Hemolytic Anemia

Hemolytic anemia is a rare form of anemia in which red blood cells (also called erythrocytes) do not live as long as healthy cells; they are destroyed and removed from the bloodstream prematurely. Healthy red blood cells usually live about 120 days in the bloodstream before the body removes them. In hemolytic anemia, the body breaks down and removes red blood cells faster than it can replace them. The breakdown of red blood cells is called hemolysis. The hemolysis can occur in the bloodstream or in an organ called the spleen. The bone marrow increases production of red blood cells to replace the hemolyzed blood cells, but it can't produce them fast enough to meet the body's needs.

Image of blood cells. The red blood cell is the round one on the left. Source: Wikimedia Commons

Other Names

There are several different types of anemia that can be hemolytic:

• Alloimmune hemolytic anemia
• Autoimmune hemolytic anemia
• Drug-induced hemolytic anemia
• Hemoglobin anemia, caused by glucose-6-phosphate dehydrogenase deficiency
• Hemolytic anemia, caused by chemicals and toxins
• Hereditary elliptocytosis
• Hereditary ovalocytosis
• Hereditary spherocytosis
• Idiopathic autoimmune hemolytic anemia
• Immune hemolytic anemia
• Microangiopathic hemolytic anemia
• Paroxysmal nocturnal hemoglobinuria
• Pyruvate kinase deficiency
• Sickle cell anemia
• Thalassemia

Types

In some types of hemolytic anemia, the body makes abnormal red blood cells that break down and hemolyze on their own. These types are classified as inherited hemolytic anemias. In other types, the body's immune system, infections, certain drugs, or other agents attack normal red blood cells, causing them to hemolyze. These types are classified as acquired hemolytic anemias.

Inherited hemolytic anemia

Inherited hemolytic anemias are passed from parents to children. In the inherited hemolytic anemias, one or more of the genes that control the production of red blood cells is defective, causing the bone marrow to make abnormal cells.

Sickle cell anemia

In sickle cell anemia, the body makes an abnormal type of hemoglobin. This hemoglobin causes misshapen red blood cells: Instead of their normal shape, the red blood cells turn into a sickle (crescent) shape. Sickle cells die and are removed from the bloodstream prematurely. In the United States, sickle cell anemia occurs most often in African Americans.

Thalassemia

The thalassemias are a group of anemias in which the body does not make enough of certain types of hemoglobin. This leads to abnormal red blood cells that die and are removed from the body prematurely. Thalassemia is most common among people of Mediterranean, African, or Southeast Asian descent.

Hereditary spherocytosis

In hereditary spherocytosis, the red blood cell membrane is abnormal and causes the cells to form spheres. These spheres have a short lifespan. Hereditary spherocytosis is the most common cause of hemolytic anemia among people whose ancestors come from Northern Europe.

Hereditary elliptocytosis

Like hereditary spherocytosis, hereditary elliptocytosis, shortens the lifespan of red blood cells because of structural defects in the cell membrane. In this anemia, the red blood cells oval-shaped and less flexible than healthy red blood cells. This anemia is also known as hereditary ovalocytosis.

Glucose-6-Phosphate dehydrogenase Deficiency

In glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), the red blood cells are missing an important enzyme called G6PD. G6PD is part of the normal chemistry inside red blood cells. In G6PD deficiency, if red blood cells come into contact with certain substances in the bloodstream, the missing enzyme causes the cells to rupture and die prematurely. The hemolysis can be triggered by sulfa or antimalarial medicines, fava beans, or an infection. G6PD deficiency mostly affects males of African or Mediterranean descent. It affects about one in ten African American males.

Pyruvate kinase deficiency

Pyruvate kinase deficiency is a hemolytic anemia in which red blood cells lack the enzyme pyruvate kinase. This deficiency causes red blood cells to break down easily. This disorder is more common among the Amish than other groups.

Acquired hemolytic anemia

In acquired types of hemolytic anemias, the red blood cells may be normal, but some other disease or factor causes the body to destroy the red blood cells and remove them from the bloodstream. The destruction of the red blood cells can occur in the bloodstream or, more commonly, in the spleen.

Immune hemolytic anemia

In immune hemolytic anemia, the immune system destroys the body’s red blood cells. There are three main types of immune hemolytic anemia: autoimmune, alloimmune, and drug-induced.

In autoimmune hemolytic anemia (AIHA), the immune system mistakenly produces antibodies directed against the body’s own red blood cells. Normally, antibodies can distinguish between “self” and foreign and help rid the body of the foreign invaders. In this anemia however, the red blood cells are recognized as foreign and are attacked by the immune system. One-half of all cases of hemolytic anemia are AIHA. The cause of AIHA is unknown. It may come on very quickly and become serious. It’s most common in people over age 40 years.

