The plasma protein ____________________ is essential for coagulation

Diseases of the Blood

C H A P T E R

Learning Objectives

After studying this chapter, you should be able to

■ Distinguish between formed elements and formed elements of the blood

■ Delineate the function of red blood cells, white blood cells, and platelets

■ Identify the etiology, signs and symptoms, diagnostic tests, and treatment for selected diseases of the blood7

Sickling of red blood cells re- sults from inadequate oxygen saturation of red blood cells.

Fact:In 1948, using the new technique of protein electro- phoresis, Linus Pauling and Harvey Itano showed that ab- normal hemoglobin, the oxygen- binding protein in red blood cells, was responsible for sickle cell disease. Under low-oxygen conditions, the abnormal hemoglobin causes red blood cells to sickle. Sickle cell dis- ease was the first disorder linked to the presence of a spe- cific abnormal protein.

Fact or Fiction?

Peripheral blood smear show- ing blast crisis of chronic myelogenous leukemia. (Courtesy of the CDC/Stacy Howard, 1994.)

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Clinical Use of Leeches

T he first clinical use of medicinal leeches (Hirudo medicinalis) occurred approximately 2500 years ago. This small invertebrate can produce a small bleeding wound that mimics venous circu- lation in an area of compromised blood flow. Upon biting a

host, the leech releases important substances including an anticoagu- lant, a local vasodilator, and local anesthetic. These substances allow continued bleeding up to 10 hours after the animal has detached.

Today, medicinal leeches are used by plastic and reconstructive surgeons to restore venous circulation in regrafting procedures for amputated appendages such as fingers or toes. Severed blood vessels are often so damaged that they lack the ability to clear blood. Leeches apply enough suction to initiate blood flow when the pa- tient’s own blood supply isn’t adequate. Research indicates that after about 3 to 5 days, new vessels in growth around flap margins develop sufficiently to restore effective venous drainage.

Disease Chronicle

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Introduction

Blood is the medium for transporting oxygen, carbon dioxide, water, nutrients, proteins, and hormones where needed throughout the body and waste products to excretory organs of the body. The cellular components of the blood in- clude the red blood cells, or erythrocytes, white blood cells, or leukocytes, and clotting cells, or platelets. These cells travel through the circula- tory system suspended in the fluid portion of the blood called plasma.

Red Blood Cells Erythrocytes, or red blood cells (RBCs), make up about half of the blood’s volume. Red blood cells are the most abundant cells in the human body. Erythrocytes normally number about 5 million/ mm3 in males and about 4.5 million/mm3 in females.

Unlike other cells in the human body, red blood cells are biconcave sacs filled with an iron-rich oxygen carrying protein called hemo- globin. Hemoglobin is the most important com- ponent of red blood cells. It is composed of a protein called globulin and a heme molecule which binds to iron.

In the lungs, heme binds to oxygen in ex- change for carbon dioxide. The oxygenated red blood cells are then transported to the body’s tissues, where the hemoglobin releases the oxy- gen in exchange for carbon dioxide. The average life span of a red blood cell is 120 days. Old red blood cells are removed from the body by the liver and the spleen.

Erythrocytes are produced in the red marrow of the bones such as the vertebrae and the body of the sternum. The process of red blood cell formation, called erythropoeisis, is regulated by the hormone erythropoietin. Red blood cell syn- thesis begins with large nucleated stem cells that progress through many stages before emerging as mature red blood cells. In the process, hemoglobin accumulates within the cytoplasm and the nucleus disappears. Mature red blood cells emerge from the bone marrow as reticulocytes.

▼ Diagnostic Tests for Diseases of the Blood

Blood tests are diagnostic for systemic diseases as well as specific blood disorders. Blood analy- sis measures total blood counts (red blood cells, white blood cells, and platelets), hemoglo- bin, hematocrit, serum chemistry, and enzyme and hormone levels within the body. Differen- tial blood analysis provides qualitative informa- tion such as size, shape, and ratio of one cell type to another.

A bone marrow smear is used to diagnose malignant blood disorders and increases or de- creases in blood counts without any apparent cause. Bone marrow samples are obtained by needle aspiration of the bone marrow from the bone marrow cavity. Bone marrow analysis pro- vides information on the function of the bone marrow and the qualitative characteristics of stem cells that give rise to all blood cells.

Anemia

Anemia is a condition of reduced numbers of red blood cells. Potential causes, including hemor- rhage, excessive destruction of red blood cells, nutritional deficiency, and chronic disease, de- crease the number of red blood cells and oxygen delivery to the cells and tissues.

The clinical diagnosis of anemia requires a microscopic examination and analysis of red blood cells. A detailed medical history, including information on dietary habits, family history of anemia, and information regarding the patient’s concurrent medical problems provides data for the potential etiology of the anemia.

The symptoms of anemia are due to tissue hypoxia, or lack of oxygen. Acute hemorrhages re- sults in rapid appearance of symptoms and, if se- vere, many result in shock. Most patients develop anemia slowly and have few symptoms. Usual complains are fatigue, decreased tolerance for ex- ercise, dyspnea, and palpitations. In physical ex- amination, the major sign of anemia is pallor. Jaundice and enlargement of the spleen occurs with anemia caused by hemolysis, or red blood

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cell death. Cardiac signs of anemia include tachy- cardia, or rapid heartbeat, and heart murmurs.

