Definition and causes of anemia

Anemia is defined as a reduction in the concentration of hemoglobin in the peripheral blood below the reference range for the age and gender of an individual (see Table 1.3 for reference ranges). It may be inherited or acquired and results from an imbalance between red cell production and red cell loss (Table 6.1). In general terms the causes of anemia are:

Table 6.1 Mechanisms of anemia

This chapter outlines the clinical features of anemia and the process for investigation and classification of anemia. It will set the scene for the following chapters which detail the specific mechanisms of anemia.

Clinical features of anemia

A detailed clinical history is critical in determining the cause of anemia. Table 6.2 lists some of the important personal, dietary, drug and family history issues to be explored. The symptoms and signs of anemia result from decreased tissue oxygenation leading to organ dysfunction as well as from adaptive changes, particularly in the cardiovascular system.^1,2 The nature and severity of symptoms is influenced by:

Table 6.2 Clinical history in the investigation of anemia

Symptoms of anemia include lassitude, easy fatigability, dyspnea on exertion, palpitations, angina and intermittent claudication, headache, vertigo, light-headedness, visual disturbances, drowsiness, anorexia, nausea, bowel disturbances, menstrual disturbances and loss of libido. Physical signs include pallor, signs of a hyperkinetic circulation (tachycardia, wide pulse pressure with capillary pulsation, cardiac murmurs), signs of congestive cardiac failure, and hemorrhages and exudates in the retina. Severe anemia may also cause slight proteinuria, mild impairment of renal function and low-grade fever.

A moderate degree of chronic anemia is usually associated with only mild symptoms accompanied by slight increases in cardiac output at rest and slight decreases in mixed venous PO₂. This is because there is a substantial shift of the oxygen dissociation curve to the right (see Chapter 1), mainly due to an adaptive increase in the levels of red cell 2,3-diphosphoglycerate. When the hemoglobin falls below 7–8 g/dl symptoms usually become more marked. The intra-erythrocytic adaptation cannot by itself maintain adequate oxygen delivery to the tissues and other compensatory mechanisms come into effect. These include:

The blood count and red cell indices in anemia

The mean cell volume (MCV) is the most useful red cell parameter for the assessment of the underlying cause of anemia. By using the MCV, anemias can be categorized by red cell size as microcytic (MCV <80 fl), normocytic (normal MCV) or macrocytic (MCV >100 fl). This provides a practical and rapid way of assessing possible causes and guiding further investigations (see below and Table 6.3). The mean cell hemoglobin (MCH) and mean cell hemoglobin concentration (MCHC) are generally of less value than the MCV in the assessment of anemia. The red cell distribution width (RDW), a quantitative measure of the degree of variation in red cell size, can be useful in the assessment of some types of anemia. Usually erythrocytes are of a standard size (6–8 µm) and the RDW is 12–14%. A high RDW indicates that there is variation in erythrocyte size and gives a quantitative measure of anisocytosis. For example, in microcytic anemias, a normal RDW is generally seen in thalassemias whereas in iron deficiency it is mildly elevated. The graphical depiction of red cell features on blood count histograms, such as red cell number versus MCV, may also give an indication of anisocytosis, or the presence of dimorphic populations of erythrocytes.

Table 6.3 Practical classification of anemia based on mean cell volume

The reticulocyte count can be used as a guide to distinguish between reduced bone marrow erythropoiesis and accelerated red cell loss as the primary cause of the anemia. An inappropriately low reticulocyte count for the degree of anemia indicates that there is impaired marrow erythroid response to the anemia, i.e., the underlying cause is interfering with marrow erythropoiesis. This may be due to a chronic infective or inflammatory process, bone marrow failure or infiltration, reduced hematinics, ineffective erythropoiesis (dyserythropoiesis) or inadequate erythropoietin as occurs in renal failure. In contrast an appropriate reticulocytosis is evidence that the marrow is responding to the anemia and the cause is likely to be peripheral (i.e. hemolysis or blood loss). Other red blood cell measurements, such as the nucleated red cell count and immature reticulocyte fraction, do not generally add significant value to the investigation of anemia.

The leukocyte and platelet counts will distinguish isolated anemia from pancytopenia. Neutrophilia and/or thrombocytosis can be seen in response to acute blood loss and hemolysis. The presence of abnormal leukocytes in the presence of anemia (e.g. blast cells) may indicate underlying bone marrow failure as a result of a neoplastic infiltrate.

Red cell morphology in anemia

Blood film examination to review red cell morphology has a critical role in the investigation and diagnosis of anemia. The identification of red cell morphological abnormalities may lead to a definitive or differential diagnosis and guide further investigations (Fig. 6.1A–F). The film should be prepared from a freshly collected blood sample, well-stained and coverslipped. Blood stored for >6 hours in anticoagulant prior to the preparation of the film can result in artifacts (e.g. red cell crenation) that can interfere with interpretation of the true red cell morphology. Morphological artifacts can also result from the blood being stored at incorrect temperatures (hot or cold) prior to preparation of the blood film. The film should be examined in an area where only occasional red cells overlap. In such an area normal red cells are primarily round and show a central area of pallor which occupies less than a third of the diameter of the cell. The film should be assessed systematically for:

Fig. 6.1 Examples of red cell morphological abnormalities seen in anemia. (A) Oval macrocytes, a megaloblastic late normoblast and basophilic stippling in megaloblastic anemia due to folate deficiency. (B) Hypochromic red cells and mild poikilocytosis in severe iron deficiency anemia. (C) Spherocytes and basophilic stippling in hemolytic anemia secondary to clostridial septicemia. (D) Schistocytes, target cells, echinocytes, acanthocytes and polychromasia in sepsis with disseminated intravascular coagulation, renal and hepatic impairment. (E) Sickle-shaped red cells in sickle cell disease. Target cells are also present. (F) Acanthocytes in end-stage liver disease (‘spur’ cell anemia). May–Grünwald–Giemsa stain. × 1000.

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