usually absent, but they may sometimes be observed in patients with chronic cold agglutinin disease.

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.[27, 15, 47] Other findings, including hepatomegaly, relate to the presence of underlying or associated disease states. Signs of congestive heart failure or shock are rare but may be present when anemia is severe.

Approach Considerations

Ensure proper handling of specimens when looking for cold agglutinins (ie, keeping the blood warm until it is tested). Blood specimens are commonly placed in a laboratory refrigerator until they are tested, but this practice must be avoided when testing for cold agglutinins. Blood studies used in the diagnosis of cold agglutinin disease include the following:

Note that the direct Coombs test (direct antiglobulin test [DAT]) should be performed with samples at 35-37°C, using polyspecific and monospecific Coombs sera, including monospecific anti-C3 and IgG antisera.

Significant findings on other blood tests include the following:


Perform urinalysis with microscopic assessment for red blood cells (RBCs) and a chemical test for hemoglobin to differentiate between hematuria and hemoglobinuria. Urinalysis can reveal hemoglobinuria, hemosiderinuria, and elevated urobilinogen.

Processing only fresh urine samples is an important means of avoiding in vitro hemolysis of RBCs in the urine, leading to an incorrect diagnosis of hemoglobinuria.

Urine immunoelectrophoresis should be performed if serum globulins are abnormal; only a 24-hour urine sample can be used to conclusively exclude the presence of light chains.

Imaging studies

A chest radiograph is obtained if pneumonia is suggested; pulmonary infiltrates are found in cases of Mycoplasma pneumoniae infection. Findings may also indicate lymphadenopathy. Computed tomography (CT) scans of the chest and abdomen are performed to assess for lymphadenopathy and splenomegaly when lymphoma is suggested.

Complete Blood Cell Count and Peripheral Smear

If the cold agglutinin is operative at room temperature, then a falsely high mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC) with a low RBC count are obtained due to agglutination of RBCs in the cold automated counter.

Agglutination may also be seen in anticoagulated blood at room temperature. This agglutination worsens with storage and cooling of blood to 4°C and disappears rapidly upon warming the blood to 37°C, unlike with rouleaux formation. Repeating the complete blood count (CBC) after warming the blood to 37°C avoids this problem. Thus, the clinical laboratory is frequently the first to report the presence of a cold agglutinin. Agglutination in the cold may also interfere with typing and cross-matching of blood.

In patients with chronic cold agglutinin disease, a mild to moderate stable anemia is present; occasionally, the anemia is severe. Leukocytosis may be evident during hemolytic episodes. Peripheral blood smears may reveal clumps of RBCs (see the image below).

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Peripheral blood smear showing several clumps of RBCs with the largest in the center. These are typical of aggregates seen in persons with cold agglut....

Reticulocytes and Spherocytes

The results of the reticulocyte count are usually increased in patients with cold agglutinin disease, with polychromasia in the peripheral blood smear. The mean corpuscular volume (MCV) is elevated because of reticulocytosis, as well as agglutination of the RBCs.

However, reticulocytosis may be inadequate for the degree of anemia in the patient. This may be due to decreased erythropoiesis caused by an underlying infection.

Spherocytes may be present, although less prominently than in warm autoantibody–induced hemolytic anemias. (See the image below).

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Blood smear showing spherocytic and agglutinated red blood cells.

Blood Typing

Blood typing is performed in the event that a transfusion is needed. The presence of autoantibodies may interfere with blood typing because they may react with the RBCs of potential donors, making detection of alloantibodies difficult. Several techniques are available to improve compatibility testing. These include testing the patient's serum for anti-A and anti-B hemagglutinins and performing the compatibility testing reactions at 37°C to avoid inaccurate test results due to nonspecific agglutination in the cold.

Electrophoresis and Immunoelectrophoresis

Perform serum protein electrophoresis and serum immunoelectrophoresis (immunofixation) as initial tests to look for a dysproteinemia.

Quantitation of serum levels of IgG, IgA, and IgM should follow when a dysproteinemia is suggested based on results from the first 2 tests. These test results may be normal or abnormal (increased IgM with κ or λ light chains).