Iron Deficiency Anemia Iron balance in the body is tightly controlled and designed to conserve iron for reutilization. There is no excretory pathway for iron, and the only means of iron loss from the body are blood loss and the loss of epidermal cells from the skin and the gut. Normally iron is replaced by sufficient di- etary intake or from medicinal supplementation.

The amount of iron required in the diet to re- place losses is approximately 1.0 to 1.4 mg of el- emental iron per day. In the United States, the average iron intake in an adult male is 15 mg/d and 11 mg/d for females. Iron absorption takes place in the small intestine and is a carefully regulated process.

Iron deficiency anemia is the condition in which there is anemia with evidence of iron defi- ciency. The first stage in the development of iron deficiency anemia is a negative iron balance, in which the demands for iron exceed the body’s ability to absorb iron from the diet. This stage can result from a number of physiological prob- lems, including blood loss, pregnancy, rapid growth spurts in children and adolescents, and inadequate dietary intake. During pregnancy, the demands for red blood cell production by the fetus exceed the mother’s ability to provide iron. During the first stage of iron deficiency, anemia may not be present.

The second stage of iron deficiency anemia occurs when the iron stores of the body become depleted. At this point the synthesis of hemoglo-

bin becomes impaired and a period of iron defi- ciency ensues. With progression of iron defi- ciency, the red blood cells lose their shape and appear as cigar- or pencil-shaped forms upon microscopic analysis on a peripheral blood smear (Figure 7–1 �).

Iron deficiency anemia is the leading cause of anemia worldwide. The prevalence of iron de- ficiency anemia is greatest among preschool children and adolescent and adult females. Ap- proximately 52% of pregnant women in nonde- veloped countries and approximately 23% of pregnant women in developed countries have iron deficiency anemia. The prevalence of iron

Figure 7–1 � Iron-deficient red blood cells. (Joaquin Carrillo Farga/Photo Researchers, Inc.)

Prevention PLUS! Anemia For a half a billion women in developing countries worldwide, anemia is a lifelong burden that affects most of their in- fants and young children. Controlling anemia in these vulnerable groups could significantly reduce maternal and infant morbidity. It would also enhance intellectual and work capacity, thereby improving family, community, and national so- cioeconomic development.

Despite international efforts led by United Nations, the global prevalence of anemia has failed to decline. The reasons for this lack of improvement include the failure to identify the etiology of the anemia, underfunding, and poor health care with inadequate vitamin supplementation.

Source: From WHO, 2007, “Iron Deficiency Anemia, Assessment Prevention, and Control. A Guide for Programme Managers.”

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deficiency anemia among preschool children ranges from 20% in developed countries to 39% in nondeveloped countries.

The most frequent cause of iron deficiency in men and postmenopausal women is gastroin- testinal bleeding. In premenopausal women, iron deficiency occurs most frequently sec- ondary to loss of iron with menstruation and during pregnancy. Dietary deficiency of iron most commonly seen in young children occurs when intake of iron does not keep pace with rapid growth and development.

Decreases in iron absorption occur with mal- absorption syndromes and chronic disease. Iron absorption requires an intact gastrointestinal tract with healthy intestinal mucosal cells. Chronic disease, removal of the stomach, and bowel disorders limit the availability of iron.

Iron deficiency anemia is associated with weakness and fatigue. Mild to moderate iron de- ficiency can affect cognitive performance, be- havior, and growth in preschool- and school- aged children. Iron deficiency during pregnancy increases overall infant mortality or death.

The treatment of choice for iron deficiency is oral iron supplementation. Injectable iron sup- plements are available for individuals with mal- absorption or those who cannot tolerate oral supplements.

Anemia of Chronic Disease Anemia of chronic disease occurs in patients with chronic inflammatory, infectious, and au- toimmune diseases. The etiology of anemia of chronic disease most often is a defect in the synthesis of red blood cells, or erythropoeisis.

The severity of the anemia of chronic disease depends on the primary condition. For example, patients with chronic disease such as rheuma- toid arthritis or chronic infections with tubercu- losis may have severe anemia due to depletion of iron stores. Moderate anemia is associated with cardiac conditions such as angina pectoris and exercise intolerance.

The anemia of chronic disease may resolve if the underlying disease is treated. In some cases, therapy with erythropoietin, a hormone secreted by the kidney that stimulates synthesis

of red blood cells, will stimulate production of red blood cells.

Anemia of Renal Disease Chronic kidney or renal failure is associated with moderate to severe anemia; the level of anemia correlates with the severity of renal disease. This type of anemia is due to a failure to pro- duce adequate amounts of erythropoietin and a reduction in red blood cell survival. Assessment of iron status provides information to distin- guish the anemia of renal disease from iron de- ficiency anemia. Patients with anemia of renal disease usually have normal serum iron; how- ever, individuals on chronic hemodialysis may develop iron deficiency from blood loss through the dialysis procedure.

