Cold-reactive antibodies, those which react maximally at temperatures between 4 and 20°C and not usually above 32°C, account for 10 to 20 percent of patients with immune hemolytic anemia. There are two types of diseases where this occurs: cold agglutinin disease and paroxysmal cold hemoglobinuria. These antibodies react with the RBCs in the superficial microcirculation where it is cool, then the hemolysis occurs when the red blood cells reenter the central circulation and are warmed.
COLD AGGLUTININ DISEASE This can be an acute, transient disease mostly seen in younger people or a chronic disease primarily in older patients. It is typically caused by an IgM antibody, and the Coombs' test will only be positive for C3, because the IgM will not be attached to the RBCs at warmer temperature. The acute form of this disease is mostly seen in patients with Mycoplasma pneumonia or infectious mononucleosis; the IgM antibodies are directed against the I antigen or i antigen on the RBC surface, respectively. Only rare patients develop significant hemolysis, but severe anemia and renal failure can occur. The acute form of this disease is self-limited. Chronic cold agglutinin disease is more common than the acute form and primarily occurs in patients with underlying lymphoid neoplasms. These patients typically have a mild to moderate anemia that results from hemolysis occurring in portions of the body exposed to lower temperatures (acrocyanosis). These patients should be kept in a warm environment, and treatment is directed against the underlying disease. Some of the hemolysis may respond to treatment with prednisone.
PAROXYSMAL COLD HEMOGLOBINEMIA This disease is characterized by acute episodes of hemolysis following exposure to cold. Two groups of patients can be affected by this disease: (1) those with congenital or tertiary syphilis that is untreated and (2) patients with viral illnesses such as mumps or measles. In this disease, the immune hemolysis is caused by an IgG antibody called the Donath-Landsteinerantibody, which is directed against the P-antigen complex on the RBC surface. Clinically, after exposure to cold, affected patients will have hemoglobinuria, chills, fever, and pain involving the back, legs, and abdomen. The direct Coombs test is only positive during an acute attack. When associated with syphilis, this disease goes away after appropriate antibiotic therapy. Now most commonly seen in patients with viral infections, the hemolysis is self-limited but can cause transient severe anemia.
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