Hemolytic anemia results when there is premature red cell destruction. Although premature, accelerated destruction of erythrocytes is a clinical manifestation of many diseases. In hemolytic anemia this destruction is the predominant event.
Although the red blood cell (RBC) formation (erythropoiesis) is normal, their lifespan is shortened considerably – by as much as 100 days. This is extensive when the normal cell survives for only 120 days.
As the RBCs are destroyed, their membrane ruptures, and iron and heme are released from the hemoglobin to circulate back to the liver. The heme portion of hemoglobin is of no further use and is converted to bilirubin, a bile pigment, and excreted by the liver in bile. The iron is placed in ferritin (one of the forms in which iron is stored in the body). This destruction of RBCs is called hemolysis. When hemolysis occurs earlier than the normal cycle, hemolytic anemia is the result.
Hemolytic anemia may be acquired or hereditary. Acquired forms are generally caused by such extrinsic (extracellular) defects as infection, systemic disease, drugs or toxins, liver or kidney disease, or abnormal immune responses.
Hereditary forms are the result of intrinsic (cellular) abnormalities, typically of the erythrocyte’s plasma membrane or cytoplasmic contents (enzymes of hemoglobin). Congenital hemolytic anemias are present at birth and may or may not be inherited.
The presence and severity of signs and symptoms of hemolytic anemia depend on the degree of hemolysis and the success of compensatory erythropoiesis.
The spleen enlarges as it removes more and more dead or defective erythrocytes from the circulation. Jaundice (icterus) occurs if heme breakdown exceeds the liver’s ability to conjugate and excrete bilirubin.
Acute conditions frequently develop if other diseases, particularly viral infections, are also present. Crises are associated with further declines in levels of hemoglobin in the peripheral blood and occasionally bone marrow hypoplasia or aplasia.
In severe cases, the bones become deformed as a result of expansion of hematopoietic bone marrow, and pathologic features often occur. Cardiovascular and respiratory manifestations vary with the degree of anemia.
Hemolytic anemia is sometimes caused by a vitamin E deficiency. Occasionally, red blood cells (RBCs) will have an abnormal membrane as a result of a deficiency of this vital nutrient. This abnormality causes the cell to rupture releasing hemoglobin into the plasma. As this situation increases, physical symptoms of edema and some of its consequences, begin to take place, including swollen extremeties, puffy eyelids, noisy breathing or difficulty breathing, and so on.
Severe deficiency can result in encephalomalacia (softening of the brain tissue). If vitamin E supplements are taken, iron should not be taken at the same time as iron will interfere with the utilization of vitamin E.
Treatments of hemolytic anemias vary according to the cause; that is, removing the cause or treating the underlying disorder. Acute, fulminating hemolytic anemic crisis is treated with fluid and electrolyte replacement to prevent shock and renal damage from clogging the kidney tubules by red cell debris.
Transfusions of blood products are sometimes given. Splenectomy is performed if the spleen is the major site of hemolysis and is significant to the condition. Sometimes treatment with such hormones as ACTH and cortisone are helpful. Some nutritional supplementation is also advocated, especially that of vitamin E.
Types of hemolytic disorders and their causes or associated disorders include the following:
- Acquired forms
- Hypophosphatemic hemolysis: results from diminished cellular production of substances required for erythrocyte life and function, which results in hypophosphatemia (a phosphate deficiency in plasma).
- Immune system: results when antibody-mediated erythrocytes are destroyed by enzymes of the complement system. This can happen as a result of a transfusion reaction or hemolytic disease of the newborn.
- Infectious hemolysis: caused by infection of erythrocytes by such bacterial infections as clostridia, cholera, typhoid fever, or from such protozoal infections as malaria or toxoplasmosis.
- Physical hemolysis: occurs after heat or radiation injury that can happen from burns or radiation exposure.
- Toxic (chemical) hemolysis: results from chemical injury of erythrocytes as a result of exposure to toxic chemical agents, hemodialysis or uremia, or venoms.
- Traumatic hemolysis: results in response to a physical destruction of erythrocytes by “mechanical” means; that is, trauma which includes the presence of prosthetic heart valves, structural abnormalities of the heart, hemolytic uremic syndrome, disseminated intravascular coagulation, or hemodialysis.
- Hereditary forms
- Defects of globin synthesis or structure: This results in three conditions: sickle cell disease (increased membrane fragility and deformation during a sickle crisis); thalassemia, (defective hemoglobin structure and function); and other miscellaneous hemoglobin defect disorders that result from defective hemoglobin structure and function.
- Enzyme deficiencies: The cause is diminished cellular function, resulting in a deficiency of glycolytic enzymes and metabolic enzymes.
- Structural defects: They result from the fragility of the erythrocytes which can lead to plasma membrane defects.
