CHAPTER 162
Myeloproliferative Disorders
In myeloproliferative disorders (myelo = bone marrow, proliferative = rapid multiplication), the blood-producing cells in the bone marrow (precursor cells) develop and reproduce excessively or are crowded out by an overgrowth of fibrous tissue. Typically, these disorders are acquired and not inherited, although rarely there are families in which several members have these disorders. It is likely that family members inherit a predisposition to the disorder rather than the disorder itself.
Three major myeloproliferative disorders are polycythemia vera, myelofibrosis, and thrombocythemia. The proliferation of blood-producing cells is always noncancerous (benign) when it begins. However, in a small number of people, a myeloproliferative disorder progresses or transforms to a cancerous (malignant) condition, such as leukemia.
Polycythemia Vera
Polycythemia vera (primary polycythemia) is a disorder of the blood-producing cells of the bone marrow that results in overproduction of red blood cells.
The cause is not known.
People may feel tired and weak, light-headed, or short of breath.
Blood tests are done for diagnosis.
Phlebotomy is done to remove excess red blood cells.
In polycythemia vera, the excess of red blood cells increases the volume of blood and makes it thicker, so that it flows less easily through small blood vessels. Sometimes the spleen and liver also produce excess blood cells.
Polycythemia vera occurs in about 2 in every 100,000 people. The average age at which the disorder is diagnosed is 60, and it rarely occurs in people younger than 20. More men than women develop polycythemia vera. The cause is not known.
Symptoms and Complications
Often, people with polycythemia vera have no symptoms for years. The earliest symptoms usually are weakness, tiredness, headache, light-headedness, shortness of breath, and night sweats. Vision may be distorted, and people may have blind spots or see flashes of light. Bleeding from the gums and more bleeding than would be expected from small cuts are common. The skin, especially the face, may look red. People may itch all over, particularly after bathing or showering. Burning sensations in the hands and feet or, more rarely, bone pain may be felt.
Sometimes the first symptoms are from a blood clot. A clot may form in almost any blood vessel, including those of the arms, legs, heart (causing a heart attack), brain (causing a stroke), or lungs. Blood clots may also block blood vessels that drain blood from the liver (Budd-Chiari syndrome).
MAJOR MYELOPROLIFERATIVE DISORDERS
| DISORDER | BONE MARROW CHARACTERISTICS | BLOOD CHARACTERISTICS |
| Polycythemia vera | Increased number of cells that produce the circulating blood cells | Increased number of red blood cells Often, increased number of platelets and white blood cells |
| Myelofibrosis | Excess fibrous tissue | Increased number of immature red and white blood cells Misshapen red blood cells Decreased overall number of red blood cells (anemia) The numbers of white blood cells and platelets often eventually decrease, but in some people they increase |
| Thrombocythemia | Increased number of cells that produce platelets (megakaryocytes) | Increased number of platelets |
In some people, the number of platelets (cell-like particles that help the body form blood clots) in the bloodstream increases. The liver and spleen may enlarge as both organs begin to produce blood cells. The spleen also enlarges as it removes red blood cells from the circulation. As the liver and spleen enlarge, a sense of fullness in the abdomen may develop. Pain can suddenly become intense should a blood clot develop in blood vessels of the liver or spleen.
The excess of red blood cells may be associated with other complications, including stomach ulcers, gout, and kidney stones. Rarely, polycythemia vera progresses to leukemia.
Diagnosis
Polycythemia vera may be discovered through routine blood tests done for another reason, even before people have any symptoms. The level of the protein that carries oxygen in red blood cells (hemoglobin) and the percentage of red blood cells in the total blood volume (the hematocrit) are abnormally high. The number of platelets and white blood cells may also be increased.
Most doctors consider a high hematocrit result to be an indication of polycythemia vera. However, the diagnosis cannot be based solely on the hematocrit result. Therefore, to help make the diagnosis, a test that uses radioactively labeled red blood cells to determine the total number of red blood cells in the body (red blood cell mass) is sometimes done.
