You are in: eMedicine Specialties >
Pediatrics: General Medicine > Hematology
Cold Agglutinin Disease
Article Last Updated: Jun 22, 2006
AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Thomas W Loew, MD, Director, Clinical Associate Professor of Pediatrics, Pediatric Hematology/Oncology Subspecialty Training Program, University of Iowa Hospitals and Clinics
Thomas W Loew is a member of the following medical societies: American Academy of Pediatrics, American College of Physician Executives, American Society of Clinical Oncology, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Coauthor(s):
Nicolas A Camilo, MD, Consulting Staff, Mountain States Tumor Institute, Division of Pediatric Hematology-Oncology, St Luke's Regional Medical Center
Editors: Gary R Jones, MD, Associate Medical Director, Clinical Development, Berlex Laboratories; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Gary D Crouch, MD, Program Director of Pediatric Hematology-Oncology Fellowship, Department of Pediatrics, Associate Professor, Uniformed Services University of the Health Sciences; Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University; Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center, Washington, DC; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Author and Editor Disclosure
Synonyms and related keywords:
cold agglutinin disease, cold antibody disease, autoimmune hemolytic anemia, chronic cold agglutinin disease, transient cold agglutinin disease
Background
Cold agglutinin disease is a form of autoimmune hemolytic anemia due to cold-reacting autoantibodies. Autoantibodies that bind to the erythrocyte membrane leading to premature erythrocyte destruction (hemolysis) characterize autoimmune hemolytic anemia. Autoimmune hemolytic anemia is classified as primary or secondary; it is subclassified according to the type of autoantibody.
In primary autoimmune hemolytic anemia, no underlying systemic disease explains the presence of autoantibodies, whereas secondary autoimmune hemolytic anemia results from a systemic disease. The autoantibody may be immunoglobulin G (IgG), immunoglobulin M (IgM), or, rarely, immunoglobulin A (IgA); it may be warm reacting or cold reacting. Autoimmune hemolytic anemia syndromes associated with cold-reacting autoantibodies include cold agglutinin disease and paroxysmal cold hemoglobinuria. Cold agglutinin disease is the subject of this article. IgM antibodies generally cause it. Paroxysmal cold hemoglobinuria is caused by IgG antibodies (Donath-Landsteiner antibody) and discussed in a separate eMedicine article (see Hemoglobinuria, Paroxysmal Cold).
Cold agglutinin disease is classified as primary (idiopathic) or secondary. 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 at approximately age 70 years. Secondary cold agglutinin disease may be associated with either monoclonal or polyclonal cold-reacting autoantibodies. Secondary cold agglutinin disease is predominantly caused by infection and lymphoproliferative disorders. Secondary cold agglutinin disease in children and young adults is usually transient and is caused by infection.
Pathophysiology
Cold agglutinins or cold autoantibodies occur naturally in nearly everyone. 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 is caused by pathologic cold-reacting autoantibodies—usually IgM, occasionally IgG, and rarely IgA. The autoantibodies may be polyclonal, with the presence of k and l light chains, or monoclonal, with a single type of light chain, most commonly k.
Primary cold agglutinin disease is usually associated with monoclonal cold-reacting autoantibodies. Secondary cold agglutinin disease may be associated with either monoclonal or polyclonal cold-reacting autoantibodies. The autoantibodies occur in a high concentration, resulting in hemolysis.
The hemolytic ability of an autoantibody depends on its thermal maximum, the highest temperature at which it binds the antigen on the red blood cell (RBC). Usually, no agglutination occurs at 37șC. Rarely, the thermal maximum may reach 37șC. For all cold-reacting antibodies, the antigen with which they react is polysaccharide or the polysaccharide parts of glycoproteins.
For cold agglutinins, the antigens are the i antigen, the I antigen, Pr antigens, and rare sialylated polysaccharides. The cold agglutinins of anti-I and anti-i specificity are strikingly similar to one another in the structure of the antigen-binding site. These antibodies all react with a monoclonal antibody that identifies the product of the VH4-34 gene segment. Other antibodies (eg, monoclonal anti-Rhesus system antibodies) use the same gene segment for the variable portion of the heavy chain and also have cold agglutinin activity against the i and I antigens. 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.
