eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Cold Agglutinin Disease: Treatment & Medication

Author: Sharon Georgy, MD, Resident Physician, Department of Internal Medicine, University of South Florida
Coauthor(s): Richard F Lockey, MD, University Distinguished Health Professor, Professor of Medicine, Pediatrics and Public Health, Joy McCann Culverhouse Chair in Allergy and Immunology, University of South Florida College of Medicine; Director, Division of Allergy and Immunology, James A Haley Veterans' Hospital; Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems; Harry L Messmore, Jr, MD, Professor, Department of Medicine, Division of Hematology/Oncology, Loyola University Stritch School of Medicine
Contributor Information and Disclosures

Updated: Feb 16, 2009

Treatment

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

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.

Consultations

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

Diet

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

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.

Medication

Folic acid supplementation is advisable in individuals with cold agglutinin disease to meet the increased requirements of increased RBC 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 (PO) for 5 days, with some beneficial effect in an anecdotal case.17 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 at least 4 years.17

Bear in mind that one uncommon reported adverse effect of fludarabine is the appearance of a warm autoantibody–induced autoimmune hemolytic anemia. However, according to the authors' experience, persons 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.52

Chlorambucil has also been used to treat cold agglutinin disease.53 Corticosteroids alone may not be routinely useful in all 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.

In general, 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. Only currently used drugs are discussed. These will change as newer drugs become available for use.

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 of such therapy for an essentially benign disorder.

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.

Immunosuppressive Alkylating Agents

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.


Cyclophosphamide (Cytoxan)

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; the leukemogenic potential should be kept in mind. Primary (idiopathic) form of the disease is unlikely to require use of this class of drugs.

Adult

Dose should be determined based on the combination regimen used to treat the underlying malignancy when cold agglutinin disease is secondary to an underlying malignancy

Pediatric

Not established

Allopurinol may enhance myelosuppressive effects; may reduce digoxin serum levels and antimicrobial effects of quinolones; coadministration with high doses of phenobarbital may increase leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; coadministration with succinylcholine may increase neuromuscular blockade by inhibiting cholinesterase activity

Documented hypersensitivity; severely depressed bone marrow function

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Monitor for hematopoietic suppression with regular examination of the patient's hematologic profile (particularly neutrophils and platelets); regularly examine the urine for RBCs, which may precede hemorrhagic cystitis.

During chemotherapy, encourage patients to empty their bladder at night before bedtime and to drink plenty of water to maintain good diuresis.

Glucocorticoids

Glucocorticoids are used for their immunosuppressant properties.


Prednisone (Deltasone, Sterapred, Meticorten)

Immunosuppressant for treatment of autoimmune or lymphoproliferative disorders. Modulates lymphocytes and decreases antibody production. Frequently used with alkylating agents.

Adult

60-80 mg/d (up to 1-2 mg/kg/d) PO as starting dose; used for suppression of antibody production; taper dosages after several weeks, with close monitoring of adverse effects; determine dosing regimen based on the multidrug regimen chosen to treat specific the underlying malignancy

Pediatric

Not established

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase the metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with the coadministration of diuretics.

Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI disease

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia (potential contraindication, assess each patient carefully), edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur with glucocorticoid use; sleep deprivation/alteration in sleep cycle common; check potassium levels and advise patients to eat plenty of fruits and vegetables to obtain adequate potassium; weight gain due to stimulation of appetite is possibly a serious issue (advise patients of this possibility); watch for development of depression; occasionally, mania or altered sleep cycle may occur; muscle weakness and wasting may become a serious problem; hypertension can be exacerbated by steroids

Interferons

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.


Interferon alfa-2b (Intron-A)

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. Interferon alfa is manufactured by recombinant DNA technology. 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, CGL) and modulation of host immune response may play important roles.

Adult

3-5 million U/m2 SC 3 times/wk; tailor dosage as tolerated based on adverse effects (dosage has been used in lymphoproliferative disorders)

Pediatric

Not established

Potential risk of renal failure when administered concurrently with interleukin-2; theophylline may increase toxicity by reducing clearance; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity

Documented hypersensitivity (anaphylactic sensitivity to mouse immunoglobulin [IgG], egg protein, or neomycin); autoimmune hepatitis, presence of severe depression

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Depression and suicidal ideation may be adverse effects, but the drug may sometimes be tolerated by patients with depression (decide on an individual basis); before initiation of therapy, perform CBC count for platelets, Hb/Hct, and WBC with differential; monitor periodically during treatment to determine response to treatment; monitor for hypothyroidism; past history of severe depression may warrant caution because of risk of recurrence; caution in cardiac arrhythmias

Vitamin, Water Soluble

Water-soluble vitamins are necessary for hematopoiesis.


Folic acid (Folvite)

Important cofactor for enzymes used in the production of RBCs. Chronic hemolytic process requires additional folate.

Adult

1 mg PO qd; up to 5 mg PO qd, depending on frequency and aggressiveness of hemolysis

Pediatric

Not established

Increase in seizure frequency and subtherapeutic levels of phenytoin reported when used concurrently

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Benzyl alcohol may be contained in some products as a preservative (associated with fatal gasping syndrome in premature infants); resistance to treatment may occur in patients with alcoholism and deficiencies of other vitamins

Immunosuppressant Agent

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


Rituximab (Rituxan)

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.

Adult

375 mg/m2 IV qwk for 4 doses (days 1, 8, 15, 22)

Pediatric

Not established

Coadministration with cisplatin is known to cause severe renal toxicity including acute renal failure; may interfere with immune response to live virus vaccine (MMR) and reduce efficacy (do not administer within 3 months of vaccine)

Documented hypersensitivity; IgE-mediated reaction to murine proteins

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Use with caution in patients with dormant infections such as hepatitis B, hepatitis C, or CMV due to risk of reactivation; hypotension, bronchospasm, and angioedema may occur, premedication with acetaminophen and diphenhydramine may decrease incidence; discontinue treatment if life-threatening cardiac arrhythmias occur; must administer by slow IV infusion, do not administer IV push or bolus

More on Cold Agglutinin Disease

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

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  62. Pascual V, Victor K, Spellerberg M, et al. VH restriction among human cold agglutinins. The VH4-21 gene segment is required to encode anti-I and anti-i specificities. J Immunol. Oct 1 1992;149(7):2337-44. [Medline].

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Further Reading

Related eMedicine Topics

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Keywords

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

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

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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.

Medical Editor

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

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

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

CME Editor

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

Chief Editor

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Chief, Section of Allergy and Immunology, Washington Hospital Center; Medical Director, Institute for Asthma and Allergy
Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, and Association of American Physicians
Disclosure: Abbott Consulting fee Consulting; Alcon Consulting fee Consulting; Glaxo Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting; Schering Consulting fee Consulting; Teva  Consulting; Meda Honoraria Speaking and teaching

 
 
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