Some diseases or infections increase the risk of AIHA:

• many blood cancers, e.g., chronic lymphocytic leukemia, non-Hodgkin's lymphoma
• Epstein-Barr virus (which causes infectious mononucleosis)
• cytomegalovirus
• mycoplasma pneumonia (a lung infection)
• hepatitis;
• human immunodeficiency virus (HIV).

In some types of AIHA, the antibodies produced by the body are called warm antibodies. This means they are active (that is, they destroy red blood cells) at warm temperatures, such as body temperature. In other types of AIHA, the body produces cold-reactive antibodies,” which means they become active when exposed to colder temperatures. Cold-reactive antibodies can become active when the body (typically the hands or feet) is exposed to temperatures of less than 32 to 50 degrees Fahrenheit (0 to 10 degrees Celsius). Warm antibody AIHA is more common than cold-reactive antibody AIHA.

In alloimmune hemolytic anemia, antibodies are produced against the red blood cells obtained during a blood transfusion, and they cause the transfused cells to die. This occurs if the blood type used for the transfusion is different than the recipient’s blood type.

Alloimmune antibodies also can develop as a result of the mixing of blood between a pregnant woman and her baby at delivery. If the mother's blood type is Rh-negative and the baby's is Rh-positive, the mother can produce antibodies against the baby's blood type. If a mother develops anti-Rh antibodies as a result of one pregnancy, they can cross the placenta during the next pregnancy and harm the fetus. To prevent this, a medicine called RhoGam can be given at the time of delivery to block the mother’s body from developing antibodies against the baby’s blood type.

Some hemolytic anemias are drug-induced. Some drugs can cause a reaction that develops into hemolytic anemia. These drugs include high doses of penicillin and related drugs, acetaminophen, quinine and other drugs to treat malaria, anti-inflammatory drugs, and levodopa used for Parkinson disease.

Mechanical hemolytic anemias

The membranes of red blood cells are sensitive to damage by a variety of environmental stresses:

• change in the structure of small blood vessels
• artificial heart valve or other device used in blood vessels
• heart-lung bypass machine
• preeclampsia or eclampsia (elevated blood pressure and protein in the urine after the 20th week of pregnancy)
• marathons or other strenuous activities

Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired genetic disorder in which the red blood cells are abnormal due to a lack of certain proteins. The body destroys these cells more rapidly than normal. The destruction may occur continuously at a low level and flare up at times (paroxysmal). People with PNH are at increased risk for blood clots in the veins and low levels of white blood cells and platelets.

Other causes of damage to red blood cells

Infections and other agents can invade and damage red blood cells. Malaria and “blackwater fever,” tick-borne diseases, snake venom, and toxic chemicals can attack and destroy red blood cells, causing hemolytic anemia.

Symptoms

Symptoms of hemolytic anemia depend on the type and severity. People with mild hemolytic anemia often have no symptoms. However, if the anemia is severe, the symptoms increase and become more serious.

The most common symptom of hemolytic anemia is fatigue (tiredness). Fatigue develops because the tissues of the body don’t receive enough oxygen. The hemoglobin in red blood cells picks up oxygen in the lungs and circulates it to the tissues of the body. If there aren't enough red blood cells, or not enough hemoglobin in the red blood cells, the blood can't carry enough oxygen to the rest of the body.

The lack of oxygen in the blood has other effects, in addition to fatigue:

• dizziness
• weakness
• headache
• feeling short of breath
• passing out when standing from a seated or lying position

Since the heart must work harder to circulate the low oxygen levels, symptoms of anemia may also include a fast or irregular heartbeat or a heart murmur.

People with anemia may have pale skin, tongue, gums, and nail beds due to the low levels of hemoglobin.

The breakdown of red blood cells, and the accumulation of the breakdown products, can also cause some symptoms:

• jaundice, which is a yellowish discoloration of the skin and eyes; Jaundice is caused by the accumulation of bilirubin, a breakdown product of hemoglobin.
• pain in the upper abdomen due to gallstones or an enlarged liver; If high levels of bilirubin and cholesterol are present(from the breakdown of red blood cells), they can form into stones in the gallbladder, which can become painful.
• leg ulcers and pain; In people with sickle cell anemia, the abnormal cells can clog small blood vessels, blocking blood flow in the legs and producing pain throughout the body

A severe reaction to a blood transfusion is also a sign of hemolytic anemia. These transfusion reactions include fever, chills, low blood pressure, and shock (a life-threatening condition that occurs when the body is not getting enough blood flow).

