Classification by Origin
Hemolytic anemias are broadly divided into two major groups based on the underlying etiology:
- Primary (Hereditary and Congenital). Caused by intrinsic genetic defects within the erythrocytes themselves. The defect may involve the cell membrane, intracellular enzymes, or the hemoglobin molecule.
- Secondary (Acquired). Occur when initially normal erythrocytes are destroyed due to extrinsic factors such as antibodies, mechanical obstacles, toxins, or parasites.
Hemolysis may be intravascular (occurring directly within the bloodstream) or extravascular (occurring within macrophages of the spleen).
Primary Anemias: Intrinsic Erythrocyte Defects
This group results from structural abnormalities within the red blood cells:
- Membranopathies. Caused by structural protein defects (protein-dependent) or lipid abnormalities (lipid-dependent). This alters cell shape (poikilocytosis), decreases osmotic fragility, and leads to premature destruction of erythrocytes outside blood vessels. Examples: hereditary spherocytosis, elliptocytosis. The only major exception is paroxysmal nocturnal hemoglobinuria (PNH), which is acquired.
- Enzymopathies. The most common form is glucose-6-phosphate dehydrogenase (G6PD) deficiency. Normally, this enzyme generates NADPH to maintain reduced glutathione, protecting the cell against oxidative stress. In its deficiency, free radicals damage membrane lipids and denature proteins (forming Heinz bodies). Common triggers include certain medications, infections, or fava beans.
- Hemoglobinopathies. Impaired synthesis of globin chains caused by point mutations. In sickle cell anemia, valine is substituted for glutamic acid at position 6 of the $\beta$-globin chain. This produces abnormal hemoglobin S (HbS), which polymerizes under low oxygen tension. Erythrocytes become rigid, assume a sickle shape, undergo destruction in the spleen, and occlude small blood vessels, leading to tissue ischemia and infarction.
Secondary Anemias: Extrinsic Aggression
In these conditions, normal erythrocytes are subjected to adverse systemic environments:
- Immune-mediated. Cells are destroyed by cytotoxic immunoglobulins. Subtypes include autoimmune (antibodies directed against self-antigens), alloimmune (destruction of foreign erythrocytes via transfusion reactions or hemolytic disease of the newborn), heteroimmune (reactions against drug haptens bound to the membrane), and transimmune (maternal antibodies crossing the placenta to the fetus).
- Mechanical. Erythrocytes are physically damaged by turbulent blood flow or mechanical barriers. Causes: severe hypertension, mechanical heart valves, disseminated intravascular coagulation (DIC).
- Infectious. Hemolysis is triggered by bacterial endotoxins or intracellular parasites (e.g., Plasmodium species causing malaria).
Pathogenesis of Destruction and Blood Profile
The universal mechanism of erythrocyte destruction follows this sequence: damaging factor $\rightarrow$ increased membrane permeability $\rightarrow$ influx of ions (Na⁺, Ca²⁺) $\rightarrow$ cytosolic hyperosmolality $\rightarrow$ cell swelling (spherocytosis) $\rightarrow$ plasma membrane rupture.
Laboratory Findings:
- Bone marrow: compensatory erythroid hyperplasia.
- Peripheral blood: erythropenia (except in thalassemia), reticulocytosis, polychromasia, and poikilocytosis.
- Biochemistry: unconjugated (indirect) hyperbilirubinemia.
Principles of Management
Therapy is based on three main pillars:
- Etiologic. Elimination of the hemolytic trigger or supportive measures (e.g., riboflavin, antioxidants).
- Pathogenetic. Prevention of cell destruction (definitive management includes splenectomy), management of iron overload using iron chelators (e.g., deferoxamine), and treatment of hypoxia (packed red blood cell transfusions, antioxidants).
- Symptomatic. Administration of buffer solutions to correct acid-base status and supportive care for cardiac, renal, and hepatic function.