Megaloblastic Anemia The megaloblastic anemias are disorders caused by impaired DNA synthesis. Megaloblas- tic red blood cells tend to be large and contain an increased ratio of RNA to DNA. The number of red blood cells produced is decreased by inef- fective erythropoeisis. Most megaloblastic ane- mias are due to a deficiency in vitamin B12 and/or folic acid.

Vitamin B12 Deficiency Anemia Vitamin B12 is a complex compound that cannot be synthesized by the human body and must be supplied by the diet. The minimum daily re- quirement for vitamin B12 is about 2.5 micro- grams. Normally about 2 micrograms of vitamin B12 are stored in the liver and another 2 micro- grams are stored elsewhere in the body. It would take approximately three to six years for a normal individual to become deficient in vita- min B12 if absorption were to cease abruptly.

Vitamin B12 deficiency anemia, or pernicious anemia, is caused by inadequate absorption or intake of vitamin B12 or a deficiency in a protein called intrinsic factor. Intrinsic factor is pro- duced in the stomach and is essential for the absorption of vitamin B12 from the small intes- tine. Without vitamin B12 and intrinsic factor, the membranes of immature red blood cells rupture easily within the chemical environment

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of the bloodstream. The result is fewer than nor- mal red blood cells and consequently a reduced oxygen-carrying capacity.

Causes of pernicious anemia include inade- quate diet, inadequate absorption, inadequate utilization, increased requirements, and in- creased excretion of vitamin B12. Principal di- etary sources of vitamin B12 come from animal products. Strict vegetarians who restrict all ani- mal products develop pernicious anemia unless they consume vitamin B12 supplements. Abnor- mal bacterial growth in the small intestine and bowel disorders induce pathological changes that either impair absorption or enhance elimi- nation of vitamin B12. Removal of the stomach or the bowel impairs availability of intrinsic fac- tor and limits absorption of vitamin B12.

Symptoms of pernicious anemia include ab- dominal distress, such as nausea and vomiting, and burning of the tongue. Neurological distur- bances include numbness, weakness, and yel- low and blue color blindness.

Vitamin B12 supplementation effectively re- verses the effects of pernicious anemia. Because vitamin B12 cannot be absorbed into the blood- stream, it must be replaced by injection. Vitamin B12 supplementation is required for life for strict vegetarians and for those with chronic bowel disorders or individuals who have had their stomach or bowel partially or fully removed.

Folic Acid Deficiency Anemia Folic acid is synthesized by many different types of plants and bacteria. Fruits and vegetables constitute the primary dietary source of folic acid. The minimum daily requirement is nor- mally about 50 micrograms, but this may be in- creased during periods of enhanced metabolic demand such as pregnancy.

Normal individuals have about 5 to 20 micro- grams of folic acid in various body stores, half of which is in the liver. Folic acid deficiency can occur within months if dietary intake or intesti- nal absorption is decreased.

Folic acid deficiency anemia is common in the Western world, where consumption of raw fruits and vegetables is low. Inflammation of the bowel, as in Crohn’s disease, and adverse effects

of certain medications impair absorption of folic acid. Body stores of folic acid are small, and folic acid deficiency anemia occurs within a few months. Pregnant and lactating females, alcohol abusers, and individuals with kidney disease are especially susceptible to folic acid deficiency anemia due to increased metabolic demands.

Measurement of serum folic acid levels is con- clusive for folic acid deficiency anemia. Oral folic acid supplementation is effective in replacing folic acid and meeting increased requirements for those with increased metabolic demands.

Hemolytic Anemia Red blood cells normally survive 90 to 120 days in the circulation. The lifespan of the red blood cells may be shortened by a number of disor- ders, often resulting in anemia if the body is not able to replenish the prematurely destroyed red blood cells.

Hemolytic anemia is a reduction in circulat- ing red blood cells that is caused by pathological conditions that accelerate destruction of red blood cells. Inherited abnormalities such as he- moglobin defects, enzyme defects, and mem- brane defects impair intrinsic physical proper- ties that are needed for optimal red blood cell survival. Infectious agents, certain medications, and immune disorders may also reduce red blood cell survival.

Significant red blood cell destruction pro- duces symptoms similar to those of other ane- mias. Unlike other anemias, hemolytic anemia produces increased serum levels of bilirubin that result from the degradation of heme in de- stroyed red blood cells. Accumulation of biliru- bin causes a jaundiced or yellow-orange appear- ance in the tissues, urine, and feces.

Treatment of hemolytic anemia depends on the underlying etiology. Splenectomy, or removal of the spleen, is recommended in cases of inher- ited causes of hemolytic anemia. Removal of the spleen decreases the risk of gallstones, he- molytic crises, and pathological changes to the bone marrow. Blood transfusions are recom- mended in cases of severe blood loss such as trauma. Infectious causes can be adequately treated with appropriate antibiotics and other

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supportive therapies. Similarly, immune disor- ders can be treated with various immune sup- pressive therapies. Offending medications are discontinued and rarely restarted in patients who develop hemolytic anemia.

Hemoglobinopathies Hemoglobin is critical for normal oxygen delivery to the tissues. Hemoglobinopathies are disorders affecting the structure, function, or production of hemoglobin. These conditions are usually in- herited and vary in the severity of symptoms.

