CHAPTER 30 CLINICAL MANIFESTATIONS AND CLASSIFICATION OF ERYTHROCYTE DISORDERS
CHAPTER 30 CLINICAL MANIFESTATIONS AND CLASSIFICATION OF ERYTHROCYTE DISORDERS
ALLAN J. ERSLEV
Pathophysiology and Manifestations
Pathophysiolgy and Manifestations
Anemias and polycythemias are characterized, respectively by a decreased or increased size of the red cell mass. Since the anemias are associated with a decrease in the oxygen-carrying capacity of blood, they are usually expressed in terms of hemoglobin concentration and cause symptoms because of tissue hypoxia. The clinical manifestations are primarily due to hypoxia-induced compensatory features designed to prevent or ameliorate dangerous anoxia. Among these, the most important is an increase in the renal erythroid growth factor; however, almost all appear to be initiated by a single hypoxia-inducible transcription factor, HIF. The classification of anemia is evolving, since it must take into account new kinetic and molecular findings, and the classification given here is tentative and not always followed in this textbook.
The polycythemias are best expressed in terms of the hematocrit percentage, since their clinical manifestations are primarily related to the size of the red cell mass and to the viscosity of blood. The classification is less complex than that for anemias, and is based on arterial oxygen saturations, associated changes in other blood counts, and erythropoietin concentrations.
Acronyms and abbreviations used in this chapter include: HIF-1, hypoxia inducible factor.
Erythrocyte disorders are traditionally divided into two groups: (1) anemia and (2) polycythemia. Although this division is based on the presence of too few red cells (erythrocytopenia) and too many red cells (erythrocytosis), anemia is functionally best characterized by a hemoglobin concentration below normal and polycythemia by a hematocrit above normal. This use of two different erythroid parameters in the characterization of anemia and polycythemia is based on clinical considerations. Anemia is a disorder in which the patient suffers from tissue hypoxia, the consequence of a low oxygen-carrying capacity of the blood. Polycythemia, on the other hand, is a disorder in which the clinical manifestations are related to increased whole blood viscosity and increased blood volume, both consequences of a high hematocrit.
PATHOPHYSIOLOGY AND MANIFESTATIONS
The clinical manifestations of anemia are to some extent determined by its etiology and pathogenesis. Certain signs and symptoms, however, are general and can be attributed to a reduction in oxygen-carrying capacity. Although the red cells also carry carbon dioxide from the tissues to the lungs and help distribute nitric oxide throughout the body, the transport of these gases does not appear to be dependent on the number of red cells available and stays normal in anemic patients. A reduction in oxygen-carrying capacity, on the other hand, will cause tissue hypoxia and in turn mobilize a number of compensatory mechanisms designed to prevent or ameliorate destructive tissue anoxia.
Tissue hypoxia occurs when the pressure head of oxygen in the capillaries is too low to provide distant cells with enough oxygen for their metabolic needs. This may happen despite the presence of several times the needed amount of oxygen in the circulating blood. Using approximate figures for a normal adult, the red cell mass has to provide the tissues with about 250 ml/min of oxygen to support life. Since the oxygen-carrying capacity of normal blood is 1.34 ml per gram hemoglobin, or about 20 ml/dl of normal blood, and the cardiac output is about 5000 ml/min, 1000 ml/min of oxygen is available at the tissue level. The extraction of one-fourth of this amount will reduce the oxygen tension of 100 mmHg in the arterial end of the capillary to 40 mmHg in the venous end. This partial extraction will ensure the presence of sufficient diffusion pressure throughout the capillaries to provide all cells within a truncated cone segment with enough oxygen for their metabolic needs (Fig. 30-1). In anemia, the extraction of the same amount of oxygen would lead to greater hemoglobin desaturation and a lower oxygen tension at the venous end of the capillary. Since this would result in destructive cellular hypoxia or anoxia in the immediate vicinity, a number of compensatory and frequently symptomatic adjustments in the supply of blood and oxygen are initiated selectively throughout the body.