Once the increased red blood cell mass (polycythemia) is discovered, doctors must determine whether it is polycythemia vera or polycythemia caused by some other condition (secondary polycythemia). The medical history may help differentiate between polycythemia vera and secondary polycythemia, but sometimes doctors must investigate further.
Blood levels of erythropoietin, a hormone that stimulates the bone marrow to produce red blood cells, also may be measured. Levels of erythropoietin are extremely low in polycythemia vera, but they are often, but not always, normal or high in secondary polycythemia. Rarely, cysts in the liver or kidneys and tumors in the kidneys or brain produce erythropoietin; people with these conditions have high levels of erythropoietin and may develop secondary polycythemia.
Removal of a sample of bone marrow for examination under a microscope (bone marrow biopsy—see page 1025) can also be helpful to diagnose polycythemia vera.
Prognosis and Treatment
Without treatment, about half of the people who have polycythemia vera with symptoms die in less than 2 years. With treatment, they live an average of 15 to 20 years.
Treatment does not cure polycythemia vera, but it does control it and can decrease the likelihood of complications, such as the formation of blood clots. The aim of treatment is to decrease the number of red blood cells. Usually, blood is removed from the body in a procedure called phlebotomy, similar to the way blood is removed when donating blood. A
What Are the Other Types of Polycythemia?
Polycythemia vera (which literally translates as “true polycythemia”) is also known as a type of primary polycythemia. Primary means that the polycythemia is not caused by another disorder.
Congenital polycythemias are present at birth, usually caused by an inherited genetic disorder. Diagnosis is typically made when symptoms begin at an early age or when there is a family history. Certain blood tests can also help with the diagnosis, as well as identifying the specific genetic disorder.
Secondary polycythemia is caused by oxygen deprivation, which can result, for example, from smoking, severe lung disease, or heart disease. In secondary polycythemia, a high concentration of red blood cells results from an actual increase in the erythropoietin level in the blood. People who spend long periods of time in circumstances low in oxygen, such as people who live at high altitude, sometimes develop polycythemia but do not have polycythemia vera (see box on page 2005).
Secondary polycythemia may be treated with oxygen. Smokers are advised to quit and are offered treatments to assist quitting. Any underlying disorder that is causing the oxygen deprivation and secondary polycythemia is treated as effectively as possible. Phlebotomy is used to lower the number of red blood cells.
In relative polycythemia, a high concentration of red blood cells results from abnormally low levels of fluid (plasma). The low plasma level can result from burns, vomiting, diarrhea, drinking an inadequate amount of fluids, and the use of drugs that speed elimination of salt and water by the kidneys (diuretics). Relative polycythemia is treated by giving fluids by mouth or intravenously and by treating any underlying conditions that are contributing to the low plasma level.
pint of blood is removed every other day until the hematocrit reaches a normal level. Then blood is removed every few months as needed to maintain the hematocrit at a normal level.
Because phlebotomy may increase the number of platelets and does not reduce the size of an enlarged liver or spleen, people who undergo phlebotomy may need drugs to suppress production of red blood cells and platelets. Hydroxyurea, a chemotherapy drug, is frequently given, but when used for many years there is concern that it may increase the risk of transformation to leukemia, although this risk has not been proven. Alternative drugs for lowering the number of platelets, such as interferon-alpha and anagrelide, are sometimes used in younger people who may need treatment for long periods. Some people are given radioactive phosphorus intravenously, but doctors restrict this type of treatment to people older than 70 because of the potential for transformation to leukemia. Baby aspirin has been proven to decrease the risk of blood clots.
Other drugs can help control some of the symptoms. For example, antihistamines can help relieve itching, and aspirin can relieve burning sensations in the hands and feet as well as bone pain.
Myelofibrosis
Myelofibrosis is a disorder in which fibrous tissue replaces the blood-producing cells in the bone marrow, resulting in abnormally shaped red blood cells, anemia, and an enlarged spleen.