Hemoglobinopathies are mutations that re- sult from the synthesis of abnormal hemoglo- bin. The most common hemoglobinopathies are sickle cell anemia and thalassemia.

Sickle Cell Anemia Sickle cell anemia is a geneti- cally transmitted disorder marked by severe he- molytic anemia, episodes of painful crisis, and increased susceptibility to infections. Approxi- mately 10% of African Americans have the sickle cell trait or are heterozygous for the disorder. Those with the disease are homozygous or have inherited two genes (one from each parent).

In sickle cell disease, red blood cells contain an abnormal form of hemoglobin, or hemoglobin S. As the red blood cell deoxygenates, hemoglo- bin S forms cross-links with other hemoglobin S molecules, and long crystals develop. Crystals

continue to form as oxygen is released, and the red cells assume a sickled shape.

Sickled red blood cells are inflexible and rigid and cause mechanical obstruction of small arte- rioles and capillaries, leading to pain and is- chemia. Sickled cells are also more fragile than normal, leading to hemolysis. Patients with sickle cell disease suffer from hemolytic anemia. Tissue death secondary to ischemia causes painful crises that progress to organ failure with repeated occlusive episodes.

Sickle cell disease is diagnosed on the basis of symptoms and by microscopic examination of red blood cells. The diagnosis is usually estab- lished in childhood, and genetic counseling is recommended for parents.

Sickle cell anemia cannot be cured. Patients with sickle cell disease require continuous care. Treatment is aimed at preventing sickle cell cri- sis, controlling the anemia, and relieving painful symptoms. Painful crises are adequately man- aged with narcotic analgesics. Blood transfusions and fluid replacement expand blood volume and oxygen exchange needed for reperfusion of oc- cluded vessels.

Thalassemia Thalassemia is a group of inherited blood disorders in which there is deficient syn- thesis of one or more alpha or beta chains re- quired for proper formation and optimal perfor- mance of the hemoglobin molecule. Several

▲ Normal red blood cells. (© Phototake NYC)

SIDE by SIDE ■ Sickle Cell Anemia

▲ Sickle red blood cells. (© Photo Researchers, Inc.)

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Chapter Seven Diseases of the Blood ■ 157

different categories of thalassemia produce mild to severe symptoms.

Thalassemias are the most common genetic disorders in the world, affecting nearly 200 mil- lion people worldwide. About 14% of African Americans are silent carriers for alpha tha- lassemia. Beta thalassemia has a 10% to 15% in- cidence in persons of Mediterranean and South- east Asia origin. The number of severe cases of thalassemia in the United States is about 1000 annually.

The most severe forms of thalassemia pro- duce severe, life-threatening anemia, bone mar- row hyperactivity, enlargement of the spleen, growth retardation, and bone deformities. Blood transfusions are required to sustain life, and life expectancy is reduced.

The diagnosis of most forms of thalassemia is readily made during childhood as children pre- sent with symptoms of severe anemia. The red blood cells in patients with thalassemia resem- ble red blood cells of severe iron deficiency ane- mia. Antenatal diagnosis of thalassemia syn- dromes is currently widely available through examination of fetal DNA obtained by amnio- centesis or chorionic villus biopsy.

Polycythemia Vera Polycythmia describes a condition in which red blood cell mass is increased. This condition is categorized as relative or absolute. In relative polycythemia, the increase in red blood cell mass is due to a loss of plasma volume without a corresponding decrease in red blood cells. This may occur in cases of dehydration or ex- cessive use of diuretics. Absolute polycythemia, also known as polycythemia vera, is a rise in red blood cell mass accompanied by an increase in white blood cells and platelets in the absence of a recognizable physiological stimulus.

Polycythemia vera is most commonly seen in men between the ages of 40 and 65 years. The etiology of this disease is unknown, although chromosomal abnormalities have been docu- mented in some cases.

Signs and symptoms of this disease are due to increased viscosity of hemoglobin formed cells in the plasma. Uncontrolled growth of the blood cells can lead to neurologic symptoms such as

dizziness, headaches, and visual disturbances. Hypertension accompanies increases in red blood cell mass. Because of the increased con- centration of blood cells, patient may experience itching and pain in the fingers and toes. Throm- boembolism with death may occur in severe un- diagnosed cases of polycythemia vera.

Treatment of polycythemia vera is aimed at decreasing the thickness of the blood. This can be done by intravenously removing blood to reduce red blood cell volume. Chemotherapeutic agents may help suppress the production of all blood cells by the bone marrow. The symptoms of the disease can be managed with administration of pain medications, and antihistamines can help relieve the discomfort associated with itching.

Disorders of Hemostasis

Disorders of hemostasis, commonly known as bleeding disorders, include a range of medical problems that lead to poor blood clotting and continuous bleeding. Bleeding disorders result from platelet dysfunction or deficiency, vitamin K deficiency, and clotting factor deficiencies. Platelets are blood elements produced in the bone marrow that are essential for blood clot- ting in response to immediate injury and for the mobilization of clotting factors. Clotting factors are formed in the liver and released in response to disuse injury and platelet fragments to form insoluble fibrin clots. Vitamin K is required for the synthesis of the prothrombin and thrombin clotting factors. Platelets, prothrombin, throm- bin, vitamin K, and calcium are essential for hemostasis, or the arrest of bleeding.