FIGURE 30-1 Theoretical tissue segment provided with oxygen from one capillary. With an arterial diffusion pressure of oxygen of 100 mmHg and partial oxygen extraction resulting in a venous oxygen pressure of 40 mmHg, one capillary can provide oxygen to cells within a truncated cone segment. With complete oxygen extraction, however, oxygen cannot be supplied to cells within a rim of tissue around the apex of the cone.
Many of these protective adjustments involve the production and stabilization of a single protein complex, HIF-1. This protein was first identified as a transcriptional factor for the erythropoietin gene1 (see Chap. 29). Subsequent studies have shown that it is also capable of activating other genes involved in protection against hypoxia. For example, HIF-1 transcribes genes coding for many glycolytic enzymes, for growth factors controlling vessel formation, and for proteins regulating vasomotor function.2,3 and 4 It appears that the HIF-1 complex consists of two parts, HIF-1a and HIF-1b. Both are constitutively produced, but while HIF-1b is stable, HIF-1a has a very short lifespan and is continually destroyed under normoxic conditions. However, in the absence of oxygen, it is also stable, and the HIF-1 complex becomes functional as a transcriptional protein. The oxygen-sensitive process of destruction may be controlled by a hypothetical heme protein which, when deoxygenated under hypoxic conditions, inactivates the degradation process.4 Alternatively, degradation may be controlled by an enzyme sensitive to the presence or absence of oxygen.5 Although HIF-1 may be present and functional in all hypoxic cells, its action varies from cell to cell. Consequently, tissue-specific and still unknown interacting factors must be present to explain the mobilization of the many compensatory mechanisms listed below that permit survival under hypoxic conditions.
DECREASED OXYGEN CONSUMPTION
The activation of genes coding for glycolytic enzymes2 will save oxygen but at the expense of using less-efficient metabolic pathways. Actually anaerobic glycolysis is not employed extensively in chronic well-tolerated anemias,6 and the overall consumption of oxygen in anemia may actually be 10 to 15 percent higher than normal because of the metabolic cost of cardiac and pulmonary overactivity.7
DECREASED OXYGEN AFFINITY
One of the earliest and least costly adjustments of oxygen delivery is a decrease in the affinity of hemoglobin for oxygen. This permits increased oxygen extraction without jeopardizing oxygen pressure8,9 (Chap. 28). Since there is no consistent decrease in the pH of blood or evidence of impaired CO2 removal from the tissues, the observed change in oxygen affinity cannot be accounted for by a simple Bohr shift to the right. However, the red cells of patients with anemia generate increased amounts of 2,3-bisphosphoglycerate,9 and this phosphate compound has the capacity to combine with deoxygenated hemoglobin and decrease its affinity for oxygen (Chap. 28). The reason for increased synthesis of 2,3-bisphosphoglycerate in anemia is not fully understood but is related, in part, to a rise in the intracellular pH of red cells (Chap. 26). Accumulation of 2,3-bisphosphoglycerate has also been demonstrated in red cells of individuals with high-altitude hypoxemia.10
INCREASED TISSUE PERFUSION
The effect of a decreased oxygen-carrying capacity on the tissue tension of oxygen can be offset if, by using all potential capillary channels, the distance from tissue cells to oxygen supply is reduced. This can be accomplished via HIF-1 activation of genes regulating both vasomotor activity and angiogenesis.2 Since in most anemias the blood volume is not changed significantly (Fig. 30-2),11 increased tissue perfusion has to be performed selectively with blood shunted from presumably nonvital donor areas to oxygen-sensitive recipient organs. The major donor areas for the redistribution of blood in moderate acute anemia in the experimental animal are the mesenteric and iliac beds.12 However, in chronic anemia in humans the donor areas appear to be the cutaneous tissue13 and the kidneys.14 Vasoconstriction and oxygen deprivation in the dermal tissue appear to be well tolerated but are in part responsible for the characteristic pallor of anemia. Whether they also are responsible for the retinal hemorrhages seen occasionally in severe anemia is unknown, but no better explanation is available.15 Although the kidney can hardly be thought of as a nonvital area, the oxygen supply under normal conditions is in excess of oxygen demands. The arteriovenous oxygen difference in the kidney is as low as 1.4 ml/dl (compared with the myocardium, where it may be as high as 20 ml/dl), indicating that even a severe reduction in the kidney perfusion will not limit oxidative cellular metabolism. Nevertheless, enough renal hypoxia must be present to activate HIF-1 and generate increased amounts of erythropoietin and in turn new red cells (Chap. 33). The effect on renal excretory mechanisms is slight, since the reduction in renal blood flow is offset by the high plasmacrit and, even in severe anemia with the renal blood flow reduced by almost 50 percent, the renal plasma flow is only moderately curtailed.
