Cold agglutinin
Encyclopedia
Cold agglutinin disease is an autoimmune disease
characterized by the presence of high concentrations of circulating antibodies, usually IgM
, directed against red blood cell
s. It is a form of autoimmune hemolytic anemia
, specifically one in which antibodies only bind red blood cells at low body temperatures, typically 28-31°C.
It was first described in 1957.
At body temperatures of 28-31°C, such as those encountered during winter months, and occasionally at body temperatures of 37°C, antibodies (generally IgM
) bind to the polysaccharide
region of glycoprotein
s on the surface of red blood cells (typically the I antigen, i antigen, and Pr antigens). Binding of antibodies to red blood cells activates the classical pathway of the complement system
. If the complement response is sufficient, red blood cells are damaged by the membrane attack complex, an effector of the complement cascade. In the formation of the membrane attack complex, several complement proteins are inserted into the red blood cell membrane, forming pores that lead to membrane instability and intravascular hemolysis
(destruction of the red blood cell within the blood vessels).
If the complement response is insufficient to form membrane attack complexes, then extravascular lysis will be favored over intravascular red blood cell lysis. In lieu of the membrane attack complex, complement proteins (particularly C3b and C4b) are deposited on red blood cells. This opsonization enhances the clearance of red blood cell by phagocyte
s in the liver
, spleen
, and lungs, a process termed extravascular hemolysis.
Individuals with cold agglutinin disease present with signs and symptoms of hemolytic anemia
. Those with secondary agglutinin disease may also present with an underlying disease, often autoimmune.
Treatment with rituximab
has been described.
Autoimmune disease
Autoimmune diseases arise from an overactive immune response of the body against substances and tissues normally present in the body. In other words, the body actually attacks its own cells. The immune system mistakes some part of the body as a pathogen and attacks it. This may be restricted to...
characterized by the presence of high concentrations of circulating antibodies, usually IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
, directed against red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
s. It is a form of autoimmune hemolytic anemia
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia occurs when antibodies directed against the person's own red blood cells cause the RBCs to burst , leading to insufficient plasma concentration. The lifetime of the RBCs is reduced from the normal 100–120 days to just a few days in serious cases...
, specifically one in which antibodies only bind red blood cells at low body temperatures, typically 28-31°C.
It was first described in 1957.
Etiology
There are two forms of cold agglutinin disease: 1-primary and 2-secondary.- The primary form is by definition idiopathicIdiopathicIdiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
, a disease for which no cause is known.
- Secondary cold agglutinin disease is a result of an underlying condition.
- In adults, this is typically due to a lymphoproliferative disease such as lymphomaLymphomaLymphoma is a cancer in the lymphatic cells of the immune system. Typically, lymphomas present as a solid tumor of lymphoid cells. Treatment might involve chemotherapy and in some cases radiotherapy and/or bone marrow transplantation, and can be curable depending on the histology, type, and stage...
and chronic lymphoid leukemia, or infection. - In children, cold agglutinin disease is often secondary to an infection, such as Mycoplasma pneumoniaMycoplasma pneumoniaMycoplasma pneumonia is a form of bacterial pneumonia which is caused by the bacteria species Mycoplasma pneumoniae....
, mononucleosisMononucleosisMononucleosis , is a disease most commonly caused by the Epstein-Barr virus . The EBV virus affects the lymphocytes- white blood cells that battle infections by attacking antibodies. Mononucleosis can also be caused by Cytomegalovirus , a herpes virus most commonly found in body fluids...
, and HIVHIVHuman immunodeficiency virus is a lentivirus that causes acquired immunodeficiency syndrome , a condition in humans in which progressive failure of the immune system allows life-threatening opportunistic infections and cancers to thrive...
.
- In adults, this is typically due to a lymphoproliferative disease such as lymphoma
Pathophysiology
All individuals have circulating antibodies directed against red blood cells, but their concentrations are often too low to trigger disease (titers under 64 at 4°C). In individuals with cold agglutinin disease, these antibodies are in much higher concentrations (titers over 1000 at 4°C).At body temperatures of 28-31°C, such as those encountered during winter months, and occasionally at body temperatures of 37°C, antibodies (generally IgM
IGM
IGM as an acronym or abbreviation can refer to:* Immunoglobulin M , the primary antibody against A and B antigens on red blood cells* International Grandmaster, a chess ranking* intergalactic medium* Intragroup medium - see: Intracluster medium...
) bind to the polysaccharide
Polysaccharide
Polysaccharides are long carbohydrate molecules, of repeated monomer units joined together by glycosidic bonds. They range in structure from linear to highly branched. Polysaccharides are often quite heterogeneous, containing slight modifications of the repeating unit. Depending on the structure,...
region of glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
s on the surface of red blood cells (typically the I antigen, i antigen, and Pr antigens). Binding of antibodies to red blood cells activates the classical pathway of the complement system
Complement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
. If the complement response is sufficient, red blood cells are damaged by the membrane attack complex, an effector of the complement cascade. In the formation of the membrane attack complex, several complement proteins are inserted into the red blood cell membrane, forming pores that lead to membrane instability and intravascular hemolysis
Hemolysis
Hemolysis —from the Greek meaning "blood" and meaning a "loosing", "setting free" or "releasing"—is the rupturing of erythrocytes and the release of their contents into surrounding fluid...
(destruction of the red blood cell within the blood vessels).
If the complement response is insufficient to form membrane attack complexes, then extravascular lysis will be favored over intravascular red blood cell lysis. In lieu of the membrane attack complex, complement proteins (particularly C3b and C4b) are deposited on red blood cells. This opsonization enhances the clearance of red blood cell by phagocyte
Phagocyte
Phagocytes are the white blood cells that protect the body by ingesting harmful foreign particles, bacteria, and dead or dying cells. Their name comes from the Greek phagein, "to eat" or "devour", and "-cyte", the suffix in biology denoting "cell", from the Greek kutos, "hollow vessel". They are...
s in the liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
, spleen
Spleen
The spleen is an organ found in virtually all vertebrate animals with important roles in regard to red blood cells and the immune system. In humans, it is located in the left upper quadrant of the abdomen. It removes old red blood cells and holds a reserve of blood in case of hemorrhagic shock...
, and lungs, a process termed extravascular hemolysis.
Individuals with cold agglutinin disease present with signs and symptoms of hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
. Those with secondary agglutinin disease may also present with an underlying disease, often autoimmune.
Treatment
- Avoid cold weather.
- Treat the underlying lymphoma.
Treatment with rituximab
Rituximab
Rituximab, sold under the trade names Rituxan and MabThera, is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells...
has been described.