Pathophysiology of Anemia and Polycythemia

Introduction

• Alterations in red cell mass are classified into anemia and polycythemia.
• Anemia refers to decreased red cell mass, whereas polycythemia denotes increased red cell mass.
• In anemia, reduced hemoglobin lowers the oxygen-carrying capacity of blood.
• Clinical manifestations mainly result from tissue hypoxia and compensatory responses such as increased cardiac output.
• Therefore, anemia is commonly assessed using hemoglobin concentration.
• Polycythemia is best evaluated using hematocrit percentage, which reflects the volume of red cells.
• Its clinical effects are related to increased blood viscosity and impaired microcirculation.
• Although it may involve all formed elements, it usually indicates increased red cell mass.

Anemia

• Anemia is defined as a reduction in hemoglobin concentration or red blood cell count.
• It is detected primarily by measuring hemoglobin levels.
• Additional evaluation includes red blood cell count and packed cell volume estimation.
• Clinically, anemia presents with pallor, especially in the conjunctiva and nail beds.
• Classification of anemia relies on blood indices, which help identify morphological types and guide diagnosis.

Classification

• Anemia can be classified morphologically based on red cell size and hemoglobin content, or etiologically based on underlying cause.
• Common causes include nutritional deficiencies, especially iron, vitamins, and proteins.
• Bone marrow failure leads to reduced red cell production.
• Chronic diseases and renal failure also impair erythropoiesis.
• Inherited disorders such as thalassemia affect hemoglobin synthesis.
• Blood loss and hemolysis increase red cell destruction.
• Broadly, anemia is grouped into decreased production and increased destruction of red cells.

Morphological Classification

• Morphological classification of anemia is based on red cell size and hemoglobin content using blood indices.
• It includes hypochromic microcytic, normochromic normocytic, and macrocytic normochromic types.

Hypochromic Microcytic Anemia

• Hypochromic microcytic anemia shows reduced mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration.
• Red cells appear small and pale due to defective hemoglobin synthesis.
• Bone marrow may show micronormoblastic changes.
• Common causes include iron deficiency, affecting heme synthesis, and thalassemia, affecting globin synthesis.

Normochromic Normocytic Anemia

• Normochromic normocytic anemia presents with normal red cell indices.
• Red cells maintain normal size and hemoglobin concentration in peripheral smear.
• It commonly occurs in acute blood loss, hemolysis, or reduced production due to bone marrow failure.
• Chronic renal disease may also lead to this pattern due to decreased erythropoietin production.

Macrocytic Normochromic Anemia

• Macrocytic normochromic anemia is characterized by increased mean corpuscular volume with normal hemoglobin concentration.
• Red cells are enlarged, indicating macrocytosis.
• Bone marrow typically shows megaloblastic changes with abnormal nuclear maturation.
• Peripheral smear may reveal hypersegmented neutrophils and nuclear remnants such as Howell Jolly bodies.
• This type is commonly associated with deficiency of vitamin B12 or folic acid.
• Morphological classification assists in identifying the underlying mechanism and guides further diagnostic evaluation and management.

Etiological Classification

• Etiological classification of anemia is based on the underlying cause, including blood loss, decreased production, or increased destruction of red cells.

Blood Loss Anemia

• Blood loss anemia results from either acute or chronic hemorrhage.

Acute hemorrhage:

• In acute hemorrhage, there is an immediate reduction in blood volume.
• Initially, hemoglobin concentration may remain normal due to proportional loss of plasma and cells.
• After several hours, fluid shifts cause hemodilution, leading to a fall in measured hemoglobin.
• Therefore, early hemoglobin estimation may underestimate the severity of anemia.

Chronic hemorrhage:

• Chronic hemorrhage leads to gradual depletion of iron stores and progressive anemia.
• Common sources include gastrointestinal bleeding, such as peptic ulcer, malignancy, or parasitic infestation.
• Respiratory conditions causing hemoptysis or recurrent epistaxis may contribute to chronic blood loss.
• Genitourinary disorders producing hematuria or hemoglobinuria also result in anemia.
• In females, excessive menstrual bleeding or uterine pathology is a frequent cause.
• Chronic blood loss often presents as iron deficiency anemia, with reduced hemoglobin synthesis and microcytic changes.

Table 15.1: Classification of anemia.

Category	Mechanism	Examples
Decreased production	Stem, progenitor, or precursor failure	Aplastic anemia, chronic renal disease, megaloblastic anemia, iron deficiency, thalassemia
Increased destruction or loss	Hemolysis or bleeding	Acute blood loss, hypersplenism, immune hemolysis, membrane, enzyme, and globin defects

Table 15.2: Causes of aplastic anemia.

Category	Etiology	Examples
Acquired	Toxic, drug-induced, radiation, infections	Benzene, anticancer drugs, chloramphenicol, radiation, viral infections
Hereditary	Genetic marrow failure syndromes	Fanconi anemia, Shwachman syndrome
Idiopathic	Unknown cause	Most common, about 65% cases

Aplastic Anemia

• Aplastic anemia is characterized by reduced red blood cell production due to failure of bone marrow activity.
• Bone marrow examination reveals marked reduction or absence of hematopoietic precursor cells.

