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Bleeding and Clotting Disorders
Reduced White Blood Cells
Blood is the fluid that circulates through the arteries, capillaries, and veins, delivering oxygen and nutrients to body cells. Blood rich in oxygen has a bright red color, but after providing oxygen to body tissues, it is dark purple. The liquid portion of blood is called plasma, and the cellular portion is made of red cells, white cells, and platelets. Red blood cells hold hemoglobin, which carries oxygen to body tissues. White blood cells actively participate in the immune system to provide defense from bacteria, viruses, and other environmental hazards. Platelets assist in blood clotting. In general, the blood and its components change very little with aging, but diseases that produce abnormalities in the blood are commonly seen in older people.
Anemia is defined as a low level of hemoglobin in the blood--hemoglobin is the essential oxygen-carrying component of red blood cells. For practical purposes, physicians consider the lower limit of normal hemoglobin in both elderly men and women to be 12 grams per deciliter of blood. This is roughly equivalent to a hematocrit of 36 percent (the hematocrit is the percentage of the blood volume composed of red blood cells). In healthy people, anemia is not a consequence of advancing age. However, it is a common finding in older people and an attempt should be made to discover the reason for its occurrence.
Table 28. Causes of Anemia in Elderly People
The causes of anemia are summarized in Table 28.
Anemias Caused by Decreased Red Cell Production. The majority of anemias found in older people are caused by decreased production of red cells due to (1) chronic inflammation, (2) malnutrition, and (3) blood loss. These anemias are usually characterized by an iron deficiency in the bone marrow, which in turn limits the production of red blood cells. While this iron deficiency can be caused by a lack of iron in the body, chronic anemia can be associated with normal or even high iron stores. Special blood tests can determine the size of the iron stores and whether the iron is binding appropriately to various proteins. The problem appears to involve the body's difficulty in recycling the iron released when older red blood cells are destroyed. This problem is different from anemia due to bleeding in the gastrointestinal tract, which reduces the body's iron stores.
In both men and women, a progressive increase of iron stores occurs with advancing age. Therefore, nutritional iron deficiency is very rare in elderly people despite the prominence of other nutritional problems. When unexplained iron deficiency does occur, it is almost exclusively due to blood loss from the gastrointestinal tract often due to ulcers, polyps, irritation of the lining of the gastrointestinal tract, or cancer.
Inflammation associated with chronic disease is another important cause of anemia among older people. Such inflammation can result from bacterial infection, tissue damage, various forms of arthritis, and benign or malignant tumors. Treatment of this form of anemia consists of addressing the underlying cause of the inflammation. This anemia is almost never severe enough to require transfusion; iron therapy is usually not effective because absorption of iron is very limited in the presence of inflammation.
Malnutrition in elderly people can cause an anemia with normalappearing blood cells. This type of anemia is usually seen in hospitalized individuals, and is usually accompanied by a history of weight loss; laboratory studies may indicate a reduced level of albumin in the blood. Correction of the nutrient deficiency and its underlying cause can significantly improve the hemoglobin level, thereby eliminating the anemia.
Bone marrow failure due to a problem with the marrow cells that produce red blood cells also occurs in older people. The disorder is usually associated with reductions of all the blood elements (red blood cells, white blood cells, and platelets). Common causes include drugs, immune diseases, intrinsic problems in the bone marrow, and replacement of the bone marrow by malignant cells or fibrous tissue.
Anemias Caused by Ineffective Red Cell Production. These anemias indicate that although there may be a sufficient level of red blood cells, there is a problem with their maturation. Red blood cells with maturation problems are unable to leave the bone marrow and enter into circulation. The red blood cells in the circulation can be large, small, and normal, and anemias of this type can be classified according to the size of the red blood cell. Anemias with small and normal-sized cells are usually due to heredity diseases or rare disorders.
Anemias with very large blood cells in older people are almost always due to deficiencies in either vitamin B12 or folic acid (another vitamin). When anemia is caused by such deficiencies, the bone marrow generally contains mature-looking cells with immature-looking nuclei (the nucleus is the site of the maturation problem).