Careful sample processing, avoiding exposure of blood to the cold, and maintaining the blood at 37°C before testing is essential. If the blood sample is cooled and not kept warm from the time it is collected to the time it is tested, the cold agglutinin attaches to the RBCs and is removed from the serum, causing a false-negative result.

Cold Agglutinin Titers

With the cold agglutinin titer, a titer of greater than 1:64 is considered abnormal when blood is tested at 4°C. Obtain the cold agglutinin titers also at 30°C and 37°C, when needed. Testing at temperatures higher than 4°C is extremely valuable, particularly if the patient is to undergo hypothermia for surgery.

Cold agglutinin disease is usually associated with very high cold agglutinin titers of greater than 1:10,000 at 4°C, with a thermal amplitude of up to 30-32°C. The addition of bovine serum albumin (BSA) while testing for the cold agglutinin titer and thermal amplitude results in a better correlation with clinical hemolytic anemia than does obtaining data in the absence of BSA, using saline-suspended cells.[8]

Infectious and Vascular Disease Testing

Tests for the following infectious diseases can be performed if these disorders are being considered in the etiology of cold agglutinin disease:

If collagen vascular disease is a possibility, blood tests for the following disorders should be performed:


Perform bone marrow aspiration and biopsy only when they are needed to exclude certain neoplastic or immunoproliferative diseases. Flow cytometry studies of bone marrow are helpful in defining the presence of an abnormal monoclonal population of lymphocytes.

A lymph node biopsy is necessary when unexplained lymphadenopathy is present. Fine-needle aspiration is not reliable in comparison with excision of the largest lymph node for diagnostic purposes; nodal architecture is important for making an accurate diagnosis and is preserved in a lymph node biopsy. The addition of flow cytometry to define the presence of 1 or more abnormal monoclonal lymphocyte populations is also useful.


Depending on the underlying precipitating illness, changes may be seen in the bone marrow and lymph nodes of patients with cold agglutinin disease. The presence of a malignant lymphoproliferative disorder may also be evident in biopsy samples. Clumps of RBCs may be observed in the peripheral smear. (See the images below.)

View Image

Peripheral blood smear showing several clumps of RBCs with the largest in the center. These are typical of aggregates seen in persons with cold agglut....

View Image

Blood smear showing spherocytic and agglutinated red blood cells.

Approach Considerations

The treatment of cold agglutinin disease depends on the gravity of the clinical manifestations, as determined by the characteristics of the antibody and the presence of associated disease(s). Most patients with cold agglutinin disease can manage their disorder successfully just by wearing appropriate clothing and avoiding cold exposure. Special protective clothing is sometimes necessary in extreme cases. Therapy is directed at serious symptoms and, in cases of secondary cold agglutinin disease, to the underlying disorder.

Keep in mind that the idiopathic variety of cold agglutinin disease is generally a benign disorder with prolonged survival. Spontaneous exacerbations and remissions in the course of the disease are to be expected. Acute postinfectious syndromes usually resolve spontaneously.

Anemia is generally mild. Only patients who have serious symptoms related to anemia or have a Raynaud-type syndrome that constitutes a threat to health or quality of life require active therapy.

Case studies report benefit from treatment with rituximab or the complement inhibitor eculizumab. Red blood cell (RBC) transfusion is indicated in severe, acute disease. Glucocorticoids are generally not useful in IgM-induced cold agglutinin disease but may occasionally work in selected patients. The presence of an associated malignancy requires specific therapy.

Cold agglutinin disease is so uncommon in children that no specific recommendations for therapy are available. Intravenous immunoglobulin (IVIG) was used successfully in an infant with IgA-associated autoimmune hemolytic anemia.[49]


Plasmapheresis effectively, albeit temporarily, removes IgM antibody from plasma, reducing its concentration. This procedure is valuable for emergencies and allows time for drugs to have an effect. Plasmapheresis can also be used to prepare patients for hypothermic surgical procedures.[14, 50]

Plasmapheresis is effective because the autoantibodies, which are most often IgM, are loosely bound to the erythrocytes, and IgM antibodies are incapable of diffusing into the extravascular space.[51] The specifics of each exchange (ie, volume, frequency, duration) must be individualized, planned by an appropriate consultant, and monitored closely.