Hemolytic Anemia

• Hemolytic anemia results from increased destruction of red blood cells exceeding their production.
• Causes are classified into intracorpuscular defects, originating within red cells, and extracorpuscular factors, acting from external influences.

Common Anemias

Iron-deficiency Anemia (IDA)

• Iron deficiency anemia is the most common type of anemia, especially in developing regions.
• It results from insufficient availability of iron for hemoglobin synthesis.
• Major causes include increased physiological demand, such as during pregnancy, lactation, and growth in children.
• Inadequate dietary intake of iron is a frequent contributing factor.
• Chronic blood loss from gastrointestinal lesions, parasitic infestation, or recurrent bleeding also leads to deficiency.
• This anemia is typically microcytic and hypochromic, indicating small and pale red cells.
• Laboratory findings show reduced mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration.
• Peripheral smear reveals microcytic hypochromic cells, and bone marrow shows decreased iron stores.

Table 15.3: Causes of hemolytic anemia.

Hereditary Spherocytosis

• Hereditary spherocytosis is a hemolytic anemia caused by defects in red cell membrane proteins, especially reduced spectrin.
• Red cells become spherical with decreased deformability and are destroyed in the spleen.
• It is an autosomal dominant disorder affecting both sexes equally.
• Clinical features include anemia, jaundice, splenomegaly, and pigment gallstones.
• Peripheral smear shows spherocytes, with increased osmotic fragility and reticulocytosis.
• Bilirubin levels are elevated due to increased hemolysis.
• The anemia is usually normocytic and normochromic.
• Splenectomy reduces hemolysis and improves clinical condition.

Sickle-cell Anemia

• Sickle cell anemia is a hereditary disorder due to abnormal hemoglobin called hemoglobin S.
• It results from substitution of valine for glutamic acid at the sixth position of the beta chain.
• In low oxygen states, red cells become rigid and assume a sickle shape, leading to hemolysis.
• Diagnosis includes sickling tests, hemoglobin solubility testing, and hemoglobin electrophoresis.
• Repeated splenic infarctions lead to hyposplenism and possible autosplenectomy.
• The anemia is typically normocytic and normochromic with ongoing hemolysis.

Thalassemia

• Thalassemia is a group of inherited disorders characterized by reduced synthesis of one or more globin chains of hemoglobin.
• It is a common monogenic disorder with variable clinical severity.
• Two major types are alpha thalassemia and beta thalassemia, depending on the affected globin gene.

β thalassemia

• In beta thalassemia, reduced beta chain production leads to excess alpha chains that damage red cells and their precursors.
• It exists in major and minor forms, with the major form presenting early in infancy.
• Clinical features include severe anemia, splenomegaly, hepatomegaly, and skeletal deformities.
• The anemia is usually microcytic and hypochromic, though variations may occur.

α-thalassemia

• In alpha thalassemia, reduced alpha chain synthesis causes excess beta or gamma chains, leading to hemolysis.
• This form is often more hemolytic than due to defective production alone.
• Aggregation of excess chains forms inclusion bodies such as hemoglobin H.
• Diagnosis involves hemoglobin electrophoresis, detection of inclusion bodies, and assessment of globin chain synthesis.
• Additional tests include alkali denaturation and acid elution methods for detailed evaluation.

Polycythemia

• Polycythemia refers to an increase in red blood cell mass, although it may involve other formed elements.
• It is classified into primary, secondary, and relative types based on underlying mechanisms.
• Primary polycythemia, also called polycythemia vera, is a clonal disorder of hematopoietic stem cells.
• It results in uncontrolled proliferation of erythroid, granulocytic, and megakaryocytic lineages.
• This leads to increased red cells along with leukocytosis and thrombocytosis.
• Secondary polycythemia occurs due to increased secretion of erythropoietin.
• It may be an appropriate response to hypoxia, such as in chronic lung disease or high altitude.
• It may also occur inappropriately due to certain tumors producing erythropoietin.
• In this form, the rise is mainly limited to red blood cells.
• Relative polycythemia is not a true increase in red cell mass but results from reduced plasma volume.
• Dehydration is a common cause leading to apparent elevation in hematocrit.

Types of Polycythemia

Polycythemia Vera

• Polycythemia vera typically presents in later adulthood with headache, dizziness, and plethoric appearance.
• Patients may develop pruritus, thrombotic events, and bleeding tendencies.
• Bone marrow shows hypercellularity involving all cell lines.
• Laboratory findings include markedly increased erythrocyte count, leukocytosis, and thrombocytosis.
• Management includes phlebotomy, which reduces blood viscosity by removing approximately 500 milliliters of blood periodically.
• Cytoreductive therapy with myelosuppressive drugs may be used to control marrow proliferation.
• Polycythemia increases blood viscosity, impairing circulation and predisposing to vascular complications.

Table 15.4: Types of polycythemia.

Type	Mechanism	Representative causes
Primary polycythemia	Clonal marrow proliferation	Polycythemia vera
Secondary polycythemia	Increased erythropoietin	Hypoxia (high altitude, lung disease), tumors (renal, hepatic), endocrine disorders
Relative polycythemia	Reduced plasma volume	Dehydration, fluid redistribution