Autoimmune hemolytic anemia

Definitions & Key takeaways

Autoimmune hemolytic anemia (AIHA) is a blood disorder that occurs when a person's own antibodies attack and destroy healthy red blood cells. The cause is not completely understood, but it may be associated with other conditions such as an infection, or leukemia. AIHA causes several symptoms, including fatigue, jaundice, shortness of breath, and an enlarged spleen.

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Introduction0:00–0:54

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.

Physiology0:54–1:34

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.

Classification1:34–2:06

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 Anemia2:06–3:15

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.
In this reaction, immune cells including macrophages, neutrophils, natural killer cells, or CD8+ T-cells bind to the Fc portion of the antibody via a cell membrane receptor called the Fc receptor.
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.

Cold Autoimmune Hemolytic Anemia3:15–4:19

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.

Pathology4:19–6:56

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.
With intravascular hemolysis, hemoglobin is bound by a protein called haptoglobin and they’re excreted into bile and removed from the body through feces.
So with ongoing hemolysis, haptoglobin levels decrease. Also, when haptoglobin gets overwhelmed, the rest of hemoglobin goes via the blood through the kidneys and into the urine resulting in hemoglobinuria.
Now, when hemoglobin is inside the renal tubules, it’s reabsorbed by the cells lining the renal tubules. The heme component of hemoglobin contains iron, which is stored inside tubular cells as hemosiderin.
Hemosiderin is an amorphous collection of heme, proteins, and lipids. And after a few days, when tubular cells slough into urine, this results in hemosiderinuria.
Hemoglobinuria and hemosiderinuria can damage the kidneys causing renal insufficiency. Finally, with extravascular hemolysis, RBCs are destroyed outside the vessels and so, haptoglobin is normal and there’s no hemoglobin or hemosiderin in the urine.
Now, there are multiple etiologies for warm autoimmune hemolytic anemia but most cases are idiopathic, or without underlying cause.

Causes6:56–7:50

In children, viral infections are a common precipitant. Other causes include systemic lupus erythematosus, lymphomas, and leukemia, to name a few, as well as some drugs such as beta-lactam antibiotics like penicillin and cephalosporins.
Cold autoimmune hemolytic anemia, on the other hand, has different causes depending on presentation. With chronic disease, causes also include leukemia and lymphomas, while acute forms are more often caused by infections like viral pneumonia, mycoplasma, and infectious mononucleosis.
The acute form of the disease is often referred to as paroxysmal cold hemoglobinuria and is more common in children. Autoimmune hemolytic anemia usually progresses slowly, over days to weeks, but sometimes hemolysis occurs at a rapid rate, over the course of hours, which is called a hemolytic crisis.

Symptoms7:50–8:43

Symptoms of a hemolytic crisis include those of profound anemia, leading to a bounding heart rate, which is when the person feels their heart is pounding, severe shortness of breath, and potentially signs of multiorgan failure from lack circulating red blood cells.
In chronic forms of the disease symptoms include fatigue, pallor, and shortness of breath from the anemia. Jaundice or yellowing of the skin may occur due to the buildup of bilirubin and there may be hepatosplenomegaly.
Oliguria or low urine output may occur from renal insufficiency if significant intravascular hemolysis occurs. The diagnosis of both conditions starts with routine laboratory work and hemolysis labs, which will demonstrate a normocytic anemia, low haptoglobin as well as elevated reticulocytes and lactate dehydrogenase.

Diagnosis8:43–9:46

Definitive diagnosis of warm and cold autoimmune hemolytic anemia gets made by the direct coombs test or direct antigen test.
The direct coombs test detects if there are any antibodies bound to the surface of a person's red blood cells. To perform this test, a sample of blood is taken and placed in a test tube.
Next, coombs antibodies are added to the person's blood. If antigens are present on the surface of the red blood cell, the coombs antibodies will bind, and cause the red blood cells to agglutinate or clump together, indicating a positive test.
In the case of warm autoimmune hemolytic anemia, the direct antigen test will result positive for IgG and a complement protein called C3D, where as with cold it will only be positive for C3D.

Treatment9:46–10:34

Treatment of both warm and cold autoimmune hemolytic anemia involves initial assessment of the degree of anemia, with lab studies, like hemoglobin level.
If hemoglobin is less than seven, transfusion is generally indicated. First line therapy for warm autoimmune hemolytic anemia includes steroids and refractory cases can be treated with splenectomy to decrease the degree of phagocytosis, or other immunosuppressive medications.
On the other hand, for cold autoimmune hemolytic anemia, no treatment is usually required. For severe anemia, however, plasmapheresis may be recommended.
This is where the blood plasma is filtered to remove the harmful IgM antibodies causing hemolysis. All right, as a quick recap, autoimmune hemolytic anemia, arises when the immune system makes antibodies against specific antigens on red blood cells.

Review10:34–11:24

With warm autoimmune hemolytic anemia, there are usually IgG antibodies directed against Rh antigens, and RBCs are destroyed via antibody-dependent cell mediated cytotoxicity.
With cold autoimmune hemolytic anemia, the culprits are IgM antibodies that bind to antigens L, I, and P on RBCs, and RBCs are destroyed following activation of the classical complement pathway.
Most often, the disease is idiopathic, and treatment may involve corticosteroids for warm autoimmune hemolytic anemia and plasmapheresis for cold autoimmune hemolytic anemia.