Alterations of Erythrocyte, Platelet, and Hemostatic Function (McCance 29) PDF

CHAPTER 29 Alterations of Erythrocyte, Platelet, and Hemostatic Function Kathryn L. McCance, Neal S. Rote http://evolve.elsevier.com/McCance/ Content Updates Chapter Summary Review Review Questions Case Studies Animations CHAPTER OUTLINE Anemia, 926...

CHAPTER 29 Alterations of Erythrocyte, Platelet, and Hemostatic Function Kathryn L. McCance, Neal S. Rote http://evolve.elsevier.com/McCance/ Content Updates Chapter Summary Review Review Questions Case Studies Animations CHAPTER OUTLINE Anemia, 926 Alterations of Platelets and Coagulation, 947 Classification and General Characteristics, 926 Disorders of Platelets, 947 Anemias of Blood Loss, 928 Disorders of Coagulation, 952 Anemias of Diminished Erythropoiesis, 932 Myeloproliferative Red Blood Cell Disorders, 945 Polycythemia Vera, 945 Iron Overload, 947 Alterations of erythrocyte function involve either insufficient or excessive diarrhea, excessive use of diuretics) with a normal red blood cell mass numbers of red blood cells (RBCs) in the circulation or normal numbers may indicate a relative polycythemia or abnormally elevated red cell count of cells with abnormal components. Anemias occur when there is an because of hemoconcentration. Severe dehydration can correlate with inadequate number of RBCs or an insuficient volume or mass of RBCs increased hematocrit and hemoglobin levels. Fluid retention is associated in the blood, while polycythemias develop when the number or volume with hemodilution rather than a true decrease in red blood cell mass. of RBCs is excessive. Each of these conditions has many causes and is a pathophysiologic manifestation of a variety of disease states. Classification and General Characteristics The primary role of clotting (hemostasis) is to stop bleeding through There are several ways to classify anemias. A useful way is by the under- an interaction among vascular endothelium, platelets, and the clotting lying main mechanism (Table 29.1). Another way to classify anemias system. Many disease states are associated with clinically signiicant is based on changes that affect the erythrocyte’s size or hemoglobin aberrations in any of these three necessary components of clotting. content. The terminology relects these characteristics: terms that end This chapter discusses alterations of platelets and various components in “-cytic” refer to cell size, whereas “-chromic” refers to hemoglobin of clotting and their control systems. content. Microcytic-hypochromic anemias are caused by disorders of hemoglobin synthesis, particularly iron deiciency. Macrocytic anemias arise commonly from abnormalities that hinder the maturation of ANEMIA erythroid precursors in the bone marrow. Various etiologies occur in Anemia is a reduction in the total circulating red cell mass or a decrease normocytic-normochromic anemias, and the specific shapes of the in the quality or quantity of hemoglobin. Anemias commonly result from red blood cell can help determine the cause. Additional descriptors of (1) blood loss (acute or chronic), (2) impaired erythrocyte production, (3) erythrocytes associated with some anemias include anisocytosis (assum- increased erythrocyte destruction, or (4) a combination of these factors. ing various sizes) or poikilocytosis (assuming various shapes) (Fig. 29.1). Total circulating red blood cell mass is reflected by changes in plasma The main physiologic manifestation of anemia is a reduced oxygen- volume caused by dehydration and luid retention. For example, decreased carrying capacity of the blood resulting in tissue hypoxia. Symptoms plasma volume from dehydration (less water intake, prolonged vomiting, of anemia vary, depending on the body’s ability to compensate for 926  CHAPTER 29 Alterations of Erythrocyte, Platelet, and Hemostatic Function 927 TABLE 29.1 CLASSIFICATION OF ANEMIA ACCORDING TO UNDERLYING MECHANISM MECHANISM SPECIFIC EXAMPLES Blood Loss Acute blood loss Trauma Chronic blood loss Gastrointestinal tract lesions, gynecologic disturbances* Increased Red Cell Destruction (Hemolysis) Inherited Genetic Defects Red cell membrane disorders Hereditary spherocytosis, hereditary elliptocytosis Enzyme deficiencies Hexose monophosphate shunt enzyme deficiencies G6PD deficiency, glutathione synthetase deficiency Glycolytic enzyme deficiencies Pyruvate kinase deficiency, hexokinase deficiency Hemoglobin abnormalities Deficient globin synthesis Thalassemia syndromes Structurally abnormal globins (hemoglobinopathies) Sickle cell disease, unstable hemoglobins Acquired Genetic Defects Deficiency of phosphatidylinositol-linked glycoproteins Paroxysmal nocturnal hemoglobinuria Antibody-mediated destruction Hemolytic disease of the newborn (Rh disease), transfusion reactions, drug-induced, autoimmune disorders Mechanical trauma Microangiopathic hemolytic anemias Hemolytic uremic syndrome, disseminated intravascular coagulation, thrombotic thrombocytopenia purpura Cardiac traumatic hemolysis Defective cardiac valves Repetitive physical trauma Bongo drumming, marathon running, karate chopping Infections of red cells Malaria, babesiosis Toxic or chemical injury Clostridial sepsis, snake venom, lead poisoning Membrane lipid abnormalities Abetalipoproteinemia, severe hepatocellular liver disease Sequestration Hypersplenism Decreased Red Cell Production Inherited Genetic Defects Defects leading to stem cell depletion Fanconi anemia, telomerase defects Defects affecting erythroblast maturation Thalassemia syndromes Nutritional Deficiencies Deficiencies affecting DNA synthesis B12 and folate deficiencies Deficiencies affecting hemoglobin synthesis Iron deficiency anemia Erythropoietin deficiency Renal failure, anemia of chronic disease Immune-mediated injury of progenitors Aplastic anemia, pure red cell aplasia Inflammation-mediated iron sequestration Anemia of chronic disease Primary hematopoietic neoplasms Acute leukemia, myelodysplasia, myeloproliferative disorders Space-occupying marrow lesions Metastatic neoplasms, granulomatous disease Infections of red cell progenitors Parvovirus B19 infection Unknown mechanisms Endocrine disorders, hepatocellular liver disease *The usual cause of anemia is iron deficiency, not actual bleeding. G6PD, Glucose-6-phosphate dehydrogenase. From Kumar V, Abbas A, Aster JC: Robbins & Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders. reduced oxygen-carrying capacity (Fig. 29.2). Anemia that is mild and compensatory effects become more apparent. Compensation generally develops gradually is usually easier to compensate and may cause involves the cardiovascular, respiratory, and hematologic systems. problems for the individual only during physical exertion. As the (Hematologic indings associated with various anemias are listed in reduction in the number of red blood cells (RBCs) continues, symptoms Table 29.2 and progression and manifestations of anemias are shown become more pronounced and alterations of specific organs and in Fig. 29.2.) 928 UNIT VIII The Hematologic System WHAT’S NEW? Patient-Centered Blood Management Red blood cell transfusion is the main treatment to correct anemia; however, it is one of the top five overused procedures and carries its own risk and A B C economic burdens. In an effort to improve patient outcomes, patient blood management (PBM) is a patient-centered and multidisciplinary approach to effectively manage anemia, reduce iatrogenic blood loss, and improve outcomes for those with anemia. Some hospitals are implementing PBM in practice. Data from Meybohm P et al: Perioper Med 6:5, 2017. D E F cardiopulmonary congestion. These compensatory mechanisms may lead to heart failure. Tissue hypoxia creates additional demands and compensatory actions on the pulmonary and hematologic systems. The rate and depth of breathing increase in an attempt to increase the availability of oxygen. These demands are accompanied by an increase in the release of oxygen from hemoglobin. (Mechanisms of oxygen transport and release by G H I hemoglobin are described in Chapter 28.) All of these compensatory mechanisms may cause individuals to experience shortness of breath (dyspnea); a rapid, pounding heartbeat (palpitations); dizziness; and fatigue. In mild, chronic conditions, these symptoms might be present only when the demand for oxygen is increased (e.g., during physical exertion), but in severe conditions they may be experienced