Continued C1 activation of the classical complement pathway leaves patients with CAD chronically compromised by an unstable hemolytic state1,2
*C1 amplifies the activation of C3, resulting in extravascular hemolysis and chronic inflammation.
†Complement activity can activate C5, leading to intravascular hemolysis and chronic inflammation.
Watch how CAD works
Cold agglutinin disease, or CAD, is a rare form of autoimmune hemolytic anemia in which the body mistakenly recognizes the antigens on the surface of red blood cells as foreign. This is due to the production of cold agglutinins, CA, autoantibodies that activate the classical complement pathway, leading to chronic red blood cell destruction, or hemolysis. These CAs are usually IgMs. In CAD, CAs preferentially bind to the antigens on red blood cells at temperatures below core body temperature, resulting in agglutination. The activated CAs bind to the C1 complex, thereby activating the classical complement pathway. This C1-activation alone drives red blood cell destruction. C1 activates C3 convertase, resulting in the cleavage of C3 to C3a and C3b. C3b then binds to the surface of the red blood cells. C3-bound red blood cells are sequestered mainly in the liver, where they are destroyed by macrophages in a process called extravascular hemolysis. In some cases, chronic complement activation can also trigger intravascular hemolysis, during which red blood cells are destroyed in the circulation. Chronic complement activation and hemolysis result in anemia and increase the risk of complications occurring. Primary CAD, the most common form, accounts for around 15% of all autoimmune hemolytic anemia cases. It occurs where there are no associated underlying conditions and is thought to be caused by the clonal expansion of B cells within the bone marrow. However, CAD can also develop due to other conditions, such as lymphoma or viral infections, and in such cases, is classified as secondary CAD. Symptoms of CAD include acrocyanosis, extreme fatigue, dyspnea, and hemoglobinuria, most of which are secondary to chronic anemia caused by ongoing complement-mediated hemolysis. Patients with CAD are potentially more likely to experience thrombotic events, such as deep vein thrombosis, pulmonary embolism, and myocardial infarction. These events can potentially be severe. Patients may also be at risk of experiencing acute hemolytic crises, requiring emergency treatment. There are currently no approved treatments for CAD. Managing symptoms by avoiding the cold has shown limited efficacy. CAD is a complement-mediated hemolytic anemia in which most symptoms arise due to activation of the classical complement pathway. Further research evaluating alternative therapeutic approaches to treat CAD is warranted. Sanofi Genzyme is committed to transforming the care of people living with cold agglutinin disease and other rare blood disorders.