What are the intrinsic and extrinsic causes of hemolysis?

Causes of Hemolysis

Classification Framework

Hemolysis is fundamentally classified into intrinsic (intracorpuscular) causes arising from defects within the red blood cell itself, and extrinsic (extracorpuscular) causes resulting from external factors that damage otherwise normal red blood cells. 1, 2

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Intrinsic (Intracorpuscular) Causes

Membranopathies (Red Cell Membrane Defects)

• Hereditary spherocytosis is characterized by spherocytes on peripheral smear, a positive family history, and a negative direct antiglobulin test (DAT), representing a primary membrane abnormality that decreases the surface area-to-volume ratio and compromises deformability 1, 3
• Hereditary elliptocytosis and stomatocytosis result from structural membrane protein defects that alter red cell shape and reduce survival 3
• These membrane disorders lead to decreased deformability and premature trapping in the spleen, causing extravascular hemolysis 3

Enzymopathies (Red Cell Enzyme Deficiencies)

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymopathy, leading to hemolysis in the presence of oxidative stress from infections, certain foods (fava beans), or medications 4, 1
• Pyruvate kinase (PK) deficiency presents with chronic hemolysis, reticulocytosis, increased LDH, reduced haptoglobin, and elevated bilirubin; patients may have unremarkable red cell morphology with occasional echinocytes (3-30%), particularly post-splenectomy 4
• PK deficiency should be suspected in transfusion-dependent patients without obvious etiology, neonates with unexplained severe hyperbilirubinemia, or when reticulocytosis increases paradoxically after splenectomy 4

Hemoglobinopathies

• Sickle cell disease causes hemolysis through intravascular destruction when hemoglobin polymerizes under deoxygenated conditions, with decompartmentalized hemoglobin promoting vasomotor dysfunction and vaso-occlusion 4, 5
• Thalassemias (alpha and beta) result in chronic hemolysis due to imbalanced globin chain production and ineffective erythropoiesis 4, 1
• Unstable hemoglobins precipitate within red cells, causing membrane damage and premature destruction 1

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Extrinsic (Extracorpuscular) Causes

Immune-Mediated Hemolysis

• Autoimmune hemolytic anemia (AIHA) occurs when antierythrocyte antibodies bind to red cell surfaces, detected by a positive direct antiglobulin test (DAT), leading to extravascular hemolysis through phagocytosis or intravascular hemolysis via complement activation 1, 2
• Drug-induced immune hemolysis can result from medications including penicillin, which trigger antibody formation against red cells 1, 2
• Transfusion reactions from ABO incompatibility cause acute intravascular hemolysis through complement fixation 6
• Alloimmune hemolysis includes hemolytic disease of the newborn from maternal-fetal blood group incompatibility 2

Microangiopathic Hemolytic Anemia (MAHA)

• Thrombotic microangiopathies (TTP, HUS, DIC) cause red cell fragmentation when cells are damaged by fibrin strands in the microcirculation, producing characteristic schistocytes on peripheral smear 1, 2
• Mechanical trauma from prosthetic heart valves or other cardiac devices directly fragments red cells, causing intravascular hemolysis 2, 6

Infectious Causes

• Malaria and babesiosis directly invade and destroy red blood cells 1, 2
• Clostridial sepsis produces toxins that cause severe intravascular hemolysis 2, 6
• Bartonellosis and other bacterial infections can trigger hemolysis 2

Chronic Hemolytic Anemias

• Sickle cell disease, thalassemia, hereditary spherocytosis, stomatocytosis, and microangiopathic hemolytic anemia are included as causes of chronic hemolysis that may result in pulmonary arterial hypertension through mechanisms related to high nitric oxide consumption 4

Systemic and Metabolic Causes

• Wilson's disease can present with Coombs-negative hemolytic anemia as the only initial symptom, or marked hemolysis associated with severe liver disease from massive copper release 4
• Hypersplenism causes sequestration and premature destruction of red cells 2
• Severe burns cause direct thermal injury to red cell membranes, leading to intravascular hemolysis 6

Oxidative and Toxic Insults

• Oxidative medications and chemicals (dapsone, nitrites, aniline dyes) cause hemolysis, particularly in G6PD-deficient individuals 2
• Venoms (snake, spider) contain hemolytic toxins that directly lyse red cells 2

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• PNH is an acquired clonal disorder with defective GPI-anchored proteins (CD55, CD59), making red cells susceptible to complement-mediated intravascular hemolysis 6

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Mechanistic Considerations

Location of Hemolysis

• Intravascular hemolysis occurs when red cells lyse within the circulation due to complement fixation, trauma, or severe oxidative stress, releasing free hemoglobin, causing hemoglobinemia, hemoglobinuria, and hemosiderinuria 6, 5
• Extravascular hemolysis (most common mechanism) occurs when the reticuloendothelial system removes red cells that are intrinsically defective or antibody-coated, predominantly in the spleen and liver 6, 3

Pathophysiological Mechanisms

• Poor deformability from membrane defects or altered hemoglobin leads to trapping and phagocytosis in the spleen 2, 3
• Antibody-mediated destruction through phagocytosis or direct complement activation 2
• Fragmentation from microthrombi or mechanical trauma 2
• Direct cellular destruction from infections or toxins 2

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Clinical Pitfalls and Diagnostic Considerations

• Reticulocytosis may be blunted in PK deficiency despite ongoing hemolysis because younger PK-deficient erythrocytes are selectively sequestered by the spleen, and oxygen delivery is relatively preserved by increased 2,3-DPG 4
• Splenectomy paradoxically increases reticulocytes in PK deficiency even as anemia improves, which can be a diagnostic clue 4
• Red cell morphology is often unremarkable in enzymopathies like PK deficiency, unlike membrane disorders where spherocytes or elliptocytes are prominent 4, 1
• Hemoglobinemia, hemoglobinuria, and hemosiderinuria occur only with severe and rapid intravascular hemolysis (incompatible transfusion, G6PD crisis, PNH, severe burns, certain infections) 6
• Direct antiglobulin test (DAT) is the critical test to differentiate immune from nonimmune causes of hemolysis 2