Cold Agglutinin Disease Treatment & Management

Updated: Feb 07, 2022
  • Author: James Carson Collie, MD; Chief Editor: Michael A Kaliner, MD  more...
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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; this may have to include avoiding cold food and beverages and wearing gloves to remove food from the refrigerator or freezer. [47] 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.

Rituximab has become the most accepted first-line therapy for cold agglutinin disease, although it is not approved for this indication in the United States or Europe. In prospective nonrandomized studies, approximately 50% of patients showed partial response to rituximab; complete response was rare. Response duration ranged from 2 to 42 months (median, 6.5 to 11 months). In relatively fit patients who are severely affected by cold agglutinin disease, rituximab may be combined with bendamustine. [48]

Small trials report benefit from treatment with the complement inhibitor eculizumab. The complement inhibitor sutimlimab, which selectively targets and inhibits C1s, was approved by the US Food and Drug Administration (FDA) in February 2022. It is indicated to decrease the need for red blood cell (RBC) transfusion in patients with hemolysis associated with cold agglutinin disease.  

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. However, patients who do respond often require unacceptably high maintenance doses for sustained response. [48] 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 antibodies 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. Rarely, splenectomy may be effective in some cases of IgG-mediated disease or in patients with a thermal amplitude approaching 37°C. [48] 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.


Pharmacologic Therapy

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.


The anti-CD20 monoclonal antibody rituximab depletes B-lymphocytes, thereby interfering with the production of cold agglutinin. [52]  In two prospective, nonrandomized studies, approximately 50% of patients with cold agglutinin disease showed partial response to treatment with rituximab; complete response was rare, however. Median response duration was 11 months (range, 2-42 months). Rituximab is given a dose of 375 mg/m2 for four cycles at 1-week intervals. [48]

The purine analog fludarabine, in combination with rituximab, induced a 76% response rate in an uncontrolled small prospective trial of 29 subjects; however, 14% of the patients experienced grade 4 neutropenia and as many as 59% experienced infection grade 1–3. [23, 53]   [54]  Long-term fludarabine toxicity is also a concern. [48]  

The combination of rituximab with the alkylating agent bendamustine has demonstrated efficacy and safety. In a prospective, nonrandomized trial, 32 of 45 patients (71%) responded; 18 (40%) achieved complete response (CR) and 14 (31%), a partial response. Of patients previously treated with rituximab alone or combined with fludarabine, 7 of 14 (50%) responded to bendamustine-rituximab, with three complete responses and four partial responses. The regimen in this study was rituximab, 375 mg/m2 on day 1, and bendamustine, 90 mg/m2 days 1 and 2 for four cycles at a 28-day interval. [55]  Thus, rituximab plus bendamustine might be considered in relatively fit patients who are severely affected by cold agglutinin disease.

The First International Consensus Group on diagnosis and therapy of autoimmune hemolytic anemia recommends rituximab, with or without bendamustine, for first-line treatment of patients with cold agglutinin disease who require therapy. [56]  


Sutimlimab was approved by the FDA in February 2022 to decrease the need for RBC transfusions in patients with hemolysis associated with cold agglutinin disease. It is a humanized monoclonal antibody directed against complement factor C1s and inhibits the classical complement pathway, which is activated in cold agglutinin disease. [57]  In the open-label phase III Cardinal trial, sutimlimab demonstrated a rapid and sustained treatment effect, preventing hemolysis, significantly increasing hemoglobin, and improving quality of life. Of the 24 patients enrolled in the study, 54% met the composite endpoint criteria, with 62.5% achieving a hemoglobin of 12 g/dL or higher or an increase of at least 2 g/dL; 83% achieved a clinically significant mean hemoglobin improvement of ≥1 g/dL. Additionally, 71% remained transfusion-free after the fifth week of treatment. [58, 59]

An open-label study of long-term maintenance treatment (2 to 20 months) in seven patients with cold agglutinin disease who had been transfusion dependent found that sutimlimab was safe, effectively inhibited hemolysis, and significantly increased hemoglobin levels. No treatment-related serious adverse events occurred and no untoward drug interactions were reported in patients receiving overlapping treatment with erythropoietin, rituximab, or ibrutinib. [60]


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 despite supportive blood transfusions and therapeutic plasma exchange. [61]

Eculizumab was safe and tolerated in 13 subjects with cold agglutinin disease enrolled in a prospective, controlled, non-randomized, multicenter phase II trial (DECAD); however, although intravascular hemolysis was significantly inhibited and most patients became transfusion independent, anemia and quality of life scores did not improve significantly. [62]


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

  • An underlying warm antibody–induced hemolytic anemia
  • A high thermal amplitude, low-titer cold agglutinin
  • A cold-reactive IgG antibody (rare)

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. 



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. [63]


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. [64]


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 the 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. [65, 66]

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. [67]

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. [67]

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:

  • Postinfectious anemia
  • Infectious mononucleosis
  • Mycoplasma pneumoniae infection
  • Acrocyanosis
  • Cold-precipitated symptoms

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:

  • Clinical examination
  • Complete blood cell count (CBC)
  • Reticulocyte count
  • Urinalysis

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

  • Clinical examination
  • CBC
  • Reticulocyte count
  • Urinalysis
  • Direct antiglobulin test
  • Cold agglutinin titer