FIGURE 30-2 Relation between hematocrit and total blood volume in normal individuals and in patients with anemia and polycythemia (Huber, Lewis, and Szur11).
The benefits derived from a redistribution of blood are obvious, and the organs with the most pressing need for oxygen, such as myocardium, brain, and muscles, will to a great extent be unhampered by a moderate reduction in oxygen-carrying capacity.
INCREASED CARDIAC OUTPUT
An increase in cardiac output is an excellent but metabolically expensive compensatory device.16,17 It will decrease the fraction of oxygen that needs to be extracted during each circulation and thereby keep the oxygen pressure high. Since the viscosity of blood in anemic patients is lower than normal, and since selective vascular dilatation will decrease peripheral resistance, a high cardiac output can be maintained without any increase in blood pressure. Nevertheless, a measurable increase in the resting cardiac output does not occur until the hemoglobin concentration is below 7 g/dl, and clinical signs of cardiac hyperactivity are usually not present until the hemoglobin concentration reaches even lower levels.18
Signs of cardiac hyperactivity include tachycardia, increased arterial and capillary pulsation, and many hemodynamic murmurs.19 The cardiac murmurs are usually systolic and are heard best at the apex or at the pulmonary valve area. Diastolic murmurs are unusual, but all murmurs in an anemic patient should be considered hemodynamic until proved otherwise. 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 these murmurs and bruits often are sensed by the patient as roaring in the ears (tinnitus), especially at night. Their characteristic feature is that they disappear promptly after the hemoglobin concentration has been restored to normal.20 The normal myocardium will tolerate a prolonged period of sustained hyperactivity. However, angina pectoris and high-output failure may supervene if anemia is so extreme that it impairs coronary oxygen demands or if the patient has coronary artery disease.21,22 Cardiomegaly, pulmonary congestion, ascites, and edema have been observed, and they require emergency treatment with oxygen, intravenous furosemide, and transfusion of packed red cells.
INCREASED PULMONARY FUNCTION
Since at sea level blood, regardless of oxygen-carrying capacity, is nearly completely oxygenated in the lungs, the oxygen pressure of arterial blood in an anemic patient should be the same as that in a normal individual, about 100 mmHg. Nevertheless, an increase in respiratory rate or vital capacity will decrease the oxygen gradient from ambient air to alveolar air and will increase the amount of oxygen available to oxygenate a greater than normal cardiac output. Consequently, exertional dyspnea and orthopnea are characteristic clinical manifestations of severe anemia.18,19
INCREASED RED CELL PRODUCTION
The most appropriate response to anemia is a compensatory increase in the rate of red cell production. In anemia this increase may reach 6 to 10 times normal and is powered by an increased synthesis of renal erythropoietin (see Chap. 33). The rate of synthesis of erythropoietin is inversely and logarithmically related to the hemoglobin concentration and produces an erythropoietin concentration in plasma ranging from about 10 mU/ml at normal hemoglobin concentrations to 10,000 mU or more per milliliter in severe anemia (Fig. 30-3).24,25 The change in erythropoietin levels ensures that in most cases red cell production will balance red cell destruction or red cell loss at a hemoglobin concentration much higher than that which would be found if the rate of red cell production had stayed the same. The administration of exogenous human recombinant erythropoietin augments or replaces endogenous synthesis. Using pharmacologic amounts, the effect on hemoglobin concentration will be most noticeable if endogenous production is subnormal due to renal failure or systemic illnesses.26 In severe anemias in which endogenous production of erythropoietin already has increased red cell production to its utmost, no amount of recombinant erythropoietin will be of help and the patients will become transfusion-dependent. Clinically increased erythroid activity can occasionally be recognized by sternal tenderness and diffuse bone aches or pains. An increase in the number of circulating reticulocytes is the most significant laboratory reflection of accelerated red cell production. Since the erythroid transit time through the marrow is shortened, “stress reticulocytes” with increased volume and reticulum appear, and nucleated red cells may be observed.27,28 and 29
FIGURE 30-3 Erythropoietin levels in plasma of normal individuals and patients with anemia uncomplicated by renal or inflammatory disease. The lower limit of accuracy of the erythropoietin assay is 3 mU/ml and is indicated by a broken line.
