Content Reviewers:Viviana Popa, MD
Autoimmune hemolytic anemia refers to increased red blood cell hemolysis, or breakdown, that results when a person’s own antibodies target red blood cells for destruction.
And this results in a lower than normal amount of red blood cells anemia.
The disease is most often idiopathic, or without a known cause, but it can be related to a medication side effect, or an underlying disease process.
Normally, red blood cells, or RBCs, are made in the bone marrow and contain hemoglobin, which is an oxygen binding protein that delivers oxygen to tissues.
Red blood cells live about 100-120 days after which they are recycled in the bone marrow or consumed by macrophages in the spleen, liver, or lymphatic system.
Now, autoimmune hemolytic anemia is an extrinsic type of hemolytic anemia, because the immune system mistakenly believes our own red blood cells are foreign, or non-self, structures, so it secretes antibodies against proteins found on the RBC membrane.
If there had been a primary defect in the RBC membrane, then it would have been called an intrinsic hemolytic anemia.
And usually, hemolysis happens in the spleen or liver, so this is considered an extravascular hemolytic anemia - although in severe cases, RBC hemolysis can also happen intravascularly, or inside blood vessels.
Now, autoimmune hemolytic anemia gets classified as either warm or cold.
Warm is the more common type, and it’s when hemolysis occurs at temperatures greater than or equal to core human body temperature of 37º celsius.
Cold autoimmune hemolytic anemia is much rarer, and it occurs when people’s blood is exposed to cold temperatures, usually in the range of 0º to 10º celsius - like when a person goes out into cold weather during winter.
Warm autoimmune hemolytic anemia is almost always due to IgG antibodies, termed “warm agglutinins” that react with antigens, which are proteins on the surface of the red blood cell.
The main red blood cell antigen that reacts with these IgG antibodies is the Rh antigen.
When these antibodies bind to the antigen on the RBC membrane, they bind to the surface of the red blood cell and trigger a process called antibody-dependent cell mediated cytotoxicity.
Once bound, a conformational change occurs in the Fc receptor on the immune cell that induces hemolysis of the red blood cell.
This may occur via direct cytotoxins like superoxide granules from neutrophils or phagocytosis by macrophages.
Phagocytosis mostly occurs in the spleen, where there’s a high density of macrophages, which can result in an enlarged spleen.
In contrast, with cold autoimmune hemolytic anemia, the culprits are IgM type antibodies and the primary red blood cell antigens are termed L, I, and P.
In the chronic form of disease, which is the most common, RBC hemolysis primarily occurs in the liver, via the complement system.
The complement system is a group of plasma proteins that act together to destroy pathogens.
Specifically, IgM activates the classical complement pathway, and the complement proteins eventually assemble into a membrane attack complex, or MAC for short.
MAC is a specialized structure that drills pores in the RBC membrane, which results in RBC destruction.
In the acute form of disease, this process can also occur intravascularly in the toes or fingers causing Raynaud’s phenomenon.
This is a fancy way to say that microemboli clog the tiny capillaries in the toes and fingertips, making them turn purple or blue.
Now, no matter the type temperature at which it occurs, hemolysis leads to a cascade of events.
First, the bone marrow revs up and starts pumping out immature RBCs called reticulocytes.
Since these red blood cells are normal in size, approximately 80-100 fL, autoimmune hemolytic anemia is considered normocytic.
Additionally, with intravascular hemolysis, when RBCs are broken down, an intracellular enzyme called lactate dehydrogenase, or LDH, spills out directly into the plasma, so LDH plasma levels increase.
Hemoglobin also spills out of the RBC and some of this hemoglobin breaks up into heme and globin.
Heme is converted into unconjugated, or indirect, bilirubin which is then taken up by the liver cells and eventually secreted out with bile.
Some of the bilirubin is converted to urobilin which is what gives urine that yellow color, but if there’s too much of it, the urine becomes a much darker color, like black tea.
If there’s too much bilirubin in the bile, that may cause bilirubin, or pigmented, gallstones to form.
Finally, if more RBCs are broken down than the liver cells can handle, the excess bilirubin stays in the blood and causes jaundice, which is when bilirubin deposits in the skin and eyes, causing them to turn yellow.
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- "Cold Agglutinin-Mediated Autoimmune Hemolytic Anemia" Hematology/Oncology Clinics of North America (2015)
- "Autoimmune hemolytic anemia" American Journal of Hematology (2002)