Causes

The immediate cause of hemolytic anemia is the early destruction of red blood cells. The cause of this premature destruction is either inherited or acquired. Sometimes, the cause of early hemolysis is not known.

Inherited

Inherited hemolytic anemias are characterized by genetic mutations that alter the production of red blood cells. People with an inherited hemolytic anemia received a defective red blood cell gene from one (or both) of their parents. Different types of defective genes account for the different types of inherited hemolytic anemias. The red blood cell abnormality can involve the cell membrane (the outer covering of the cell), the chemistry inside the cell, or the production of abnormal types or amounts of hemoglobin. The abnormal cells may be fragile and break down on their own while circulating in the bloodstream. Also, the body's immune system may recognize that the red blood cells are abnormal, and the spleen may remove the cells from the bloodstream.

Acquired

In acquired types of hemolytic anemia, the body produces normal red blood cells, but some disease or other factor destroys the cells prematurely (see “Types”).

Diagnosis

Hemolytic anemia is diagnosed using a combination of medical and family histories, physical exam, and diagnostic tests. Diagnosis and care can involve many types of doctors and specialists:

• primary care doctors (a family doctor or pediatrician)
• hematologist (blood disease specialist)
• cardiologist (heart specialist)
• genetics counselor

Medical and family history

Doctors use symptoms, personal medical history, and family medical history, including past episodes of anemia, to determine the cause and severity of hemolytic anemia. They also consider recent illnesses, medication use, and implantation of artificial heart valve.

Physical exam

Several symptoms of hemolytic anemia can be revealed by a physical exam:

• jaundice
• a rapid or abnormal heartbeat
• rapid or uneven breathing
• enlarged spleen or liver
• internal bleeding; the doctor examines the pelvis and rectum

Diagnostic tests and procedures

Numerous diagnostic tests are available for hemolytic anemia.

Blood tests

Usually, the first test used to diagnose anemia is a complete blood count (CBC). The CBC evaluates the number and health of red blood cells in many ways:

• hemoglobin level–Hemoglobin levels below 11–15 g/dl suggests anemia.
• hematocrit level–The hematocrit level measures how much of the blood is made up of red blood cells. Anemia can occur with hematocrit levels below 32&%–43% (note: normal hematocrit levels vary according to race, so this range does not apply to everyone).

The CBC also determines the number and size of red blood cells. Predictably, anemia reduces the number of these cells. Red blood cells can be normal sized, small, or large, depending on the type of anemia.

A CDC also determines the number of white blood cells and platelets. White blood cells are involved in fighting infection, and platelets promote blood clotting.

Sometimes additional blood tests are used for diagnosis:

• Reticulocyte count–Reticulocytes are young red blood cells. The reticulocyte count measures the rate at which the bone marrow is producing new red blood cells. Typically in hemolytic anemia, the reticulocyte count is higher than normal because the bone marrow is working overtime to replace the destroyed red blood cells.
• Peripheral smear–This test involves looking at the blood cells through a microscope. Some types of hemolytic anemia involve abnormally shaped red blood cells, which can be seen through a microscope.
• Coombs’ test&–The Coombs’test measures the presence of antibodies directed against red blood cells.
• Haptoglobin, bilirubin, and liver function tests–When red blood cells break down, they release their hemoglobin into the bloodstream. The hemoglobin combines with a chemical called haptoglobin. A low level of haptoglobin in the bloodstream is an indication of hemolytic anemia. Bilirubin comes from the breakdown of hemoglobin. Liver function tests help to determine whether high bilirubin levels are from hemolytic anemia or liver/gallbladder disease.
• Hemoglobin electrophoresis–This test detects abnormal hemoglobin, which is the cause of some types of hemolytic anemia.
• Testing for PNH–In PNH, the red blood cells are missing certain proteins. The test for PNH looks for red blood cells that are missing these proteins.
• Osmotic fragility test–This test looks for abnormally fragile red blood cells, which are seen in hereditary spherocytosis.
• Testing for G6PD deficiency–This test, called a rapid fluorescent spot test, detects evidence of G6PD enzyme activity in a sample of blood.

Bone marrow tests

Doctors sometimes made a diagnosis by examining bone marrow cells under a microscope. A sample of bone marrow can be obtained with either a bone marrow biopsy or aspiration. A bone marrow biopsy is a minor surgical procedure to remove a small amount of bone marrow tissue. For a bone marrow aspiration, the doctor removes a small amount of bone marrow fluid through a needle.

Other tests

Because anemia has many causes, doctors sometimes test for kidney failure, lead poisoning, low levels of vitamins, or other possible causes.

Treatment

The goals of treating hemolytic anemia are to reduce or stop the hemolysis, to increase the red blood cell count to normal levels, and to treat the underlying cause.

