NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine and Carlo Brugnara, MD, Professor of Pathology, Harvard Medical School; Medical Director of the Hematology Laboratory, Department of Laboratory Medicine, Boston Children’s Hospital, for assistance in the preparation of this report.
Cold agglutinin disease (CAD) is a rare autoimmune disorder characterized by the premature destruction of red blood cells (hemolysis). Autoimmune diseases occur when one’s own immune system attacks healthy tissue. More specifically, CAD is a subtype of autoimmune hemolytic anemia. In this type of disorder, red blood cells are “tagged” by antibodies and are then destroyed by other types of immune cells. The disease is termed “cold” because the antibodies are active and cause hemolysis at cold temperatures, usually 3 to 4oC (37 to 39oF), which is not necessarily the case in other types of autoimmune hemolytic anemia. CAD affects about one person per million every year, and mostly develops between the ages of 40 and 80 years. Normally, the red blood cells have a life span of approximately 120 days before they are destroyed by the spleen. In individuals with CAD, the red blood cells are destroyed prematurely and the rate of production of new cells in the bone marrow can no longer compensate for their loss. A decreased number of red blood cells (anemia) may cause fatigue, weakness, a pale skin color (pallor), dizziness, palpitations, and shortness of breath (dyspnea). Hemolysis leads to an increased release from red blood cells of hemoglobin, a protein responsible for carrying oxygen in the blood. Degradation of hemoglobin into bilirubin can result in yellowing of the skin and whites of the eyes (jaundice). Hemoglobin can also pass in the urine and give it a dark brown color. Other symptoms that can be triggered by exposure to cold include sweating and coldness of the fingers and/or toes (digits) and painful bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud sign). Treatment of CAD includes avoidance of cold temperatures, treating anemia and hemolysis (if needed) and medications that modulate the immune system to decrease the production of antibodies against red blood cells. If applicable, the underlying disease that caused CAD should be treated.
CAD typically develops in individuals between the age of 40 and 80, and is more common in elderly individuals. The symptoms associated with the disease are mostly the result of either hemolysis or circulatory symptoms, both of which are triggered by exposure to cold temperatures. Some individuals, especially those with mild hemolysis and a gradual onset of anemia, may not have any obvious symptoms (asymptomatic). Symptoms of anemia include paleness of the skin (pallor), fatigue, shortness of breath (dyspnea), dizziness and palpitations. In cases of brisk and severe hemolysis, chest pain, decreased alertness (lethargy), confusion, transient loss of consciousness (syncope), and deregulation of heart rate and blood pressure (hemodynamic instability) might occur. Hemolysis also leads to increased release of hemoglobin (an oxygen-carrying protein) in the blood and urine, which can result in darkly pigmented urine. Hemoglobin is degraded into a yellow compound called bilirubin, which can accumulate and lead to yellowing of the skin and whites of the eyes (jaundice). Circulatory symptoms seen in CAD include coldness of the fingers and/or toes (digits) and painful bluish or reddish discoloration of the skin of the digits, ankles, and wrists (acrocyanosis or Raynaud phenomenon). In severe cases, ulcers may develop on the extremities of digits. There is a possibility that people living with CAD are at a higher risk of developing blood clots, although more studies are needed to clarify this potential association. CAD can be a long-standing (chronic) disease, but can be self-limited and clinically silent, especially when associated with infectious diseases (see below); although it can be caused by severe diseases, CAD itself does not seem to be associated with a significantly decreased life expectancy.
CAD occurs when antibodies produced by the immune system bind to red blood cells and identify them as targets. Antibodies are specialized proteins that bind to invading organisms and contribute to their destruction. There are five main classes of antibodies -IgA, IgD, IgE, IgG, and IgM. Most cases of CAD are due to IgM antibodies. When antibodies attack healthy tissue, they may be referred to as autoantibodies. In the case of CAD, these autoantibodies are active and can trigger hemolysis when they are exposed to cold temperatures. Once red blood cells are “tagged” by a cold-induced antibody, they can clump (agglutinate) and are then bound by another component of the immune system known as complements. Once red blood cells are bound to complements, they are attacked and destroyed by different types of immune cells, such as macrophages.
