José Luis Fedele


Classically, anemia is defined as the decrease in hemoglobin concentration below the limits considered normal for a certain group of individuals of the same age, sex and under the same environmental conditions.

These limits, although useful from a practical point of view, suffer small variations depending on the ethnic origin, eating habits and geographical area where the subjects live, so it is recommended that each laboratory or work group establish its own limits based on variables local.

In addition, there is a difference in the concentration of hemoglobin between men and women and between young and old.

The first responds to the androgenic effect on erythropoiesis.

The second has a much less clear basis, but a role is also attributed to the lower androgenic influence of the elderly on erythropoiesis, as well as to the lower secretion of erythropoietin as a consequence of the decline in renal function in the elderly.

Although anemia is almost always accompanied by a decrease in red cell mass, a decrease in the number of red cells is not required to define anemia.

In this way, situations can arise, and in fact they occur very often in clinical practice, where the decrease in hemoglobin is accompanied by a normal or even increased number of red blood cells in the absolute count and vice versa, decreased numbers of erythrocytes coexist with normal hemoglobin figures.

In these situations, it is worth highlighting the importance of a parameter, often forgotten by the clinician, the Mean Corpuscular Volume (MCV). Variations in MCV, exacerbated with the advent of automated hematology counters, are what determine these situations. When the MCV is low (Ex: Iron deficiency anemia - Thalassemia) they are associated with a decrease in hemoglobin with normal or high red values. On the contrary, a high MCV (Megalobastic Anemias), cause the antagonistic effect, that is, low red numbers with normal hemoglobin.

This is one of the first observations that the general practitioner should make when faced with a blood count of a patient, since he can already make a first approximation of the potential cause of anemia and therefore adequately direct the study of it.

Another aspect to be taken into account in the initial interpretation of the hemoglobin concentration value is the possible variation in plasma volume. There are various circumstances that can cause false increases or decreases in hemoglobin, due to hemoconcentration or hemodilution respectively.

Anemia is one of the most frequent causes of consultation due to three main reasons:

1) Its high incidence in young women and in certain populations with nutritional problems.

2) It usually accompanies numerous pathological situations in the body, which is why it becomes a common manifestation in the universe of an underlying disorder.

3) Its high incidence in certain ethnic groups (Thalassemia - Malaria - Sickle cell disease).

Diagnosing anemia can be very simple at times, and at other times, it can become arduous and difficult work. In our environment, the most frequent cause of anemia is deficiency anemia (iron deficiency), with a high incidence in young women and children of growing age. In these cases, the diagnosis is simple and its treatment, most of the time, successful.

Symptoms and signs

The clinical manifestations of anemia (Anemic Syndrome) depend on the implementation of adaptation mechanisms in the face of the decrease in tissue oxygenation, and are directly related to the age of the patient, the speed of installation of the anemia and the cardiovascular status patient prior.

When hemoglobin falls below a certain value (threshold), hypoxia activates compensation mechanisms, mainly at the level of the cardiovascular and hematopoietic system.

The cardio-circulatory system responds first, with a generalized vasoconstriction and redistribution of flow (preferably of the skin, kidney and splanchnic bed), with an increase in cardiac output, and later with an increase in plasma volume.

The objective of flow redistribution is to preserve the flow in the most noble organs, and occasionally, if the onset of anemia is very rapid and intense, hypovolemic shock can occur.

In the most chronic cases, an increase in blood volume predominates as a consequence of the increase in plasma volume, which causes hemodilution and an even greater decrease in hemoglobin levels.

This fact must be taken into account, especially in elderly patients, since when performing a transfusion, a sudden increase in blood volume with hemodynamic decompensation can occur.

Relative hypoxia at the renal level triggers the synthesis of erythropoietin by renal tubular cells, which produces a direct effect on erythropoiesis.

In addition to increasing the number of medullary erythroblasts and hemoglobinogenesis, erythropoietin reduces the number of stages of erythroblast maturation, thereby promoting the early release of erythrocytes into the circulation. This results in an increase in the absolute circulating reticulocyte count.