Treatment depends on the type, cause, and severity of the hemolytic anemia. Age, overall health, and medical history are also considered. A person with an inherited form of hemolytic anemia has a lifelong condition that may require ongoing treatment. Acquired hemolytic anemias may go away if the underlying cause can be found and corrected.

Severe hemolytic anemia usually requires ongoing treatment and can be life threatening if left untreated. A person with mild hemolytic anemia may not need treatment as long as the condition does not get worse.

Treatments for hemolytic anemia include blood transfusion, medicines, lifestyle changes, plasmapheresis (treatment to remove antibodies from red blood cells), surgery, and bone marrow or stem cell transplant.

Medications

Some types of hemolytic anemia, particularly AIHA, can be improved with medicines that weaken the immune system and prevent antibodies from attacking the red blood cells. Often the first choice is a corticosteroid like prednisone. Azathioprine, cyclophosphamide, gamma globulin, or danazol, are often used if corticosteroids are ineffective. Rituximab and eculizumab are currently being investigated as treatments for AIHA and PNH, respectively.

Blood transfusions

Blood transfusions are used to treat severe or life-threatening anemia. Transfusions are given through a vein and require careful matching of donor and recipient blood types.

Plasmapheresis

Plasmapheresis removes antibodies from red blood cells. It may help if other treatments for immune hemolytic anemia don't work.

Surgery

In some cases of hemolytic anemia, it is necessary to surgically remove the spleen. The spleen is an organ in the upper left part of the abdomen that helps remove abnormal red blood cells from the bloodstream. The spleen also can contribute to some types of hemolytic anemia. An enlarged or diseased spleen removes more red blood cells than normal, causing anemia.

Bone marrow or stem cell transplant

Hemolytic anemia that results from the failure of bone marrow to make normal red blood cells (such as in thalassemia) is sometimes treated with bone marrow or stem cell transplants. Donor marrow is usually taken from a large bone, such as the pelvis. Marrow is given by transfusion through a vein. Stem cells for a transplant can be from matched umbilical cord blood, from bone marrow donated by a family member, or from a matched but unrelated donor. Stem cells in bone marrow develop into mature blood cells.

Prevention

For people with AIHA with cold-reactive antibodies, avoiding exposure to cold temperatures can help prevent hemolysis of their red blood cells. It’s especially important to protect the fingers, toes, and ears from the cold. Typical ways to protect from cold include the following:

• wearing gloves or mittens when taking food out of the refrigerator or freezer
• wearing a hat, scarf, and a coat with snug cuffs during cold weather
• turning down air conditioning or dress warmly while in an air conditioned space
• warming up the car before driving in cold weather

People born with G6DPD can prevent the development of anemia by avoiding substances that can trigger hemolysis, such as fava beans and certain medicines.

Inherited hemolytic anemias cannot be prevented, except for G6PD.

Transfusion reactions, which can cause hemolytic anemia, can be prevented by ensuring a match of the blood types between the donor and recipient. When a pregnant woman has Rh-negative type blood and her fetus has Rh-positive type blood, a medicine called RhoGam given at the time of delivery can block the mother's body from developing antibodies against the baby's blood type.

Preventing infection may also reduce the risk of developing some anemias. Avoidance of infected people and crowds, thorough and frequent hand washing, and good dental hygiene can help reduce the risk of infection.

Living With Hemolytic Anemia

The course of hemolytic anemia depends on the cause and the severity of the anemia. Mild hemolytic anemia may need no treatment at all. However, inherited anemias are lifelong. If the anemia is caused by a medicine or infection, the anemia may go away when the medicine is stopped or the infection is cured.

For parents of children with hemolytic anemia

Parents can assist the management of a child’s anemia by watching for worsening symptoms and complications.

Expected Outcome

Hemolytic anemia can often be successfully treated or controlled.

Clinical Trials

Research on hemolytic anemias may be found here, which is a list of U.S. government funded clinical trials.

Epidemiology

Most types of hemolytic anemia are equally common in men and women and can develop at any age. Autoimmune hemolytic anemia is slightly more likely in women over age 40. G6PD deficiency is more common among males. People of all races can develop hemolytic anemia. Some types of hemolytic anemia are more likely to occur in certain populations than others.

In the United States, sickle cell anemia, one of the most common forms of hemolytic anemia, occurs primarily among African Americans. G6PD deficiency affects males of African or Mediterranean descent.

External Links

From the National Institute of Health:

• Anemia (Diseases and Conditions Index)
• Sickle Cell Anemia (Diseases and Conditions Index)
• Thalassemia (Diseases and Conditions Index)