Autoimmune hemolytic anemias are a group of hemolytic anemias in which RBC destruction occurs because of immune system componenets attacking their own RBCs. Usually the attacking immune components are antibodies (either IgG or IgM) or complement proteins but the exact trigger(s) for this reaction is not known.
When these anemias are present without any accompanying disease or disorder, it is possible that the membrane surface of the RBC is expressing a new protein (antigen) not made elsewhere in the body and therefore, not recognized as part of the normal self. In such cases, the pathologic change actually resides in the RBCs.
When the anemias are present with such autoimmune disorders as lupus or lymphoproliferative disorders, the pathologic change may actually reside within the immune system. Whatever the cause, the RBC is viewed as non-self by the immune system and is destroyed.
Autoimmune hemolytic anemias are all acquired and consist of warm antibody disease, cold antibody disease, and drug-induced anemia.
Warm antibody disease is mediated by immunoglobulin (IgG antibody) that is specific for erythrocyte antigens and binds to the surface of the erythrocyte at normal body temperatures (37°C – 98.6°F). The antibody can activate the complement cascade, resulting in intravascular destruction of the erythrocyte. Chronic anemia caused by warm antibody disease is frequently observed in association with other diseases, including chronic lymphocytic leukemia, lymphoid tumors, and systemic lupus erythematosus.
Cold antibody disease is mediated by a different immunoglobulin (IgM) specific for erythrocyte antigens. IgM binds to erythrocytes only at colder temperatures (below 31°C – 87.8°F), which may occur in the fingers and toes during cold weather. This is why it is commonly associated with Raynaud’s syndrome. Agglutination of IgM-bound erythrocytes in the extremeties produces pain and tissue deterioration. In addition, when the antibody-coated cells are warmed on re-entering the general circulation, the antibody may dissociate from the erythrocyte. If it does not, hemolysis of the cell may occur. Thus, cold antibody disease is more a problem of vascular obstruction than hemolysis and is often a complication of infectious mononucleosis, mycoplasma pneumonia infections, and lymphoid malignancies.
Drug-induced immune hemolytic anemia can be caused by either of two mechanisms. One stems from an immune reaction against a drug, resulting in the formation of antigen-antibody complexes that adhere to the surfaces of the erythrocytes. Alternately, a drug, or a metabolite of a drug, may bind directly to the surface of the erythrocyte, forming a neoantigen that attracts antibodies. Both mechanisms result in the activation of the complement cascade and hemolysis.
Congenital hemolytic anemias produce many forms resulting from defects or deficiencies of one or more enzymes within the RBC. Most of these enzymes are essential to catalyze some critical step in intracellular energy production, and more than 200 such disorders have been identified. The most common type by far is associated with a deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD), which is sometimes confused with spherocytic anemia because they have similar symptoms.
G6PD is a hereditary, sex-linked enzyme defect that results in the breakdown of red blood cells when the person is exposed to the stress of infection, toxins, compounds in foods (like fava beans), or certain drugs (phenacetin, sulfonamides, aspirin or acetylsalicylic acid, quinine derivatives, thiazide diuretics, and vitamin K derivatives). It often occurs in a mild form in African-American males, but in a more severe form in certain population groups in the Mediterranean area.
G6PD catalyzes critical reactions in the glycolytic pathway. Because RBCs contain no mitochondria (sites of high energy production), active glycolysis is essential for energy metabolism. Cells that have reduced amounts of G6PD are more susceptible to hemolysis during oxidant injuries such as those from exposure to aforementioned agents. Normal RBCs avoid injury from these agents by increasing the production of ATP and stimulating defensive metabolic processes. Newly produced RBCs from individuals with G6PD deficiency have relatively sufficient quantities of G6PD. However, as the cells age, the concentration of this enzyme diminishes drastically.
With exposure to certain drugs or infections, the individual experiences acute intravascular hemolysis lasting from seven to twelve days. During this acute period, the patient develops anemia and jaundice. The hemolytic reaction is self-limited because only older erythrocytes are destroyed.
In the 1950s, scientists discovered that there was a very high incidence of G6PD in the Mediterranean region. For centuries, villages throughout the area were plagued with residents feeling lethargic every February. They also complained of dizziness and nausea and would fall asleep easily. They would lack the energy to do their work, and some would start to pass blood in the urine.
Since these people did not suffer at any other time of the year, scientists started looking to the environment for a cause and discovered fava beans. These beans are very prolific in the region and a favorite food. Eating them raw or lightly cooked, and sometimes even breathing in the pollen, caused those with this particular deficiency to suffer the effects of hemolytic anemia. Pythagorus, 2,500 years ago, knew this, too, and would not allow any of his followers to eat the beans.
Hemolytic anemia caused by an Rh factor: This incompatability occurs when an Rh negative mother develops antibodies against the Rh positive blood of the fetus towards the end of her pregnancy. The first pregnancy is not usually affected unless the mother was previously sensitized by abortion or blood transfusion. However, in subsequent pregnancies, there are likely to be blood problems caused by the transfer of antibodies from the mother to the infant, resulting in destruction of red cells in the newborn.
