Cold agglutinins are autoantibodies—immune system proteins that mistakenly target the body’s own cells. Specifically, they are directed against antigens found on the surface of red blood cells (RBCs). These antibodies only become active and bind to RBCs when the temperature drops below the body’s core temperature of 37°C (98.6°F), which gives them their name.
While a low concentration of cold agglutinins is normal and harmless, high concentrations can cause red blood cells to clump together, leading to cold agglutinin disease (CAD). Cold agglutinins are typically immunoglobulin M (IgM) antibodies, a large type of antibody effective at activating the immune cascade.
The Mechanism of Temperature-Dependent Destruction
The destructive process begins when blood flows through cooler areas of the body, such as capillaries in the fingers, toes, nose, and ears. As the temperature drops, cold agglutinins bind to the red blood cells, causing them to stick together. This process, known as agglutination, can be observed as clumping.
The clumping of red blood cells impedes blood flow through small vessels in the affected areas. Once bound, the antibodies immediately activate the classical pathway of the complement system, a part of the immune response that helps clear damaged cells.
Complement activation continues even after the blood returns to the warmer core and the cold agglutinins detach. Although the antibody unbinds, complement proteins, particularly C3b, remain attached to the red blood cell surface. These C3b-coated cells are recognized by scavenger cells in the liver and spleen, leading to their premature destruction, called extravascular hemolysis.
In severe cases, the complement cascade proceeds to form the membrane attack complex (MAC), which punches holes into the red blood cell membrane. This causes the red blood cell to burst while still in the bloodstream, a process called intravascular hemolysis. Both types of destruction result in a shortage of red blood cells, leading to autoimmune hemolytic anemia.
Primary and Secondary Associated Conditions
Cold agglutinin-mediated destruction is categorized into two types based on the underlying cause: primary and secondary. Primary cold agglutinin disease (CAD) is a chronic, indolent lymphoproliferative disorder. It occurs when a small, clonal population of B-cells in the bone marrow spontaneously produces the cold agglutinin antibodies.
This primary form is typically slow-progressing, often affects individuals over 50, and is not the result of an external trigger. The monoclonal IgM autoantibodies produced are highly reactive and cause significant problems even at temperatures slightly below core body temperature.
Secondary cold agglutinins, or cold agglutinin syndrome, are transient and arise as a complication of another underlying condition. The most common triggers are specific infectious diseases where the immune response cross-reacts with red blood cell antigens. Infections caused by Mycoplasma pneumoniae and infectious mononucleosis (Epstein-Barr virus) are frequent causes.
Other causes include certain autoimmune diseases and lymphoproliferative disorders, such as lymphomas. Treating the underlying infection or malignancy often resolves the high concentration of cold agglutinins and stops red blood cell destruction.
Recognizing the Symptoms and Clinical Presentation
The symptoms of cold agglutinin disease revolve around two main issues: chronic anemia and the effects of cold exposure. Chronic anemia, resulting from ongoing red blood cell destruction, manifests as fatigue, pallor (pale skin), dizziness, and shortness of breath. Since RBCs carry oxygen, their shortage reduces the body’s ability to maintain energy.
Cold-associated symptoms are directly related to the agglutination process in the extremities. When exposed to cold, patients may develop acrocyanosis—a bluish discoloration of the fingers, toes, ears, and nose. This occurs because clumps of red blood cells slow blood flow in the small vessels of cooler areas.
Some patients experience a Raynaud-like phenomenon, where extremities become painful, numb, and discolored upon cold exposure. These symptoms are often worse during winter or when handling cold items. In cases of severe hemolysis, the rapid breakdown of red blood cells can cause dark urine and jaundice (yellowing of the skin) due to bilirubin release.
Testing and Management Approaches
Diagnosis typically begins with blood tests showing signs of hemolytic anemia, such as low red blood cell counts. The specific diagnosis is confirmed by identifying the presence and concentration of cold agglutinins. A common test is the Cold Agglutinin Titer, which measures the highest dilution of serum that causes red blood cells to clump at a cold temperature, often 4°C.
A positive Direct Antiglobulin Test (DAT), or Coombs test, is performed to confirm the autoimmune nature of the destruction. In CAD, this test is typically positive for complement protein C3d on the red blood cell surface and negative or weakly positive for immunoglobulin G (IgG). Proper sample handling, including keeping the blood warm until the serum is separated, is important for accurate results.
The primary management for all patients is behavioral: strict avoidance of cold exposure. This includes wearing warm clothing, minimizing time in cold environments, and avoiding cold foods and drinks. For patients with significant symptoms or severe anemia, medical intervention is necessary.
Treatment for the chronic primary disease often involves targeted therapies. These include the monoclonal antibody rituximab, which reduces the production of the harmful B-cell clone. Newer treatments, such as the complement inhibitor sutimlimab, directly prevent the complement system from destroying red blood cells. Transfusions are complicated because the blood must be warmed to prevent the transfused red blood cells from being immediately destroyed.