Cold Agglutinin Disease Treatment & Management

  • Author: Sharon Georgy, MD; Chief Editor: Michael A Kaliner, MD   more...
 
Updated: Nov 15, 2010
 

Medical Care

Cold agglutinin disease may be managed successfully using protective measures (clothing) alone in most cases. Special protective clothing is sometimes necessary in extreme cases. Therapy is directed at serious symptoms and the underlying disorder, if any is found.

In general, keep in mind that the idiopathic variety of cold agglutinin disease is generally a benign disease with prolonged survival and spontaneous exacerbations and remissions in the course of the disease.

Treatment depends on the gravity of the symptoms as determined by the characteristics of the antibody and the presence of associated disease(s).

Glucocorticoids are generally not useful in IgM-induced cold agglutinin disease but may occasionally work if an underlying warm antibody–induced hemolytic anemia is present or if a high thermal amplitude, low titer cold agglutinin is present or (rarely) when a cold reactive IgG antibody is produced.

The possibility of missing a lymphoproliferative disorder if glucocorticoids are used before obtaining necessary biopsies should be kept in mind.

The authors currently do not recommend the use of chemotherapeutic or immunosuppressive agents in the routine management of idiopathic cold agglutinin disease because of its basic benign nature.

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 life or quality of life require active therapy. The presence of an associated malignancy requires specific therapy.

Chemotherapeutic agents should be used under appropriate circumstances, such as for an associated malignancy.

When the disease is chronic and idiopathic, one must weigh the need for therapy, as dictated by the severity of the symptoms, versus the potential long-term serious consequences of chemotherapeutic or other agents used to treat monoclonal lymphoid populations. Such decisions should be made in close collaboration with well-informed patients and their families.

Note: The authors advise extreme caution in selecting any chemotherapeutic or other immunosuppressive agents for the treatment of idiopathic cold agglutinin disease because of the potential long-term effects of these agents on the bone marrow stem cells and the leukemogenic effects of alkylating agents. The authors believe that such agents are not usually needed in the treatment of patients with idiopathic cold agglutinin disease.

If the use of glucocorticoids is contemplated, keep in mind that all necessary biopsies should be performed before the start of therapy.

Plasmapheresis effectively but temporarily removes and reduces the concentration of IgM antibody from plasma. This procedure is valuable for emergencies and allows time for drugs to have an effect, or plasmapheresis can be used to prepare patients for hypothermic surgical procedures.[15] 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.[46] The specifics of each exchange (ie, volume, frequency, duration) must be individualized, planned by an appropriate consultant, and monitored closely.

When cold agglutinin disease is secondary, as in infectious disease or lymphoma, treatment is directed at avoidance of cold along with appropriate treatment of the underlying malignancy.

Cold agglutinin disease is so uncommon in children that no specific recommendations for therapy are available.

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, a chimeric anti-CD20 antibody, has been administered to patients with cold agglutinin disease with prompt response in case studies. One case series suggested higher response rates than were previously achieved with alkylators, glucocorticoids, or purine nucleoside analogues.[28, 47]

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, are being studied in combination therapy with rituximab for the treatment of primary cold agglutinin disease to achieve higher response rates and prolonged remission.[24, 48]

Intravenous immunoglobulin (IVIG) was used successfully in an infant with IgA-associated autoimmune hemolytic anemia.[49]

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Surgical Care

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.

Ischemic necrosis of fingertips or nose may require plastic surgery repair.

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

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. Preoperative preparation of the patient by reducing the titer of the cold agglutinin to reduce its effective thermal amplitude may be needed.

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. Techniques employing normothermic cardiopulmonary bypass and continuous warm blood cardioplegia have been successful.[50]

In general, transfusions should be avoided and should be reserved for patients with symptomatic anemia or a rapidly falling hematocrit value. Thus, most patients are unlikely to require a blood transfusion.

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

Washed (removes 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. Also, prescribe 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 is imminent. An in-line blood warmer is useful, as is performing the entire transfusion at 37°C whenever feasible.

Transfused RBCs may have increased susceptibility to lysis by cold agglutinins, in comparison to autologous RBCs, because they lack proteolytically cleaved complement on their surface. This may inhibit complement-mediated lysis.[51]

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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Consultations

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

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Diet

Patients should include good sources of folic acid, such as fresh fruits and vegetables, in their diet.

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Activity

Activities should be less strenuous compared with those for healthy people, particularly for patients with anemia. Jogging in the cold could be very hazardous because of the added windchill factor.

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Contributor Information and Disclosures
Author

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

Sharon Georgy, 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  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.

Specialty Editor Board

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.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

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.

Timothy D Rice, MD  Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, St 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: Alcon Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting; Schering/Merck Consulting fee Consulting; Teva Consulting fee Consulting; Meda Honoraria Speaking and teaching; Ista Consulting

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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.
 
 
 
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