Thrombocytopenia An abnormally small number of circulating platelets, or thrombocytopenia, result from con- ditions that either impair production, increase destruction, or cause sequestration of platelets. Thrombocytopenia is the most common bleed- ing problem among hospitalized patients.

Careful microscopic examination of the blood is essential in diagnosing thrombocytopenia. Bone marrow examination is useful for diagnos- ing impairments in the synthesis of platelets.

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The production of platelets can be sup- pressed by malignant diseases or by destruction of the bone marrow most often secondary to cancer chemotherapies and radiation. Up to 30% of circulating platelets are normally con- tained in the spleen. Conditions that increase the size of the spleen cause increased trapping of platelets. Autoimmune disorders may in- crease platelet destruction or impair platelet function. Massive blood transfusions dilute cir- culating platelets and decrease platelet viability.

Regardless of cause, prolonged bleeding re- sults from minor and major trauma. Sponta- neous hemorrhages are often visible on the skin as small, flat, red spots called petechiae, or as larger purplish patches called ecchymosis (Figure 7–2 �). Spontaneous hemorrhages may also occur in the mucous membranes of the mouth and internal organs.

Thrombocytopenia can usually be corrected by treating the underlying cause. Preventative measures such as bed rest to avoid accidental trauma are highly recommended until platelet counts increase to acceptable levels. Platelet transfusions are reserved for severe thrombocy- topenia or in cases of severe bleeding.

Idiopathic Thrombocytopenic Purpura Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disorder resulting in excess de- struction of platelets. ITP most commonly oc-

curs as an acute problem in children less than five years of age following a viral infection. It is characterized by the sudden appearance of pe- techiae. Most children recover in a few weeks. In adults, this disorder is chronic and rarely fol- lows an acute viral infection.

The diagnosis of ITP is based on the appear- ance of severe thrombocytopenia. In patients with a suspected immune disorder, analysis of the blood for the presence of antibodies or phagocytic cells is helpful.

The treatment of ITP depends on the age of the patient and the severity of the illness. Hem- orrhage in patients with either acute or chronic ITP can usually be controlled by administration of corticosteroid medication. Removal of the spleen is reserved for patients who do not re- spond to medications or for those who are se- verely ill.

Coagulation Defects Blood clotting or coagulation is a complex process that involves many different plasma proteins in the control of bleeding. Coagulation involves forming of a blood clot, or a thrombus, that prevents further blood loss from damaged tissues, blood vessels, or organs.

Blood coagulation disorders can result from deficiencies or impairment of one or more of the clotting factors. Deficiencies can arise because

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Figure 7–2 � (A) Ecchymosis (Scott Camazine/Photo Researchers, Inc.) and (B) petechiae (© ISM/Phototake USA).

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Chapter Seven Diseases of the Blood ■ 159

of defective synthesis, inherited disease, or in- creased breakdown of clotting factors.

Impaired Synthesis of Coagulation Factors Certain coagulation factors are synthesized in the liver. In liver disease, synthesis of these clotting factors is reduced and bleeding may result. Coagulation factors VII, IX, X, and prothrombin require the presence of vitamin K for normal activity. In vit- amin K deficiency, the liver produces an inactive form of the clotting factors. Vitamin K is a fat- soluble vitamin that is synthesized by intestinal bacteria; deficiencies occur when intestinal syn- thesis of vitamin K is interrupted or absorption of vitamin K is impaired. Vitamin K deficiency can occur in newborns before the development of in- testinal flora required for the synthesis of vita- mins occurs.

Hereditary Disorders

The most common inherited bleeding disorders involve factor VIII, also known as hemophilia A and the von Willebrand Factor (vWF). According to the National Heart and Lung Institute, hemo- philia A affects 1 in 5000 male live births and von Willebrand’s disease may affect more than 1 in every 1000.

Hemophilia A Hemophilia A is an X-linked recessive disorder that primarily affects males. The severity of the disease depends on how the genetic defect af- fects the activity of the clotting factor. In mild to moderate forms of the disease, bleeding usually does not occur unless there is a local lesion or trauma such as surgery or dental procedures. Mild disorders may not be detected in child- hood. In severe hemophilia, bleeding usually oc- curs in childhood and is spontaneous and se- vere, occurring up to several times per month.

Bleeding often occurs in the gastrointestinal tract and in the joints of the hip, knee, elbow, and ankle. The bleeding causes inflammation with acute pain and swelling. Without proper treatment, chronic bleeding and inflammation

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cause joint fibrosis that can progress to major disability. Intracranial hemorrhage is an impor- tant cause of death in severe hemophilia.

Treatment of hemophilia involves replacement of factor VIII chronically, with additional doses administered during phases of acute bleeding. Patients with mild hemophilia A can sometimes be treated with a synthetic hormone called desmopressin. Desmopressin stimulates the re- lease of the carrier for factor VIII, thus causing increases in blood concentration of factor VIII.

Von Willebrand Disease Von Willebrand disease is an inherited bleeding disorder that is most often diagnosed in adult- hood. There are many forms of this disease that cause a defect in the adhesion of platelets. Be- cause vWF carries factor VIII, its deficiency may also be accompanied by reduced levels of factor VIII, contributing to impaired clotting.

