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PATHOPHYSIOLOGY AND MANIFESTATIONS
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Effects on Oxygen Transport
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The clinical manifestations of anemia are a function of the degree of tissue hypoxia and the etiology and pathogenesis of the specific anemia (e.g., splenomegaly characteristic of hereditary spherocytosis, neurologic degeneration, or gastric atrophy of pernicious anemia). Decreased oxygen-carrying capacity mobilizes compensatory mechanisms designed to prevent or ameliorate tissue hypoxia. Red cells also transport carbon dioxide from tissues to the lungs and help distribute nitric oxide throughout the body (Chap. 50), but transport of these gases does not appear to be dependent on the concentration of red cells in the blood and is normal in anemic patients. Tissue hypoxia occurs when the pressure of oxygen in the capillaries is too low to provide cells with enough oxygen for cell metabolic needs. In an average person, the red cell mass must provide the total body tissues with approximately 250 mL/min of oxygen to support life. The oxygen-carrying capacity of normal blood is 1.34 mL per gram of hemoglobin (approximately 200 mL/L of normal blood) and cardiac output is approximately 5000 mL/min; thus, 1000 mL/min of oxygen is available at the tissue level. Extraction of one-fourth of this amount reduces the oxygen tension of 100 torr in the arterial end of the capillary to 40 torr in the venous end. This partial extraction ensures the presence of sufficient diffusion pressure throughout the capillaries to provide all cells with enough oxygen for the cell’s metabolic needs (Fig. 34–1). In anemia, extraction of the same amount of oxygen leads to greater hemoglobin desaturation and lower oxygen tension at the venous end of the capillary. The resulting hypoxia in the immediate vicinity initiates a number of compensatory, and frequently symptomatic, adjustments in the supply of blood and oxygen.
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Hypoxia-Inducible Transcription Factors
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Hypoxia-inducible transcription factor (HIF)-1 and its homologue with tissue-restricted expression, HIF-2, play a central role in the body’s response to hypoxia (Chaps. 32 and 57). HIF-1 was first identified as a factor regulating the transcriptional activity of the erythropoietin (EPO) gene (Chap. 32).1 The essential role of this transcriptional factor in global regulation of protection against hypoxia soon became clear. Its actions include respiratory control, transcriptional regulation of glycolytic enzyme genes, angiogenesis, and energy metabolism.2,3,4 The prediction that degradation of the hypoxia-regulated subunit of HIF-1 (HIF-1α) is controlled by an enzyme sensitive to the presence or absence of oxygen5 proved to be prescient. Thus, HIF’s downregulation is mediated by two principal negative regulators: von Hippel-Lindau tumor suppressor (VHL) and prolyl hydroxylase domain-containing protein 2 (PHD2). Chapter 32 describes the current knowledge of hypoxia sensing in greater detail; however, it is now clear that HIF-2, not HIF-1, is the major regulator of EPO production (Chap. 32). Tissue-specific factors are responsible for tissue-specific mobilization of the compensatory mechanisms listed below that permit survival under hypoxic conditions. Figure 34–2 outlines the regulation of some physiologic processes by hypoxia.