Vitamin B12 deficiency (also called pernicious anemia) increases significantly with advancing age, and occurs when the body cannot absorb adequate vitamin B12. This condition develops more frequently in women over the age of 60 and produces many different symptoms. A person may be weak; have a lemon yellow skin color; and experience changes in the nervous system, including a clumsy gait or numbness and tingling in the arms and legs. There may be behavioral abnormalities and confusion in severe cases. A low level of vitamin B12 in the blood confirms the diagnosis. Regardless of the underlying cause of B12 deficiency, treatment consists of periodic (usually monthly) injections of vitamin B12.
Older people can have low levels of vitamin B12 but no evidence of anemia. They can also have dementing illness and other neurological problems that are caused by vitamin B12 deficiency, but have no evidence of anemia or other abnormalities in the blood. Therefore, physicians often check the blood for the level of vitamin B12 even if anemia is not present.
A deficiency of folic acid severe enough to cause anemia in older people is most frequently seen with malnutrition and excessive alcohol consumption. Alcohol and other drugs can interfere with the body's absorption of folic acid. When the need for folic acid is increased, such as when there is an inflammation, cancer, or red cell destruction, there is a risk of developing folic acid deficiency. A diagnosis of folic acid deficiency is confirmed by finding significantly reduced quantities of folic acid in the blood. If folic acid deficiency is discovered, it is very important to also check for vitamin B12 deficiency because treatment with folic acid will correct the anemia but not the changes in the nervous system if both deficiencies are present.
Anemias Caused by Increased Destruction of Red Blood Cells. These are called hemolytic anemias. The causes of anemia due to increased red blood cell destruction in older people differ from those in younger patients. Destruction of red blood cells by the body's immune system is common in the elderly whereas it is rare in younger people. In older people, this anemia is likely to be associated with a lymph gland malignancy such as non-Hodgkin's lymphoma or a lymphocyte disease such as chronic lymphocytic leukemia (see pages 333-334 for a more complete discussion of these diseases). Immune system diseases and medications are also causes. A physician may prescribe corticosteroids or surgical removal of the spleen. Most older people with congenital disorders have had these conditions diagnosed at a younger age.
The symptoms of anemia are fatigue, weakness, shortness of breath, dizziness, and pallor. Apathy, confusion, agitation, and depression can also be symptoms of anemia. People with heart disease may notice worsening chest pain and swelling of the ankles. None of these symptoms is specific to anemia, and any of them can be produced by other conditions.
There are many conditions that can cause anemia in an older individual, and a chance exists that several of them will occur simultaneously. This makes it difficult for a physician to decide how far to take an investigation into possible causes. Once the decision is made to investigate the cause of low hemoglobin in an older person, the principles involved in the assessment are similar to those used in any age group.
The physician's evaluation of an older person with anemia generally begins with an interview, followed by a complete physical examination, and a complete blood count to evaluate red blood cell size and to estimate how fast they are being produced.
The treatment of anemia will vary depending upon the underlying cause of this condition.
Blood clotting involves three simultaneous and overlapping processes: the formation of a plug from platelets in the blood; binding the platelet plug to the site of injury to form a clot; and confining the clot to the area of injury. Normal platelets and normal clotting factors are needed for effective clotting. The older person is more prone to bleeding disorders than the younger person, and the causes for the disorders are different and more complex. A simple classification are conditions that reduce the number of platelets in the blood, platelets that do not work properly, and abnormalities in the clotting factors.
Platelets are the cells in the blood that when activated will form a plug in the blood vessel. They resemble flakes of dry oatmeal as they circulate in the blood. When activated by a vessel-wall injury, they enlarge and clump together just as cooked oatmeal does. When platelets in the blood are reduced in number, the blood does not always form a plug.
Causes of Reduced Numbers of Platelets in the Blood. The most common cause of a reduced number of platelets in the blood (assuming normal numbers of both red and white blood cells) is an excessive removal of platelets by the scavenging cells in the spleen and liver. These scavenging cells are triggered to destroy the platelets when these latter become covered with antibodies. In older people, this condition occurs with malignancies of the lymph glands, chronic lymphocytic leukemia, systemic lupus erythematosus, and the use of drugs such as penicillin, heparin, and diuretics. In fact, the list of drugs is so extensive that all medications taken by the person should be taken into consideration when a physician is determining the cause of a low platelet count.