Finally, there is usually an increase in intra-erythrocyte 2,3-DPG, which decreases the affinity of hemoglobin for oxygen, thus facilitating the release of tissue oxygen from a lower concentration of hemoglobin.

Symptoms and signs associated with anemia are outlined in Table I.


Table I

  • General Symptoms
    • asthenia
    • Pallor
  • Cardiovascular Manifestations
    • Tachycardia
    • Palpitations
    • Functional systolic murmur
  • Neurological disorders
    • Vision disturbances
    • Headaches
  • Changes in behavior and mood
    • Insomnia
  • Menstrual rhythm disturbances
    • Amenorrhea
  • Kidney disorders
    • Edema
  • Alterations of the digestive tract
    • Anorexy
    • Constipation

Among the general symptoms, asthenia is a symptom so strongly associated with anemia that for the common people it has practically the same meaning.

Other symptoms that are very frequently associated are dyspnea on exertion, orthopnea, and muscle fatigue with small efforts. Given that these symptoms are of a general nature, they must be adequately assessed in the context of the medical history, in order to rule out other causes that may cause the same symptoms.

Paleness is a universal sign of anemia and a direct consequence of generalized vasoconstriction and decreased hemoglobin levels.

When anemia is severe, it is enough to observe the straw color of the skin, but where it is best appreciated is in the soft palate, the ocular conjunctiva and the sub-nail region. According to the intensity of the anemia and the characteristics of the patient (habitual complexion of their skin), this sign can make an element of greater or lesser value when it comes to the clinical diagnosis of anemia.

From the cardiocirculatory point of view, the adaptation mechanisms mentioned above give rise to various symptoms and signs.

In the case of a previous normal cardiovascular state, even with severe degrees of anemia, only a functional systolic murmur at the top and base may appear, which are attributed to hemodynamic phenomena secondary to hemodilution with increased cardiac output. On the contrary, in patients with previous cardiocirculatory pathology, an anemia, sometimes only moderate, can facilitate decompensation and the appearance of symptoms typical of Heart Failure (jugular engorgement, edema in the lower limbs, congestive hepatomegaly, ascites, pulmonary edema); Coronary Insufficiency (angina or myocardial infarction); Acute Stroke or Intermittent Claudication.

When the speed of onset of anemia is very abrupt (acute bleeding), the circulatory symptoms are constant and the one that dominates the clinical picture. It is characterized by intense tachycardia and palpitations. If the anemia is severe (Hb <5 g / dl), tachypnea, loss of consciousness and ECG changes (ST segment) are added, secondary to cardiac hypoxia-ischemia phenomena. In cases of very severe anemia (Hb <3 g / dl), signs of cerebral hypoxia appear (continuous headache, dizziness, altered consciousness), followed by a coma that can end the life of the patient due to cerebral anoxia.

At the neurological level, changes sometimes occur so subtle that the patient does not refer to them in his report, but they appear with directed questioning. Symptoms such as headache, subtle visual disturbances, insomnia, changes in character, irritability, inability to concentrate, are the reflection of neurological disorders secondary to varying degrees of neuronal hypoxia.

A fairly frequent sign to see, especially in moderate to severe cases of anemia, is lower limb edema. Its production is attributed to increased aldosterone secretion secondary to renal hypoflux with decreased flow and glomerular filtration (secondary hyperaldosteronism).

In severe cases, serum urea and creatinine may temporarily increase.

At the digestive level, anorexia, nausea and occasionally constipation are usually appreciated. These symptoms are due to splanchnic hypoflux that occurs as mentioned before as a compensatory phenomenon. Rarely, these symptoms can lead to weight loss. If this occurs, the sign should be considered more as an expression of the underlying disease and not as secondary to anemia.