In primary cold agglutinin disease, the RBC antigen target is I. In secondary cold agglutinin disease, the RBC antigen target may be I or i. Less common RBC target antigens include Pr, Gd, F1, Vo, Li, Sa, Lud, M, N, Me, Om, D, Sdx, and P. Cold agglutinins attach to the RBCs in the peripheral cooler circulation and dissociate from the RBCs as the blood returns to the warmer central circulation.
The hemolysis is due to complement fixation. Fixation of autoantibody and complement occurs in the intravascular compartment when the blood temperature drops below the thermal maximum of the antibody. This can occur if the antibody has a high thermal maximum or if the patient is exposed to a colder environment. Fixation of complement components to the RBC membrane can result in extravascular or intravascular hemolysis.
Extravascular hemolysis occurs when activation and fixation of complement to the RBC membrane is insufficient to trigger activation of the membrane attack complex of complement. C3b and C4b present in the RBC surface interact with receptors in the phagocytes of the lungs, liver, and spleen, and the RBC is phagocytized. The liver is the predominant site of hemolysis.
Intravascular hemolysis occurs when complement fixation to the red cell membrane is in enough concentration to activate the membrane attack complex, resulting in lysis of the RBC, hemoglobinemia, hemoglobinuria, and hemosiderinuria. Clinical findings reflect the presence of anemia, hemolysis, and RBC agglutination, as well as the presence of an underlying disease.
Frequency
United States
Autoimmune hemolytic anemia has an annual incidence of 1 case per 80,000 persons. Cold agglutinin disease occurs in the pediatric population but is more frequent in the elderly population. Secondary cold agglutinin disease associated with infections is the type most commonly observed in children and young adults. Primary cold agglutinin disease is observed in older patients, usually in patients older than 50 years, with a peak incidence of 70 years of age and a slight female predilection.
Mortality/Morbidity
In general, autoimmune hemolytic anemia has a mortality rate of 10%.
- Mortality and morbidity appear higher in patients who are younger than 2 years or older than 12 years at the time of diagnosis.
- In children and young adults, cold agglutinin disease is usually self-limited, with acute hemolysis lasting 1-3 weeks and evidence of cold agglutinins disappearing within 6 months.
- In adults, cold agglutinin disease can be chronic.
Race
No racial predilection exists.
Sex
In general, no predilection exists for either sex, although some report a female predilection in older populations. Autoimmune hemolytic anemia appears to be more common in male children and female adolescents.
Age
Cold agglutinin disease occurs in the pediatric population but is more frequent in the elderly population.
History
Transient cold agglutinin disease may appear abruptly with anemia and hemoglobinuria. Recent or current symptoms of infection may be present. Chronic cold agglutinin disease has a gradual onset.
- Symptoms of anemia
- Pallor
- Fatigue
- Dyspnea
- Poor feeding
- Anemia, which may be mild, moderate, or severe
- Symptoms of hemolysis
- Jaundice
- Dark urine caused by hemoglobinuria
- Acrocyanosis, a purplish discoloration of the fingers, toes, nose, and ears, is precipitated by exposure to cold. Acrocyanosis occurs mostly in the chronic form of the disease and is due to intra-arteriolar agglutination of RBCs in relatively cool areas of the body.
Physical
- Anemia causes pallor. Signs of congestive heart failure or shock are rare but may be present when anemia is severe.
- Hemolysis causes jaundice, splenomegaly, and sometimes fever.
- Acrocyanosis may be evident in the fingertips, feet, earlobes, and nose.
- Fever, lymphadenopathy, or rash may reflect an underlying condition.
Causes
Cold agglutinin disease may be primary (idiopathic) or secondary, caused by infection, systemic autoimmunity, or neoplasm. Primary (idiopathic) cold agglutinin disease is associated with monoclonal autoantibodies. Secondary cold agglutinin disease can be associated with either monoclonal or polyclonal autoantibodies.
- Primary (idiopathic) cold agglutinin disease, monoclonal - Usually chronic, occurring in adults
- Secondary cold agglutinin disease, monoclonal - Usually chronic, occurring in adults (Cases of cold agglutinin disease in children with B-cell lymphoproliferative diseases [eg, acute lymphoblastic leukemia] induced by an associated infection have been reported.)