at rest. Manifestations of anemia may be observed in other parts of the J K L body. The skin, mucous membranes, lips, nail beds, and conjunctivae become pale as a result of reduced hemoglobin concentration. If anemia is caused by RBC destruction (hemolysis), the skin may become yellowish because of accumulation of the products of hemolysis. Tissue hypoxia of the skin results in impaired healing and loss of elasticity, as well as thinning and early graying of the hair. Nervous system manifestations M N O can occur if the anemia is caused by a vitamin B12 deiciency. Myelin degeneration may occur, causing a loss of nerve fibers in the spinal FIGURE 29.1 Appearance of Red Blood Cells in Various Disorders. cord and producing paresthesias (numbness), gait disturbances, extreme A, Normal blood smear. B, Microcytic-hypochromic anemia (iron deficiency). weakness, spasticity, and relex abnormalities. Decreased oxygen supply C, Macrocytic anemia (pernicious anemia). D, Macrocytic anemia in pregnancy. to the gastrointestinal (GI) tract often produces abdominal pain, nausea, E, Hereditary elliptocytosis. F, Myelofibrosis (teardrop). G, Hemolytic anemia vomiting, and anorexia. A low-grade fever of less than 38.5°C (less than associated with prosthetic heart valve. H, Microangiopathic anemia. I, Stomatocytes. about 101°F) occurs in some anemic individuals and may result from J, Spherocytes (hereditary spherocytosis). K, Sideroblastic anemia; note the double the release of leukocyte pyrogens from ischemic tissues. population of red blood cells. L, Sickle cell anemia. M, Target cells (after splenectomy). When the anemia is severe or acute in onset (e.g., hemorrhage), the N, Basophil stippling in case of unexplained anemia. O, Howell-Jolly bodies (after initial compensatory mechanism is peripheral blood vessel constriction, splenectomy). (From Wintrobe MM et al: Clinical hematology, ed 8, Philadelphia, diverting blood low to vital organs. Decreased blood low detected by 1981, Lea & Febiger.) the kidneys activates the renal renin-angiotensin response, causing salt and water retention in an attempt to increase blood volume. These situations are emergencies and require immediate intervention to correct A reduction in the number of blood cells in the blood causes a reduc- the underlying problem that caused the acute loss of blood; therefore tion in the consistency and volume of blood. Compensation for a reduced long-term compensatory mechanisms do not develop. blood volume causes interstitial fluid to move into the intravascular Therapeutic interventions for slowly developing anemic conditions space, expanding plasma volume. This movement maintains adequate require treatment of the underlying disorder and palliation of associated blood volume, but the viscosity (thickness) of the blood decreases. The symptoms. Therapies include provision of transfusions, correction of diluted blood lows faster and more turbulently than normal blood, dietary imbalances, and administration of supplemental vitamins or causing a hyperdynamic circulatory state. This hyperdynamic state creates iron. Effective management of an individual’s blood is described in cardiovascular changes—increased stroke volume and heart rate. These What’s New? Patient-Centered Blood Management. changes may lead to cardiac dilation and heart valve insufficiency if the underlying anemic condition is not corrected. Hypoxemia, reduced oxygen levels in the blood, further contributes Anemias of Blood Loss to cardiovascular dysfunction by causing dilation of arterioles, capillaries, Acute Blood Loss and venules, thus leading to decreased vascular resistance and increased Posthemorrhagic anemia is a normocytic-normochromic anemia low. Increased peripheral blood low and accelerated venous return (NNA) caused by acute blood loss. Acute blood loss is mainly a loss of further contribute to an increase in heart rate and stroke volume intravascular volume and the effects depend on the rate of hemorrhage in a continuing effort to meet normal oxygen demand and prevent that can lead to cardiovascular collapse, shock, and death. A major  CHAPTER 29 Alterations of Erythrocyte, Platelet, and Hemostatic Function 929 Etiologic events ↓ erythropoiesis (blood loss) ↑ destruction ↓ Red blood cells, ↓ hemoglobin (anemic condition) ↓ Oxygen-carrying capacity (hypoxemia) Liver (fatty changes; fatty Ischemia Tissue hypoxia changes can also occur in heart and kidney) Respiratory Central nervous system Claudication Weakness, Pallor (skin/ (↑ respiratory rate, depth, (dizziness, fainting, (muscle) ↑ fatigue mucous membrane) “exertional dyspnea”) lethargy) Compensatory Heart mechanisms (angina) Capillary ↑ BPG in cells ↑ Heart rate Cardiovascular Renal ↑ Oxygen demands dilation for work of heart ↑ SV ↑ Renin-aldosterone response ↑ Erythropoietin ↑ Salt and H2O retention ↑ Extracellular fluid Stimulates bone marrow ↑ Extracellular Hyperdynamic fluid circulation Cardiac High-output ↑ Release of oxygen murmurs cardiac failure from hemoglobin in tissues FIGURE 29.2 Progression and Manifestations of Anemia. BPG, Bisphosphoglycerate; SV, stroke volume. cause of acute blood loss is trauma. Severe trauma is a rising global a result of a shift of marginated leukocytes into the circulation and a problem.1 Traumatic injury results in an annual worldwide death of release of leukocytes from the bone marrow. The platelet count can more than 5.8 million people, or 1 in 10 mortalities.1,2 Uncontrolled rise to levels of about 1 million/μL. In severe blood loss, more immature posttraumatic bleeding is the leading cause of potentially preventable cells—metamyelocytes, myelocytes, and nucleated red blood cells—may death among injured individuals.1 The pathophysiologic mechanisms enter the circulation. Reduction in tissue oxygenation stimulates produc- associated with traumatic injury is an evolving ield of study (see What’s tion of erythropoietin and increasing production of erythrocytes New? Traumatic Injury, Bleeding, and Coagulopathy). Table 29.3 presents (reticulocytes) in the bone marrow. Iron recovery from destroyed classiication of estimated blood loss for a 70-kg man based on initial erythrocytes may occur if the acute blood loss is internal; however, if presentation, as developed by the American College of Surgeons Advanced blood is lost externally, iron stores may be depleted and erythropoiesis Trauma Life Support (ATLS).1 The overall reliability and validity of the may be impeded. Hemorrhage that is chronic (occult [i.e., bleeding ATLS classiication are still undergoing study. ulcer or neoplasm]) produces adaptations that are less prominent, but Volume loss reduces mean systemic filling pressure, resulting in the individual may experience an iron deiciency anemia (IDA) when decreased venous return. The initial manifestations (increased sympa- iron reserves become depleted. Initial treatment for acute blood loss is thetic nerve activation and a reduction in blood pressure, cardiac output, restoration of blood volume by intravenous administration of saline, and central venous pressure) are caused by cardiovascular adaptations to dextran, albumin, or plasma. Large volume losses may require transfusion blood volume depletion. Indexes to predict the risk of hemorrhagic shock of fresh whole blood. are proposed as useful to provide prompt and appropriate treatment.1 Successful therapy is irst indicated by a return of erythrocytes to If the acute blood loss is not severe (does not cause the preceding their normal size and shape. As the bone marrow begins to produce manifestations), complete recovery is possible. Within 24 hours of blood more erythrocytes, an increase in the number of reticulocytes (10% to loss, lost plasma is replaced by mobilizing water and electrolytes from 15% after 7 days) is seen. Changes in the appearance of erythrocytes tissues and interstitial spaces into the vascular system. The hemodilution (polychromatophilia and macrocytosis) associated with reticulocytosis that results lowers the hematocrit value; concurrently, there is often a may give the impression that an underlying hemolytic process is occur- rapid elevation of circulating neutrophils and platelets. Neutrophils ring. A normal erythrocyte count is usually noted in 4 to 6 weeks, but can rise to levels between 10,000 and 30,000/μL within a few hours as hemoglobin restoration may take 6 to 8 weeks.  