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Decreased Oxygen Consumption
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Energy metabolism at the optimal oxygen supply is sustained by energy-efficient oxidative phosphorylation. In hypoxia, energy is produced by less-efficient glycolysis accomplished by upregulation of transcription of glycolytic enzyme genes4 and increased glucose transport, a process known as the Pasteur effect. The Pasteur effect and its exception in the metabolism observed in malignant tissue, referred to as the Warburg effect, are both explained at the molecular level by changes in HIF-1 levels.4,6,7,8
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Decreased Oxygen Affinity
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Efficient increase in tissue oxygen delivery is accomplished by decreasing the affinity of hemoglobin for oxygen (right-shifted hemoglobin oxygen dissociation curve). This action permits increased oxygen extraction from the same amount of hemoglobin (Chap. 49).9 Acutely, a very small shift in pH produces a large effect on the dissociation curve because of the Bohr effect (described by Danish physician Christian Bohr in 1904: “hemoglobin’s oxygen binding affinity is inversely related both to acidity and to the concentration of carbon dioxide”).10 In chronic anemia, increased oxygen tissue delivery is accomplished by increased amounts of 2,3-bisphosphoglycerate (Chap. 47).9 The increased synthesis of 2,3-bisphosphoglycerate in anemia is accomplished by increasing the intracellular pH of red cells (Chap. 47) by respiratory alkalosis resulting from increased respiration. This effect is clearly demonstrated in individuals with high-altitude hypoxemia.11
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Increased Tissue Perfusion
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The effect of decreased oxygen-carrying capacity on the tissue tension of oxygen can be compensated acutely by increasing tissue perfusion locally via changing vasomotor activity and, in the long run, by enhanced tissue angiogenesis.2 Because in chronic anemia the blood volume is not changed (Fig. 34–3),12 increased tissue perfusion is organ selective, accomplished by shunting the blood from nonvital donor-tissue areas to oxygen-sensitive essential recipient organs. In acute anemia, the major donor areas for redistribution of blood are the mesenteric and iliac beds.13 In chronic anemia in humans, the donor areas are the cutaneous tissue14 and the kidneys.15 Vasoconstriction and oxygen deprivation in the skin cause the characteristic pallor of anemia. In the kidneys, the oxygen supply under normal conditions exceeds oxygen demands. The arteriovenous oxygen difference in the kidney is as low as 1.4 mL/dL (compared with the myocardium, where the difference can be as high as 20 mL/dL), indicating that even a severe reduction in kidney blood perfusion can be tolerated. Nevertheless, enough renal hypoxia must be present to activate HIF-2 and stimulate increased EPO production and erythropoiesis (Chap. 32). The effect on renal excretory mechanisms is slight because the reduction in renal blood flow is offset by a high plasmacrit. Even in severe anemia in which renal blood flow is reduced by almost 50 percent, the total renal plasma flow is only moderately reduced. Thus, organs with the most pressing need for oxygen, such as the myocardium and brain, are largely unimpeded by a moderate reduction in oxygen-carrying capacity, whereas in other tissues severe anemia leads to tissue hypoxia, with some tissue-specific consequences such as retinal hemorrhages.16
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Increased Cardiac Output
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Increased cardiac output is a metabolically expensive compensatory device.17 It decreases the fraction of oxygen that must be extracted during each circulation, thereby maintaining higher oxygen pressure. Because the viscosity of blood in anemia is decreased and selective vascular dilatation decreases peripheral resistance, high cardiac output can be maintained without any increase in blood pressure.18 In an otherwise healthy person, a measurable increase in resting cardiac output does not occur until hemoglobin concentration is less than 7 g/dL, and clinical signs of cardiac hyperactivity usually are not present until hemoglobin concentration reaches even lower levels.19
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Signs of cardiac hyperactivity include tachycardia, increased arterial and capillary pulsation, and hemodynamic “flow” murmurs.20 Murmurs usually are heard during systole. Murmurs and bruits have been described in many regions, such as over the jugular vein, the closed eye, and the parietal region of the skull, and may be sensed by the patient as roaring in the ears (tinnitus), especially at night. They disappear promptly after the hemoglobin concentration is restored to normal.20 The myocardium tolerates a prolonged period of sustained hyperactivity. However, angina pectoris and high-output failure may supervene if anemia is so severe that it exceeds myocardial oxygen demands or if the patient has coronary artery disease. Cardiomegaly, pulmonary congestion, ascites, and edema have been observed, and they require prompt treatment with oxygen and transfusion of packed red cells.