- B-cell neoplasms - Waldenström macroglobulinemia, lymphoma, chronic lymphoid leukemia, myeloma
- Nonhematologic neoplasms
- Secondary cold agglutinin disease, polyclonal - Usually acute, transient, and postinfectious, occurring in children and young adults
- Mycoplasma infections - Mycoplasma pneumoniae
- Viral infections - Infectious mononucleosis due to Epstein-Barr virus (EBV) or cytomegalovirus (CMV)
- Viral infections, other - Mumps, varicella, rubella, adenovirus, human immunodeficiency virus (HIV), influenza, hepatitis C
- Bacterial infections - Legionnaire disease, syphilis, listeriosis, Escherichia coli
- Parasitic infections - Malaria, trypanosomiasis
Anemia, Acute
Anemia, Chronic
Evans Syndrome
Lymphoproliferative Disorders
Non-Hodgkin Lymphoma
Paroxysmal Cold Hemoglobinuria
Systemic Lupus Erythematosus
Other Problems to be Considered
Autoimmune hemolytic anemia due to warm antibodies
Hemolytic Anemia
Lab Studies
- Hematology
- Anemia is usually mild. Exposure to cold may significantly worsen anemia. The mean corpuscular volume (MCV) is elevated because of reticulocytosis and to agglutination of the RBCs.
- Reticulocytosis may be inadequate for the degree of anemia. This may be due to decreased erythropoiesis caused by the underlying infection.
- Smear shows spherocytosis, polychromatophilia, and RBC agglutination.
- Marrow examination reveals erythroid hyperplasia and lymphocytosis. These lymphocytes have cold agglutinin as surface immunoglobulin. Marrow examination is usually unnecessary.
- Blood bank
- Blood typing is performed in the event that a transfusion is needed. The presence of autoantibodies may interfere with blood typing. The autoantibody may react with the RBCs of all potential donors, making detection of alloantibodies difficult. Several techniques are available to improve compatibility testing. These techniques include testing the patient's serum for anti-A and anti-B hemagglutinins and performing the compatibility testing reactions at 37ºC.
- Direct antiglobulin test (DAT) is positive with anti-C3 and negative with anti-IgG. The autoantibody is usually an IgM, but mixed IgG/IgM and occasionally IgA cold agglutinins can be present.
- Transient cold agglutinin disease is characterized by a moderately elevated cold agglutinin titer (1:1,000-20,000) and polyclonal cold agglutinins. The autoantibodies are anti-I in M pneumoniae infections and anti-i in EBV infections. The autoantibodies appear 2-3 weeks after onset of symptoms and disappear in 2-3 months.
- In chronic cold agglutinin disease, the cold agglutinin titer is very high (>1:100,000-1,000,000), and the cold agglutinins are monoclonal. In chronic cold agglutinin disease associated with monoclonal gammopathy and with chronic lymphocytic leukemia, the autoantibodies are monoclonal anti-I. In chronic cold agglutinin disease associated with malignant lymphomas, the autoantibodies are monoclonal anti-i.
- The autoantibodies are more reactive in the cold with diminishing reactivity as the temperature approaches 37ºC. Indirect antiglobulin test results at 37ºC are negative.
- A variant of cold agglutinin disease occurs in some patients. This variant is characterized by more severe disease, low cold agglutinin titer, and autoantibody with high thermal amplitude.
- Indirect bilirubin, lactic dehydrogenase (LDH), and plasma hemoglobin are moderately elevated.
- Urinalysis shows hemoglobinuria, hemosiderinuria, and elevated urobilinogen.
- Serology for mycoplasma, EBV, or CMV may be positive depending on the underlying cause.
Imaging Studies
- A chest radiograph is obtained if pneumonia is suspected. Chest radiography shows pulmonary infiltrates in cases of infection with M pneumoniae.
Medical Care
Treatment depends on severity of the disease and presence of an underlying cause.
- In children, cold agglutinin disease is usually mild and self-limited, requiring little, if any, intervention.
- Supportive care measures include avoiding exposure to cold and judicious use of RBC transfusions.