930 TABLE 29.2 LABORATORY FINDINGS FOR VARIOUS ANEMIAS FOLATE ANEMIA OF PERNICIOUS DEFICIENCY IRON DEFICIENCY SIDEROBLASTIC APLASTIC POSTHEMORRHAGIC HEMOLYTIC CHRONIC TEST ANEMIA ANEMIA ANEMIA ANEMIA ANEMIA ANEMIA ANEMIA DISEASE Hemoglobin Low Low Low Low Low or normal Normal or low Low Low Hematocrit Low Low Low Low Low or normal Normal or low Low Low Reticulocyte count Low Low Normal or slightly high Normal or slightly high Low Increased High Normal or low Mean corpuscular High High Low Low Normal or Slightly low Normal or high Normal or low volume slightly high UNIT VIII The Hematologic System Plasma iron High High Low High High Normal Normal or high Low Total iron-binding Normal Normal High Normal Normal Normal Normal Low capacity Ferritin High High Low High Normal Normal Normal Normal Serum B12 Low Normal Normal Normal Normal Normal Normal Normal Folate Normal Low Normal Normal Normal Normal Normal Normal Bilirubin Slightly high Slightly high Normal High Normal Normal Slightly high Normal Free erythrocyte Normal Normal High Increased or normal High Normal Normal Normal or slightly protoporphyrin high Transferrin Slightly high Slightly high Low High Normal Normal Normal Slightly low  TABLE 29.3 CLASSIFICATION OF ESTIMATED BLOOD LOSS* CLASS I CLASS II CLASS III CLASS IV Blood loss (mL) Up to 750 750–1500 1500–2000 >2000 Blood loss (% blood volume) Up to 15 15–30 30–40 >40 Pulse rate (beats/min) 140 Systolic blood pressure Normal Normal Decreased Decreased Pulse pressure Normal or increased Decreased Decreased Decreased Respiratory rate (breaths/min) 14–20 20–30 30–40 >35 Urine output (mL/hr) >30 20–30 5–15 Negligible Central nervous system/mental state Slightly anxious Mildly anxious Anxious, confused Confused, lethargic Initial fluid replacement Crystalloid Crystalloid Crystalloid and blood Crystalloid and blood *For a 70-kg man. Data from Rossaint R et al: Crit Care 20:100, 2016. WHAT’S NEW? Traumatic Injury, Bleeding, and Coagulopathy Emerging is the understanding that about one-third of all persons with bleeding to acidosis, hypothermia, hemodilution, hypoperfusion, and coagulation factor trauma are already showing signs of coagulopathy upon hospital admission. The consumption. Coagulopathy is modified by brain injury, age, genetic background, presence of coagulopathy is related to an increased risk of multiple organ failure comorbidities, inflammation, medications (especially oral anticoagulants), and and death (see Chapter 49). Acute coagulopathy associated with traumatic injury prehospital fluid administration. New terms for trauma-associated coagulopathic is now recognized as a multifactorial condition caused by bleeding-induced shock, physiology include acute traumatic coagulopathy, early coagulation of trauma, tissue-related thrombin-thrombomodulin complex generation, and activation of acute coagulopathy of trauma-shock, trauma-induced coagulopathy, and trauma- anticoagulant and fibrinolytic pathways (see Figure). The severity of the coagu- associated coagulopathy. New guidelines recommend that individuals be transferred lopathy disorder is impacted by preexisting and treatment factors that contribute directly to trauma centers to improve outcomes. Preexisting factors Age Genetics Trauma Comorbidities Tissue damage Premedication Cytokine and Blood loss hormone release Inflammation Activation of Consumption of fibrinolysis coagulation factors Shock Activation of Tissue Resuscitation hemostasis and hypoxia endothelium Crystalloid Erythrocyte Acidosis colloid transfusion Hypothermia Dilutional coagulopathy Traumatic coagulopathy FIGURE Traumatic Coagulopathy. Preexisting and trauma-related factors contribute to coagulopathy. (Box data from Firth D et al: J Thromb Haemost 8(9):1919–1925, 2010; MacLeod JB et al: J Trauma 55(1):39–44, 2003; Maegele M et al: Injury 38(3):298–304, 2007; Rossaint R et al: Crit Care 20:100, 2016. Figure adapted from Rossaint R et al: Crit Care 20:100, 2016.) 932 UNIT VIII The Hematologic System Chronic Blood Loss Megaloblastic Anemias Anemia from chronic blood loss only occurs if the loss is greater than With megaloblastic anemias the cells are challenged to make DNA; the replacement capacity of the bone marrow. If iron stores are depleted, however, RNA production proceeds normally. The cells have slow- iron deiciency anemia can occur. maturing nuclei but have normal maturing cytoplasm. Therefore megaloblastic erythroid precursors grow large before the larger nuclei Anemias of Diminished Erythropoiesis become mature enough to signal division (causing the cell to be larger The anemias of diminished red cell production are heterogeneous and than normal). Examination shows the nucleus to be more immature can be classified according to the underlying mechanism (see Table than the cytoplasm, hence the term “nuclear-cytoplasmic asynchrony.” 29.1). The most common anemias of diminished red cell production The overall nuclear-cytoplasmic asynchrony from the ineffective DNA are the result of ineffective erythrocyte DNA synthesis, commonly caused synthesis produces megaloblastic changes in the bone marrow with by nutritional deficiencies of vitamin B12 (cobalamin) or folate (folic resulting anemia. These defective erythrocytes die prematurely, called acid), coenzymes that are required for nuclear maturation and DNA eryptosis, which decreases their numbers in the circulation and causes synthesis.3 These anemias, also called macrocytic (megaloblastic) anemia. Damaged erythrocytes undergo cell shrinkage, membrane anemias, are characterized by abnormally large erythroid precursors changes (blebbing), and rearrangement of plasma membrane phos- (megaloblasts) in the marrow that mature into large erythrocytes pholipid distribution with eflux of phosphatidylserine (PS). Macrophages (macrocytes). Box 29.1 lists the various causes of megaloblastic anemia. have receptors that recognize surface PS and remove the damaged Other anemias from underproduction of red cells are secondary to erythrocytes from the circulation. renal failure and chronic inlammation. Dietary cause of vitamin B12 deiciency is decreased intake. Vitamin B12, known as cobalamin, is dependent on dietary vitamin B12 intake. Plants and vegetables contain little cobalamin and strictly vegetarian and macrobiotic diets do not provide adequate amounts.4 Another important cause that results in megaloblastic anemia is pernicious anemia, caused by autoimmune destruction of parietal cells that make intrinsic factor.3 Intrinsic factor (IF) is a protein transporter necessary BOX 29.1 CAUSES OF MEGALOBLASTIC for absorption of vitamin B12 in the intestine. The prevalence of folate ANEMIA deiciency has decreased because of food fortiication with folate; however, it does occur among the poor, elderly, and alcoholics, especially in Vitamin B12 Deficiency countries without folate fortiication. Vitamin B12 deficiency also can Decreased Intake result from malabsorption or increased cell turnover and increased Inadequate diet, vegetarianism demand.3 Impaired Absorption Abnormal asynchronous maturation may affect the neutrophil series. Intrinsic factor deficiency Neutrophil precursors create giant metamyelocytes with a tendency to Pernicious anemia have more nuclear lobes (hypersegmented) than normal. The reason Gastrectomy for this transformation is unknown. Other cells throughout the body Malabsorption states also may demonstrate enlargement and nuclear abnormalities. Diffuse intestinal disease (e.g., lymphoma, systemic sclerosis) Pernicious Anemia. Pernicious anemia (PA) is a type of mega- Ileal resection, ileitis loblastic anemia and is caused by vitamin B12 deiciency, which is often Competitive parasitic uptake associated with the end stage of type A chronic atrophic (autoimmune) Fish tapeworm infestations gastritis5 (see Fig. 29.1, C; and Fig. 29.3). Autoimmune gastritis impairs Bacterial overgrowth in blind loops and diverticula of bowel the production of IF, which is required for vitamin B12 uptake from the gut. Pernicious means highly injurious or destructive and relects the Folic Acid Deficiency fact that this condition was once fatal. It most commonly affects individu- Decreased Intake als older than age 30 (60 being the median age of diagnosis) who are Inadequate diet, alcoholism, infancy of Northern European descent; however, it has now been recognized Impaired absorption in all populations and ethnic groups. Malabsorption states PATHOPHYSIOLOGY. The principal disorder in PA is an absence Intrinsic