Splenectomy is usually ineffective for the treatment of cold agglutinin disease, because the liver is the predominant site of sequestration. However, if the patient has splenomegaly, then the disease may respond to splenectomy. More importantly, a lymphoma localized to the spleen may only be found after splenectomy.

Diet and activity

Patients with cold agglutinin disease should include good sources of folic acid, such as fresh fruits and vegetables, in their diet. Activities for these individuals should be less strenuous than those for healthy people, particularly for patients with anemia. Jogging in the cold could be very hazardous because of the added wind chill factor.


A hematologist-oncologist working in collaboration with a blood banker is helpful in complicated cases of cold agglutinin disease.

Careful planning and coordination with multiple personnel are needed if patients are to undergo a procedure during which their body temperature could fall.

Chemotherapy and Immunosuppression

Chemotherapeutic agents should be used under appropriate circumstances, such as for an associated malignancy. However, the authors currently do not recommend the use of chemotherapeutic or immunosuppressive agents in the routine management of idiopathic cold agglutinin disease. Such agents are not usually needed in these cases; they provide little benefit, given the basic benign nature of the disease, and they pose high risk because of their potential long-term adverse effects on bone marrow stem cells, including the leukemogenic effects of alkylating agents.

When idiopathic cold agglutinin disease is sufficiently severe that one must weigh the need for therapy, such decisions should be made in close collaboration with patients and their families. Patients need to be fully informed about the adverse effects of chemotherapeutic or other agents used to treat monoclonal lymphoid populations. If they decide to proceed with therapy, the agents used must be selected with extreme caution.


Glucocorticoids are generally not useful in IgM-induced cold agglutinin disease but may occasionally work in patients with one of the following:

If the use of glucocorticoids is contemplated, all necessary biopsies should be performed before starting therapy. Administering steroids before obtaining necessary biopsies risks obscuring a lymphoproliferative disorder. In patients who are pregnant, avoid all cytotoxic therapy or immunosuppressive therapy other than glucocorticoids because of the potential teratogenic effects on the fetus and the long-term effects on the mother.


The anti-CD20 monoclonal antibody rituximab depletes B-lymphocytes, thereby interfering with the production of cold agglutinin.[52] In case studies, patients with cold agglutinin disease have responded to treatment with rituximab. One case series suggests higher response rates than were previously achieved with alkylators, glucocorticoids, or purine nucleoside analogues.[1, 53]

Studies demonstrate a response rate of 54% with a median response duration of 11 months when rituximab is used as a single agent. Purine analogs, such as fludarabine, in combination with rituximab, induced a 76% response rate in an uncontrolled small prospective trial of 29 subjects.[23, 54, 55]


Eculizumab, a monoclonal antibody that inhibits the complement terminal pathway, has been used in case studies to treat paroxysmal nocturnal hemoglobinuria. It also is effective in subjects with transfusion-dependent cold agglutinin disease refractory to rituximab.[1] One case report describes the successful use of eculizumab as a bridge to rituximab therapy in a subject with severe complement-mediated hemolysis whose hemodynamic status deteriorated in spite of supportive blood transfusions and therapeutic plasma exchange.[56] Eculizumab  was safe and tolerated in 13 subjects with cold agglutinin disease enrolled in a prospective, controlled, non-randomized, multicenter phase II trial (DECAD).[57]


In preclinical studies, TNT003, a murine monoclonal antibody, prevented extravascular hemolysis medicated by C3, primarily responsible for hemolysis in cold agglutinin disease.[58, 59] TNT009, a humanized form of TNT003, improved the hematological parameters of subjects treated with TNT009 in an interim analysis of an ongoing phase Ib trial.[60] These results look promising for future treatment. 


Avoid unnecessary transfusions, because cold agglutinin disease is usually self-limited. Risks of blood transfusion include transfusion reactions and transmission of infections.

Red blood cell (RBC) transfusion is indicated in severe, acute disease. The response to transfused RBCs may be transient, but it can result in significant improvement in an acutely ill patient.

Washed (to remove complement), warmed RBCs may be transfused for cardiovascular indications (ie, heart failure) or ischemic conditions in any part of the body requiring increased oxygen-carrying capacity. These patients should also be prescribed bed rest and oxygen therapy.