- RBC transfusion is indicated in acute severe disease.
- Compatibility testing is performed using the techniques described above to minimize the interference caused by the cold agglutinin (see Workup).
- Blood warmers are used to perform the transfusion at 37ºC.
- The response to transfused RBCs may be transient but can result in significant improvement in an acutely ill patient.
- Viral infections, such as EBV, CMV, and the mumps, are usually self-limited. Causes such as mycoplasma infection, systemic autoimmune disease, or lymphoproliferative disease must be treated.
- Prednisone therapy is seldom effective. Certain patients may respond to prednisone therapy, such as those who have the variant of cold agglutinin disease characterized by a low cold agglutinin titer and high thermal amplitude.
- Plasmapheresis may serve as a temporizing measure in severe cases of acute disease. Because IgM is confined to the intravascular space, plasmapheresis can reduce the autoantibody level; however, this reduction is very transient because of the continued production of autoantibody. The use of this procedure is very limited.
- The anti-CD20 monoclonal antibody rituximab depletes B-lymphocytes and, thereby, interferes with the production of cold agglutinin. The therapeutic use of rituximab has been studied, primarily in the older patient population, with chronic primary or secondary cold agglutinin disease.
- An adult with chronic secondary cold agglutinin disease has been reported to have been treated with an environmental suit obtained from the National Aeronautics and Space Administration (NASA).
Surgical Care
Splenectomy is ineffective because the liver is the predominant site of hemolysis.
Consultations
Consult a hematologist and/or blood bank specialist to aid in diagnostic workup and management.
Activity
Patients with anemia should avoid strenuous exercise. Prevent hypothermia and exposure to cold. Migration to avoid winter may be advisable.
Drug Category: Corticosteroids
These agents elicit anti-inflammatory and immunosuppressive properties, causing profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.
| Drug Name | Prednisone (Deltasone, Meticorten, Orasone) |
|---|
| Description | Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocyte and antibody production. May be beneficial in certain cases with low titer cold agglutinin of high thermal amplitude. |
|---|
| Adult Dose | 2 mg/kg/d PO divided bid/tid; 60 mg/d divided bid/tid |
|---|
| Pediatric Dose | 2 mg/kg/d PO divided bid/tid |
|---|
| Contraindications | Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction, connective tissue infections, and fungal or tubercular skin infections; GI bleeding or ulceration |
|---|
| Interactions | Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics |
|---|
| Pregnancy | B - Usually safe but benefits must outweigh the risks.
|
|---|
| Precautions | Abrupt discontinuation of glucocorticoids may cause adrenal crisis; use with caution in patients with hypertension, diabetes mellitus, hypothyroidism, cirrhosis, thromboembolism, and heart failure; may retard bone growth; periodically monitor blood pressure and blood glucose |
|---|
Further Inpatient Care
- Hospitalization is indicated in severe disease.
Further Outpatient Care
- Weekly until stable
- Clinical examination
- Complete blood count
- Reticulocyte count
- Urinalysis
- Monthly until resolution
- Clinical examination
- Complete blood count
- Reticulocyte count
- Urinalysis
- Direct antiglobulin test
- Cold agglutinin titer
Transfer
- Transfer patients with severe anemia to a facility where pediatric hematology/oncology, blood bank, and pediatric intensive care services are available.
Deterrence/Prevention
- Currently, prevention is not possible.
Complications
- Complications are rare. Severe hemolysis and anemia can result in congestive heart failure or shock.
Prognosis
- Secondary postinfectious cold agglutinin disease is a transient self-limiting condition.
- Secondary cold agglutinin disease associated with lymphoid neoplasms is chronic, and the prognosis depends on the underlying disorder. Treatment of the underlying lymphoid neoplasm may control the hemolysis. Lymphoid neoplasms can result in significant complications and death.
- Primary cold agglutinin disease is a chronic indolent disease, with remissions and exacerbations of hemolysis. B-cell neoplasms may eventually develop.
Patient Education
- Teach patients to observe for signs of anemia, such as dyspnea, palpitations, and pallor, and to observe for signs of hemolysis, such as jaundice and dark urine.