Mild symptoms of von Willebrand’s disease in- clude frequent bruises from minor bumps, fre- quent nosebleeds, extended bleeding following dental procedures, heavy menstrual bleeds, and heavy bleeding following surgery. In severe cases, life-threatening gastrointestinal or joint hemor- rhage may resemble symptoms of hemophilia.

Mild forms of von Willebrand’s disease are often diagnosed following a severe bleeding episode. Examination of the blood for antigens, vWF activity, and examination of the structure of the vWF provides information on the type of defect as well as the severity of the defects. Ex- amination of the platelets provides information on how well the platelets are functioning.

Treatment of von Willebrand’s disease in- cludes medications and lifestyle changes to minimize trauma. Medications are used to in- crease the release of von Willebrand factor into the blood, replace von Willebrand factor, pre- vent the breakdown of clots, and control heavy menstrual bleeding in women.

Disseminated Intravascular Coagulation Disseminated intravascular coagulation (DIC) is a po- tentially life-threatening condition that involves destruction of the platelets and consumption

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Figure 7–3 � Neutrophils or white blood cells. (Carolina Biolog- ical Supply Company/Phototake NYC)

of clotting factors. DIC occurs in a variety of disorders, such as sepsis or blood infection, en- dothelial damage as in states of shock, obstetrical complications associated with delivery of a child, and various neoplasms or cancer.

The pathogenesis of DIC involves the release of thrombin into the systemic circulation, causing systemic coagulation and suppression of normal physiological anticoagulation mechanisms. Ex- tensive clotting produces diffuse tissue ischemia, organ damage, and depletion of platelets and clotting factors. The depletion of platelets and clotting factors, also known as consumptive coagu- lopathy, results in extensive bleeding.

The diagnosis of DIC is based on the presence of clinical signs of bleeding in a patient with a clinical condition known to be associated with DIC. Clinically DIC is usually diagnosed on the basis of the underlying disease, observed low platelet counts on a peripheral blood test, in- creases in bleeding times, and the presence of degradation products in the blood plasma.

Treatment of the underlying disorder is the cornerstone of therapy for DIC. Supportive med- ical treatments include platelet transfusions, administration of concentrates of coagulation inhibitors, and administration of an intra- venous anticoagulant where appropriate.

White Blood Cells

Leukocytes, or white blood cells, include neutro- phils, eosinophils, basophils, monocytes, and lymphocytes (Figure 7–3 �). White blood cells are synthesized in the bone marrow from their re- spective stem cells. The primary function of leukocytes is to defend tissues against infections and foreign substances. Quantitative abnormal- ities, inherited acquired defects, and neoplastic alterations result in disease and disability.

Disorders of White Blood Cells Neutropenia A reduction of circulating neu- trophils increases the risk for bacterial and fun- gal infections. Because neutrophils are respon- sible for most clinical findings during an acute infection, the classic signs of infection may be

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diminished or absent in a severely neutropenic individual.

Neutropenia is a frequent complication of med- ication used for cancer chemotherapy or medica- tions used for immune suppression. These med- ications suppress cellular proliferation within in the bone marrow. Infectious complications de- pend on the severity of neutropenia and are usu- ally profound and severe in cancer patients.

Immune destruction of neutrophils occurs with rheumatoid arthritis or as a primary condi- tion with unknown causes. Neutropenia may be either mild or severe, and infectious complica- tions are variable. Chronic and severe cases re- quire medical treatment with medications that increase neutrophil proliferation or medications that suppress immune function.

Patients with chronic neutropenia may expe- rience chronic infections. Acute and severe neu- tropenia may be associated with fever, skin in- flammation, liver abscesses, and septicemia, or infection in the blood.

Diagnosis of neutropenia is based on assess- ment of a complete blood count. Examination of the bone marrow is useful to diagnose bone marrow failure syndromes that may be causing the neutropenia.

The treatment of neutropenia depends on its cause and severity. Sometimes neutropenia may resolve without treatment. Those with mild neutropenia generally have no symptoms and

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Chapter Seven Diseases of the Blood ■ 161

may not need treatment. People with severe neutropenia are at risk for high fevers and se- vere infections. Hospitalization with isolation and intravenous antibiotic therapy is needed for the severely neutropenic patient.

Growth factors, called colony-stimulating fac- tors, which stimulate the production of white blood cells, are especially helpful for patients who develop neutropenia secondary to cancer treatment. Corticosteroids may help if the neu- tropenia is caused by an autoimmune reaction.

Abnormalities of Eosinophils Idiopathic Hypereosinophilic Syndrome The onset of idiopathic hypereosinophilic syndrome occurs be- tween the ages of 20 and 50 years, and there is a strong male predominance. Persistent in- creases in blood eosinophils and associated in- volvement of the heart and nervous system are responsible for the most important clinical symp- toms. Cardiac involvement produces congestive heart failure, valvular dysfunction, conduction defects, and myocarditis. Congestive heart fail- ure is a frequent cause of death. Neurologic find- ings may include altered behavior and cognitive function, spasticity, and ataxia.