intestinal disease of intrinsic factor (IF). IF is secreted by gastric parietal cells and complexes Anticonvulsants, oral contraceptives with dietary vitamin B12 in the small intestine. The B12-IF complex Increased loss binds to cell surface receptors in the ileum and is transported across Hemodialysis the intestinal mucosa. Deiciency in IF secretion may be congenital; however, it is often Increased Requirement considered an autoimmune (and possibly innate) process directed against Pregnancy, infancy, disseminated cancer, markedly increased hematopoiesis gastric parietal cells. Congenital IF deiciency is a genetic disorder that demonstrates an autosomal recessive inheritance pattern.6 The auto- Impaired Utilization immune form of the disease may have a genetic component, but no Folic acid antagonists genetic pattern of transmission has been identiied.4 PA is also frequently a component of autoimmune polyendocrinopathy, which is a cluster Unresponsive to Vitamin B12 or Folic Acid Therapy of autoimmune diseases of endocrine organs (e.g., chronic autoimmune Metabolic inhibitors of DNA synthesis and/or folate metabolism (e.g., thyroiditis [Hashimoto thyroiditis], type 1 diabetes mellitus, Addison methotrexate) disease, primary hypoparathyroidism, Graves disease, and myasthenia From Kumar V, Abbas A, Aster JC: Robbins & Cotran pathologic basis gravis) that frequently present as comorbidities. Autoimmune thyroiditis of disease, ed 9, Philadelphia, 2015, Saunders. and type 1 diabetes mellitus, in particular, are associated with PA. Other  CHAPTER 29 Alterations of Erythrocyte, Platelet, and Hemostatic Function 933 the parietal cell (see Chapter 9 for a discussion of antigenic mimicry and autoimmune disease). CLINICAL MANIFESTATIONS. PA develops slowly (possibly over 20 to 30 years); 60 years of age is the median age at time of diagnosis. Because of the slow onset of symptoms, PA is usually severe by the time the individual seeks treatment. Early symptoms are often ignored because they are nonspeciic and vague and include infections, mood swings, and gastrointestinal, cardiac, or kidney ailments. When the hemoglobin level has decreased signiicantly (7 to 8 g/dL), the individual experiences the classic symptoms of anemia—weakness, fatigue, paresthesias of the feet and ingers, dificulty walking, loss of appetite, abdominal pains, weight loss, and a sore tongue that is smooth and beefy red secondary to atrophic glossitis. The skin may become “lemon yellow” (sallow) as a result of a combination of pallor and icterus. Hepatomegaly, indicating right-sided heart failure, may be present in the elderly along with splenomegaly, which is nonpalpable. FIGURE 29.3 Bone Marrow Aspirate from Individual with Pernicious Neurologic manifestations result from nerve demyelination that may Anemia. Bone marrow aspirate smear from an individual with megaloblastic red produce neuronal death. The posterior and lateral columns of the spinal blood cell precursors and giant metamyelocytes. The chromatin in the red blood cord also may be affected, causing a loss of position and vibration sense, cell nuclei is more dispersed than that in normal red blood cell precursors at ataxia, and spasticity. The cerebrum also may be involved with manifesta- comparable stages of maturation; the giant metamyelocytes have dispersed nuclear tions of affective disorders, most commonly of the depressive types. chromatin in contrast to a normal metamyelocyte, which has condensed chromatin Low levels of vitamin B12 have been associated with neurocognitive (Wright-Giemsa stain). (From Damjanov I, Linder J, editors: Anderson’s pathology, disorders. Overall, the consequences of vitamin B12 deficiency can include ed 10, St Louis, 1996, Mosby.) encephalopathy, myelopathy, and peripheral and optic neuropathy. An increased prevalence of serum vitamin B12 deficiency has been reported among individuals with Alzheimer disease. Individuals with atrophy and metaplasia of the gastric mucosa associated with PA have an increased risk of gastric carcinoma.4 causes include surgical removal of the stomach, resection of the ileum, EVALUATION AND TREATMENT. Diagnosis of PA is based on clinical and infestation with tapeworms; in addition, various conditions related manifestations and a variety of test results (see Table 29.2), including to increased demand for vitamin B12, such as pregnancy, hyperthyroidism, blood tests, bone marrow aspiration, serologic studies, and gastric biopsy. chronic infection, and disseminated cancer, are associated with PA (see The following tests are used to diagnose PA: (1) moderate to severe Box 29.1). Environmental conditions also may contribute to chronic megaloblastic anemia, (2) leukopenia with hypersegmented granulocytes, gastritis. These include excessive alcohol or hot tea ingestion and smoking. (3) low levels of serum vitamin B12, (4) elevated serum levels of homo- Drugs known as proton pump inhibitors (PPIs) are used to decrease cysteine and methylmalonic acid, and (5) an outpouring of reticulocytes gastric acidity, but also may decrease cobalamin absorption, although and an increase in hematocrit level after about 5 days of parenteral it is not believed that they actually cause PA. Although PA is a benign administration of vitamin B12.4 The presence of circulating antibodies disorder, individuals with type A chronic gastritis also are at risk for against parietal cells and intrinsic factor is also useful in diagnosis.10 developing gastric adenocarcinoma and gastric carcinoid type I. The Gastric biopsy reveals total achlorhydria (absence of hydrochloric acid), incidence of carcinoma in these individuals is 2% to 3%. which is diagnostic for PA because it occurs only in the presence of The presence of PA with autoimmune gastritis (type A chronic this gastric lesion. gastritis) leads to gastric atrophy from destruction of parietal and Replacement of vitamin B12 (cobalamin) is the treatment of choice. zymogenic cells. Individuals with PA commonly have autoantibodies Initial injections of vitamin B12 are administered weekly until the against the gastric H+-K+ ATPase, which is the major protein constituent deiciency is corrected, followed by monthly injections for the remainder of parietal cell membranes. Early in the disease process the gastric of the individual’s life. The effectiveness of cobalamin replacement submucosa becomes iniltrated with inlammatory cells, including therapy is determined by a rising reticulocyte count. Conventional autoreactive T cells. It appears that the T-cell response initiates gastric wisdom and practice assumed that oral preparations were ineffective mucosal injury and triggers the formation of autoantibodies.4 The because there was no IF to facilitate absorption of vitamin B12. However, susceptibility to develop PA (as well as other autoimmune disorders) recent experience has shown that higher doses of orally administered is linked to genetic variants involving the inlammasome, which suggests vitamin B12 are absorbed across the small bowel and are beneicial. a relationship to innate immunity.4 Eventually, the parietal and zymogenic Untreated PA is fatal, usually because of heart failure. Death occurs cells are destroyed and replaced by mucous-containing cells (intestinal after a course of remissions and exacerbations lasting from 1 to 3 years. metaplasia). Gastric mucosal atrophy, in which gastric parietal cells are Since 1926, when replacement therapy began, mortality has been reduced destroyed, results in a deficiency of all secretions of the stomach— signiicantly. Today, death from PA is rare, and any relapses that occur hydrochloric acid, pepsin, and IF. are usually the result of noncompliance with therapy. Initiation of the autoimmune process may be secondary to a past Folate Deficiency Anemia. A deficiency of folic acid results in infection with Helicobacter pylori.7-9 Although active infection with H. a megaloblastic anemia having the same pathologic consequences as pylori is rare in individuals with PA, more than half of these individuals those caused by vitamin B12 deiciency.4 Folate (folic acid) is an essential possess circulating antibodies against this microorganism, suggesting vitamin for RNA and DNA synthesis within the maturing erythrocyte. a history of infection. The current opinion is that in genetically prone Folates are coenzymes required for the synthesis of thymine and purines individuals, antigens expressed by