Cold autoimmune hemolytic anemia (cAIHA) is defined as antibodies that can effectively react with red blood cell antigens only at temperatures below 31°C, with the highest affinity observed at 0–5°C. Cold autoimmune hemolytic anemia accounts for approximately 20%–30% of all AIHA cases. Cold antibodies can be categorized into two types:
- Cold Agglutinins, which can cause cold agglutinin disease (CAD) and cold agglutinin syndrome (CAS).
- IgG Biphasic Hemolysins, also known as Donath-Landsteiner (D-L) antibodies, which can cause paroxysmal cold hemoglobinuria (PCH).
CAD and CAS
CAD is a well-defined clinico-pathological entity, while CAS is associated with specific conditions such as infections, autoimmune diseases, B-cell lymphomas, or other malignancies. The antibodies in both CAD and CAS are mostly IgM and are classified as complete antibodies. Upon exposure to cold, these IgM antibodies can directly cause red blood cell agglutination, leading to peripheral cyanosis. They can also activate complement, resulting in intravascular hemolysis. Red blood cells that do not lyse undergo warming when passing through deeper body tissues, where the cold agglutinins dissociate, leaving behind C3 and C4 fragments. These tagged red blood cells are then cleared by macrophages in the liver, leading to chronic extravascular hemolysis. Clinical symptoms include peripheral cyanosis, which resolves with warming, anemia, and hemoglobinuria. Cold agglutinin tests are positive, and direct antiglobulin (DAT) tests typically show C3 positivity.
PCH
PCH is a rare condition that can be primary or secondary, with most cases presenting as acute episodes. Secondary PCH often occurs following viral infections. D-L antibodies bind to red blood cells and fix complement below 20°C. When the temperature increases to 37°C, the complement system is rapidly activated, causing intravascular hemolysis. Clinical manifestations include hemoglobinuria, fever, lumbar and back pain, nausea, and vomiting. Episodes are often self-limiting and typically last for only 1–2 days. A positive Donath-Landsteiner (D-L) test confirms the diagnosis.
Treatment
Treatment depends on the underlying cause. The most critical intervention is maintaining warmth to prevent hemolysis. Rituximab or other cytotoxic immunosuppressants are indicated for symptomatic cases. Complement inhibitors can help control hemolytic episodes in some CAD/CAS patients. Glucocorticoids show poor efficacy, and splenectomy is ineffective.