Anemia is a clinical and laboratory condition characterized by a reduction in hemoglobin concentration in peripheral blood, compromising the cardiovascular system’s ability to deliver adequate oxygen to tissues. It is not a disease per se, but rather a sign of an underlying—often systemic—pathology that requires thorough etiological assessment. The definition relies on threshold values that vary according to age, sex, and physiological status: according to the World Health Organization, anemia is defined as hemoglobin <13 g/dL in adult males, <12 g/dL in non-pregnant females, and <11 g/dL during pregnancy.
The clinical significance of anemia depends on its rate of onset, severity, and the patient’s overall condition. In acute forms, even a modest hemoglobin drop may have dramatic consequences, whereas in chronic cases, the body activates compensatory mechanisms that can mask symptoms for extended periods.
The mechanisms leading to anemia can be grouped into three major pathophysiological processes: reduced red blood cell production, blood loss, and increased red cell destruction (hemolysis). These processes are not mutually exclusive and may coexist in the same patient, resulting in complex clinical presentations.
Reduced production may stem from primary bone marrow failure, as seen in aplastic anemia or myelodysplastic syndromes, or from secondary conditions that impair erythroid proliferation and maturation: nutritional deficiencies, hormonal imbalances, chronic inflammation, and renal failure are among the most common causes. In such cases, the bone marrow fails to compensate for the decreased red cell mass, leading to inappropriately low reticulocyte counts.
Blood loss may be acute—such as in trauma or gastrointestinal bleeding—or chronic and insidious, as in occult gastrointestinal hemorrhage. When the bone marrow is intact and iron stores are adequate, the erythropoietic response is typically robust, with increased reticulocyte production.
Hemolysis is the result of premature red cell destruction. It may be due to intrinsic red cell defects (enzyme deficiencies, hemoglobinopathies, membrane disorders) or extrinsic causes (autoantibodies, toxins, infections, microangiopathies). Hemolytic anemia often presents with jaundice, splenomegaly, and elevated indirect bilirubin levels.
Red blood cell production takes place in the bone marrow through a process known as erythropoiesis, governed by a delicate balance between hormonal signals, hematopoietic growth factors, micronutrient availability, and the integrity of the marrow microenvironment. The main driver is erythropoietin (EPO), a glycoprotein hormone produced primarily by the kidneys in response to tissue hypoxia. EPO promotes the differentiation and survival of erythroid precursors, enhancing red cell lineage expansion.
Effective erythroid maturation requires sufficient levels of iron (an essential component of hemoglobin), vitamin B12, and folic acid (both required for DNA synthesis). Deficiency of any of these elements results in maturational arrest and production of morphologically abnormal erythrocytes.
Other endocrine factors—such as androgens, thyroid hormones, and cortisol—modulate marrow activity. In contrast, inflammatory cytokines exert an inhibitory effect on erythropoiesis and alter iron metabolism, promoting reticuloendothelial sequestration and contributing to the development of anemia of chronic disease.
The clinical manifestations of anemia mainly result from reduced oxygen-carrying capacity of the blood and the activation of hemodynamic and respiratory compensatory mechanisms. The severity and nature of symptoms depend on three key variables: the degree of anemia, its rate of onset, and the functional reserve of the affected organs.
In acute forms—such as massive hemorrhage—the clinical picture is dominated by hypovolemia and tissue hypoperfusion: sudden pallor, tachycardia, hypotension, dizziness, syncope, and shock. Conversely, in slowly evolving chronic forms, symptoms may be initially subtle or overlooked, becoming evident only during physical exertion.
Common symptoms include fatigue, dyspnea, reduced exercise tolerance, palpitations, headache, irritability, and mucosal pallor. In severe or prolonged anemia, glossitis, brittle nails, capillary fragility, and—in megaloblastic anemia—neurological manifestations such as paresthesia, ataxia, and memory disturbances may occur.
The heart is particularly sensitive to oxygen deprivation: anemia may precipitate myocardial ischemia, heart failure, or arrhythmias, especially in elderly patients or those with preexisting cardiovascular disease.
Proper classification is essential for guiding diagnostic work-up and defining a rational approach. The main criteria used for classification are: morphological, pathophysiological, and topographical.
The morphological classification is based on mean corpuscular volume (MCV), a parameter easily obtained from a complete blood count. Microcytic anemia (MCV <80 fL) typically reflects impaired hemoglobin synthesis, as in iron deficiency or thalassemia. Normocytic anemia (MCV 80–100 fL) is often associated with chronic disease, acute blood loss, or marrow failure. Macrocytic anemia (MCV >100 fL) results from defective DNA synthesis, as in vitamin B12 or folate deficiency, but may also be seen in liver disease, hypothyroidism, or marrow-toxic drug exposure.
The pathophysiological classification groups anemia according to the predominant mechanism: reduced production, blood loss, or increased destruction. This approach is especially useful for understanding the underlying pathogenesis and directing further investigations.
The topographical classification distinguishes central (bone marrow) defects—such as aplasia and myelodysplasia—from peripheral causes, including hemorrhage, hemolysis, or nutritional deficiencies. In some cases, these patterns may overlap, requiring integrated interpretation of clinical and laboratory data.
The first diagnostic tool available to clinicians is the complete blood count (CBC), which confirms the presence of anemia and provides morphological insight. Hemoglobin alone is not sufficient: hematocrit, red cell indices (MCV, MCH, MCHC, RDW), reticulocyte count, and possible leukocyte or platelet abnormalities must also be evaluated.
Reticulocyte count is the key parameter for differentiating hypoproliferative from regenerative anemias. In the context of anemia, a high reticulocyte response suggests acute blood loss or hemolysis, while a low response indicates impaired marrow production or substrate deficiency.
Based on initial findings, the diagnostic work-up expands with targeted tests: iron studies, vitamin B12 and folate assays, hemolysis markers (LDH, indirect bilirubin, haptoglobin), direct Coombs test, erythropoietin level, hemoglobin electrophoresis, and in selected cases, bone marrow biopsy.
In the following pages, each anemia subtype will be explored in detail through a coherent pathophysiological classification, guiding the reader from pathogenesis to clinical features, diagnostic criteria, and treatment strategies.