Anemia- definition & pathophysiological classifications

Overview

Anemia is defined as a decrease in the absolute number of circulating red blood cells (RBCs) or hemoglobin concentration in the blood below the normal physiological range for age and sex. Consequently, the oxygen-carrying capacity of the blood is reduced, leading to tissue hypoxia.

Normal hemoglobin values are approximately as follows:

• Adult men: above 13 g/dL
• Adult women: above 12 g/dL

Anemia is not a disease itself, but rather a clinical manifestation of an underlying disorder.

Pathophysiological Classification

Anemia develops as a result of one or more of the following fundamental pathophysiological mechanisms:

• Decreased production of red blood cells
• Increased destruction of red blood cells (hemolysis)
• Blood loss

Therefore, based on these mechanisms, anemia can be classified into three main groups:

1. Anemias caused by decreased erythrocyte production
2. Anemias caused by increased erythrocyte destruction (hemolytic anemias)
3. Anemias caused by blood loss

This classification is clinically useful as it encourages further diagnostic testing and consequently narrows the differential diagnosis.

Anemias Caused by Decreased Erythrocyte Production

These anemias are caused by insufficient production of red blood cells in the bone marrow.

Main Mechanisms

• Deficiency of essential substrates for erythropoiesis (iron, vitamin B12, folate)
• Bone marrow failure or suppression
• Reduced stimulation by erythropoietin

Examples

• Iron deficiency anemia
• Vitamin B12 deficiency anemia
• Folic acid deficiency anemia
• Aplastic anemia
• Anemia of chronic disease
• Anemia in chronic kidney disease due to reduced erythropoietin production

Pathophysiology

DNA synthesis is impaired or there are fewer hemoglobin components available. These factors will result in a decreased formation of mature erythrocytes and thus a reduced oxygen carrying capacity.

Anemias Caused by Increased Erythrocyte Destruction (Hemolytic Anemias)

These anemias are characterized by shortened (less than 120 days) survival of red blood cells due to their premature destruction.

Main Mechanisms

• Intrinsic defects of erythrocytes
• Extrinsic factors causing red blood cell damage

Intrinsic Causes

• Hereditary spherocytosis – an inherited blood disorder causing fragile, sphere-shaped red blood cells
• Glucose-6-phosphate dehydrogenase deficiency - a genetic condition where RBCs lack the enzyme glucose-6-phosphate dehydrogenase (G6PD), which protects them from damage, especially from oxidative stress
• Sickle cell disease - an inherited blood disorder where RBCs become stiff, sticky, and C-shaped (like sickles) due to abnormal hemoglobin
• Thalassemia - an inherited blood disorder where the body makes less or abnormal hemoglobin

Extrinsic Causes

• Autoimmune hemolytic anemia - antibodies bind to RBCs and cause their immune-mediated destruction
• Mechanical destruction (prosthetic heart valves) - RBCs are physically damaged by artificial surfaces and shear stress
• Infections - parasites or bacteria directly damage RBCs or trigger immune hemolysis
• Toxins and drugs - chemicals and medications cause oxidative or membrane damage leading to hemolysis

Pathophysiology

There is an increased erythrocyte destruction which exceeds the compensatory capacity of the bone marrow, leading to anemia and increased bilirubin production.

Anemias Caused by Blood Loss

These anemias result from acute or chronic loss of blood.

Acute Blood Loss

• Trauma
• Surgery
• Gastrointestinal bleeding

Chronic Blood Loss

• Peptic ulcer disease
• Colorectal cancer
• Menorrhagia
• Parasitic infections

Pathophysiology

A loss of circulating red blood cells leads to reduced oxygen delivery to tissues around the body. In chronic blood loss, iron stores become depleted, resulting in secondary iron deficiency anemia.

Clinical Features

Common Symptoms

• Fatigue
• Weakness
• Exertional dyspnea
• Dizziness
• Headache

Common Signs

• Pallor (for example on mucous membranes and conjunctivae)
• Growth impairment in chronic anemia
• Tachycardia
• Cold extremities

Compensatory Mechanisms in Anemia

To maintain oxygen delivery, the body activates several adaptive mechanisms such as:

• Increased cardiac output
• Increased respiratory rate
• Redistribution of blood flow to vital organs
• Increased erythropoietin secretion
• Increased extraction of oxygen from tissues

Basic Principles of Diagnosis

• Complete blood count
• Hemoglobin and hematocrit levels
• Red blood cell indices (mean corpuscular volume, mean corpuscular hemoglobin)
• Reticulocyte count
• Peripheral blood smear
• Iron studies, vitamin B12 and folate levels according to the suspected cause

Sources

• Guyton AC, Hall JE. Textbook of Medical Physiology. 13th ed. Elsevier; 2015. Chapter 33: Red Blood Cells, Anemia, and Polycythemia.
• Kumar V, Abbas AK, Aster JC. Robbins and Cotran Pathologic Basis of Disease. 10th ed. Elsevier; 2020. Chapter 12: Hematopoietic and Lymphoid systems.
• Silbernagl S, Lang F. Color Atlas of Pathophysiology. Thieme; 2020. Section: Anemias.
• AMBOSS. Anemia – overview and classification. https://next.amboss.com/us/article/6T0j72?q=anemia. Accessed December 2025.