Pediatric Cold Agglutinin Disease 

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, to a much lesser extent, paroxysmal cold hemoglobinuria (most paroxysmal cold hemoglobinuria cases are not caused by a cold agglutinin). Cold agglutinin disease is the subject of this article.

IgM antibodies generally cause cold agglutinin disease. Donath-Landsteiner hemolytic anemia (previously referred to as paroxysmal cold hemoglobinuria) is caused by IgG antibodies and is discussed in a separate eMedicine article.

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.

Cold agglutinins or cold autoantibodies occur naturally in nearly all individuals. 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 κ and λ light chains, or monoclonal, with a single type of light chain, most commonly κ. Whereas 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 hemolytic ability of an autoantibody depends on its thermal maximum, the highest temperature at which it binds the antigen on the RBC. Usually, no agglutination occurs at 37ºC. 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. See the image below.

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 may occur 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 is noted.

Sex

In general, no predilection for either sex is noted, 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.