Finally, a decrease in menstrual rhythm with a tendency to amenorrhea is common. If we take into account that hyper- or polymenorrhea is usually the most frequent cause of anemia in young women, this sign can be mistakenly interpreted as normalization of it. What happens is that the body reacts by regulating menstrual activity to reduce blood loss.

Other signs and symptoms frequently described within the anemia chapters are directly related to certain specific types of anemia and are described in each section separately, which is beyond the scope of this report.

Classification of Anemias

There are many and varied ways to classify anemias.

From a practical point of view, we consider it useful to classify them according to morphological (erythrocyte size) and pathophysiological (erythropoietic capacity) criteria.

Morphological Classification:

It is based on the appreciation of the size and hemoglobin content of erythrocytes.

Many years ago, Wintrobe proposed the use of “red cell indices”, based on a mathematical calculation obtained from the red cell count and the hemoglobin concentration.

For years, the estimation of these indices from manual procedures was cumbersome and most of the time, inaccurate. With the advent of automated counters, hematometric indices are now supplied by the vast majority of laboratories.

The Mean Corpuscular Volume (MCV), already discussed at the beginning of this chapter, is the most useful, the basis of the modern morphological classification of anemias, and divides them into three large groups: Normocytic (MCV: 85-95 fl); Microcytic (MCV: <85 fl) and Macrocytic (MCV:> 95 fl).

The MCV has a very close correlation with the Mean Corpuscular Hemoglobin (HCM), a quantity that informs about the average hemoglobin content of each erythrocyte. This parameter divides anemias into Hypochromic and Normochromic, with limits much less defined than the previous parameter, with the term hyperchromic not actually existing.

There is a close relationship between VCM and HCM. Microcytic anemias are always accompanied by a decrease in hemoglobin, giving rise to hypochromia, while macrocytic anemias are always normochromic since they have normal to high hemoglobin values.

The Mean Corpuscular Hemoglobin Concentration (MCHC) reflects the result of a mathematical calculation between the VCM and MCH and has very small variations, even with severe degrees of anemia. Its real value lies in the fact that a long time of anemia must elapse for this value to change. For example, in microcytic, hypochromic anemias, for the MCHC value to fall, many months must elapse. On the other hand, there is a group of anemias in which a characteristic increase in MCHC is observed, such as Hereditary Spherocytosis or Congenital Xerocytosis, diseases so rare that they make this parameter the one of least practical value.

In some situations in which there is a marked variation in the shape and size of the red blood cells (poikilocytosis, alterations in erythrocyte deformability), the MCV loses its usual value and the HCM becomes a more reliable value to classify anemias. To avoid this drawback, some modern analyzers provide the degree of scatter or red cell distribution width (RDW), with its corresponding histogram. Unfortunately, the lack of unification of criteria in the calculation of the ADE limits its applicability.

Physiopathological Classification

Although according to the previous classification, an altered MCV can already inform us about the probable pathophysiology of anemia; the pathophysiological classification adduces to the bone marrow's capacity to cope with the decrease in hemoglobin, and constitutes an essential element for the orientation of the underlying process.

A decrease in hemoglobin always has a counterpart, an increase in compensatory erythropoiesis. Therefore, when the marrow has a normal regenerative capacity, there must always be an inverse relationship between a decrease in hemoglobin and an increase in the reticulocyte count (Regenerative Anemias). On the contrary, if the anemia is not accompanied by a proportional increase in the number of reticulocytes, the response capacity of the marrow is limited (Arregenerative Anemias).

Regenerative anemias are due to a decrease in hemoglobin due to loss or hemolysis. In both cases, the erythropoietic stimulus elicits a strong erythroblastic response that manifests as reticulocytosis.

Leakage anemias are due to acute hemorrhages that can be seen on clinical examination or to more chronic losses of small volumes of blood, which by their nature tend to go unnoticed by the patient. In the latter case, a clearly regenerative anemia can be complicated by an iron deficiency component, due to chronic iron spoliation, thus becoming aregenerative.

The most common causes of chronic losses are those associated with poly-hypermenorrhea, as already mentioned, and those related to pathologies of the digestive tract.