UNCORRECTED TISSUE HYPOXIA
Despite the mobilization of compensatory mechanisms, a certain residual degree of tissue hypoxia remains. Some of this contributes the necessary driving force to sustain cardiovascular and erythropoietic adjustments, but tissue hypoxia per se may cause disturbing and even disabling symptoms. Angina pectoris, intermittent claudication, and night cramps are muscular signs of tissue hypoxia; headache, light-headedness, and faintness are cerebral signs. A number of diffuse gastrointestinal and genitourinary symptoms have been associated with anemia, but it is uncertain whether they should be attributed to tissue hypoxia, compensatory redistribution of blood, or the underlying cause of anemia.
On the basis of determination of the red cell mass, both anemia and polycythemia can be classified as (1) relative or (2) absolute. Relative anemia and relative polycythemia are both characterized by a normal total red cell mass. Such conditions are usually not thought of as hematologic disorders but rather as disturbances in the regulation of the plasma volume. However, both dilution anemia and dehydration polycythemia are of considerable clinical and differential diagnostic importance for the hematologist.
The classification of the absolute anemias with a decreased red cell mass is difficult, since it has to take into account kinetic, morphologic, and pathophysiologic interacting criteria. Initially, all anemias should be divided into anemias caused by decreased production and anemias caused by increased destruction of red cells. This differentiation is to a great extent based on the reticulocyte count. Subsequent diagnostic breakdown can be based on either morphologic or pathophysiologic criterias.
The morphologic classification subdivides anemia into (1) macrocytic anemia, (2) normocytic anemia, and (3) microcytic hypochromic anemia. The main advantages of this classification are that it is simple, it is based on readily available red cell indices (MCV and MCHC), and it forces the physician always to consider the most important types of curable anemia: vitamin B12, folic acid, and iron-deficiency anemias. Such practical considerations have led to a wide acceptance of this classification. However, pathophysiologic classification (Table 30-1) is best suited for relating disease processes to potential treatment.
TABLE 30-1 CLASSIFICATION OF ANEMIA
An attempt will be made in this chapter to present a classification based on our present concepts of normal red cell production and red cell destruction. Figure 30-4 outlines the cascade of proliferation, differentiation, and maturation that underlies the transformation of a multipotential stem cell, first to erythroid progenitor cells, then to erythroid precursor cells, and last to mature red cells. Each of these steps can become impaired and cause an anemia, and our capacity to manage these anemias depends to a great extent on identifying the defective step. The problem with such a classification is that in most anemias the pathogenesis involves several steps. For example, a decrease in the rate of production will most often result in the production of defective red cells with a shortened lifespan. Also, antibodies, cytokines growth factors, and nutritional elements usually affect several steps in the outlined cascade of production and destruction. For such reasons, the individual chapter on anemia in this textbook does not always follow this pathophysiologic classification, and the outline given here must be tentative and is provided primarily as a conceptual guide to our present understanding of the processes underlying the production and destruction of red cells.
