Anemia: overview and classification

Article written and reviewed by Dr Luca Moretti

Anemia is a clinical and laboratory condition characterized by a reduced hemoglobin concentration in peripheral blood, which decreases the capacity of the blood to transport oxygen to tissues. It is not a disease in itself but a sign of an underlying, often systemic disorder that requires careful etiologic evaluation. According to the 2024 WHO guideline, at sea level the threshold in adults aged 15–65 years is <13 g/dL in men and <12 g/dL in nonpregnant women; during pregnancy it is <11 g/dL in the first and third trimesters and <10.5 g/dL in the second trimester.

The clinical significance of anemia depends on how rapidly it develops, its severity, and the patient’s general condition. In acute forms, especially with significant blood loss, consequences may be severe because of the rapid reduction in red blood cell mass and, in hemorrhage, hypovolemia; during the first hours, hemoglobin concentration may also underestimate the magnitude of blood loss. In chronic forms, the body activates compensatory mechanisms that may mask symptoms for a long time.

General pathophysiology

The abnormalities that lead to anemia can be traced to three major pathogenetic mechanisms: reduced production of red blood cells, blood loss and increased destruction of circulating red blood cells (hemolysis). These processes are not mutually exclusive and may coexist in the same patient, producing complex clinical pictures.

Reduced production may result from primary bone marrow injury, as in aplastic anemia or myelodysplastic syndromes, or from secondary conditions that interfere with erythroid proliferation and maturation. Nutritional deficiencies, chronic inflammation, and kidney failure are among the most common causes; some endocrine deficiencies, such as hypothyroidism, may also contribute to reduced erythropoiesis. In these cases, the bone marrow cannot compensate for the reduced red blood cell mass, and the reticulocyte count is inappropriately low.

Blood loss may be acute, as in trauma or gastrointestinal hemorrhage, or chronic and insidious, as in occult gastrointestinal bleeding. With healthy bone marrow and adequate iron stores, the erythropoietic response is generally effective, with increased reticulocytosis.

Hemolysis is the consequence of premature red blood cell destruction. It may result from intrinsic red blood cell defects (enzyme abnormalities, hemoglobinopathies, membrane disorders) or extrinsic causes (autoantibodies, toxins, infectious agents, microangiopathies). Hemolytic anemia is often associated with jaundice, splenomegaly, and increased indirect bilirubin.

Physiology of erythropoiesis

Red blood cell production occurs in the bone marrow through a process known as erythropoiesis, regulated by a delicate balance among hormonal stimuli, hematopoietic growth factors, micronutrient availability, and integrity of the bone marrow microenvironment. The main mediator of this process is erythropoietin (EPO), a glycoprotein hormone produced predominantly by the kidney in response to tissue hypoxia. EPO stimulates differentiation and survival of erythroid precursors, promoting expansion of the erythroid lineage.

Effective erythropoiesis requires adequate availability of iron (an essential component of hemoglobin), vitamin B12 and folic acid (required for DNA synthesis). Iron deficiency limits hemoglobin synthesis and causes microcytic, hypochromic erythropoiesis; vitamin B12 or folate deficiency impairs DNA synthesis and causes megaloblastic maturation arrest.

Other endocrine factors, such as androgens, thyroid hormones, and cortisol, modulate bone marrow activity. Inflammatory cytokines, by contrast, inhibit erythropoiesis and alter iron metabolism, promoting reticuloendothelial iron sequestration and contributing to anemia of chronic disease.

Systemic manifestations of anemia

The clinical manifestations of anemia result mainly from reduced oxygen-carrying capacity and activation of hemodynamic and respiratory compensatory mechanisms. The severity and nature of symptoms depend on three main variables: the degree of anemia, the rate at which it develops, and the functional reserve of target organs.

In acute forms, such as those secondary to massive hemorrhage, the clinical picture is dominated by hypovolemia and tissue hypoperfusion: sudden pallor, tachycardia, hypotension, dizziness, syncope, and shock. In slowly progressive chronic forms, symptoms may initially be subtle or unrecognized and appear only with physical exertion.

The most common symptoms include fatigue, dyspnea, reduced exercise tolerance, palpitations, headache, and irritability; pallor of the skin and mucous membranes may be present as a sign. Glossitis and nail changes may occur in specific nutritional deficiencies; neurologic abnormalities such as paresthesias, ataxia, and memory impairment are much more typical of vitamin B12 deficiency, although neurologic manifestations have been described, more rarely, in isolated folate deficiency.

