Cold agglutinin disease (CAD) is a rare autoimmune disease in which autoantibodies called cold agglutinins are produced by the body in response to low temperatures (32 to 50 degrees Fahrenheit). These cold agglutinin antibodies target and attack red blood cells (RBCs), causing them to disintegrate — a biological event called hemolysis.
There are several laboratory tests to diagnose CAD including several blood and biochemical tests. Biochemical tests are usually the ones used to detect hemolysis and require a blood sample that is drawn by inserting a needle into a vein in the arm.
Lactate dehydrogenase test
Lactate dehydrogenase (LDH) is an enzyme involved in cellular respiration — the process by which energy is produced within cells. The levels of LDH are higher in tissues than in the blood. However, in certain conditions such as anemia, LDH levels in the blood increase. Therefore, elevated levels of LDH in the blood are an indicator of anemia, as a result of CAD, for example.
Aspartate aminotransferase test
Proper liver function is important to clear up the RBCs that are destroyed by the immune system. In hemolysis caused by CAD, the excess amount of dead RBCs can pose a challenge for the liver and result in the impairment of its function. The aspartate aminotransferase test (AST) is a biochemical test used to assess the health of the liver. AST is often used in conjunction with another test called alanine aminotransferase test (ALT) to determine liver health.
Total-direct bilirubin test
When dead RBCs are cleared up by the liver, the hemoglobin (the oxygen-carrying protein in RBCs) is broken down into a toxic substance called bilirubin. This bilirubin is also called indirect bilirubin or free bilirubin as it is not bound to another liver protein called albumin. Normally albumin binds to bilirubin, forming a complex that is less toxic and soluble so that it can be reabsorbed by the liver for excretion. The bilirubin bound to albumin is called direct bilirubin. The sum of direct and indirect bilirubin gives the total bilirubin concentration in the blood.
A bilirubin test helps to determine the concentration of direct, indirect, and total bilirubin in the blood. Excess indirect bilirubin concentration can result in yellowing of the skin and eyes, causing jaundice. Higher levels of total and direct bilirubin could be indicative of CAD.
Haptoglobin is a protein produced by the liver to clear free hemoglobin in the blood. During hemolysis caused by CAD, hemoglobin concentration is increased in the blood due to RBC damage and the liver can fail to cope with required haptoglobin production.
A decrease in haptoglobin level is an indication that free hemoglobin concentration in the blood is high due to the disintegration of RBCs by cold agglutinin autoantibodies and that the liver is not producing enough haptoglobin to bind to all available free hemoglobin.
The results of the haptoglobin test are interpreted alongside other tests such as hemoglobin, RBC counts, and complete blood count. Haptoglobin levels are usually low when there is severe extravascular hemolysis (or hemolysis outside the blood vessels) as the free hemoglobin is not released into circulation.
Last updated: Aug. 20, 2019
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