Transfusions should be attempted with caution, starting with a slow rate of infusion initially and discontinuing the procedure if a significant reaction appears imminent. An in-line blood warmer is useful, as is performing the entire transfusion at 37°C whenever feasible.

Typing and cross-matching may be very difficult because of clumping of the RBCs at room temperature in patients with a high thermal amplitude cold agglutinin. Therefore, all cross-matching (compatibility testing) should be performed at 37°C, with IgG-specific antiglobulin reagents used to avoid misleading results due to the cold agglutinin in the serum and the RBC-bound C3d.

Transfused RBCs may have increased susceptibility to lysis by cold agglutinins, compared with autologous RBCs, because they lack proteolytically cleaved complement on their surface. This may inhibit complement-mediated lysis.[61]


When cold-induced autoimmune hemolytic anemia occurs in pregnant women, the pregnancy may be continued with frequent blood transfusions. Transfusions may be continued until the thirty-seventh week, when fetal lungs have matured. Mode of delivery is not affected by the anemia and should be defined by obstetric indications. Ironically, these women are still subject to thrombophlebitis of pregnancy.[62]

Management of Surgical Patients

Critical planning is needed if a patient with a high titer, high thermal amplitude cold agglutinin requires cooling for cardiovascular surgery. Antibody activation may lead to hemolysis, renal failure, hepatic failure, and myocardial or cerebral infarctions.

The temperature below which antibody activation occurs should be quantified preoperatively. These patients may require monitoring of core body temperatures to avoid cooling to temperatures at which the cold agglutinin is still active. Reducing the titer of the cold agglutinin to lower its effective thermal amplitude may be needed during preoperative preparation of the patient.

Ambient operating room temperatures usually result in cooling of the patient and require close attention.

In patients requiring bypass surgery, a high titer of cold agglutinin is reduced by a combination of plasmapheresis and hemodilution achieved by standard techniques used in open-heart surgery. The laboratory can help to assess the temperature range of cold agglutinin activity after the titer has been reduced so that a minimum target temperature may be estimated. Surgical techniques employing normothermic cardiopulmonary bypass and continuous warm blood cardioplegia have been successful.[63, 64]

In one study at the Mayo Clinic of 16 patients undergoing cardiopulmonary bypass procedures, 6 patients were found to have cold hemagglutinin disease. In 3 of the patients, cold agglutinin detection was made intraoperatively. The lowest recorded intraoperative core temperature, in 1 case, was under 34° C. None of the patients had evidence of permanent myocardial dysfunction, had a neurologic event, required dialysis, or died within 30 days.[65]

The authors of the Mayo study noted that patients with cold hemagglutinin disease should undergo laboratory testing, including cold agglutinin titers and thermal amplitude, and hematology consultation before cardiac surgery is begun. One patient underwent preoperative plasma exchange. In 2 of 16 procedures that utilized cardioplegia, cold blood cardioplegia was used; in the other procedures, warmer blood cardioplegia was used. One patient experienced cold agglutinin-related postoperative hemolysis requiring transfusion, which was resolved with active warming.[65]

Organs that are used for transplantation (eg, kidneys) are usually kept cool with cold perfusate to preserve organ function. However, if patients with cold agglutinin disease require transplants, the organs may require perfusion with warm solutions before the transplantation, to prevent cold-induced damage by the cold agglutinin present in the recipient.


Transfer is necessary if an institution is unable to handle the needs of a patient with a high titer, high thermal amplitude cold agglutinin hemolytic anemia who requires open heart surgery—which is usually performed under hypothermic conditions—and needs monitoring of thermal amplitude and core body temperature. Consultation with a hematologist and the support of a blood bank are also required.

Transfer patients with severe anemia to a facility where pediatric hematology/oncology, blood bank, and pediatric intensive care services are available.


Idiopathic cold agglutinin disease itself cannot be prevented. Protective measures for patients with cold agglutinin disease include avoidance of cold by covering the hands; feet; and, if possible, face in cold weather or low wind-chill temperatures.