Myelofibrosis may occur on its own or as a result of other blood disorders.
People may feel tired and weak, have frequent infections, and bleed easily.
Blood tests and a bone marrow biopsy are done for diagnosis.
Drugs and other treatments lessen the severity of anemia, increase red blood cell production, and fight infections.
Sometimes stem cell transplantation is used.
In normal bone marrow, cells called fibroblasts produce fibrous (connective) tissue that supports the blood-producing cells. In myelofibrosis, the fibroblasts produce too much fibrous tissue, which crowds out the blood-producing cells. Consequently, red blood cell production decreases, fewer red blood cells are released into the bloodstream, and anemia develops, becoming progressively more severe. In addition, many of these red blood cells are immature or misshapen. Variable numbers of immature white blood cells and platelets also may be present in the blood. As myelofibrosis progresses, the number of white blood cells may increase or decrease, and the number of platelets typically decreases.
Myelofibrosis is rare, affecting fewer than 2 of 100,000 people in the United States. It occurs with a peak incidence at age 76.
Myelofibrosis may develop on its own (in which case it is also called idiopathic myelofibrosis or agnogenic myeloid metaplasia) or may accompany other blood disorders, such as chronic myelocytic leukemia, polycythemia vera, thrombocythemia, multiple myeloma, lymphoma, and myelodysplasia. It may also occur in people with tuberculosis, pulmonary hypertension, systemic lupus erythematosus (lupus), and systemic sclerosis (scleroderma) and in people in whom a cancer has spread to the bones.
Symptoms, Complications, and Diagnosis
Often, myelofibrosis produces no symptoms for years. However, in some people it rapidly leads to anemia, low levels of platelets in the blood, or leukemia. Eventually, anemia becomes severe enough to cause weakness, tiredness, weight loss, and a general feeling of illness (malaise). Fever and night sweats may occur. With the reduced number of white blood cells, the body is at risk for infections, so people often have frequent infections. With the reduced number of platelets, the body is at risk for bleeding.
The liver and spleen often enlarge as they try to take over some of the job of making blood cells. The spleen also destroys abnormal red cells and platelets made in the bone marrow. The destruction of so many red blood cells and platelets contributes to the spleen enlargement. Enlargement of the liver and spleen may cause pain in the abdomen and may lead to abnormally high blood pressure in certain veins (portal hypertension—see page 217) and bleeding from varicose veins in the esophagus (esophageal varices—see page 217).
Anemia and the misshapen, immature red blood cells, seen in blood samples viewed under a microscope, suggest myelofibrosis. However, a bone marrow biopsy (see page 1025) is needed to confirm the diagnosis.
Prognosis and Treatment
Because myelofibrosis generally progresses slowly, people who have it may live for 10 years or longer, but outcomes are determined by how well the bone marrow functions. Occasionally, the disorder worsens rapidly. Treatment aims to delay the progression of the disorder and to relieve complications. However, only stem cell transplantation can cure the disorder.
The combination of androgen (a male sex hormone) and prednisone temporarily lessens the severity of the anemia in about one third of people with myelofibrosis. In a few people, red blood cell production can be stimulated with erythropoietin or darbepoietin, drugs that stimulate the bone marrow to produce red blood cells. In other people, blood transfusions are needed to treat the anemia. Bacterial infections are treated with antibiotics.
Hydroxyurea, a chemotherapy drug, or interferon-alpha, a drug that affects the immune system, may decrease the size of the liver or spleen, but either drug may worsen the anemia. Rarely, the spleen becomes extremely large and painful and may have to be removed. Removal of the spleen may increase the number of red blood cells and reduce the need for transfusions.
Stem cell (bone marrow) transplantation is sometimes offered to people who are in otherwise good health and who have an appropriate matched donor (see page 1133). A transplant is the only treatment available that may cure myelofibrosis, but it also has significant risks.
Thrombocythemia
Thrombocythemia (primary thrombocythemia) is a disorder in which excess platelets are produced, leading to abnormal blood clotting or bleeding.
