by Juan Carlos Dupont

Paleness is the most common physical finding associated with anemia, although its usefulness in recognizing it is limited by a series of factors that alter skin coloration. Racial characteristics, skin thickness and texture, and momentary circulatory conditions influence color. Furthermore, acquired diseases such as hemochromatosis, Addison's disease, jaundice, or certain toxic effects of drugs (for example, busulfan) can also interfere with the possibility of detecting anemic pallor. However, even in highly pigmented individuals the presence of anemia can be investigated in the palms, mucosa, nail beds and eyelid conjunctivae.

There are two important determinants in the development of paleness. One is the decrease in hemoglobin concentration and the second is the hemodynamic condition of the skin. When blood flow is redistributed to vital organs during acute bleeding, the intensity of pale skin color increases.

Anemia . The term "anemia" is commonly used to refer to a reduction in the concentration of hemoglobin or red blood cells below the values ​​considered normal for the reference population (Table 17-1). A decrease of more than 10% of the mean value is considered diagnostic. It should also be remembered that normal mean values ​​depend on age, type of population, and height above sea level (Table 17-1). It is important to bear in mind that the reference values ​​can include 20-30% of the population lacking in iron, as indicated by some authors and the World Health Organization.

"Spurious" anemia . Normally, the reduction in the concentration of red blood cells reflects the reduction in their total mass. Alterations in the hydro-electrolyte balance that cause an increase in plasma volume, as occurs in the third trimester of pregnancy or secondary to overhydration in oliguric renal failure and in congestive heart failure, can be erroneously considered as anemic states, when in reality there are only hemodilution. In return, the decrease in plasma volume for various reasons can lead to an underestimation of anemia. The clinical situations that can most often mask anemia by this mechanism are: severe childhood diarrhea and diabetic acidosis and intestinal obstruction in adults (Table 17-2).

Symptoms and signs of anemia

The symptoms of anemia depend on the speed of its installation and the subject's cardiorespiratory adjustment capacity. Furthermore, if there is an asymptomatic localized vascular disease, the development of anemia may be manifested by angina pectoris, intermittent claudication, or transient cerebral ischemia.

The common thing for individuals with mild anemia is that they are asymptomatic. At times, exercise causes dyspnea and palpitations. Patients with severe anemia have symptoms still at rest and are regularly unable to tolerate physical exertion.

In adult individuals, a decrease in hemoglobin below 8 g per 100 ml causes a hyperdynamic state that is manifested by tachycardia, a broad pulse, sometimes an ejective systolic murmur in the foci of the base, and in those in which the myocardial reserve is decreased, heart failure develops.

Other symptoms attributable to circulatory disorders are headaches, dizziness, tinnitus, and eventually unconsciousness. Some patients report insomnia and irritability. Gastrointestinal symptoms such as anorexia, dyspepsia, or nausea result from decreased splanchnic flow. In the sexual sphere the most common manifestation in men is the decrease in libido and in women amenorrhea or hypermenorrhea.

Physiological concepts

Hemoglobin . In the most elementary forms of life, oxygen travels dissolved in interstitial fluids. In more developed species, such as mollusks, metalloproteins appear, which increase the oxygen transport capacity. Higher animals have hemoglobin, which is a protein with a molecular weight of 64,500 with a prosthetic group called heme.

Proper hemoglobin synthesis involves three pathways: a) iron metabolism, b) heme biosynthesis, and c) globin synthesis.

Iron metabolism. The absorption of iron in the proximal portion of the jejunum is carried out in at least two ways: a) as iron bound to the heme group, or b) as reduced iron (Fe ++ ). Initially, the acidity of the gastric juice separates the globinic portion from the different biological proteins that contain iron, and the hemin group (heme + Fe +++ ) is absorbed intact. The iron contained in other foods in forms other than heme 4 + Fe +++ must be reduced to Fe ++ so that it can then be absorbed.

When the heme-shaped iron enters the mucosa cell, the porphyrinic ring is olivated by hemoxygenase, and in the same way as the Fe ++ ion, remains a few hours in said cell. Then it goes to the plasma where it circulates bound to the transferrin, which is a 74,000 molecular weight iron transporting glycoprotein. In normal subjects the amount of iron in the body remains relatively fixed at 35 to 50 mg / kg of weight. 0.1% circulates in plasma bound to transferrin, 30% is found in its storage forms (ferritin and hemosiderin), and the rest is part of hemoglobin and myoglobin. The daily need for iron is 1 mg, which is what is lost due to epithelial desquamation of the intestine. This need is doubled in women who menstruate and triples during pregnancy. The precursors of the mature erythrocyte, from the pronormoblast to the reticulocyte, incorporate up to 80% of the circulating iron in the plasma.

