Primary cold-agglutinin disease is a type of cold agglutinin disease (CAD) whose cause is unknown. A chronic autoimmune disorder, it mostly manifests later in life.
About primary CAD
The presence of autoantibodies called cold-agglutinins characterizes cold-agglutinin disease. These autoantibodies attack red blood cells when exposed to temperatures below a person’s normal body temperature. They attach to the surface of red blood cells and cause them to clump together, leading to their premature degradation by the immune system.
Based on what triggers CAD, the disease is classified into two types: primary CAD and secondary CAD. The causes of primary CAD are unknown, while secondary CAD develops due to another underlying condition, such as a viral infection or lymphoid cancers.
Although the causes of primary CAD are not clear, a study has shown that some primary CAD patients have mutations in the KMT2D and CARD11 genes, both of which are directly or indirectly involved in regulating the immune system.
Unlike secondary CAD, primary CAD is mainly mediated through monoclonal cold agglutinins — autoantibodies produced by a single type of immune cell that bind to one specific substance on the surface of red blood cells.
Symptoms of primary CAD
Most CAD-associated symptoms are common to both its primary and secondary forms, and worsen in cold temperatures. Symptoms are primarily due to the excessive and rapid breakdown of red blood cells and its impact on blood flow. Some symptoms include:
- Hemolytic anemia, or low levels of red blood cells due to their disintegration in cold temperatures
- Acrocyanosis, or skin discoloration due to poor blood circulation, especially in the fingers and toes
- Raynaud’s phenomenon, caused due to difficulties with blood flow
- Pain
- Fatigue
- Headache
- Dizziness
- Vomiting
Diagnosis of primary CAD
The diagnosis of primary CAD, like that of secondary CAD, is based on physical examination and laboratory tests to determine red blood cell counts and cold-agglutinin levels.
A healthcare team may also perform other tests to rule out secondary CAD and other autoimmune conditions that cause hemolytic anemia.
Treatment of primary CAD
Unlike secondary CAD, whose symptoms usually subside upon treatment of the underlying condition, people with primary CAD may need to address their symptoms directly to manage them.
In most cases, the cold-induced symptoms of primary CAD can be managed by avoiding cold temperatures. Based on their severity, symptom relief can come through exposure to warmth.
Patients with severe anemia may require transfusions of pre-warmed red blood cells.
Plasma (the liquid portion of the blood), which contains high levels of autoantibodies, can also be replaced with pre-warmed fresh plasma from a healthy compatible donor, or a plasma substitute, using plasmapheresis.
Immunotherapy may also be beneficial in cases where cold avoidance is insufficient. It works by reducing autoantibody production. Commonly used immunotherapeutic agents include rituximab either as a single therapy or in combination with other medications.
Last updated: Aug. 17, 2019
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