FIGURE 30-4 An outline of the process of differentiation, proliferation, and maturation underlying the production and destruction of red blood cells. The multipotential stem cells responding to a number of growth factors, granulocyte-monocyte colony-stimulating factors (GM-CSF). Interleukin-3 (IL-3), insulin growth factor (IGF-1), and stem-cell factor (SCF) among others, will differentiate to progenitor cells committed to erythroid development. The progenitor cells, burst-forming units (BFU-E), and colony-forming units (CFU-E) will proliferate under the control of erythropoietin (EPO) and finally differentiate to precursor cells (erythroblasts). In the presence of adequate amounts of nutrients, such as B12, folic acid, and iron, the precursor cells will proliferate and mature into nucleated red cells, reticulocytes, and mature red blood cells. After a 120-day lifespan, these cells will age and be destroyed.
PATHOPHYSIOLGY AND MANIFESTATIONS
The production and presence of an increased number of red cells are associated with certain general and specific effects generated by changes in blood viscosity and blood volume.
At hematocrit readings higher than 50 percent, the viscosity of blood increases steeply (Fig. 30-5). The resulting decrease in blood flow will reduce the transport of oxygen, with optimal values found at hematocrit readings between 40 and 45 percent. In a study of the red cells from a number of animal species, it was found that the optimal value of oxygen transport corresponds closely to their normal hematocrits30 and may explain the evolutionary choice of certain hematocrit levels as optimal.30 However, before concluding that polycythemia always is a suboptimal condition, it is important to realize that it may be premature to translate viscosity readings, derived from blood tested in a rigid glass viscosimeter (Ostwald) or even in a cone-plate viscometer into blood flow through tiny distensible vessels in vivo.32 First, the flow through these narrow channels is rapid (high shear rate), which in a non-Newtonian fluid such as blood causes a marked decrease in viscosity. Second, blood flowing through narrow channels in vivo is axial with a central core of packed red cells sliding over a peripheral layer of lubricating low-viscosity plasma. Finally and most important, absolute polycythemia is not normovolemic but is accompanied by an increase in blood volume, which in turn enlarges the vascular bed and decreases the peripheral resistance. Since the blood pressure remains stable, the increase in blood volume must be associated with an increase in cardiac output and an increase in oxygen transport (cardiac output times hematocrit). Using measurements of cardiac output in dogs33 and tissue oxygen tension in rats and mice,34 it is possible to construct curves (Fig. 30-6) that relate oxygen transport to hematocrit in normovolemic and hypervolemic states. These curves show that hypervolemia per se will increase oxygen transport and that the optimum oxygen transport in these conditions is found at higher hematocrit values than in normovolemic states. Consequently, despite the increase in viscosity, a moderate increase in hematocrit is of benefit. The same may not be true of a more pronounced increase in hematocrit. Here observations in humans35 and experimental animals36 indicate that high viscosity causes a reduction in blood flow to most tissues and may be responsible for the cerebral and cardiovascular impairment experienced occasionally by high-altitude dwellers37 and patients with severe polycythemia,38,39 and also in athletes self-administering overdoses of erythropoietin (see Chap. 52).
FIGURE 30-5 Viscosity of heparinized normal human blood related to hematocrit (Hct). Viscosity is measured with an Ostwald viscosimeter at 37°C and expressed in relation to viscosity of saline solution. Oxygen transport is computed from Hct and O2 flow (1/viscosity) and is recorded in arbitrary units.