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Increased Pulmonary Function
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Significant anemia leads to a compensatory increase in respiratory rate that decreases the oxygen gradient from ambient air to alveolar air and increases the amount of oxygen available to oxygenate a greater than normal cardiac output. Consequently, exertional dyspnea and orthopnea are characteristic clinical manifestations of moderate to severe anemia.19,20,21,22
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Increased Red Cell Production
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The most appropriate response to anemia is a compensatory increase of red cell production, which may increase about twofold to threefold acutely and fourfold to sixfold chronically, and 10-fold in the most extreme case. The increase is mediated by increased production of EPO. The rate of EPO synthesis is inversely and logarithmically related to hemoglobin concentration (Chap. 32). EPO concentration can increase from approximately 10 mU/mL at normal hemoglobin concentrations to 10,000 mU/mL in severe anemia (Fig. 34–4).23,24 The change in EPO levels ensures that red cell production increases in response to hemolytic and other anemias or subacute blood loss. If the former is mild, the anemia may be compensated and, if iron is available, the blood loss will be repaired after it ceases. Augmented erythroid activity expands marrow space, which, if intense, can cause sternal tenderness and diffuse bone pains. The proportion and number of reticulocytes increase. Because erythroid transit time through the marrow is shortened, “stress reticulocytes” have increased cell volume and surface area (see Chap. 32, Fig. 32–2). They develop characteristic surface folds as a result of the increased surface-area-to-volume ratio that can be identified in the blood film. Nucleated red cells may be observed in the blood in severe anemia.25
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Administration of human recombinant EPO augments or replaces endogenous synthesis. In pharmacologic amounts, the effect on hemoglobin concentration is most noticeable if endogenous production is subnormal as a result of renal failure or systemic illnesses (Chap. 37). In severe anemia where endogenous EPO production (providing production is not impaired) has already increased red cell production maximally, administration of EPO rarely helps, and the patients require transfusion.24
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Uncorrected Tissue Hypoxia
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A certain residual degree of tissue hypoxia remains despite mobilization of compensatory mechanisms. Hypoxia is essential for initiation of adequate cardiovascular and erythropoietic compensation mechanisms, but severe tissue hypoxia can cause the following symptoms: dyspnea on exertion or even at rest; angina; intermittent claudication; muscle cramps, typically at night; headache; light-headedness; and fatigue. A number of diffuse gastrointestinal symptoms are associated with anemia (e.g., abdominal cramps, nausea), but whether the symptoms should be attributed to tissue hypoxia, compensatory redistribution of blood, or the underlying cause of anemia is uncertain.
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Based on determination of the red cell mass, anemia can be classified as either relative or absolute. Relative anemia is characterized by a normal total red cell mass in an increased plasma volume, resulting in a dilution anemia, a disturbance in plasma volume regulation. However, dilution anemia is of clinical and differential diagnostic importance for the hematologist.
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Classification of the absolute anemias with decreased red cell mass is difficult because the classification has to consider kinetic, morphologic, and pathophysiologic interacting criteria. Anemia of acute hemorrhage is not a diagnostic problem and is usually a genitourinary or gastrointestinal matter, not a hematologic consideration. Initially, all anemias should be divided into anemias caused by decreased production and anemias caused by increased destruction of red cells. The differentiation is based largely on the reticulocyte count. Subsequent diagnostic breakdown can be based on either morphologic or pathophysiologic criteria.
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Morphologic classification subdivides anemia into (1) macrocytic anemia, (2) normocytic anemia, and (3) microcytic hypochromic anemia. The main advantages of this classification are that the classification is simple, is based on readily available red cell indices, for example, mean corpuscular volume (MCV) and mean corpuscular hemoglobin concentration (MCHC), and forces the physician to consider the most important types of curable anemia: vitamin B12, folic acid, and iron-deficiency anemias. Such practical considerations have led to wide acceptance of this classification.
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Pathophysiologic classification (Table 34–1) is best suited for relating disease processes to potential treatment. In addition, anemia resulting from vitamin or iron-deficiency states occurs in a significant proportion of patients with normal red cell indices.
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This chapter presents a classification based on our present concepts of normal red cell production and red cell destruction. Figure 34–5 outlines the cascade of proliferation, differentiation, and maturation underlying the transformation of a multipotential stem cell, first to erythroid progenitor cells, then to erythroid precursor cells, and finally to mature red cells. Each of these steps can become impaired and cause anemia. Therapeutic intervention depends on identifying the defective step and instituting the specific therapy. The limitation of such a classification is that, in most anemias, the pathogenesis involves several steps. For example, a decreased rate of production most often results in production of defective red cells with a shortened life span. Thus, the outline provided is a conceptual guide to our present understanding of the processes underlying the production and destruction of red cells.
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