COLD AGGLUTINATION:

Background
Cold agglutinin disease is a form of autoimmune hemolytic anemia caused by 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 and is subclassified according to
autoantibody type.
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. (See the image
below.)

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.
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.)
IgM antibodies generally cause cold agglutinin disease. Donath-Landsteiner hemolytic anemia
(previously referred to as paroxysmal cold hemoglobinuria) is caused by IgG antibodies.
Primary and secondary disease
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 in the seventh and eighth decades. (See Epidemiology.)
Secondary cold agglutinin disease may be associated with either monoclonal or polyclonal cold-
reacting autoantibodies. It predominantly is caused by infection and lymphoproliferative
disorders. Monoclonal secondary disease is usually chronic, occurring in adults. Polyclonal
secondary cold agglutinin disease, which occurs in children and young adults, is usually
transient.
Requirements for induction of active hemolytic anemia
Several factors play a role in determining the ability of a cold agglutinin to induce an active
hemolytic anemia.
[1, 2]
These include the following:
Ability to initiate
Extent of antibody-induced complement activation
Concentration of the antibody
Range of temperatures, including the highest temperature at which the antibody interacts with
the RBC (its thermal amplitude)
Qualitative binding of IgM to the RBC
Modification of the antibody's ability to fix complement components onto the RBCs
History
A common complaint among patients with cold agglutinin disease is painful fingers and toes
with purplish discoloration associated with cold exposure. In chronic cold agglutinin disease, the
patient is more symptomatic during the colder months.
Cold agglutininmediated acrocyanosis differs from Raynaud phenomenon. In Raynaud
phenomena, caused by vasospasm, a triphasic color change occurs, from white to blue to red,
based on vasculature response. No evidence of such a response exists in cold agglutinin
disease.
[24]

Other symptoms of cold agglutinin disease include the following:
Respiratory symptoms - May be present in patients with M pneumoniae infection
Hemoglobinuria (the passage of dark urine that contains hemoglobin) - A rare symptom
that results from hemolysis, this may be reported following prolonged exposure to cold;
hemoglobinuria is more commonly seen in paroxysmal cold hemoglobinuria
Chronic fatigue - Due to anemia
Anemia in patients with cold agglutinin disease may be mild, moderate, or severe. Along with
fatigue, symptoms of anemia include pallor, dyspnea, and poor feeding.
Other symptoms of cold agglutinin disease, such as a history of weight loss and adenopathy, can
be related to the underlying disease state associated with the production of cold agglutinins.
The severity of the clinical manifestations of the cold agglutinins themselves varies from an
inconsequential laboratory finding, in cases of the benign variety, to serious manifestations, such
as acute hemolytic crises and Raynaud-type phenomena, in cases of the more malignant variety.

Patient Education
It is essential to educate patients with chronic cold agglutinin disease about the importance of
keeping all body parts warm at all times and avoiding cooling of body parts. Appropriate
clothing is necessary in cold environments, and avoidance of cold foods and working in cold
storage areas is also important.
Patients must comprehend the importance of their daily folic acid intake, which supplies a
needed hematinic. Folic acid could easily become a rate-limiting hematinic in a patient with a
chronic hemolytic process.
Teach patients to watch for signs of anemia, such as dyspnea, palpitations, and pallor, and to
observe for signs of hemolysis, such as jaundice and dark urine.

















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