Disease Overview

Cold agglutinin disease (CAD) is a type of autoimmune hemolytic anemia. Cold agglutinin disease can be separated into two subtypes: primary or secondary. Primary CAD is a chronic disorder caused by cold-reacting antibodies that bind to the erythrocyte membrane and lead to premature red blood cell destruction (hemolysis). Primary CAD is characterized by a clonal lymphoproliferative disorder. Secondary CAD is associated with either monoclonal or polyclonal cold-reacting autoantibodies. It’s primarily caused by an infection or malignancy. Monoclonal secondary CAD is seen in adults and is a chronic condition. Polyclonal secondary CAD mainly affects children and is a temporary condition.

Signs and Symptoms

Patients with cold agglutinin disease often experience symptoms such as pain in fingers and toes, as well as purplish discoloration at the fingertips and toes when exposed to cold temperature. These symptoms appear more during the colder months of the year. Patients may also experience chronic fatigue, pale discoloration, loss in appetite, and shortness of breath from their anemia. 

Diagnosis

A diagnosis of hemolytic anemia involves a comprehensive assessment, including a detailed patient history and thorough clinical evaluation to identify characteristic symptoms. Diagnostic tests play a crucial role, such as blood tests measuring hemoglobin levels and hematocrit to assess red blood cell count and volume. These tests also monitor reticulocyte levels, which indicate increased red blood cell production in response to premature destruction. Further diagnostic indicators include elevated bilirubin and lactate dehydrogenase (LDH), and low haptoglobin levels. A Coombs test detects antibodies on red blood cells; if autoimmune hemolytic anemia (AIHA) is suspected, this may be followed by a cold agglutinin titer test to assess cold agglutinin presence and its response to treatment. Once CAD is confirmed, a comprehensive evaluation aims to uncover potential underlying conditions contributing to the disorder, including infections, autoimmune diseases, or other hematologic disorders. Tailored investigations depend on the clinical context and individual circumstances, ensuring a thorough approach to diagnosis and management.

Disease Management and Treatment

Patients with idiopathic CAD have limited treatment options. The primary option is to take protective measures against cold temperatures by wearing gloves to remove items from the refrigerator or freezer or avoiding cold foods and beverages. Since patients in this specific population do not know what is causing this disorder, they should expect spontaneous exacerbation or remission. In patients with severe, acute cases of CAD can receive red blood cell transfusions as treatment. Alternatively, patients may use Sutimlimab. This therapy is indicated to decrease the need for red blood cell transfusion in patients with hemolysis associated with CAD. Also, Rituximab, with or without fludarabine or bendamustine, has an off-label use in patients with refractory cases of CAD. 

Patients with CAD should incorporate adequate amounts of vegetables and fruits in their diet. This is because fruits and vegetables are high in folic acid, which helps produce red blood cells. In addition, patients with CAD should engage in less fatiguing activities such as jogging.