Symptoms and Treatment of Bleeding and Clotting Disorders Due to Reduced Platelet Count. People with this condition usually bleed from the mouth, the gastrointestinal tract, or the urinary system. The treatment of the low platelet count is directed at the cause. In most circumstances, corticosteroid therapy is used. If the person does not respond to this, the spleen may have to be surgically removed. When the low platelet count is caused by infections or cancer, especially cancer of the prostate, then restoration of a normal platelet count is dependent on effective treatment of these primary disorders.
The most common bleeding problem due to platelet abnormalities (when no reduction in the normal number of platelets is evident) is a disorder called von Willebrand's disease (named for the Finnish physician E. A. von Willebrand). This disorder occurs when the amount of the proteins required to form von Willebrand's factor is reduced. Von Willebrand's factor is a substance that makes it possible for platelets to stick to the blood vessel walls. Von Willebrand's disease is congenital and causes bleeding from the mouth, gastrointestinal tract, or urinary system, and abnormal blood-clotting tests but normal numbers of platelets. Other causes of platelet abnormalities include cancer, kidney failure, having a cardiopulmonary bypass as part of surgery, and a large number of medications (most commonly, aspirin).
Deficiency of vitamin K is a common cause of bleeding problems in older people. The deficiency can result from not taking in enough vitamin K, from decreased ability to absorb this vitamin, or, most often, from the administration of coumarin anticoagulants (blood thinners). Anticoagulants inhibit blood clotting by interfering with the amount of vitamin K, which helps to activate the production of clotting factors by the liver. Vitamin K deficiency can be diagnosed through specific blood tests.
Another common cause of a clotting problem in elderly people is liver disease, which disrupts blood clotting by a number of mechanisms. The production of substances required for clotting (clotting factors) can be decreased as the result of liver damage. Alternatively, clots break down more easily because blood factors responsible for clot removal are not broken down rapidly enough to stop their clot-removing activities. Frequently, liver disease uses up substances required for clotting in the liver's blood vessels. Treatment for clotting disorders includes administration of vitamin K and, for the actively bleeding patient, replacing platelets and blood.
The medical term for blood poisoning is septicemia, and it is caused by the continued and infecting presence of microorganisms or bacterial products in the blood. The implication of this is serious; the body can no longer contain the infection. People over the age of 60 account for between 40 percent and 60 percent of all cases of septicemia. Generally, the mortality rate increases with age.
A sudden change in mental function is often the first clue to septicemia. Additional symptoms are rapid, shallow breathing, a rapid pulse, a flushed face, and fever. These clues may not be present, though, and any older person with a sudden change in function should be promptly evaluated. Suspected blood poisoning is a medical emergency and calls for urgent attention.
The site of infection is usually the urinary tract, lungs, gall bladder, gastrointestinal tract, or skin.
Because many different organisms may be implicated, intravenous antibiotics need to be given promptly. In addition, the physician will search for the source of the infection and monitor carefully the function of the heart, lungs, and kidneys.
Leukemia (from the Greek roots meaning "white blood condition") is the malignant proliferation of abnormal white blood cells. Leukemias are subdivided into acute and chronic.
The incidence of acute leukemia increases with age, with half of the cases occurring in people who are older than 60. Risk factors appear to be radiation exposure, benzene exposure, and previous treatment of cancer with chemotherapy. Acute leukemia usually produces signs of infection (sudden high fever, change in mental function), progressive weakness, fatigue, pallor, or easy bruising and bleeding. The physician's evaluation usually consists of a complete blood count and a bone marrow examination.
Treatment of Acute Leukemias. Unfortunately, increased age is associated with a poor outlook in terms of response to treatment. It is not clear whether the poor prognosis is due to decreased sensitivity of the leukemia cells, to the drugs, or to an increased risk of death from treatment complications. Age-related changes in the biology of the disease that might explain a poor prognosis are involvement of more than one type of cell in the leukemic process; rapid growth of cells in the laboratory; preexisting problems in the bone marrow; and leukemia cells with a high number of chromosome abnormalities.
The management of acute leukemia involves treatment to induce a remission and then maintenance treatment. Remission is characterized by having no leukemia cells appear in the blood and having less than 5 percent leukemia cells in the bone marrow. In general, remission is accomplished with high-dose chemotherapy; maintenance therapy usually involves prolonged treatment with low doses of the same drugs used in the chemotherapy. In most cases, cytarabine is the cornerstone of initial and follow-up treatment. High doses of this drug, however, can cause problems in the cerebellum, the part of the brain that controls body coordination. Furthermore, it cannot be used when kidney function is poor.
