Cold agglutinin disease (CAD)
Cold agglutinin disease (CAD) is a rare autoimmune disorder that falls under the category of autoimmune hemolytic anemias (AIHAs). In CAD, the immune system mistakenly attacks and destroys its own red blood cells, leading to anemia due to the rapid loss of these cells. This condition is particularly triggered by exposure to cold temperatures, typically between 28–31°C (82–88°F), which distinguishes it from other types of AIHA. Symptoms of CAD can include pain and discoloration in the extremities (Raynaud's phenomenon), fatigue, shortness of breath, and more severe indications such as jaundice and splenomegaly.
Causes of CAD can be classified into primary and secondary types; primary CAD has unclear origins, while secondary CAD is often linked to infections or certain cancers. Treatment approaches vary, with mild cases managed by avoiding cold temperatures and enhancing nutrition, while more severe cases may require therapies like Rituximab, plasmapheresis, or immune-suppressing medications. With a prevalence of approximately 1 in 300,000 people, CAD is a condition that necessitates careful management and, in some cases, relocation to warmer climates for relief.
Cold agglutinin disease (CAD)
Disease/Disorder
Anatomy or system affected: Blood, blood vessels, chest, circulatory system, ears, feet, hands, immune system, liver, lungs, lymphatic system, nose, respiratory system, skin, spleen, urinary system
Definition: A disease characterized by the production of antibodies against red blood cells that destroy them and cause anemia.
Key terms:
anemia: a deficiency of the oxygen-carrying protein hemoglobin or the red blood cells that contain hemoglobin
antibodies: a blood protein produced by B-lymphocytes in response to the introduction of antigens into the body that binds to and neutralizes these antigens
antigens: toxins or other foreign substances introduced into the body that induce an immune response against it
complement proteins: a group of proteins in blood that initiate a biochemical cascade when an antibody is bound to a cell surface that culminates in the destruction of that cell and its clearance from the body
hemolysis: the destruction of red blood cells
plasmapheresis: a clinical procedure that removes blood from the body, separates it into liquid or plasma and cells, and then returns the cells to the body without the plasma and its components
Causes and Symptoms
Cold agglutinin disease (CAD) is one of a group of blood disorders known as autoimmune hemolytic anemias (AIHAs). The immune systems of patients who suffer from AIHAs attack their own red blood cells, which cause routine red blood cell destruction (hemolysis). Destruction of red blood cells faster than they can be replaced leads to anemia or an abnormally low number of red blood cells. Exposure to cold initiates symptoms in CAD patients, which sets it apart from other types of AIHA. Approximately 1 in 300,000 people suffer from CAD.
Everyone tends to have circulating antibodies against their own red blood cells. Because the concentration of these antibodies tends to be rather low, they usually do not cause any problems. However, in some people, the concentration of these anti-red blood cell antibodies increases. In the case of primary CAD, the increase in the concentration of these antibodies occurs for reasons that remain unclear. In the case of secondary CAD, though, certain types of bacterial infections and viral infections or particular kinds of white blood cell cancers boost the concentration of these red blood cell-specific antibodies.
At low body temperatures (usually between 28–31°C or 82–88°F), which usually prevail during the winter months, the anti-red blood cell antibodies bind to the surfaces of red blood cells. The bound antibodies cause them to aggregate and activate complement proteins. Activation of the complement pathway culminates in the boring of small holes in red blood cell membranes and hemolysis. Those red blood cells that escape destruction by complement proteins are marked by them for destruction, and are filtered out by the liver and spleen and destroyed.
The whole-scale destruction of red blood cells causes anemia and other symptoms as cell debris becomes lodged in small blood vessels and blocks blood flow. CAD symptoms include pain and a purplish tinge in the fingers and toes (Raynaud's phenomenon), pallor, trouble breathing (dyspnea), and fatigue. Upon physical examination, patients with CAD may show purplish discoloration of the ears, forehead, tip of the nose, and digits (acrocyanosis). Enlargement of the spleen (splenomegaly), jaundice, and fever are also seen in more severe CAD patients.
Treatment and Therapy
Most cases of secondary CAD result from diseases that are, themselves, self-limiting and only of short duration. For most cases of primary CAD, avoidance of the cold prevents the onset of symptoms. CAD patients should eat foods rich in folic acid (e.g., fresh fruits and vegetables) and iron (e.g., meat, egg yolks, beans, artichokes), which help build red blood cells.
For more severe cases of CAD, intravenous administration of Rituximab promptly resolves the disease. A genetically engineered antibody, Rituximab binds to the surfaces of B-lymphocytes—the cells that produce antibodies—and removes them from the body. Rituximab can provide relief for up to one year. Combination treatments with purine analogs (e.g., fludarabine, azathioprine, etc.) may achieve faster responses and longer remission times. Other immune-suppressing drugs that have been used to treat severe cases of CAD include cyclophosphamide, chlorambucil, prednisone, vincristine, and interferons, all with varying degrees of success.
For emergencies, plasmapheresis can reduce the concentration of those antibodies that bind red blood cells in the blood. Because it acts quickly, plasmapheresis provides time for drugs to act, or for the patient to undergo surgery. Blood transfusions with warmed, washed, carefully matched red blood cells are only used as a last resort.
CAD patients should strongly consider relocating to warmer climates and should wear protective clothing to prevent chilling the body.
Perspective and Prospects
Karl Landsteiner first described cold agglutinins in 1903. In 1918, M. C. Clough and I. R. Richter identified the pathologic association between the presence of cold agglutinins and red blood cell destruction and its occurrence during respiratory infections. D. M. Horstmann and H. Tatlock reported the first case of secondary CAD in 1943 when they detected cold agglutinins in the serum of patients with pneumonia. In 1957, W. H. Christenson, J. H. Dacie and colleagues identified antibodies as the cold agglutinins, but H. Schubothe actually coined the phrase “cold agglutinin disease” in 1966.
Other types of drugs that have been developed to treat non-Hodgkin lymphoma and multiple myeloma may also effectively treat CAD. For example, a drug called bortezomib prevents cells from degrading damaged or unwanted proteins and has been approved for the treatment of multiple myeloma. Bortezomib depletes B-cells and might be effective as a treatment for CAD. Other experimental drugs might also prove useful as future treatments for recalcitrant cases of CAD.
Bibliography
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Jeskowiak, Antonia, and Tobias Goerge. “Images in Clinical Medicine: Cutaneous Necrosis Associated with Cold Agglutinins.” New England Journal of Medicine 369 (July 2013): e1.
Rodak, Bernadette F., George A. Fritsma, and Elaine Keohane. Hematology: Clinical Principles and Applications. 4th ed. St. Louis: Elsevier, 2012.
Swiecicki, Paul L., Livia T. Hegerova, and Morie A. Gertz. “Cold Agglutinin Disease.” Blood 122, no. 7 (August 2013): 1114–1121.
Vorvick, Linda J. "Febrile/Cold Agglutinins." MedlinePlus. US Natl. Lib. of Medicine, Natl. Inst. of Health, 31 May 2012. Web. 17 Mar. 2015.