Hemolytic anemia occurs when the half-life of erythrocytes in circulation is shortened due to their rupture in the blood vessels, a process called “intravascular hemolysis”, or due to excessive elimination by the Monocytic-Macrophage System (Spleen-Liver-Bone Marrow ) known in this case as “Extravascular Hemolysis”.

In this case too, a clearly regenerative state, if prolonged long enough, can deplete folate reserves and aggravate the anemic condition with megaloblastic anemia, of an arregenerative lineage.

Hemolytic anemias can be congenital or acquired.

The former are due to structural alterations of the red blood cell located in the membrane, the hemoglobin itself, or in the enzymes of intraerythrocyte metabolism.

The second are due to the direct action on the red blood cells of different factors, among which are antibodies (immune hemolytic anemias), chemical toxins (arsenic, copper, some snake venoms), germs (Systemic bacterial infections, Clostridium Welchii), parasites (malaria, bartonellosis), mechanical disorders (Thrombotic Thrombocytopenic Purpura, mechanical cardiac prostheses), or various metabolic disorders (liver cirrhosis, Zieve syndrome).

Study methodology

Carrying out a careful anamnesis and a detailed physical examination always constitute the basis for the diagnosis of anemia.

It is important to keep in mind that anemias are never a disease in and of themselves, but are always the sign of an underlying disorder. With this premise in mind, it is essential, when an anemia is detected, not only to think about correcting it but in parallel to work to detect this cause, which will allow applying the most appropriate treatment.

According to the previously stated concepts, it is important to take into account the patient's age and the form of presentation (acute or chronic, time of evolution and existence of a previous history of anemia).

In the case of acute anemias, after ruling out an acute hemorrhage, the diagnostic possibilities are limited to a few variables, with which the anamnesis is of crucial importance in these cases, to determine precisely which diagnostic tests should be requested.

When anemia is chronic, the diagnostic possibilities are much broader, and the first attitude of the clinician should be aimed at determining whether they are congenital or acquired. In these cases, we once again see that the anamnesis, with a correct questioning of the antecedents, becomes important.

In young subjects, chronic anemia with a history of neonatal jaundice and a family history of anemia or jaundice (often attributed to never-documented hepatitis) may be indicative of congenital hemolytic anemia.

In older adults, a long-standing hemolytic syndrome with exacerbations in crisis can lead to Paroxysmal Nocturnal Hemoglobinuria.

The appearance of an acute hemolytic process, with compromised renal and neurological function, should suggest Thrombotic Thrombocytopenic Purpura.

The profession (contact with lead, solvents and other toxins), and the characteristics of the diet (adequate consumption of iron and folate), and habits (alcoholism, smoking, drug use), are data of hierarchy to establish or guide and diagnosis.

The recent intake of medications is another aspect to bear in mind in the initial anamnesis. There are many compounds that can act on the bone marrow or on the erythrocytes directly and lead to anemia.

In all cases, the physical examination provides invaluable information. In addition to the skin-mucosa pallor, the presence of sub-jaundice associated with splenomegaly leads to a chronic hemolytic process. The appearance of a red, hairless tongue, with cheilosis and / or koilonychia, helps to guide the process towards the deficiency. The presence of ankle ulcers points to a long-standing hemolytic process and the observation of telangiectasias in the oral mucosa, towards Rendú-Osler disease.

In the abdomen, the detection of splenomegaly, associated with collateral circulation and other stigmata of chronic liver disease, will be associated with liver cirrhosis.

It is important not to miss the neurological examination, since vitamin B12 deficiency is associated with loss of vibratory and postural sensitivity of the extremities, characteristic of the subacute combined degeneration of the spinal cord caused by it.

The presence of B symptoms (fever, night sweats, weight loss) may be indicative of an underlying neoplastic process. If we add polyadenopathy and splenomegaly to this, the possibility of a lymphoproliferative process should be considered.