An exact temperature cannot be defined, because symptoms are due to the thermal amplitude and other characteristics of the antibody. In some individuals, a wind-chill temperature of 15°C, if sustained, precipitates symptoms; more commonly, a temperature of 10°C would precipitate symptoms. Sleeping uncovered may result in symptoms when the room temperature is 21°C.

Recommendations to move to a warm climate have merit in severe cases in which symptoms and hemolysis are less likely to develop at higher ambient temperatures.

For patients with cold agglutinin disease, avoid cooling blankets for any reason; in rare cases, these may precipitate gangrene.

Long-Term Monitoring

Long-term follow-up care, with or without therapy, is a vital aspect of managing cold agglutinin disease. Vigilance for the development of systemic symptoms of any lymphoproliferative disorder is necessary. Follow-up also includes monitoring for infection, declining renal function, and evidence of ischemia. Among the findings that indicate the need for follow-up care are the following:

Monitor patients periodically for signs of worsening or improvement that might prompt changes in management. The frequency of reassessment varies with the severity of the disease. Periodic checkups may vary from daily to weekly to monthly and may eventually occur as infrequently as every 2-3 months. Make reevaluations more often in colder weather than in warmer weather.

The following tests can be performed weekly until the patient’s condition is stable:

The following tests can be performed monthly until the cold agglutinin disease has resolved:

Medication Summary

Folic acid supplementation is advisable in individuals with cold agglutinin disease to meet the increased requirements for red blood cell production, due to hemolytic anemia.

Immunosuppressive and immunomodulating drugs are seldom necessary; however, in cases with underlying malignancies, these agents are required to treat the malignancy. Potent immunosuppression to reduce the production of monoclonal antibody and to reduce/eliminate the abnormal lymphocyte clone has been achieved with cyclophosphamide (1200 mg) and vincristine (2 mg) administered intravenously (IV) on day 1 and prednisone (80 mg/d) administered orally for 5 days, with some beneficial effect in an anecdotal case.[16]

The same patient was treated 10 months later with IV fludarabine (25 mg/m2) daily for 5 days and then every 28 days for 3 courses. Following a third course of treatment, the patient went into remission that lasted for at least 4 years.[16]

Corticosteroids alone may not be routinely useful in patients with cold agglutinin disease, although occasionally a patient may have a clinical response. Patients with mixed cold and warm immune hemolytic anemia are more likely to have a response because of the warm antibody component.

The corticosteroid-sparing agent chlorambucil has also been used to treat cold agglutinin disease.[66]

Rituximab and fludarabine

Rituximab has been widely recognized as being very effective for treating cold agglutinin disease. One study documented a high response rate and durable remissions following therapy using a combination of fludarabine and rituximab. While the results from this study appear positive, extreme caution should be exercised, because the immunosuppressive effects of rituximab superimpose on those of fludarabine.[55]

Bear in mind that one uncommon reported adverse effect of fludarabine is the appearance of a warm autoantibody–induced autoimmune hemolytic anemia. However, in the authors' experience, patients with Coombs-positive hemolytic anemias have been treated effectively with fludarabine. Responses to interferon alfa therapy have been reported. This therapy may be useful for some B-cell neoplasms.[67]


The reader is advised to read the package insert approved by the US Food and Drug Administration (FDA) before using any of the agents listed.

In general, the use of chemotherapeutic agents—which have long-term consequences for the patient and are associated with secondary malignancies, such as leukemias, that are hard to treat—requires very careful decision making in collaboration with a well-informed patient. These agents should be used only for life-threatening, severely symptomatic disease. Therapy also may need to be administered intermittently or infrequently, as the case demands. Tailor therapy to individual needs.

Although alkylating agents have been used in the past and references to these treatments are part of standard texts, the authors suggest that these drugs not be used in patients with cold agglutinin disease, because of the potential for long-term adverse effects from such therapy.

Identifying the proper drug for use in a patient depends on patient characteristics and patient participation in the decision-making process. No guarantees of success can be given with any therapy in cold agglutinin disease.


Clinical Context:  This agent is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells. Cystitis can develop with long-term administration, and the leukemogenic potential should be kept in mind. The primary (idiopathic) form of cold agglutinin disease is unlikely to require use of this class of drugs.