H. pylori mimic the parietal cell H+-K+ (adenine and guanine) and the conversion of homocysteine to ATPase, resulting in production of an antibody that binds and damages methionine. Deicient production of thymine, in particular, affects cells 934 UNIT VIII The Hematologic System undergoing rapid division (e.g., bone marrow cells undergoing eryth- made to maintain adequate intake. An intake of folate (400 mcg/day) ropoiesis). Humans are totally dependent on folate dietary intake to is recommended as a measure to reduce the risk of heart disease and meet the daily requirement of 50 to 200 mcg/day. Increased amounts stroke. The symptoms of vitamin B12 deficiency also respond to folate are required for pregnant and lactating females. Absorption of folate therapy; however, it is essential to exclude vitamin B12 deficiency as occurs primarily in the upper small intestine and does not depend on the cause of anemia because folate does not prevent the neurologic the presence of any other facilitating factor, such as IF. After absorption, deicits (and may even exacerbate symptoms) found with vitamin B12 folate circulates through the liver, where it is stored. Folate deiciency deiciency.4 is more common than B12 deficiency, particularly in alcoholics and individuals with chronic malnourishment. Alcohol interferes with folate Microcytic-Hypochromic Anemias metabolism in the liver, causing a profound depletion of folate stores. The microcytic-hypochromic anemias are characterized by abnormally Fad diets and diets low in vegetables also may cause folate deiciency small erythrocytes that contain unusually reduced amounts of hemo- because of the absence of plant sources of folate. It is estimated that globin (see Fig. 29.1, B). The most common nutritional disorder of at least 10% of North Americans have a folate deiciency, although microcytic-hypochromic anemia—iron deficiency anemia—is discussed the incidence has been on the decrease in the United States since here; others are discussed in Chapter 31. the fortiication of foods with folate and the increased use of folate Iron Deficiency Anemia. Iron deficiency anemia (IDA) is the supplements. Box 29.1 lists the various causes of folic acid deiciency most common type of nutritional disorder worldwide, occurring in including (1) decreased intake, (2) increased requirement, and (3) both developing and developed countries and affecting as many as impaired utilization. one-ifth of the world population. The prevalence of IDA is higher in PATHOPHYSIOLOGY. Impaired DNA synthesis secondary to folate developing countries, but IDA is common in the United States, par- deiciency results in megaloblastic cells with clumped nuclear chromatin. ticularly in toddlers, adolescent girls, and women of childbearing age.4 Anemia may result from apoptosis of erythroblasts in the late stages Populations also at increased risk for IDA include individuals living in of erythropoiesis. In addition to anemia, folate deiciency in pregnant poverty; infants consuming cow’s milk, which has poor bioavailability women is associated with neural tube defects of the fetus. Folate is of iron; older individuals ingesting restricted diets; and teenagers eating necessary for the reduction of circulating levels of homocysteine, a risk poor (junk-food) diets. The daily requirement of iron is 7 to 10 mg for factor for the development of atherosclerosis (see Chapter 33); thus a adult men and 7 to 20 mg for adult women. The bioavailability of iron folate deiciency increases the risk for developing coronary artery disease. is especially important because only about 10% to 15% of ingested A deficiency of folate also is implicated in the development of cancers, iron is absorbed.4 Men typically ingest more iron than women, and speciically colorectal cancers. premenopausal women, particularly during pregnancy, have an increased CLINICAL MANIFESTATIONS. Clinical manifestations are similar requirement. Increased requirement is an important cause of iron to the cachectic, malnourished appearance of individuals with PA. deiciency in growing infants, children, and adolescents. The causes of Speciic symptoms include severe cheilosis (scales and issures of the IDA include (1) dietary deiciency, (2) impaired absorption, (3) increased lips and corners of the mouth), stomatitis (inlammation of the mouth), requirement, and (4) chronic blood loss. Impaired absorption can occur and painful ulcerations of the buccal mucosa and tongue, characteristic in sprue, disorders involving alterations of fat absorption, and chronic of burning mouth syndrome. Burning mouth syndrome may be secondary diarrhea.4 Other causes for both genders include use of medications to a large number of disorders (e.g., extremely dry mouth, infection, that cause GI bleeding (such as aspirin or nonsteroidal antiinflammatory autoimmune disease, nutritional deiciencies, and other conditions). drugs [NSAIDs]); surgical procedures that decrease stomach acidity, The mechanisms underlying folate deiciency as a cause remain unknown. intestinal transit time, and absorption (e.g., gastric bypass); and eating Gastrointestinal (GI) symptoms may be present and include dysphagia disorders, such as pica, which is the craving and eating of nonnutritional (dificulty swallowing), latulence, and watery diarrhea, as well as substances, such as dirt, chalk, and paper. The clinical manifestations histologic and roentgenographic changes of the GI tract suggestive of are mostly related to the reduction in adequate levels of hemoglobin. sprue (a chronic malabsorption syndrome). Undiagnosed inlammatory Females have a higher incidence of hypoferremia (13.9%) than do bowel disease (e.g., Crohn disease, ulcerative colitis) may be the underly- males (8.3%), as well as IDA (4% to 6% in females and 4% in males). ing cause of folate malabsorption in some individuals, and folate The incidence peaks in females during their reproductive years and deficiency may suppress proliferation of the intestinal mucosa, leading decreases after menopause. Those at highest risk are black females living to exacerbation of gastrointestinal damage. Neurologic manifestations, in urban poverty.11 Males have a higher incidence during childhood such as those that occur in PA, are generally not seen in folate deficiency and adolescence, with a decrease occurring during young adulthood anemia. Any neurologic symptoms are usually caused by a thiamine and an increase during late adulthood. An increased prevalence of iron deiciency, which often accompanies folate deiciency. deiciency has been observed in overweight children, adolescents, women, EVALUATION AND TREATMENT. Evaluation of folate deficiency is and those undergoing bariatric surgery.12 based on measurement of serum folate levels and documentation of In developed countries, pregnancy and a continuous loss of blood symptoms. Treatment requires daily oral administration of folate are the most common causes of IDA. A blood loss of 2 to 4 mL/day (1 preparations until adequate blood levels are obtained and clinical to 2 mg of iron) is enough to cause IDA. Menorrhagia (excessive symptoms are reduced or eliminated; 1 mg daily is suficient for most menstrual bleeding) causes primary IDA in females. Males may experience individuals, although persons with alcoholism may require 5 mg/day. bleeding as a result of ulcers, hiatal hernia, esophageal varices, cirrhosis, Prophylactic dosages of 0.1 to 0.4 mg/day are sometimes given during hemorrhoids, ulcerative colitis, or cancer. An occult bleeding source, pregnancy. Parenteral administration of folic acid (citrovorum factor such as gastrointestinal cancer or other lesion, can lead to IDA; the or leucovorin) generally is not used except in situations in which an astute clinician who understands the cause of IDA may be a cancerous individual has been using drugs that inhibit dihydrofolate reductase. lesion can save a life. After administration of folate, the manifestations of anemia disappear Children in developing countries often are affected by chronic parasite within 1 to 2 weeks. infestations that result in intestinal blood and iron loss that outpaces After the folate deficiency has been corrected, long-term treatment dietary intake.13 Treatment of helminth infections results in an improve- with folate is not necessary if the appropriate dietary adjustments are ment in the anemia as well as in appetite and growth. H. pylori infections  CHAPTER 