A disorder that is idiopathic or secondary to a
malignancy, resulting in immune-hemolytic anemia with exacerbation upon
exposure to cold.
Cold Agglutinin Disease; Cold Hemagglutinin Disease.
First described in 1903 by Karl Landsteiner, an Austrian
pathologist and immunologist, who is considered the father of modern
transfusion medicine, since he also discovered the ABO system, for which he
was awarded the Nobel Prize in 1930.
It has been estimated that approximately 5 to 20% of
all autoimmune hemolytic anemias are caused by cold agglutinins
(approximately 1:300,000). No ethnic predilection has been reported,
however, females are affected slightly more often than males (1.5:1). All
age groups can be affected, although it most often occurs in patients in the
seventh decade of life or older and rarely in children. Even in otherwise
healthy persons, low cold agglutinin titers (1:64 or less) are common.
Significantly higher titers may be associated with infections by Mycoplasma pneumoniae, cytomegalovirus, human
immunodeficiency virus, influenza virus, Epstein-Barr virus, mumps virus,
with malaria, listeriosis, and trypanosomiasis, but these increased levels
are transient and the development of cold agglutinin syndrome is relatively
uncommon, at least in the classic chronic form.
Trisomy 3 has been found in some patients with
this disorder. However, cold agglutinin syndrome is acquired and not inherited.
Cold agglutinin syndrome as a secondary disease
usually is associated with a hematologic malignancy (e.g., Waldenström
macroglobulinemia [production of monoclonal IgM paraprotein], multiple
myeloma, lymphomas, Kaposi sarcoma) and infections. Activated B lymphocytes
produce pathogenic antibodies (most commonly monoclonal IgM, rarely IgA or
IgG, directed against the I antigen of the erythrocyte membrane in adults;
rarely the antibodies are targeted against the fetal i antigen). When the
blood cools below the “thermal threshold” (approximately 32°C, i.e.,
in acral areas), these autoantibodies cause red cell agglutination,
slugging, and complement binding in peripheral vessels. Upon returning to
the central circulation (warmer areas), the IgM antibodies dissociate,
leaving complement on the cell surface. In severe cases, the red
cell-antibody complexes activate the complement system, which may result in
intravascular hemolysis. Sequestration of opsonized red cells occurs, mainly
by the Kupffer cells in the liver.
Based on the clinical picture with exacerbation on
exposure to cold (finger pain and paresthesias). Anemia, spherocytosis,
reticulocytosis, and in vitro agglutination of blood that resolves upon
rewarming are characteristic.
Usually mild chronic anemia is present. Red blood cell
agglutination may result in a Raynaud-like phenomenon upon exposure to cold
(acrocyanosis, livedo reticularis). Purpura, acral gangrene, and immune
complex nephritis are rare complications, but have been described. Hemolysis
may lead to worsening of anemia, hemoglobinuria, and renal failure, mild
hepatomegaly, jaundice, and/or splenomegaly. The presence of circulating
inhibitors of specific coagulation factors has been reported and must be
considered because they may be associated with hemorrhage.
Prevention of hemagglutination by
keeping the patient warm is paramount. Check for anemia, which most often is ...