Heme biosynthesis . In the mitochondria, succinyl-coenzyme A binds to regulatory glycine by 3-aminolevulinic acid synthetase. Then, outside the mitochondria, the synthesis of the tetrapyrrolic ring is carried out, which, once again in the mitochondrial crest and already converted to protoporphyrin 9, binds to iron through the heme synthetase enzyme and then passes to the cytoplasm.

Globin synthesis . This protein is a tetramer composed of two pairs of polypeptide chains designated alpha, beta, gamma, and delta, each of which is covalently linked to the heme group. Globin synthesis occurs in the proerythroblast. Each of the chains is regulated by a gene inherited from each of the parents.

In the cytoplasm these tetramers bind to the heme prosthetic group and form hemoglobin. 97% of adult Hb is HbA (Alpha 2 Beta 2 ) and 3% is HbA2 (Alpha 2 Delta 2 ). In the fetus there is hemoglobin F (Alpha 2 Gamma 2 ), which in the last trimester of pregnancy changes to beta chain synthesis.

Hemoglobin function . During circulation through the lung, hemoglobin is almost completely saturated with oxygen (1.34 ml of O 2 per gram of Hb). In the capillary bed, oxygen is extracted by the tissues. This mechanism is made possible by changing the affinity for oxygen at different partial pressures of oxygen (sigmoid curve) (see Fig. 16-2). The affinity for oxygen is also influenced by pH, PCO 2, and 2,3-diphosphoglycerate (2,3-DPG). Each of these factors, when increased, shift the curve to the right, increasing hemoglobin delivery of O2 .

2,3-DPG binds to the p chain of deoxyhemoglobin, further decreasing its affinity for oxygen (see Figure 17-2).

Erythropoiesis . The erythrocytes derive from a pluripotent stem cell, which also gives rise to the granulocytic, monocytic, megakaryocytic and lymphocytic cells.

At least two erythrocyte precursors have been recognized in in vitro cultures of circulating blood. EBFUs ( erythroid burst forming units ) appear late (10-15 days) in cultures and represent earlier stages of erythrohlast evolution. ECFUs ( erythroid colony forming units ) appear earlier (4 to 7 days) in cultures, are sensitive to erythropoietin, and are also regulated by T lymphocyte subpopulations.

Erythropoietin is a 32,000 dalton protein that circulates in plasma as an apoenzyme. The kidneys produce an activating factor for erythropoietin in hypoxic conditions. Once activated, it interacts with erythroblasts, through receptors, inducing mitosis and increasing hemoglobin synthesis. When the latter is completed, the nucleus is expelled from the normoblast and the cell enters the circulation as a reticulocyte, then losing its mitochondria and ribosomes within 24 hours, thus transforming itself into a mature erythrocyte (Fig. 17-3).

Evaluation of a patient with anemia

Assessment of the patient with anemia (Table 17-3) requires, as in all clinical disciplines, a meticulous questioning and physical examination so that the initial orientation saves unnecessary steps in the investigation of its origin. Next, the study of an anemic patient will be schematically synthesized.

After establishing that a patient has anemia, the first question to ask is whether it corresponds to a deficit of production or an increase in destruction. Reticulocytes, which are immature red blood cells, allow this response. Reticulocytosis involves a high degree of production and, therefore, if anemia exists, it will have been caused by a hemolytic mechanism or by recent acute bleeding. There are other reasons for reticulocyte increase in anemic patients such as spinal invasion by tumors or granulomas (myeloptysis) and recent injection of vitamin B12 in patients with pernicious anemia. The most appropriate way to determine the rate of red blood cell production is:

Reticulocyte index = % of reticulocytes x (hematocrit of the patient / normal hematocrit)

If the index is greater than 1 it is considered hyperregenerative and if it is less than 1 hypogenerative. When the medulla is highly stimulated and there are red blood cells in peripheral blood, this index should be divided by two.

Examination of the blood smear . The importance of paving lies in the ease with which it is obtained and in the information it provides on size, coloration and shape alterations; likewise, it allows detecting the existence of inclusions.