Collagen diseases are almost invariably accompanied by anemia, and in addition to the classic joint symptoms, fever is usually present.

Also invariably, anemia accompanies processes such as chronic and acute Renal Insufficiency, even with creatinine values ​​not too high, as well as imbalances of the thyroid gland.

An anemia with an erythrocyte sedimentation rate greater than 100 makes it necessary to look for neoplasia or the presence of monoclonal gamma disease.

Finally, in the presence of chronic anemia, especially when associated with fever of unknown origin, consideration should be given to ruling out the presence of the human immunodeficiency virus (HIV).

In children, the diagnosis of anemia is simplified, because the number of possible causes is much more limited. Thus, in newborns, the cause of anemia is limited to bleeding or a hemolytic process. During early childhood, hemorrhages lose prominence, and the chances of a pure red blood cell aplasia increase, generally associated with infection by Parbovirus B19.

From 6 months to 2 years, nutritional causes are the most frequent, along with acute inflammatory processes, although at this age, acute Thalassemias or Leukemia may appear. Finally, in adolescence, nutritional causes are again the most frequent.

Laboratory exams

Confirmation of anemia requires demonstration of decreased hemoglobin on a common blood count.

Although the number and characteristics of complementary tests vary widely to determine the cause of anemia, there are four tests that are mandatory, namely: general hematometric parameters, among which, as mentioned before, the MCV; examination of the peripheral smear, the reticulocyte count, and the erythrocyte sedimentation rate.

We already mentioned the importance of indices earlier.

Regarding the peripheral smear, it should be noted that even with the advent of highly reliable automated equipment, direct morphological observation continues to be an irreplaceable contribution to the evaluation, especially initial, of anemia.

It provides data, not only on the morphology of the red series, but also on the hemopathies that present with alteration of the white and / or platelet series.

The reticulocyte count helps determine if the anemia is regenerative or aregenerative depending on their number. This count can be expressed as a relative percentage with respect to the total red blood cell count or in absolute numbers. When they are expressed as a percentage, this must be corrected, since it is being calculated based on an always decreased number of red blood cells (anemia), and also does not take into account their premature exit from the bone marrow.

The correction is carried out as follows:

 Reticulocyte index: Reticulocytes (%) x Hematocrit Patient / 2
Normal Hematocrit

The importance of the erythrocyte sedimentation rate was also mentioned.

It is worth mentioning the bone marrow study.

In cases where the cause of anemia has not been clarified with complementary less invasive methods, and only in those cases, it is convenient to study the bone marrow.

The medullogram informs about the morphological characteristics of the myelogram and the ratio between myeloid and erythroid cells.

In addition, the medullogram is usually complemented with other tests that help to clarify the origin of the anemias, such as the staining of the medullary iron (Perls stain), which helps to differentiate, for example, between iron deficiency anemia, sideroblastic anemia and anemia of chronic diseases .

Another technique that is almost invariably used today is immunotyping of cellular elements. This technique, which has very important value in oncohematology, also helps in many instances of the study of anemias.

The cytochemical study, cytogenetics, and bone marrow cultures complete the battery of studies that can be performed on bone marrow samples.

For its part, the bone marrow biopsy informs us about the architecture of the bone, the arrangement of the cells as a whole and their proportion in relation to adipose cells and other non-hematopoietic (reticular) cells.

Treatment of anemia will obviously be directed by the underlying cause.

Repeating the advice given in previous paragraphs, "anemia is always a consequence of an underlying disorder", it is easy to understand that we will not be able to adequately treat anemia if we do not have an etiological diagnosis of it, even when with initial treatments (usually substitutes), let's see an adequate therapeutic response.

As general concepts, the treatment of anemia should be aimed at:

1) Improve the patient's symptoms and signs by reestablishing normal hemoglobin values

2) Treat the underlying cause

3) Avoid recurrence

Given the breadth of etiological causes, it is impossible to establish a general treatment guideline and is beyond the objectives of this chapter, therefore they should be treated with each section in particular.