The heart is one of the organs most sensitive to reduced oxygenation: anemia may precipitate myocardial ischemia, heart failure, or arrhythmias, especially in older patients or those with preexisting cardiovascular disease.

Classifications of anemia

To guide the diagnostic workup and establish a rational strategy, anemia must be classified correctly. Established clinical criteria primarily include morphologic and pathophysiologic approaches; the four-group scheme shown below is the teaching and functional framework used on this page, not a standard international classification.

The morphologic classification is based on mean corpuscular volume (MCV), a parameter readily obtained from the complete blood count. Microcytic anemias (MCV <80 fL) are typically associated with impaired hemoglobin synthesis, as in iron deficiency or thalassemias. Normocytic anemias (MCV 80–100 fL) are often associated with chronic disease, acute hemorrhage, or bone marrow failure. Macrocytic anemias (MCV >100 fL) include megaloblastic forms due to impaired DNA synthesis, as in vitamin B12 or folate deficiency, and nonmegaloblastic forms associated, for example, with liver disease, hypothyroidism, reticulocytosis, or certain medications.

The pathophysiologic classification distinguishes anemia according to the predominant mechanism: reduced production, blood loss, or increased destruction. This approach is particularly useful because it rapidly frames the pathogenesis and guides further testing.

Finally, topographic classification separates anemias due to reduced red blood cell production, including aplasia, myelodysplasia, nutritional deficiencies, kidney failure, and inflammation, from anemias due to peripheral loss or destruction, such as hemorrhage and hemolysis. In some cases, the distinction between these patterns is not clear-cut and integrated clinical and laboratory assessment is required.

Pathogenetic classification of anemia: the four main groups

Alongside morphologic and pathophysiologic criteria, this page uses a teaching subdivision into four groups. This scheme is not a standard international classification and should be interpreted together with MCV, reticulocytes, and the pathophysiologic mechanism. In addition to providing a logical and systematic framework for the different forms, this subdivision helps target the diagnostic and therapeutic approach.

• Group I Anemias: Impaired Erythroblastogenesis (Erythroblastopenias): the defect affects the initial phase of erythroid production, with reduced formation of erythroblasts, the precursors of red blood cells.
• Group II Anemias: Ineffective Erythropoiesis (Ineffective erythropoiesis): the defect involves maturation and differentiation of erythroblasts, which fail to develop into mature red blood cells.
• Group III Anemias: Reduced Hemoglobin Synthesis (Hemoglobin disorders): include conditions in which hemoglobin synthesis is quantitatively reduced, such as iron deficiency and thalassemias; structural hemoglobinopathies do not necessarily belong to this group and may cause anemia predominantly through hemolysis.
• Group IV Anemias: Increased Red Blood Cell Destruction (Hemolytic anemias): red blood cell lifespan is reduced by hemolytic processes of congenital or acquired origin.

This subdivision facilitates an integrated clinical approach by highlighting the main pathogenetic mechanisms and directing the diagnostic workup toward specific causes, many of which are discussed in detail on dedicated pages in this chapter.

Initial diagnostic approach

The first diagnostic tool available to the clinician is the complete blood count, which identifies the presence of anemia and helps characterize its morphology. Hemoglobin documents anemia relative to appropriate diagnostic thresholds but is not sufficient to define morphology and etiology; hematocrit, red blood cell indices (MCV, MCH, MCHC, RDW), reticulocyte count, peripheral blood smear, and any abnormalities of the white blood cell differential or platelet count must also be assessed.

The reticulocyte count is the key parameter for distinguishing hypoproliferative from regenerative anemias. The response should be interpreted using the absolute count and, when appropriate, the reticulocyte production index, which adjusts for the degree of anemia. In anemia, a high reticulocyte response suggests acute blood loss or hemolysis, whereas a low response suggests impaired bone marrow production or substrate deficiency.

Depending on the initial findings, the diagnostic workup is supplemented with targeted tests: iron studies, vitamin B12 and folate levels, hemolysis markers (LDH, indirect bilirubin, haptoglobin), direct antiglobulin test, erythropoietin level, hemoglobin electrophoresis and, in selected cases, bone marrow biopsy.

The following pages examine each category of anemia individually using a consistent etiopathogenetic framework, guiding the reader from pathophysiology and clinical features to diagnosis and treatment.

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