Prognosis for the idiopathic hypereosinophilic syndrome historically has been poor, with me- dian survival of approximately one year. How- ever, chemotherapy has recently been reported to produce 70% survival at 10 years.

Eosinophilia-Myalgia Syndrome A recently de- scribed disorder, eosinophilia-myalgia syndrome, is a chronic, multisystem disease with a spectrum of clinical symptoms ranging from self-limited

myalgias, or muscle pain, and fatigue to a pro- gressive and potentially fatal illness character- ized by skin changes, nervous system abnormal- ities, and pulmonary hypertension. Elevation of circulating levels of eosinophils is a universal fea- ture of this disorder, and the illness has been re- lated to ingestion of the dietary supplement L-tryptophan.

Age-Related Diseases Anemia is the most common blood disorder in persons greater than 75 years of age. The causes of anemia in older adults are blood loss and nutritional deficiencies, chronic illness, and chronic renal failure. Decreased physical per- formance, mental status changes, and an in- crease in mortality are among the consequences of untreated anemia in older adults. White blood cell disorders, platelet disorders, and im- mune deficiency are often due to malignant disease. Neutropenia, thrombocytopenia, and nutritional anemias develop secondary to the malignancy and cancer treatments.

R E S O U R C E S

National Institutes of Medicine: www.nlm.nih.gov/ medlineplus/bloodandblooddisorders.html

Centers for Disease Control: www.cdc.gov/ncbddd/hbd/default.htm

World Health Organization: www.who.int/nutrition/ publications/anaemia_iron_pub/en

National Heart, Lung, and Blood Institute: www.nhlbi.nih. gov/health/dci/Diseases/vwd/vwd_whatis.html

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DISEASES AT A GLANCE Blood

DISEASE ETIOLOGY SIGNS AND SYMPTOMS DIAGNOSIS

Iron deficiency anemia Iron loss Fatigue, decreased exercise tolerance, shortness of breath

Blood test

Anemia of chronic disease and renal disease

Defect in erythropoiesis Fatigue, decreased exercise tolerance, shortness of breath

Blood test, evidence for primary disease

Vitamin B12 deficiency anemia

Impaired intake or absorption of vitamin B12

Abdominal distress, nausea, vomiting, and burning of the tongue

Blood test, health history

Folic acid deficiency anemia Impaired intake, depletion of body stores

Fatigue, decreased exercise tolerance, shortness of breath

Blood test

Sickle cell anemia Genetics: results in formation of abnormal hemoglobin

Pallor, fatigue, shortness of breath, painful sickle cell crisis

Genetic testing, blood test

Thalassemia Genetics: results in formation of defective hemoglobin

Pallor, fatigue, shortness of breath Genetic testing, blood test

Polycythemia vera Idiopathic, unknown Dizziness, headaches, and visual disturbances

Blood test

Idiopathic thrombocytopenic purpura

Viral infection in children Unknown in adults

Bleeding Blood test

Hemophilia A Genetic: results in deficiency of clotting factor VIII

Bleeding Genetic test, blood test

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Chapter Seven Diseases of the Blood ■ 163

TREATMENT PREVENTION LIFESPAN

Iron replacement Iron fortified diet, iron replacement in high-risk individuals

Can occur at any age

Administration of injectable erythropoietin and iron Treatment of the underlying disease Can occur at any age

Replacement of vitamin B12 Treatment of underlying condition impairing vitamin B12 absorption

Can occur at any age

Replacement of folic acid Folic acid–fortified diet Can occur at any age

Prevention of sickle cell crisis; supportive therapy during crisis; blood transfusion

Cannot prevent sickle cell disease Diagnosed in childhood and persists throughout life

Supportive care; blood transfusion if anemia is severe; treatment of iron overload from frequent blood transfusions

Cannot prevent thalassemia Diagnosed in childhood and persists throughout life

Chemotherapeutic agents, blood letting Unknown Can occur at any age

Corticosteroid medications, splenectomy Unknown Can occur at any age; more common in adulthood

Replacement of factor VIII Cannot prevent hemophilia Diagnosed in infancy and persists throughout life

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164 ■ Chapter Seven Diseases of the Blood

DISEASES AT A GLANCE Blood (continued)

DISEASE ETIOLOGY SIGNS AND SYMPTOMS DIAGNOSIS

Von Willebrand’s disease Genetic: results in decreased platelet adhesion

Bleeding Genetic test, blood test

Disseminated intravascular coagulation

Sepsis, endothelial damage, shock

Bleeding Blood test; clinical signs and symptoms in high-risk patients

Neutropenia Medications, cancer, chemotherapy, immune disorders

Infection, fever, skin inflammation, and fever

Blood test

Idiopathic hypereosinophilic syndrome

Unknown Cardiac symptoms can lead to congestive heart failure

Blood test

Eosiniphilia myalgias syndrome

Ingestion of contaminated L-tryptophan

Skin changes, nervous system abnormalities, pulmonary hypertension

Blood test

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Chapter Seven Diseases of the Blood ■ 165

TREATMENT PREVENTION LIFESPAN

Desmopressin; lifestyle changes to prevent trauma and bleeding

Cannot prevent von Willebrand’s disease Can occur at any age

Supportive; treatment of the underlying condition; platelet transfusions

Cannot prevent this condition; difficult to predict when this will occur

Can occur at any age

Administration of medications to increase neutrophil count; antibiotics to prevent infections