Anisocytosis is called the presence of erythrocytes of different sizes: a) normocytes, which vary between 7.2 and 7.9 microns; b) macrocytes, which are red cells with a size generally greater than 9 microns; they may correspond to young red blood cells (reticulocytes) or megalocytes from megaloblastic anemia, and c) microcytes, in which the diameter is less than 6 microns. They are observed in disorders of hemoglobin synthesis (iron deficiency, thalassemia, sideroblastic anemia).

The irregular distribution of the hemoglobin content in different erythrocytes is called anisochromia : a) the normochromic ones have normal Hb content and the central pallor does not occupy more than a third of its diameter, and b) in the hypochromic ones, there is an overall decrease in coloration. and increased central pallor. They are usually microcytes and their appearance responds to the same causes.

The poikilocytosisis the term that defines the presence of red blood cells in different ways: a) in spherocytes the normal biconcave shape has been replaced by the spherical shape, thus reducing the diameters (6 microns) but not the volume; they give the false impression of being hyperchromic; b) the elliptocytes are oval or elliptical in shape; c) the target cells are produced by decreasing the hemoglobin content or by increasing the surface / volume ratio in certain liver diseases (lecithin-cholesterol-acyl-transferase deficiency); what is observed is an atypical distribution of hemoglobin, with the center stained mimicking a shooting target; d) sickle cells are elongated crescent-shaped red blood cells, produced in the presence of hemoglobin S; e) Schistocytes are irregularly shaped fragments of erythrocytes, small and with two or three points that regularly appear when there are capillary lesions (uremic-hemolytic syndrome, disseminated intravascular coagulation) or heart valve prostheses; f) dacryocytes are gout red blood cells characteristic of myelofibrosis, although they can also be seen in some hemolytic states (Hb H, thalassemia).

In general, for any of the alterations to be hierarchical in terms of diagnostic orientation, it must be present in more than 10 to 30% of erythrocytes.

Intracytoplasmic inclusions . In basophilic stippling, these are grayish-blue granulations representing ribosomes and mitochondria precipitated by staining. They are regularly seen in disorders of hemoglobin synthesis.

The Howell-Jolly bodies are spherical and correspond to nuclear debris. They are normally extracted from the red blood cells in the spleen, and are therefore an expression of asplenia.

The Cabot rings are filiform formations purple, circular or folded into eight, and are observed in disorders dyserythropoietic primary or secondary (leukaemias, myelofibrosis).

Microscopic examination of the bone marrow . It is indicated when the mechanism of anemia cannot be explained with the available clinical elements. Most samples can be obtained by puncture of the posterior superior iliac crest, which causes less discomfort than sternal puncture. The anemone medullogram provides information on: a) total and erythroid cellularity; b) the myeloerythroid ratio; c) the quality of erythropoiesis; d) the presence of cells foreign to the bone marrow (tumors, granuloma), and e) the existence of hemosiderin deposits (Perls stain).

Four main types of erythropoiesis disorders can be identified:

1. Sideropenic . There is moderate erythroid hyperplasia, frequently with arrest of maturation at the level of basophilic erythroblasts and small erythroblasts with scarce cytoplasm and sometimes with frayed edges. If Perls staining is performed, hemosiderin deposits and sideroblasts are negative. In chronic disorders, sideroblasts are negative, but hemosiderin deposits are high.
2. Sideroblastic . Pathological sideroblasts (ring deposits) and greatly increased hemosiderin are seen.
3. Megaloblastic . Nuclear maturation disorders are produced by folic acid or vitamin B12 deficiency, which is manifested by erythroid hyperplasia with giant erythroblasts (megaloblasts), nuclear fragmentation, mitosis, and nuclear remnants in the more mature erythroblasts.
4. Dysplastic . Generally, there is hyperplasia of the erythroid sector, with alterations in the size, shape, and number of nuclei (bi, tri, tetranucleated), which may be accompanied by megaloblastic changes and ring erythroblasts. These alterations are frequent in refractory anemias and in preleukemic syndromes.

Hematimetric indices . With the advent of electronic meters (Coulter type), the corpuscular volume and hemoglobin concentration indices have been made much more precise than with manual methods. Counters make a direct measurement of erythrocytes (GR / microliters) and mean corpuscular volume (MCV)