While treatment for acute leukemia is generally aggressive, less aggressive therapy is indicated for those over age 65 because of the very high toxicity and side effects of the treatments.
Chronic leukemias have a more benign course than the acute leukemias. They are classified by the type of white cell involved: Myeloid cell involvement, the type of cells that mature to become granulytes, produces chronic myelocytic leukemia whereas lymphoid involvement, the cells that mature to become lymphocytes, is called chronic lymphocytic leukemia.
Chronic myelocytic leukemia is usually a disease of middle age but does occur in elderly people. The hallmark of the condition is a change in the chromosomes, which produces an abnormal chromosome called the Philadelphia chromosome. This abnormal chromosome is produced by joining parts of chromosomes 9 and 22. This change may have a role in the development and progression of the disease. The drug hydroxyurea is the standard treatment for this condition; however, the medication does not eliminate the cells carrying the Philadelphia chromosome and, ultimately, its impact on overall survival has been minimal. More promising results have been found by using moderate daily doses of alpha interferon, a drug that affects the immune system. Alpha interferon causes the disappearance of the Philadelphia chromosome in 15 to 25 percent of people; it may provide a more prolonged control of the problem. However, alpha interferon is more expensive and more toxic than hydroxyurea.
Chronic lymphocytic leukemia is the most common malignant disease affecting the blood system of older people. The most common symptoms are loss of energy, fatigue, decreased activity, and a reduced sense of well-being. Many people with the condition have no symptoms.
Management of Chronic Leukemias. The management depends upon the extent of the disease. If the disease has reached an advanced stage (meaning it has spread extensively throughout the body), the prognosis is not good. When these factors are not present, it is generally not necessary to treat less extensive diseases. However, treatment is always necessary for extensive disease, usually with a drug like chlorambucil combined with prednisone. More aggressive chemotherapy has been reported to improve survival.
The lymph nodes and spleen form a major part of the immune system. Lymphoma is a malignancy of the lymph nodes and frequently involves the spleen. When lymphoma spreads to the blood it can manifest as leukemia. It is diagnosed by lymph node biopsy.
Lymphomas are classified into Hodgkin's disease and non-Hodgkin's lymphoma. Hodgkin's disease spreads in a predictable way from one lymph node to another in a continuous manner. Non-Hodgkin's lymphomas are more widespread and can involve other body organs.
Hodgkin's disease is a type of lymphoma involving the lymph nodes (often in the neck) that spreads throughout the lymph tissue and forms nodular growths in body organs. (It is named after Thomas Hodgkin, who described it in 1832.) It appears to be more common in men and woodworkers.
Symptoms and Treatment of Hodgkin's Disease. The disease produces painless, asymmetric enlargement of the lymph glands, usually in the neck, which sometimes feel rubbery. Other symptoms are more variable, including fever, weakness, itching, or weight loss. Anemia is often present. In a small percentage of patients, ingestion of alcohol produces pain in the tissues involved with Hodgkin's disease. The cause of the condition is not known.
Although the outlook for Hodgkin's disease worsens after age 40, advanced age should not by itself constrain treatment, and durable remissions are obtainable even in older patients.
Treatment involves radiation therapy and chemotherapy, alone or in combination, depending upon the extent of the disease.
Non-Hodgkin's lymphoma is divided into low-grade (not very aggressive), intermediate-grade, and high-grade (aggressive) lymphomas. High-grade lymphomas are not common in elderly people, but the incidence of low-grade lymphomas increases with age.
Symptoms and Treatment of Non-Hodgkin's Lymphoma. Most people with non-Hodgkin's lymphoma notice large painless lymph glands in their neck or groin. Lymph nodes around the elbow suggest the disease. However, problems in the skin, liver, gastrointestinal tract, bones, and nervous system can be present.
While non-Hodgkin's lymphoma is usually managed with chemotherapy, the treatment for low-grade non-Hodgkin's lymphoma is controversial. People usually survive seven to ten years, and treatment does not appear to change these survival figures significantly. Generally, treatment is started only if a person has significant symptoms or has rapidly progressing disease. Sometimes lowgrade non-Hodgkin's lymphoma may evolve to a more aggressive form. Any rapid change of disease progression suggests the need for another lymph node biopsy.
Intermediate-grade non-Hodgkin's lymphoma is the most common form in adults; the median survival rate for people without treatment is approximately 18 months. However, several different combinations of chemotherapy are capable of producing complete remissions in 50 to 80 percent of cases and about half of these people remain free of disease at least five years. Nevertheless, the most effective regimen remains a matter of controversy. The treatment of intermediate-grade lymphoma with full-dose combination chemotherapy has been associated with significant toxicity and disability in people older than 65.
Multiple myeloma (from the Greek roots meaning "marrow swelling") is a form of cancer involving the bone marrow not usually encountered in people under the age of 50. In multiple myeloma there is an uncontrolled growth of one family (clone) of cells that make antibodies. In most cases these cells make large amounts of a single protein called myeloma protein. The effects of multiple myeloma on the body usually result from the protein they produce or from the invasion of body tissues by myeloma cells.
People with the condition may experience weakness, loss of appetite, and weight loss. In more advanced disease the person may have bone pain, anemia, kidney problems, neurologic difficulties, or repeated infections. The outlook for people with multiple myeloma depends upon the extent of the disease.
The assessment of the severity and extent of the disease is determined by four factors: the amount of myeloma protein in the blood, the level of hemoglobin in the blood, the amount of calcium in the blood, and the presence or absence of bone lesions. More recently, a simple assessment system based on the level of a compound in the blood called beta2 macroglobulin has been proposed.
Treatment may be delayed in older people who do not have symptoms of early multiple myeloma. In a small number of these people, the disease may remain stable for many years and will not require chemotherapy. Fluid intake should be increased to two to three quarts a day to help protect kidney function. Because multiple myeloma can accelerate bone loss, people with the disorder should remain active to help promote healthy bones. People with multiple myeloma are usually evaluated three or four times a year and chemotherapy is generally started if there is any evidence of disease progression. Complete remissions in multiple myeloma are rare. However, more than half of patients experience a partial remission, which entails a 50 to 75 percent decrease in the concentration of circulating myeloma protein. After the level of myeloma protein has stabilized, treatment with oral medications is continued for about six months. Recent evidence suggests that newer medicines such as alpha interferon may prolong treatment of multiple myeloma. Chemotherapy also provides effective relief of symptoms and is well tolerated even in the oldest patients.
The white blood cell plays an essential role in combating bacterial infection. It is also an essential component in the body's handling of inflammation. An abnormally low number of white blood cells due to the effects of certain drugs is the most common problem with this part of the immune system.
The three major causes for white blood cell reduction are shown in Table 29. The production of white blood cells by the bone marrow may be impaired. This occurs if the bone marrow is affected by a tumor or its activities suppressed by drugs or poisons. Severe malnutrition can also decrease the production of white blood cells. The second cause is ineffective production of white cells. In this setting, white blood cells that are abnormal in structure or functional capacities may actually increase in the marrow. These abnormal white blood cells cannot enter the circulation and are destroyed in the bone marrow. The ultimate result is a reduction in the number of mature white blood cells in the blood. Deficiencies of vitamin B12 and folic acid are the classic causes for this ineffective white blood cell production. Finally, normal, well-functioning white blood cells can be increasingly destroyed as a consequence of immune problems, such as those associated with rheumatoid arthritis, medications, severe infections, or through a disorder of the spleen. A severe infection may both suppress the functioning of bone marrow and simultaneously destroy white blood cells. In the case of a spleen disorder, the spleen traps white blood cells, becoming enlarged while depleting the rest of the body's store of the cells.
Table 29. Causes of Reduced White Blood Cells in Older People
The most common causes of a low white blood cell count in older people are chemotherapy for cancer, ionizing irradiation, and ingestion of toxins. In some cases, the decrease in white blood cells is dependent on the dosage of chemotherapy, irradiation, or toxins, and in other cases the decrease of white blood cells is thought to be due to allergic or immune reactions unconnected to dosage. Furthermore, various drugs can reduce white blood cell numbers in elderly people.
There are no specific symptoms of a reduced white blood cell count. If the white blood count declines below 1,000, the likelihood of infection increases. The types of infections depend upon which white cells are affected. For example, bacterial and fungal disease is more common if one type of white blood cell is reduced (neutrophils).
The evaluation of reduced numbers of white blood cells generally includes an examination of the blood marrow to determine the underlying cause of the low white blood cell count. Treatment depends upon the underlying cause.