[2] It is a form of autoimmune hemolytic anemia, specifically one in which antibodies bind red blood cells only at low body temperatures, typically 28–31 °C.
This eventually causes red blood cells to be prematurely destroyed (hemolysis) leading to anemia and other associated signs and symptoms.
Symptoms may arise suddenly leading to abrupt onset of severe anemia and hemoglobinuria or develop more gradually and insidiously in the background without patient's consciousness and precaution.
Signs and symptoms of hemolytic anemia may include:[4] Many people with CAD also experience pain and bluish coloring of the hands and feet (acrocyanosis) or Raynaud's disease.
[16] Secondary cold agglutinin syndrome occurs when autoantibodies bind to red blood cells, rendering them subject to attack by the complement system.
[16] In adults, this is typically due to: In children, cold agglutinin disease is often secondary to an infection, such as Mycoplasma pneumonia, mononucleosis, and HIV.
In some cases, cold agglutinin may be multifactorial[18] which means that multiple environmental factors and genes likely interact to predispose a person to developing the condition.
[4] All individuals have circulating antibodies directed against red blood cells, but their concentrations are often too low to trigger disease (titers under 64 at 4 °C).
This opsonization enhances the clearance of red blood cell by phagocytes in the liver, spleen, and lungs, a process termed extravascular hemolysis.
Detection of antibodies in serum of the patient (still circulating in the blood, that have not yet formed any complexes with RBC) is an indirect Coombs antiglobulin test.
[citation needed] A diagnosis of cold agglutinin disease may be made after several types of tests are performed by a health care provider.
[21] The treatment of cold agglutinin disease depends on many factors including the severity of the condition, the signs and symptoms present in each person, and the underlying cause.
Rituximab (an antibody that selectively reduces specific types of immune cells) is effective in about 60% of cases of severe cold agglutinin disease.
Combined treatment with rituximab and fludarabine has resulted in higher response rates (76% of cases) and longer periods of remissions (on average, 6.5 years).
Finally, plasmapheresis, which involves filtering blood to remove antibodies, may be useful in acute hemolytic crisis and before surgery requiring hypothermia, however its effect is only short term.
[24] The long-term outlook (prognosis) for people with cold agglutinin disease varies based on many factors including the severity of the condition, the signs and symptoms present in each person and the underlying cause.
Those with cold agglutinin disease caused by HIV infection or certain types of cancer generally have a poor prognosis due to the nature of the underlying condition.
[26][28] More than 90% of patients with primary CAD have Cold-induced circulatory symptoms ranging from moderate acrocyanosis to severe Raynaud phenomena precipitated even by very slight cold exposure.