In severe cases, there may be almost complete destruction of the infant’s red cells and damage to the brain by the accumulation of bilirubin. Treatment of a severely affected infant may require a total blood exchange. For the mother, the treatment involves the administration of a substance called RhoGam® which blocks antibody production by the mother by transferring antibodies (passive immunity) to the sensitized woman and blocking her production of antibodies against Rh negative/positive blood. This should be administered to Rh negative women when they first show signs of sensitization – usually after the first pregnancy or abortion.
Microangiopathic hemolytic anemia literally means the anemia is caused by disease in the small blood vessels. The most straightforward way to destroy red cells is to beat them up. Since they are nothing more than bags of fluid, they are subject to destruction by any significantly strong compressive or shearing force. If there is an obstruction in the small blood vessels, red cells will either get backed up behind the obstruction or be torn apart while trying to squeeze past it.
In several conditions, formation of intravascular obstructions is just big enough to tear apart red cells without completely stopping the flow of blood. These obstructions are composed of fibrin, a protein that makes up a normal blood clot. Many red cells are ‘clotheslined’ when forced across a fibrin clot and destroyed in the process. However, those that are able to pass are eager to regain their cellular competence and reassemble themselves.
These abnormally shaped cells often look like solder’s helmets and are called just that, helmet cells (schizocytes). They are readily identifiable on a blood smear, which is why it is important to examine a blood smear when hemolytic anemia is suspected. There are several diseases in which there is extensive abnormal formation of fibrin clots throughout the body leading to microangiopathic hemolytic anemia. These include the following:
- Disseminated intravascular coagulopathy (DIC)
- This condition is not a disease in itself but is a common complication of a fairly large variety of other serious acute diseases. DIC displays an abnormal and inappropriate activation of the blood clotting system so that clots form within normal blood vessels. Normally, clots form only in the immediate vicinity of an injured vessel; but, in this case, red cells are jammed against damaged areas of the tiny vessels and are sheared apart. For some reason, fibrinogen (the plasma protein that is converted to fibrin) is no longer available to form normal clots at any site of vessel injury. When circulating levels of platelets and clotting proteins are sufficiently low, the normal clotting system no longer works, and abnormal bleeding occurs.DIC was first seen in women suffering from a variety of obstetrical complications, but is now seen more often in the elderly with severe bacterial infections. The list of diseases that cause DIC is long, but the main point to remember is that it can occur as a result of almost any disease that makes the patient severely and acutely ill. Treatment is often paradoxical, placing the doctor between “a rock and a hard place”. To stop abnormal clotting, the patient can be given heparin, which will stop the clotting all right, but it will also inactivate what feeble amounts of clotting proteins are left. Transfusions will replace depleted platlets and clotting proteins, but this only adds more fuel to the fire of what caused the abnormal clotting in the first place. Sometimes the cause is apparent and can be dealt with, as in the case of abnormal pregnancy problems or burns. Sometimes it is not as obvious.
- Thrombotic thrombocytopenic purpura (TTP)
- This disease literally means bruising as a result of bleeding into the tissues. It is another clot-forming condition that causes low platelet counts, resulting in bleeding. Although rare and the cause virtually unknown, TTP appears to be mediated by the immune system. Whatever the cause, there is damage to the internal lining of small blood vessels and clots form at these sites. Despite the fact that this clotting uses up the patient’s platelets, clotting proteins are not used up – a contrast to DIC. Nevertheless, since normal clotting cannot occur without platelets, the patient bleeds (hence, the name purpura). The hemolytic anemia that occurs as a result may be very severe, requiring a transfusion.A distinctive feature of TTP is that the effects of interrupted blood flow are especially apparent in the brain and may result in a bizarre variety of neurological symptoms. Another target is the kidney, which can also be seen in DIC. In the past, the mortality rate for TTP was around 90%; but, today, about 70% can be controlled by therapy.Often, a plasma exchange is effective. This involves the complete removal of the patient’s plasma and replacing it with normal plasma. Modern plasma exchanges are done with automated machinery that continuously draw off a small quantity of the patient’s whole blood, separates the cells from the plasma, returns the cells to the patient, and replaces the patient’s plasma with donated plasma from volunteers. Plasma exchange is done daily until the patient improves – about nine days on average. Most cases of TTP are acute, occurring once, and either killing the patient or never returning. A few, however, are recurrent or chronic.
Spherocytic anemia or ‘familial hemolytic jaundice’ is a hereditary disorder in which the red cells are shaped like spheres instead of being doughnut-shaped (toroidal). Jaundice results from excessive destruction of the abnormal cells by the spleen. The effects include the yellowish skin color and whites of the eyes (jaundice), and a reduction in the number of circulating red cells. There is no cure except for the surgical removal of the spleen, which usually takes care of the jaundice and excessive red cell destruction.