Class Summary

The metabolites of immunosuppressive alkylating agents cross-link DNA, thereby interfering with cell proliferation. These agents are not needed in patients with idiopathic cold agglutinin disease. Immunosuppressant agents also include antibodies directed against the CD20 antigen found on the surface of B-lymphocytes.


Clinical Context:  This agent is an immunosuppressant used for the treatment of autoimmune or lymphoproliferative disorders. Prednisone modulates lymphocytes and decreases antibody production. It is frequently used with alkylating agents.

Prednisone may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte activity. It stabilizes lysosomal membranes and suppresses lymphocyte and antibody production. Prednisone may be beneficial in certain cases with low-titer cold agglutinin of high thermal amplitude.

Class Summary

These agents elicit anti-inflammatory and immunosuppressive properties, causing profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Interferon alfa-2b (Intron-A)

Clinical Context:  Interferon alfa is manufactured by recombinant DNA technology. Its mechanism of effect is not clearly understood. However, direct antiproliferative effects against many different kinds of malignant cells have been shown in clinical disease states (eg, lymphoma, melanoma, chronic granulocytic leukemia), and modulation of the host immune response may play an important role.

Class Summary

Interferons have had variable success in cold agglutinin–induced hemolytic anemia. Expense and serious adverse effects are issues to consider up front before choosing this class of drug. Interferons are used in the treatment of lymphoproliferative disorders.

Folic acid (Folacin-800)

Clinical Context:  Folic acid is an important cofactor for enzymes used in the production of RBCs. Chronic hemolytic process requires additional folate.

Class Summary

Water-soluble vitamins are necessary for hematopoiesis.

Rituximab (Rituxan)

Clinical Context:  Effective lowering of IgM and IgG levels is achievable with this anti–B cell antibody. Hypersensitivity reactions can be severe; users of the drug should become completely familiar with the adverse reactions known to occur.

Class Summary

Immunosuppressive agents include antibodies that are directed against the CD20 antigen found on the surface of B-lymphocytes.


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

Disclosure: Nothing to disclose.


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

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

Disclosure: Nothing to disclose.


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

Disclosure: Nothing to disclose.

Max J Coppes, MD, PhD, MBA Senior Vice President, Center for Cancer and Blood Disorders, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University School of Medicine; Clinical Professor of Pediatrics, George Washington University School of Medicine and Health Sciences

Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Gary D Crouch, MD Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences

Gary D Crouch, MD is a member of the following medical societies: American Academy of Pediatrics and American Society of Hematology

Disclosure: Nothing to disclose.

Sharon Georgy, MD Resident Physician, Department of Internal Medicine, University of South Florida College of Medicine

Sharon Georgy, MD is a member of the following medical societies: Phi Beta Kappa

Disclosure: Nothing to disclose.

James L Harper, MD Associate Professor, Department of Pediatrics, Division of Hematology/Oncology and Bone Marrow Transplantation, Associate Chairman for Education, Department of Pediatrics, University of Nebraska Medical Center; Assistant Clinical Professor, Department of Pediatrics, Creighton University School of Medicine; Director, Continuing Medical Education, Children's Memorial Hospital; Pediatric Director, Nebraska Regional Hemophilia Treatment Center

James L Harper, MD is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Federation for Clinical Research, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Council on Medical Student Education in Pediatrics, and Hemophilia and Thrombosis Research Society

Disclosure: Nothing to disclose.

Gary R Jones, MD Associate Medical Director, Clinical Development, Berlex Laboratories

Gary R Jones, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Pediatric Hematology/Oncology, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Jeffrey Lee Kishiyama, MD Assistant Clinical Professor of Medicine, University of California, San Francisco, School of Medicine; Consulting Staff, Allergy and Asthma Associates of Santa Clara Valley Research Center

Disclosure: Nothing to disclose.

Thomas W Loew, MD Director, Clinical Associate Professor of Pediatrics, Pediatric Hematology/Oncology Subspecialty Training Program, University of Iowa Hospitals and Clinics

Disclosure: Nothing to disclose.

Rajalaxmi McKenna, MD, FACP Southwest Medical Consultants, SC, Department of Medicine, 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.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.


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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.

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.

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.

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.