Approach to Anemia in the Adult and Child

Overview of Erythropoiesis

Erythropoiesis is the regulated process leading to the production of mature RBCs or erythrocytes. Bone marrow (BM) stem cells stimulated by the hormone erythropoietin and other factors, proliferate and differentiate along a pathway of recognizable erythroid precursors that ultimately leads to extrusion of the nucleus to facilitate efficient RBC rheology after the production and accumulation of a high concentration of hemoglobin and RBC enzymes ( Fig. 35.1 ). Reticulocytes, the early maturing RBCs, are released with residual RNAs and ribosomes, which they lose by degradation within a day, but no other organelles. Special staining for RNA identifies reticulocytes . The reticulocyte count is useful for both qualitative and quantitative measure of the relative rate of peripheral blood erythropoiesis. Mature RBCs survive in blood circulation 100 to 120 days before being removed from the circulation by macrophages in the spleen and other cells of the reticuloendothelial system. At steady state under physiologic conditions, the production and destruction of erythrocytes are equivalent. Control of this homeostatic system process is driven in large part by the hormone erythropoietin, which is produced in a regulated fashion by periglomerular cells in the kidney (~90%) and constitutively by the liver (~10%). Because preservation of oxygen delivery to tissues is so important, the oxygen-sensing regulatory proteins located in the kidney respond to decreased oxygen tension from any cause such as blood loss, high altitude, or cardiac shunts with the production of erythropoietin ( Fig. 35.2 ). This hormone then travels through the bloodstream and stimulates RBC production in the bone marrow. Provided that there are adequate nutrients, including folate, vitamin B ₁₂ , and iron, the precursors in the BM proliferate and mature and are released into the circulation, ultimately expanding the pool of erythrocytes. The increase in oxygen delivery to the kidney then reduces the stimulus for erythropoietin production.

Definition, PhysioloGic Consequences and Symptoms of Anemia

Anemia is typically defined as a reduction in the RBC mass, but a clinically useful definition requires a more nuanced expansion of that statement. While there are established “normal” values based on age and gender ( Table 35.1 , discussed in more detail below), these values are based on results obtained by testing large populations of healthy individuals at rest under normal conditions of oxygenation, altitude, etc. In terms of its clinical implications, “anemia” has to be defined in somewhat relative terms, relative to the person’s physiological circumstances, environment, and chronic baseline values. For example, a hematocrit in the “normal” range would be abnormally low in someone living in the high altitude, low oxygen environment of the high Andes plains, or a child with right to left shunting caused by congenital heart defects such as tetralogy of Fallot. Similarly, some whose hematocrit has stably dropped by four points from the high-normal to the normal range is actually anemic relative to his or her baseline and requires evaluation. With regard to this latter consideration, the clinical importance of anemia does not always correlate with its severity. A modest drop in red cell mass in a 50-year-old individual could reflect chronic low grade blood loss due to an otherwise clinically silent colon cancer, while a severe and symptomatic anemia due to iron or deficiencies are readily corrected with iron or vitamin supplementation, and, depending on the underlying cause of the deficiency (e.g., gastritis due to overuse of aspirin or a non-steroidal anti-inflammatory drug [NSAID]), may have an excellent prognosis. Similarly, the degree to which an individual is physiologically compromised or symptomatic does not always correlate with the severity of the anemia. Some children with profound iron deficiency anemia (so called milk-fed babies) may be only modestly symptomatic while some elderly patients with compromised cardiopulmonary status can be significantly compromised and at risk for ischemic events with only a modest reduction in red cell mass. Any evaluation of anemia must therefore be approached in the context of the patient’s comprehensive medical history, including family and social history, living environment, physical examination, and comorbidities. This is essential not just for establishing the basis of the anemia but, importantly, for determining the kinds and urgency of therapeutic interventions.

Finally, it is important to recognize that the laboratory values evaluating red cell mass are themselves relative values. The hemoglobin, hematocrit, and red cell count are measured per unit volume of whole blood. Dehydration can artifactually elevate counts, by reducing the relative volume of plasma, while overhydration artifactually lowers counts by increasing the relative volume of plasma.

The RBC mass normally changes during the lifespan of an individual and may be different in males and females. Understanding the changes that occur is critical to appropriately identifying what constitutes anemia (see Table 35.1 ). The relatively elevated levels of hemoglobin present at birth reflect the lower arterial oxygen saturation extant in utero and the predominance of fetal hemoglobin, which exhibits a higher oxygen affinity, and, therefore, is less efficient at delivering oxygen to tissues. The hemoglobin level declines over the first few months of life, as fetal hemoglobin is replaced by adult hemoglobin, to levels that are lower than those seen in adulthood. In later childhood, the hemoglobin values are similar and increase modestly over time. Around puberty, girls have reached adult levels of hemoglobin, but androgenic steroids lead to a continued increase in hemoglobin in boys through about age 18 years. This approximately 1.5 g/dL difference between males and females persists through much of adult life until about age 70 years, when the hemoglobin value in men begins to decline. Over the next two decades, the hemoglobin value declines by about 1 g/dL in men while decreasing by only approximately 0.2 g/dL in women. Thus, at age 90 years, there is only a modest difference between the mean hemoglobin values observed in men and women (14.1 vs. 13.8 g/dL).

The physiologic impact of anemia, defined in context as just discussed, arises from the primary function of red cells and their hemoglobin, which is to deliver oxygen to tissues. The primary symptoms of virtually all anemias are thus those due to inadequate tissue oxygenation: reduced exercise tolerance, fatigue, malaise, palpitations, dyspnea on exertion, anginal or claudication symptoms to cardiac or muscle hypoxia, and changes in mental state. Pallor results from the effect of reduced hemoglobin pigment content of blood perfusing the skin. As discussed later, anemias arising at least in part from accelerated RBC destruction may generate findings reflecting the accelerated catabolism of the RBCs and hemoglobin: jaundice or premature biliary tract disease due to the accelerated turnover of heme; hepatosplenomegaly, due to the destruction of red cells in liver and spleen; elevated red cell lactate dehydrogenase (LDH) levels in serum, etc. A large array of other symptoms and findings (e.g., pagophagia in iron deficiency anemia, long tract neurological signs in pernicious anemias, vaso-occlusive crises in sickle cell anemia) depend on the etiology of the anemia and are discussed extensively in the chapters in this section that focus on these conditions.

As already mentioned, individual patients vary widely in their symptomatology relative to the degree of the anemia. This is because anemia triggers an array of compensatory responses that can mitigate the impact of reduced red cell mass on tissue oxygenation. One response is increased cardiac output combined with reduced afterload, likely due to systemic vasodilatation. This has the effect of delivering more blood per minute to counterbalance the presence of less oxygen content per unit volume of blood due to the anemia. For complex reasons, anemia also triggers a reduction on red cell 2, 3-DPG, a cofactor that, when bound to hemoglobin, increases it O ₂ affinity. Reduced 2, 3-DPG leads to a lower affinity, meaning that the hemoglobin gives up more oxygen at the oxygen tension of capillary blood (see Chapters 34 and 44 ). These and other adaptations, such as increased minute ventilation, point to the importance of the cardiopulmonary and vascular status of the anemic patient in modulating symptoms and functional tolerance of the anemia.

Mechanisms of Anemia

Although a complete review of all of the mechanisms leading to anemia is beyond the scope of this chapter, an appreciation of some of the mechanisms is useful before approaching the diagnosis of anemia in adults and children. Three broad categories of anemia are blood loss anemia, hypoproliferative anemia, and hemolytic anemia.