FIGURE 30-6 Oxygen transport at various hematocrit levels in normovolemic, mildly hypervolemic, and severely hypervolemic individuals. The oxygen transport is estimated by multiplying hematocrit by cardiac output. As can be seen in (1), the optimal oxygen transport for the normovolemic subjects is at a hematocrit of about 45 percent with a progressive rise in the optimal hematocrit as the blood volume increases. A suboptimal hematocrit in a hypervolemic person (anemia of pregnancy), as in (2), may be associated with a higher oxygen transport than that of a normovolemic person with normal hematocrit. However, a high hematocrit without an increase in blood volume (3) may be associated with an absolute reduction in oxygen transport and tissue hypoxia. Only high hematocrit coupled with high blood volume (4) enhances oxygen transport to the tissues. (Adapted from Murray and colleagues33 and Thorling and Erslev.34)
Although the rate of red cell production is increased in erythrocytosis, changes in marrow morphology may be quite unimpressive. Under normal conditions, the rate of red cell production is adjusted to maintain the red cell mass at about 30 ml per kilogram of body weight. Since the lifespan of the red cells in polycythemia is normal, a mere doubling of the daily rate of red cell production would be adequate to maintain a red cell mass of 60 ml/kg or, in other words, to maintain a very substantial erythrocytosis. Consequently, the morphology and volume of the marrow are only moderately altered in polycythemia in comparison with the changes observed in some types of hemolytic anemia, in which the rate of red cell production may be 6 to 10 times normal. In erythrocytosis, the number of red cells destroyed daily would merely cause a slight increase in bilirubin levels and the presence of secondary gout and splenomegaly are usually signs of a myeloproliferative disorder rather than of erythrocytosis alone. Although, there is a considerable homology between erythropoietin and thrombopoietin,40 erythropoietin-driven erythrocytosis is not associated with an increase in platelet production.
The increase in viscosity and vascular space are responsible for many of the signs and symptoms of polycythemia. The characteristic “ruddy cyanosis” in patients with polycythemia vera is caused by excessive deoxygenation of blood flowing sluggishly through dilated cutaneous vessels. Nonspecific symptoms such as headaches, dizziness, tinnitus, and a feeling of fullness of the face and head are probably also caused by a combination of increased viscosity and vascular dilatation.
Hemorrhages from the nose or stomach in patients with normal platelets and coagulation proteins can be attributed to capillary distention, but circulatory stagnation causing ischemia and necrosis may be contributory. Thromboses are common in polycythemia vera, but they also occur in erythrocytosis when aggravated by plasma loss (dehydration). Since coronary blood flow is decreased in polycythemia,38 it has been assumed that the risk of coronary thrombosis in patients with a high hematocrit is increased, but statistical analyses have yielded equivocal results.39,41,42 It has actually been claimed that polycythemia does not pose a risk in surgical patients.43 Although cerebral blood flow is materially reduced in patients with moderately elevated hematocrit,44 such reductions may have little practical significance.
Polycythemia, or erythrocytosis, is defined as a condition in which the hematocrit percentage is above the upper limit of normal or in men above 51 percent and in women above 48 percent. It can be classified as relative, in which the red cell mass is normal but the plasma volume is decreased, or absolute, in which the red cell mass is increased above normal (Table 30-2). At hematocrits of less than 60 percent differentiation of absolute from relative polycythemia may, at times, be difficult. The designation of a measured red cell mass as normal is very imprecise, since it depends on the age, sex, weight, height, and body frame of the individual and since only increases above the mean greater than 25 percent are considered abnormal. This leaves a number of conditions with increased hematocrits but a “normal” red cell mass. Such conditions are usually associated with the same illnesses involved in the pathogenesis of absolute erythrocytosis. If the hematocrit is above 60 percent, the red cell mass is almost always increased.
TABLE 30-2 CLASSIFICATION OF POLYCYTHEMIA (ERYTHROCYTOSIS)
Absolute polycythemia may be primary, representing uncontrolled overproduction of all marrow cells (polycythemia vera) or only the erythroid elements (erythremia). In both cases the level of circulating erythropoietin is low or absent. Polycythemia can be secondary due to increased production of erythropoietin either appropriate due to hypoxia caused by exposure to high altitude, cardiopulmonary disorders, or left-shifted oxygen dissociation curve of hemoglobin, or inappropriate due to excessive erythropoietin production by tumors or cysts.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn