Cold Agglutinin Disease Treatment & Management

Updated: Apr 21, 2017
  • Author: Salman Abdullah Aljubran, MD; Chief Editor: Michael A Kaliner, MD  more...
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Treatment

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

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

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.

Consultations

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.

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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

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.

Rituximab

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

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]

TNT003/TNT009

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. 

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Transfusions

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]

Pregnancy

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]

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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.

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Transfer

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.

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Deterrence

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.

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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
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