CAD may also occur as a secondary disorder in association with a number of different underlying disorders such as certain infectious diseases (e.g., mycoplasma infection, mumps, cytomegalovirus, infectious mononucleosis), immunoproliferative diseases (e.g., non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, monoclonal gammopathy of unknown significance), or connective tissue disorders (e.g., rheumatoid arthritis, systemic lupus erythematosus). A secondary cause of CAD might be present in up to 70% of affected individuals.
CAD most commonly affects people between the ages of 40 and 80. The median age at symptom onset is around 65 years, meaning that half of affected individuals develop symptoms before this age, and the other half after this age. The disease is present in about 16 people per million (prevalence), and develops in one person per million every year (incidence). The disease is almost twice as common in women compared to men. Those living with conditions associated with CAD (see “causes” section above) are more likely to develop the disease. CAD is also potentially more common, or at least more recognized, in colder climates.
A diagnosis of hemolytic anemia may be suspected based on a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms and a variety of tests such as blood tests that measure values of hemoglobin and the percentage of the total blood volume occupied by red blood cells (hematocrit). Blood tests may also show an elevated value of immature red blood cells (reticulocytes), which occurs when the body is forced to produce extra red blood cells to make up for those that are destroyed prematurely. Some individuals with hemolytic anemia have elevated values of bilirubin in the blood (hyperbilirubinemia). Hemolytic anemia also leads to increased values of lactate dehydrogenase (LDH) in the blood, as it is released when red blood cells are destroyed. Haptoglobin is a hemoglobin scavenger that gets consumed when hemoglobin is released in the blood due to hemolysis. Haptoglobin values are therefore low in hemolytic anemia. When hemolytic anemia is suspected to be autoimmune in origin, specialized tests such as a Coombs test may be performed. This test is used to detect antibodies bound to red blood cells or other biological mediators, like complement (component 3, C3), which accompanies the binding of immunoglobulin to their targets. A sample of blood is taken and then exposed to the Coombs reagent. A positive test is indicated when the red blood cells clump in the presence of the reagent. In CAD, the immunoglobulin may not be picked up with the Coombs test, but this test most often picks-up the presence of C3 on the red cells, A thermal amplitude test then has to be performed to measure the reactivity of the detected antibodies at different temperatures. It is important to know how much of this cold agglutinin is present in each patient, especially to determine how it changes with treatment. This is done by determining the titer for the cold agglutinin, which is done by progressively diluting the serum of the patient until the agglutination of the red cells disappears.
After a diagnosis of CAD is made, patients should be evaluated to attempt to identify a possible underlying condition such as an infection, autoimmune disease, or another blood disorder. The tests that will be performed depend on the clinical situation and the affected individual. In summary, the following sequence allows the diagnosis of CAD: 1) detection of anemia, 2) determination that the anemia is caused by hemolysis, based on elevated bilirubin and LDH and low haptoglobin, 3) determination that CAD is the cause of hemolytic anemia with a Coombs test and a cold agglutinin titer, and 4) investigation for a secondary cause of CAD.
Avoidance of cold exposure, particularly to the head, face, and extremities, is important to decrease hemolysis and circulatory symptoms. Other measures have to be taken in certain circumstances, such as prewarming of infusions (e.g. intravenous fluids) in hospitalized patients. If symptoms are mild or if destruction of red blood cells seems to be slowing of its own accord, usually no treatment is needed. If the rate at which red blood cells are being destroyed appears to be increasing, medication might be needed. Rituximab is an artificially-created antibody (monoclonal antibody) that targets certain white blood cells that create the antibodies which prematurely destroy red blood cells. It is considered first-line therapy in CAD and can be combined with the chemotherapy agents fludarabine or bendamustine or with prednisone. Although patients tend to respond well to rituximab, relapses are common. Rituximab can also be used to treat relapses of CAD. If an underlying condition is identified as the cause of CAD, it should be treated. In the case a patient develops rapid hemolysis or is severely anemic, blood transfusions or plasma exchange might be required. Plasma is the component of the blood in which antibodies circulate, so plasma exchange can momentarily decrease the autoantibody burden in a patient. However, these two measures do not treat the cause of the anemia and provide only temporary relief. In cases in which blood transfusions are necessary, certain guidelines must be followed because of the temperature sensitivities involved.
Since the activation of complement plays a key role in the destruction of the red cells, the use of new drugs that inhibit or prevent the activation of complement is being very actively studied. None of these therapies have received approval by the FDA for CAD, but several studies are ongoing, and some of the published results look promising.
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