29 Alterations of Erythrocyte, Platelet, and Hemostatic Function 935 also have been found to cause IDA of unknown origin, although H. pylori impairs iron uptake. Iron deiciency anemia is associated with an increased absorption of other elements such as lead (Pb) and cadmium (Cd).14 Heavy exposure to Pb and Cd causes hypochromic-microcytic anemia.15 Treatment of the iron deiciency is associated with a decrease in lead levels. Deiciencies in vitamins C, B1, and B6 may enhance sensitiv- ity toward Cd and Pb toxicity.16 PATHOPHYSIOLOGY. IDA is a hypochromic-microcytic anemia. A Anemia occurs when iron stores are depleted. With inadequate dietary intake or excessive blood loss, there is no intrinsic dysfunction in iron metabolism; however, both conditions deplete iron stores and reduce hemoglobin synthesis. With metabolic or functional iron deiciency, various metabolic disorders lead to either insufficient iron delivery to bone marrow or impaired iron use within the marrow. Paradoxically, iron stores may be sufficient but delivery is inadequate to maintain heme synthesis, thus producing a functional or relative iron deiciency. Iron in the form of hemoglobin is in constant demand by the body. Iron is recyclable; therefore the body maintains a balance between iron B that is contained in hemoglobin and iron that is in storage and available for future hemoglobin synthesis (see Chapter 28). Blood loss disrupts this balance by creating a need for more iron, thus depleting the iron stores more rapidly to replace the iron lost from bleeding. Iron also contributes to immune function by regulating immune effector mechanisms (i.e., cytokine activities [interferon-gamma (IFN-γ)], nitric oxide formation, and T-cell proliferation). Acquired hypoferremia may be part of the body’s response to infection. Anemia can be part of the nonspecific acute phase response to any type of inflammation C of suficient degree. Many pathogens require iron for survival; thus FIGURE 29.4 Manifestations of Iron Deficiency Anemia. A, Pallor and iron hypoferremia would hamper their growth. However, the precise beneits deficiency. Pallor of the skin, mucous membranes, and palmar creases in an individual or detriments of iron deiciency and immunity are still controversial. with a hemoglobin level of 9 g/dL. Palmar creases become as pale as the surrounding IDA occurs when the demand for iron exceeds the supply and develops skin when the hemoglobin level approaches 7 g/dL. B, Koilonychia. The nails are slowly through three overlapping stages. In stage I, the body’s iron stores concave, ridged, and brittle. C, Glossitis. Tongue of individual with iron deficiency are depleted. Erythropoiesis proceeds normally, with the hemoglobin anemia has bald, fissured appearance caused by loss of papillae and flattening. content of erythrocytes remaining normal. In stage II, iron transportation (From Hoffbrand AV, Pettit JE, Vyas P: Color atlas of clinical hematology, ed 4, to bone marrow is diminished, resulting in iron-deicient erythropoiesis. London, 2009, Mosby; B courtesy Dr. S.M. Knowles.) Stage III begins when the small hemoglobin-deicient cells enter the circulation to replace the normal aged erythrocytes that have been removed from the circulation. The manifestations of IDA appear in stage III when there is depletion of iron stores and diminished hemo- lesions is not well understood, but the lesions have the potential to globin production. become cancerous. CLINICAL MANIFESTATIONS. Symptoms of IDA begin gradually, Nonheme iron is a component of many enzymes in the body (e.g., and individuals usually do not seek medical attention until hemoglobin cytochromes, myoglobin, catalases, peroxidases), particularly those levels have decreased to about 7 to 8 g/dL. Early symptoms are nonspeciic involved in the metabolism of amine neurotransmitters, the reduction and include fatigue, weakness, shortness of breath, and pale earlobes, of nucleotides, and the biosynthesis of methionine. Abnormalities and palms, and conjunctivae (Fig. 29.4, A). deficiencies of iron-dependent enzymes may account for many of the As the condition progresses and becomes more severe, structural clinical manifestations of IDA. Individuals with IDA also exhibit gastritis, and functional changes occur in epithelial tissue (see Fig. 29.4). The neuromuscular changes, irritability, headache, numbness, tingling, and fingernails become brittle, thin, coarsely ridged, and “spoon-shaped” vasomotor disturbances. Gait disturbances are rare. The pathogenesis or concave (koilonychia) as a result of impaired capillary circulation of neurologic symptoms is unknown but may be caused by hypoxia in (Fig. 29.4, B). IDA also is associated with unexplained burning mouth already compromised cerebral vessels. In the elderly, mental confusion, syndrome, as was discussed for folate deiciency. Tongue papillae atrophy memory loss, and disorientation are often associated with anemia and and cause soreness along with redness and burning (glossitis) (Fig. may be wrongly perceived as “normal” events related to aging. 29.4, C). The degree of pain experienced is directly associated with the Iron deiciency in children is associated with numerous adverse amount of iron deiciency, and these changes can be reversed within 1 health-related manifestations, especially cognitive impairment, which to 2 weeks of iron replacement therapy. Individuals also experience may be long-lasting and even irreversible (see Chapter 31). Teens with dryness and soreness in the epithelium at the corners of the mouth, a history of iron deiciency as infants are likely to score lower on cognitive known as angular stomatitis. Dificulty in swallowing is associated with and motor tests, even if the iron deiciency was identiied and treated an esophageal “web,” a thin, concentric, smooth extension of normal in infancy. esophageal tissue consisting of mucosa and submucosa at the juncture EVALUATION AND TREATMENT. Initial evaluation is based on clinical between the hypopharynx and esophagus. The duration of iron deiciency symptoms and decreased levels of hemoglobin and hematocrit. Anemia required for web formation is uncertain. Dysphagia also is exacerbated appears only when iron stores are depleted and is accompanied by lower by hyposalivation. The pathophysiology associated with these epithelial than normal serum iron, ferritin, and transferrin saturation levels.4 936 UNIT VIII The Hematologic System Laboratory indings for IDA are included in Table 29.2. Iron stores may TABLE 29.4 UNDERLYING CAUSES be measured directly by bone marrow biopsy and iron staining or indirectly by laboratory tests for serum ferritin level, transferrin satura- OF ACD tion, or total iron-binding capacity. Serum ferritin is a widely accepted ESTIMATED and available measurement of iron status that has been used for the ASSOCIATED DISEASES PREVALENCE (%) past 25 years; 1 mcg/L serum ferritin corresponds to 8 to 10 mg or Infections 18–95 120 mcg of storage iron per kilogram body weight. A limitation on Acute and chronic; viral infections including interpretation of serum ferritin levels is that values may be elevated HIV infection, bacterial, parasitic, fungal independently of iron status during acute or chronic inflammation, Cancer 30–77 malignancy, liver disease, or alcoholism. A sensitive indicator of heme Hematologic, solid tumor synthesis is the amount of free erythrocyte protoporphyrin (FEP) within Autoimmune 8–71 erythrocytes. A test that determines the concentration of soluble fragment Rheumatoid arthritis, systemic lupus transferrin receptor differentiates primary IDA from IDA that is associated erythematosus and connective tissue with chronic disease. diseases, vasculitis, sarcoidosis, inflammatory An indicator of iron levels is the level of serum transferrin receptor bowel disease (sTfR). Transferrin receptors are membrane glycoproteins that bind Chronic rejection after solid-organ transplantation 8–70 circulating transferrin for transport into cells. Soluble forms of the CKD and inflammation 25–30 receptor are found in serum. The ratio of serum levels of transferrin receptor to ferritin (R/F) estimates body iron stores and differentiates ACD, Anemia of chronic disease; CKD, chronic kidney disease. primary IDA from anemia secondary to chronic disease. A major draw- Data from Weiss G, Goodnough LT: N Engl J Med 352(10):1011– back, however, is the lack of proper standardization for the sTfR assay. 