- Instruct patients to avoid exposure to cold and strenuous exercise.
- For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.
Medical/Legal Pitfalls
- The diagnosis of cold agglutinin disease is usually straightforward; however, some cases may be confused with warm-antibody autoimmune hemolytic anemia, particularly those cases in which the antibody has a high thermal amplitude.
- Limit the use of prednisone only to patients in whom an autoantibody with high thermal amplitude exists because these are the only patients likely to benefit from this drug. Overuse of prednisone may lead to unnecessary risk in patients who are unlikely to respond.
- Blood transfusion is indicated only for selected cases. Avoid unnecessary transfusions because the disease is usually self-limited. Risks of blood transfusion include transfusion reactions and transmission of infections.
- Avoid inappropriate use of plasmapheresis because this procedure is of very limited benefit.
- Reserve the use of rituximab for patients referred to a pediatric hematologist.
| Media file 1:
Blood smear showing spherocytic and agglutinated red blood cells. |
 |  View Full Size Image | |
Media type: Photo
|
- Berentsen S, Ulvestad E, Gjertsen BT, et al. Rituximab for primary chronic cold agglutinin disease: a prospective study of 37 courses of therapy in 27 patients. Blood. Apr 15 2004;103(8):2925-8. [Medline]. [Full Text].
- Camou F, Viallard JF, Pellegrin JL. [Rituximab in cold agglutinin disease]. Rev Med Interne. Aug 2003;24(8):501-4. [Medline].
- Gehrs BC, Friedberg RC. Autoimmune hemolytic anemia. Am J Hematol. Apr 2002;69(4):258-71. [Medline].
- Gertz MA. Cold agglutinin disease and cryoglobulinemia. Clin Lymphoma. Mar 2005;5(4):290-3. [Medline].
- Hadnagy C. Agewise distribution of idiopathic cold agglutinin disease. Z Gerontol. May-Jun 1993;26(3):199-201. [Medline].
- Hamblin T. Management of cold agglutination syndrome. Transfus Sci. Feb-Apr 2000;22(1-2):121-4. [Medline].
- Inaba H, Geiger TL, Lasater OE, Wang WC. A case of hemoglobin SC disease with cold agglutinin-induced hemolysis. Am J Hematol. Jan 2005;78(1):37-40.
- McNicholl FP. Clinical syndromes associated with cold agglutinins. Transfus Sci. Feb-Apr 2000;22(1-2):125-33. [Medline].
- Nanan R, Scheurlen W, Gerlich M, Huppertz HI. Severe low-titer cold-hemagglutinin disease responsive to steroid pulse therapy. Ann Hematol. Aug 1995;71(2):101-2. [Medline].
- Ness PM, Bell WR, Shirey RS. Transfusion medicine illustrated. Novel management of cold agglutinin disease. Transfusion. Jul 2003;43(7):839. [Medline].
- Nydegger UE, Kazatchkine MD, Miescher PA. Immunopathologic and clinical features of hemolytic anemia due to cold agglutinins. Semin Hematol. Jan 1991;28(1):66-77. [Medline].
- Potter KN. Molecular characterization of cold agglutinins. Transfus Sci. Feb-Apr 2000;22(1-2):113-9. [Medline].
- Rosse WF, Hillmen P, Schreiber AD. Immune-mediated hemolytic anemia. Hematology (Am Soc Hematol Educ Program). 2004;48-62. [Medline].
- Teachey DT, Felix CA. Development of cold agglutinin autoimmune hemolytic anemia during treatment for pediatric acute lymphoblastic leukemia. J Pediatr Hematol Oncol. Jul 2005;27(7):397-9.
- Terada K, Tanaka H, Mori R, et al. Hemolytic anemia associated with cold agglutinin during chickenpox and a review of the literature. J Pediatr Hematol Oncol. Mar-Apr 1998;20(2):149-51. [Medline].
- Vassou A, Alymara V, Chaidos A, Bourantas KL. Beneficial effect of rituximab in combination with oral cyclophosphamide in primary chronic cold agglutinin disease. Int J Hematol. Jun 2005;81(5):421-3. [Medline].
Cold Agglutinin Disease excerpt Article Last Updated: Jun 22, 2006
|