The cause is not known.
The hands and feet may tingle, and the fingertips may feel cold.
Routine blood tests usually provide a diagnosis, but sometimes a bone marrow biopsy is needed.
Treatments that suppress symptoms and decrease platelet production are given.
Platelets (thrombocytes) are normally produced in the bone marrow by cells called megakaryocytes. In thrombocythemia, megakaryocytes increase in number and produce too many platelets.
Thrombocythemia affects about 2 to 3 of 100,000 people. It usually occurs in people older than 50 and more frequently in women. The cause of thrombocythemia is unknown.
Symptoms
Often, thrombocythemia does not produce symptoms. However, an excess of platelets can cause blood clots to form spontaneously, blocking the flow of blood through blood vessels, especially smaller ones but also in large vessels, including vessels in the brain, liver, and heart. Older people with thrombocythemia are much more likely to form clots than are younger people.
Other Causes of a High Platelet Count
When the cause of thrombocythemia is known, the disorder is called secondary thrombocythemia. Bleeding, removal of the spleen, infections, rheumatoid arthritis, certain cancers, premature destruction of red blood cells (hemolysis), iron deficiency, and sarcoidosis can cause secondary thrombocythemia.
People with secondary thrombocythemia may have no symptoms related to the high number of platelets. Symptoms of the underlying condition usually dominate. When symptoms from a high number of platelets do occur, they are similar to those of primary thrombocythemia. Secondary thrombocythemia is diagnosed—and distinguished from primary thrombocythemia—when people with high platelet counts have a condition that readily accounts for the high number of platelets.
Treatment is aimed at the cause. If the treatment is successful, the platelet count usually returns to normal.
Symptoms are due to the blockage of blood vessels and may include tingling and other abnormal sensations in the hands and feet (paresthesias), cold fingertips, chest pain, vision changes, headaches, weakness, and dizziness. Bleeding, usually mild, may occur, often consisting of nosebleeds, easy bruising, slight oozing from the gums, or bleeding in the digestive tract. The spleen and liver may enlarge.
Diagnosis
Doctors make a diagnosis of thrombocythemia on the basis of the symptoms or after finding increased platelets during routine screening of the blood. Blood tests may be used to confirm the diagnosis. In addition, microscopic examination of the blood may reveal abnormally large platelets, clumps of platelets, and fragments of megakaryocytes.
To distinguish primary thrombocythemia, whose cause is unknown, from secondary thrombocythemia, which has a known cause, doctors look for signs of other conditions that could increase the platelet count. Removal of a sample of bone marrow for examination under a microscope (bone marrow biopsy—see page 1025) is sometimes helpful and can exclude chronic myelocytic leukemia as a cause of an increased platelet count.
Treatment
Thrombocythemia may require treatment with a drug that decreases platelet production. Such drugs include hydroxyurea, anagrelide, and interferonalpha. Treatment with one of these drugs is typically started when clotting complications develop. The age of the person, the other risks present, and previous history of forming blood clots (thrombosis) determine the need for such treatment. The drug is continued until the platelet count falls into a safe range. The dose must be adjusted to maintain an adequate number of platelets and other circulating cells. Small doses of aspirin, which makes platelets less sticky and impairs clotting, may also be used.
If drug treatment does not slow platelet production quickly enough, it may be combined with or replaced by plateletpheresis, a procedure reserved for emergency situations. In this procedure, blood is withdrawn, platelets are removed from it, and the platelet-depleted blood is returned to the person.
SPOTLIGHT ON AGING
Thrombocythemia is more likely to occur in older people. They are also more likely to have blockages of crucial large blood vessels, such as those in the heart and brain, because older people are more likely to have conditions, such as atherosclerosis, that also may result in blood vessel blockage.
Older people are given the same drugs as younger people. They are able to tolerate the side effects fairly well. However, because older people may have other disorders and decreased marrow reserve, they may not be able to tolerate any therapy as well as younger people.