1023, 2005. The first step in treatment of IDA is to identify and eliminate sources of blood loss.17 With ongoing bleeding, any replacement therapy is likely to be ineffective. Iron replacement therapy is required and very not progress. Individuals may be asymptomatic or the anemia may effective. Initial doses are 150 to 200 mg/day. Hematocrit levels should be a coincidental clinical inding. ACD shares features observed in improve within 1 to 2 months of therapy; however, the serum ferritin individuals with chronic obstructive pulmonary disease; in persons level is a more precise measurement of improvement and total body with critical illnesses after acute events such as major surgery, severe stores of iron. Once the serum ferritin level reaches 50 mcg/L, adequate trauma, myocardial infarction, and sepsis; and in the elderly. It shares replacement of iron has occurred. A rapid decrease in fatigue, lethargy, some features with anemia noted in multiple myeloma and malignant and other associated symptoms is generally seen within the irst month lymphoma.18 of therapy. Replacement therapy usually continues for 6 to 12 months ACD is one of the most common conditions encountered in medicine after the bleeding has stopped but may continue for as long as 24 and is probably only secondary to IDA in overall incidence. In individuals months. Menstruating females may need daily oral iron replacement older than age 65, anemia is present in 10% of those who live in the therapy (325 mg/day) until menopause. community and in more than 50% of those who reside in nursing Parenteral iron replacement is used in instances of uncontrolled homes, with two-thirds of these cases being ACD or unexplained anemia. blood loss, intolerance to oral iron, intestinal malabsorption, or poor The elderly may be predisposed to ACD related to age-associated adherence to oral therapy. Iron dextran has been the only parenteral hematopoietic restriction and generally have increased concentrations agent available in the United States. Intramuscular injection is the of inlammatory cytokines, which play a signiicant role in the develop- recommended method; however, intravenous (IV) administration is ment of ACD. The elderly who present with characteristics of ACD generally preferred because of the ability to administer larger doses. without an underlying malignancy or inlammatory condition are A significant concern in the use of IV dextran is the potential for described as having primary defective iron utilization syndrome. severe anaphylactic reaction. Delayed allergic reactions are also major PATHOPHYSIOLOGY. ACD results from a combination of (1) concerns. decreased erythrocyte life span, (2) suppressed production of erythro- Medications that have recently been approved for parenteral therapy poietin, (3) ineffective bone marrow erythroid progenitor response to in treating IDA are sodium ferric gluconate complex in sucrose (Ferrlecit) erythropoietin, and (4) altered iron metabolism and iron sequestration and iron sucrose injection (Venofer). Iron dextran is recommended as in macrophages.19 During chronic inflammation a large variety of the irst choice in spite of its higher rate of adverse reactions. For cytokines are released by lymphocytes, macrophages, and the affected individuals who are intolerant of iron dextran, the two newer agents tissue.20 These include tumor necrosis factor-alpha (TNF-α), IFN-γ, are safe and effective alternatives. Drawbacks to their use include higher interleukin-1β (IL-1β), IL-3, and IL-621 (also see Chapters 7 and 8). cost and the need for multiple infusions. Impaired iron metabolism is partially the result of iron sequestration.22 IL-6 in particular affects hepatocytes and increases the release of the Anemia of Chronic Disease peptide hepcidin, which regulates the activity of ferroportin. Ferroportin Anemia of chronic disease (ACD, also called anemia of inflammation is the primary transporter for the export of iron from macrophages to [AI]) is a mild to moderate anemia resulting from decreased erythro- the plasma, and increased levels of hepcidin result in decreased ferroportin poiesis and impaired iron utilization in individuals with conditions of activity and suppression of iron release (Fig. 29.5). chronic systemic disease or inlammation (e.g., infections, cancer, and Erythrocyte destruction is the result of eryptosis (described earlier chronic inlammatory or autoimmune diseases). ACD is a common in this chapter). Most of the diseases responsible for ACD damage type of anemia in hospitalized individuals. Table 29.4 lists the possible erythrocytes, resulting in increased efflux of plasma membrane phos- causes of ACD. This form of anemia also is commonly noted in the phatidylserine and susceptibility to removal by macrophages. Normal presence of congestive heart failure (CHF). The anemia develops after iron transport by transferrin also may be decreased as a result of 1 to 2 months of disease activity. The initial severity is related to that competitive iron binding by inflammation-related increases in the levels of the underlying disorder but, although persistent, it usually does of circulating lactoferrin and apoferritin. Lactoferrin is a member of  CHAPTER 29 Alterations of Erythrocyte, Platelet, and Hemostatic Function 937 Ingestion/digestion of iron sources from food Absorption by GI system and bound Fe!!! Fe!! with gastroferrin for transport Gastroferrin Storage as Apoferritin ferritin Lactoferrin Fe!! Chronic hemosiderin inflammation/ infection Transferrin Activates Macrophage (LFFe) TrFe Removal by Blood plasma MPS system Cytokines Normocytic- normochromic anemia Decreased Increased Erythropoiesis production destruction Erythrocytes FIGURE 29.5 Pathophysiology of Anemia of Chronic Disease. Normal iron metabolism is indicated by the blue arrows. Abnormal mechanisms that are instrumental in the development of anemia of chronic inflammation are indicated by red arrows. See discussion in text. GI, Gastrointestinal; LFFe, lactoferrin bound to iron; MPS, mononuclear phagocyte system; TrFe, transferrin bound to iron. the transferrin family of nonheme iron-binding glycoproteins, and under in the bone marrow, thus resulting in diminished bone marrow eryth- normal conditions is present in the blood in only small amounts. During ropoiesis.24 Uremic toxins (e.g., uric acid, sulfates, phosphates) that inflammation neutrophils release lactoferrin to bind iron and reduce increase in the blood secondarily to renal failure may suppress bone its availability for bacteria. However, the afinity of iron for lactoferrin marrow function and damage erythrocytes, which undergo eryptosis. is 260 times greater than that for transferrin. Lactoferrin-bound iron Platelet function also may be defective in these individuals, which results is removed by the mononuclear-phagocyte system and converted into in chronic bleeding and loss of erythrocytes. ferritin, the storage form of iron. Apoferritin also has a higher affinity Anemia may arise from the direct action of bacterial toxins. For for iron and affects available iron in a similar manner. example, Clostridium perfringens (gas gangrene and a cause of food The erythropoietic defect in ACD is failure to increase erythropoiesis poisoning) produces an alpha toxin. This toxin has enzymatic activity in response to decreased numbers of erythrocytes. In part, decreased (phospholipase C, sphingomyelinase) that disrupts the membrane of erythropoiesis results from diminished production of erythropoietin cells. If the cells are erythrocytes, hemolysis will result. by the kidneys. The kidney is frequently affected by chronic inlammatory CLINICAL MANIFESTATIONS. The anemia of ACD is usually in the processes caused by circulating immune complexes and other factors mild to moderate range, with few additional complications. If hemoglobin that deposit in the kidney and activate secondary inlammatory mecha- levels drop signiicantly, clinical manifestations of IDA appear. nisms. In addition, the failure in erythropoiesis may relect decreased EVALUATION AND TREATMENT. Morphologically, ACD is initially responsiveness of erythroid progenitors to erythropoietin. Decreased normocytic-normochromic, but as the condition persists it becomes availability of iron would diminish the rate of erythropoiesis. Proliferation hypochromic and microcytic. ACD is characterized by abnormal iron of erythroid cells is also inhibited by