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506 Part VI: The Erythrocyte Chapter 34: Clinical Manifestations and Classification of Erythrocyte Disorders 507

blood film. Nucleated red cells may be observed in the blood in severe classification is that, in most anemias, the pathogenesis involves several
anemia. 25 steps. For example, a decreased rate of production most often results in
Administration of human recombinant EPO augments or replaces production of defective red cells with a shortened life span. Thus, the
endogenous synthesis. In pharmacologic amounts, the effect on hemo- outline provided is a conceptual guide to our present understanding of
globin concentration is most noticeable if endogenous production is the processes underlying the production and destruction of red cells.
subnormal as a result of renal failure or systemic illnesses (Chap. 37).
In severe anemia where endogenous EPO production (providing pro- POLYCYTHEMIA (ERYTHROCYTOSIS)
duction is not impaired) has already increased red cell production
maximally, administration of EPO rarely helps, and the patients require PATHOPHYSIOLOGY
transfusion. 24
The production and presence of an increased number of red cells are
Uncorrected Tissue Hypoxia associated with general and specific effects generated by changes in
A certain residual degree of tissue hypoxia remains despite mobilization blood viscosity and blood volume.
of compensatory mechanisms. Hypoxia is essential for initiation of ade- The viscosity of blood increases logarithmically with an increase
quate cardiovascular and erythropoietic compensation mechanisms, in hematocrit (Fig. 34–6). At hematocrits above the normal range, the
but severe tissue hypoxia can cause the following symptoms: dyspnea increase in blood viscosity impairs blood flow and increases cardiac
on exertion or even at rest; angina; intermittent claudication; muscle workload. The resulting decrease in blood flow reduces the transport of
cramps, typically at night; headache; light-headedness; and fatigue. A oxygen, with average optimal values at hematocrit readings between 40
26,27
number of diffuse gastrointestinal symptoms are associated with anemia and 45 percent. In a study of red cells from a number of animal spe-
(e.g., abdominal cramps, nausea), but whether the symptoms should be cies, the optimal value of oxygen transport corresponded closely to their
28
attributed to tissue hypoxia, compensatory redistribution of blood, or normal hematocrits, which may explain the evolutionary determina-
29
the underlying cause of anemia is uncertain. tion of optimal hematocrit levels. However, before concluding that
polycythemia always is a suboptimal condition, consider that it may be
inappropriate to correlate viscosity readings, derived from blood tested
CLASSIFICATION in a rigid glass viscometer (Ostwald) or even in a cone-plate viscometer,
30
Based on determination of the red cell mass, anemia can be classified with those in flowing blood through tiny distensible vessels in vivo.
First, the flow through these narrow channels is rapid (high shear rate),
as either relative or absolute. Relative anemia is characterized by a nor- which in a nonnewtonian fluid such as blood causes a marked decrease
mal total red cell mass in an increased plasma volume, resulting in a in viscosity. Second, blood flowing through narrow channels in vivo is
dilution anemia, a disturbance in plasma volume regulation. However, axial, with a central core of packed red cells sliding over a peripheral
dilution anemia is of clinical and differential diagnostic importance for layer of lubricating low-viscosity plasma. Finally, and most impor-
the hematologist. tantly, absolute polycythemia is not normovolemic but is accompanied
Classification of the absolute anemias with decreased red cell mass by increased blood volume, which, in turn, enlarges the vascular bed
is difficult because the classification has to consider kinetic, morpho- and decreases peripheral resistance. Because blood pressure remains
logic, and pathophysiologic interacting criteria. Anemia of acute hem- stable, the increased blood volume must be associated with increased
orrhage is not a diagnostic problem and is usually a genitourinary or cardiac output and increased oxygen transport (cardiac output times
gastrointestinal matter, not a hematologic consideration. Initially, all hemoglobin concentration). Using measurements of cardiac output
anemias should be divided into anemias caused by decreased pro- in dogs and tissue oxygen tension in rats and mice, construction of
30
31
duction and anemias caused by increased destruction of red cells. The curves (Fig. 34–7) that relate oxygen transport to hematocrit in nor-
differentiation is based largely on the reticulocyte count. Subsequent movolemic and hypervolemic states is possible. These curves show that
diagnostic breakdown can be based on either morphologic or patho- hypervolemia per se increases oxygen transport and that the optimum
physiologic criteria. oxygen transport in these conditions occurs at higher hematocrit val-
Morphologic classification subdivides anemia into (1) macrocytic ues than in normovolemic states. Consequently, despite the increased
anemia, (2) normocytic anemia, and (3) microcytic hypochromic ane- viscosity, a moderate increase in hematocrit is beneficial. The same may
mia. The main advantages of this classification are that the classifica- not be true of a more pronounced increase in hematocrit. Observations
tion is simple, is based on readily available red cell indices, for example, in humans and experimental animals indicate that high viscosity
32
31
mean corpuscular volume (MCV) and mean corpuscular hemoglo- causes reduced blood flow to most tissues and may be responsible for
bin concentration (MCHC), and forces the physician to consider the the cerebral and cardiovascular impairment experienced occasionally
most important types of curable anemia: vitamin B , folic acid, and by high-altitude dwellers, patients with severe polycythemia, 34,35 and
33
12
iron-deficiency anemias. Such practical considerations have led to wide athletes self-administering overdoses of EPO (Chap. 57).
acceptance of this classification.
Pathophysiologic classification (Table 34–1) is best suited for
relating disease processes to potential treatment. In addition, anemia MANIFESTATIONS
resulting from vitamin or iron-deficiency states occurs in a significant The rate of red cell production is increased in true polycythemias, but
proportion of patients with normal red cell indices. changes in erythroid marrow cellularity can be difficult to assess by
This chapter presents a classification based on our present con- microscopy means, although the marrow is hypercellular in a typical
cepts of normal red cell production and red cell destruction. Figure patient with polycythemia vera. Under normal conditions, the rate of
34–5 outlines the cascade of proliferation, differentiation, and matura- red cell production is adjusted to maintain the red cell mass at approx-
tion underlying the transformation of a multipotential stem cell, first to imately 30 mL per kilogram of body weight. Because the life span of
erythroid progenitor cells, then to erythroid precursor cells, and finally red cells in polycythemia is normal, a doubling of the daily rate of red
to mature red cells. Each of these steps can become impaired and cause cell production is adequate to maintain a polycythemic red cell mass of
anemia. Therapeutic intervention depends on identifying the defec- 60 mL/kg. Consequently, the morphology and volume of the marrow
tive step and instituting the specific therapy. The limitation of such a are only moderately altered in polycythemia compared with the changes

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