Cannot prevent Can occur at any age

Chemotherapy agents Unknown Can occur at any age

Discontinue use of the offending agent Unknown as contaminants can be present without notice

Can occur at any age

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166 ■ Chapter Seven Diseases of the Blood

7. A disease of increased viscosity of the blood with associate neurological symptoms is known as ____________________.

a. polycythemia vera b. disseminated intravascular coagulation c. sickle cell anemia d. thalassemia

8. ____________________ is an autoimmune disorder result- ing in destruction of platelets.

a. Disseminated intravascular coagulation b. Polycythemia vera c. Hemophilia A d. Idiopathic thrombocytopenic purpura

9. ____________________ is an X-linked recessive disorder that primarily affects males and results in a deficiency of clotting factor VIII.

a. Disseminated intravascular coagulation b. Polycythemia vera c. Hemophilia A d. Idiopathic thrombocytopenic purpura

10. ____________________ is a reduction in circulating red blood cells that increases the risk for severe bacterial and fungal infections.

a. Hemophilia b. Neutropenia c. Thrombocytopenia d. Coagulopathy

1. The most important component of red blood cells is ____________________.

a. vitamin B12 b. folic acid c. erythropoietin d. hemoglobin

2. In anemia of chronic disease and anemia of chronic renal failure, the defect in the synthesis of red blood cells is due to a lack of ____________________.

a. erythropoeisis b. iron c. hemoglobin d. folic acid

3. Pernicious anemia is due to inadequate absorption of ____________________.

a. vitamin B12 b. folic acid c. erythropoietin d. hemoglobin

4. The minimum daily requirement of folic acid is about ____________________ micrograms.

a. 200 b. 150 c. 100 d. 50

5. Disorders affecting the structure and function or production of hemoglobin are classified as ____________________.

a. hemolytic anemia b. iron deficiency anemia c. hemoglobinopathy d. folic acid deficiency anemia

6. Deficient synthesis of one or more of the alpha or beta chains of the hemoglobin molecule is characteristic of ____________________.

a. hemolytic anemia b. thalassemia c. sickle cell anemia d. iron deficiency

2. B.K. is a 65-year-old male admitted to the hospital for surgery. BK had been on blood thinners in the past for the treatment of a clotting disorder. He is fearful of going to the hospital, because last time he had a severe bleeding episode. What conditions should BK’s doctors be concerned about? What are some of the symptoms and diagnostic tests that should be considered for this patient?

1. E.T. is a 42-year-old female who has been “all tired out” for the past few months. The onset of her illness was poorly defined, and aside from a lack of energy she has no other complaints. She reported being easily winded or short of breath when climbing the stairs or walking for any prolonged distance. She told her doctor that she had recently experienced a slight weight loss following the loss of her mother. What diseases or conditions should be considered in this patient? What addi- tional information do you need to make a correct diagnosis?

Interactive Exercises

Cases for Critical Thinking

Multiple Choice

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True or False

_______ 1. Chemotherapy increases survival in patients with idiopathic hypereosinophilic syndrome.

_______ 2. Hemoglobin is the most important component of white blood cells.

_______ 3. The production of red blood cells is regulated by a kidney hormone, erythropoietin.

_______ 4. The symptoms of neutropenia are due to hypoxia.

_______ 5. The clinical diagnosis of blood disorders requires careful microscopic examination of blood in a peripheral blood smear.

_______ 6. Vitamin K is required for the synthesis of clotting factors.

_______ 7. Von Willebrand’s disease is a hereditary deficiency of vitamin K.

_______ 8. The depletion of platelets in disseminated intravascular coagulation is also known as a consumptive coagulopathy.

_______ 9. Enlargement of the spleen occurs in anemia caused by hemolysis.

_______ 10. The amount of iron needed in the diet to replace losses is approximately 1.0 to 1.4 mg of elemental iron per day.

Fill-Ins

1. White blood cells are called ____________________.

2. Mature red blood cells are called ____________________.

3. Sickle cell disease causes formation of ____________________ that forms cross links and sickling of red blood cells.

4. Thrombocytopenia is a disease in the circulating levels of ____________________.

5. The most severe, life-threatening forms of thalassemia are ____________________ and ____________________.

6. The leading cause of anemia worldwide is ____________________.

7. Vitamin B12 and folic acid deficiency anemia are also called ____________________.

8. Red blood cells normally survive in the circulation for about ____________________ days.

9. A rise in red blood cell mass accompanied by an increase in white blood cells and platelets is known as ____________________.

10. The pathogenesis of disseminated intravascular coagulation involves the release of ____________________ into the circulation, causing extensive coagulation followed by consumption of platelets and clotting factors.

Chapter Seven Diseases of the Blood ■ 167

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168 ■ Chapter Seven Diseases of the Blood

Labeling Exercise

Use the blank lines below to label the following photos.

1 2

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Multimedia Preview

Additional interactive resources and activities for this chapter can be found on the Companion Web- site. For videos, audio glossary, and review, access the accompanying DVD-ROM in this book.