proinlammatory cytokines, metabolism with low levels of circulating iron (less than 60 mcg/dL) especially TNF-α, IFN-γ, and IL-1β. TNF-α also directly induces apoptosis and reduced levels of transferrin. The most signiicant inding of ACD of erythroid progenitors, thus diminishing the number of responsive is very high total body iron storage, although inadequate iron is released cells. In individuals who had anemia secondary to rheumatoid arthritis, from the bone marrow for erythropoiesis. Very often the irst indication the bone marrow contained elevated levels of IL-3, which correlated of ACD is a failure to respond to conventional iron replacement therapy. with diminished expression of integrins on the surface of cells of the Levels of erythropoietin are generally lower than expected for the degree erythroid series.23 Loss of integrins may prevent adequate interaction of anemia. The affected individuals also frequently present with low or with stromal cells and matrix proteins and inhibit erythropoiesis. normal total iron-binding capacity (TIBC), normal or high serum ferritin Anemia associated with chronic renal failure may result from a variety levels, and low concentrations of soluble transferrin receptor (blood of simultaneous mechanisms. Damage to the kidney affects the secretion test indings are listed in Table 29.2). Occasionally it may be dificult to of erythropoietin, a necessary hormone for production of erythrocytes differentiate ACD from IDA; however, measurement of sTfR (key receptor 938 UNIT VIII The Hematologic System BOX 29.2 MAJOR CAUSES OF APLASTIC ANEMIA Acquired Methylphenylethylhydantoin Idiopathic Carbamazepine Acquired stem cell defects Penicillamine Immune mediated Gold salts Chemical Agents Physical Agents Dose Related Whole-body irradiation Alkylating agents Viral infections Antimetabolites Hepatitis (unknown virus) Benzene Cytomegalovirus infections Chloramphenicol Epstein-Barr virus infections A Inorganic arsenicals Herpes zoster (varicella zoster) Idiosyncratic Inherited Chloramphenicol Fanconi anemia Phenylbutazone Telomerase defects Organic arsenicals From Kumar V, Abbas A, Aster JC: Robbins & Cotran pathologic basis of disease, ed 9, Philadelphia, 2015, Saunders. (Box 29.2). The incidence of AA is relatively rare (annual rate of two to ive new cases per million per year). The incidence in developing countries is somewhat higher and may be related to greater exposure to certain chemicals known to cause AA. The incidence is bimodal, with one peak occurring between 15 and 25 years of age and a second B peak occurring in individuals older than age 60. AA is equally distributed FIGURE 29.6 Aplastic Anemia. A, Normal bone marrow of an adult. Hema- between genders. topoietic cells account for approximately 40% of marrow’s cellularity. B, There is AAs are the most common type of bone marrow aplasia, with a marked reduction in hematopoietic cells with expansion of fat cells. (From Damjanov idiopathic AA (primary acquired) accounting for approximately 75% I, Linder J: Pathology: a color atlas, St Louis, 2000, Mosby.) of all conirmed cases and being an autoimmune disease. Secondary AA, which accounts for approximately 15% of cases, is caused by a variety of known chemical agents and ionizing radiation. Chemical for iron acquisition by erythroid cells) may be useful. Levels of sTfR do agents and drug effects are included in Table 29.5. The development not respond to iron supplementation in ACD but do so in IDA. of AA with use of these agents is generally dose related, and the effect Use of erythropoietin in treatment of ACD associated with arthritis, can be controlled with diminished dosages. In other instances, AA might malignancies, and acquired immunodeiciency syndrome (AIDS) has met develop after the use of small amounts of these drugs (idiosyncratic), with limited success. Individuals with severe anemia secondary to chronic with the anemia following a severe, rapid, irreversible progression. Liver kidney disease (CKD) can be treated successfully with erythropoietin disease (seronegative hepatitis) is also recognized as a cause of AA. and treatments to increase iron stores.25 However, the optimal degree AA is constitutional or familial in origin or is associated with one of restoration of hemoglobin levels (a measure of anemia) has not or more somatic abnormalities in approximately 5% to 10% of affected been determined; achievement of normal levels increases the risk of individuals. A subset of these is found to have defective telomerase hypertension, stroke, and death.26 Transfusion of critically ill individuals RNA, resulting in shortened telomeres. This abnormality also is found may worsen the outcome and increase morbidity and mortality.27 The in some individuals with idiopathic AA. principal treatment is alleviation of the underlying disorder. Individu- Total body irradiation also causes AA and in certain instances may als who have ACD but demonstrate no evidence of inlammatory or be used therapeutically for this effect. Infections are also known to infectious conditions are screened for the presence of malignancies. cause AA, with viruses being the most common agent. These include infections with the human immunodeiciency virus (HIV), Epstein-Barr Aplastic Anemia virus (EBV), and hepatitis (non-A, non-B, non-C, and non-G forms Aplastic anemia (AA) is a hematopoietic failure or bone marrow aplasia of the virus). Persistent parvovirus B19 infection also has been identiied characterized by reduction in the effective production of mature cells as producing bone marrow failure resulting in AA. Parvovirus B19 has by the bone marrow, causing peripheral pancytopenia (anemia, neu- been identiied as the cause of aplastic crisis in children who have sickle tropenia, and thrombocytopenia), which is a reduction or absence of cell hemoglobinopathies and hereditary spherocytosis. all three blood cell types (Fig. 29.6). Although the pathogenesis is not Another condition associated with AA is pure red cell aplasia (PRCA), clearly defined, mechanisms include immune-mediated destruction of in which only the erythrocytes are affected. PRCA is a rare disorder and hematopoietic stem cells or their progenitors at various stages of has been associated with autoimmune, viral, and neoplastic (leukemias) differentiation.28 disorders; iniltrative disorders of the bone marrow (myeloibrosis); renal The known causes of AA are from chemicals and drugs, physical failure; hepatitis; mononucleosis; and systemic lupus erythematosus. It agents, or unpredictable exposures; AA can be inherited or idiosyncratic also is a well-recognized but infrequent complication of allogeneic bone  CHAPTER 29 Alterations of Erythrocyte, Platelet, and Hemostatic Function 939 TABLE 29.5 ANEMIAS SECONDARY TO DRUG EFFECTS DRUG HEMOLYTIC MEGALOBLASTIC SIDEROBLASTIC APLASTIC Antibiotics Amphotericin B X Trimethoprim-sulfamethoxazole (Bactrim) X Chloramphenicol (Chloromycetin) XX XXXX Erythromycin X X Sulfisoxazole (Gantrisin) X Penicillin XXX X Sulfanilamide/Sulfonamides XX X, X* Streptomycin X X Anticonvulsants Phenytoin (Dilantin) XXX XXX, X* Mephenytoin XXX XXX Primidone (Mysoline) XX Phenobarbital XX Trimethadione (Tridione) XXX Antiinflammatories ASA (aspirin) X* Colchicine X? Gold compounds XX Ibuprofen (Motrin) X X Indomethacin (Indocin) X Phenacetin XXX X Phenylbutazone XX, X* Antihypertensives/Diuretics Methyldopa (Aldomet) XXX Acetazolamide (Diamox) X Thiazides X Tranquilizers Chlordiazepoxide (Librium) X Chlorpromazine (Thorazine) XX X Meprobamate X Oral Hypoglycemics Chlorpropamide (Diabinese) X Tolbutamide (Orinase) X, X* Immunosuppressants Azathioprine (Imuran) X X* Cyclosporine X Continued 940 UNIT VIII The Hematologic System TABLE 29.5 ANEMIAS SECONDARY TO DRUG EFFECTS—cont’d DRUG HEMOLYTIC MEGALOBLASTIC SIDEROBLASTIC APLASTIC Miscellaneous Agents Benzene XX XX Cimetidine (Tagamet) X Heparin X* Potassium perchlorate XX Quinine/quinidine XX Acetaminophen (Tylenol) X X Antituberculosis Agents INH (isoniazid) XX PASA (para-aminosalicylic acid) XX X Pyridium (phenazopyridine HCl) XX ASA, Acetylsalicylic acid; X, rare number of reported cases; XXXX, substantial number of reported cases; XX and XXX, intermediate number of reported cases; X*, “pure red cell” aplasia; X?, uncertain. marrow transplantation, particularly when there is donor-recipient ABO to be the main culprits, although the causative antigen has yet to be mismatch. A thymoma o