What are the intrinsic and extrinsic causes of hemolytic anemia?

Hemolytic Anemia Causes

Hemolytic anemias result from premature red blood cell destruction through either intrinsic defects within the red cells themselves or extrinsic factors acting upon normal red cells. 1

Pathophysiologic Framework

The causes of hemolytic anemia are systematically divided into three categories based on the location of the defect 2:

• Intrinsic (hereditary) abnormalities: Defects within the red blood cell structure or function
• Extrinsic (acquired) abnormalities: External factors damaging otherwise normal red cells
• Blood loss: Though technically distinct, often considered in the differential

Intrinsic Causes (Hereditary)

Red Cell Enzyme Deficiencies (Enzymopathies)

• Pyruvate kinase deficiency: The most common cause of hereditary nonspherocytic hemolytic anemia, resulting from mutations in the PKLR gene causing ATP depletion in red cells 3
• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Leads to hemolysis in the presence of oxidative stress 4
• Other rare glycolytic pathway enzyme defects 2

Red Cell Membrane Disorders (Membranopathies)

• Hereditary spherocytosis: Characterized by spherocytes on peripheral smear, positive family history, and negative direct antiglobulin test 4
• Hereditary stomatocytosis: Notably, splenectomy is contraindicated in this condition due to thrombophilic risk 2
• Other membrane protein defects 1

Hemoglobinopathies

• Sickle cell anemia: Characterized by chronic hemolysis from abnormal hemoglobin polymerization 4
• Thalassemias: Result from imbalanced globin chain production 4
• Unstable hemoglobin variants: Cause hemolysis through protein instability 2

Congenital Dyserythropoietic Anemias

• Rare disorders with dyserythropoietic features that may mimic enzyme deficiencies 2

Extrinsic Causes (Acquired)

Immune-Mediated Hemolysis

• Autoimmune hemolytic anemia: Diagnosed by positive direct antiglobulin (Coombs) test confirming anti-erythrocyte antibodies 5
• Drug-induced immune hemolysis: Medications trigger antibody formation against red cells 1, 4
• Transfusion reactions: Alloantibodies cause acute hemolysis 4
• Secondary to malignancies or autoimmune disorders: Underlying disease drives antibody production 2

Microangiopathic Hemolytic Anemia

• Thrombotic microangiopathies: Red cell membrane damage from microthrombi in circulation produces characteristic schistocytes on peripheral smear 1
• Disseminated intravascular coagulation (DIC): Diagnosed with DIC panel showing consumption coagulopathy 2
• Mechanical trauma: Direct physical damage from prosthetic heart valves or other mechanical factors 1

Infectious Agents

• Malaria and babesiosis: Parasites directly invade and destroy red blood cells 4
• Other bacterial and viral infections: Various mechanisms of red cell destruction 1

Chemical and Oxidative Insults

• Medications: Multiple mechanisms including oxidative damage, immune-mediated destruction, and direct toxicity 1
• Toxins and venoms: Direct cellular destruction 1

Physical Agents

• Thermal injury: Burns cause direct red cell membrane damage 1
• Radiation: Can contribute to hemolysis in combination with other factors 2

Systemic Diseases

• Hypersplenism: Sequestration and destruction of red cells in enlarged spleen 5
• Liver disease: Multiple mechanisms including altered red cell membrane lipids 1
• Renal insufficiency: Though primarily causing decreased production, can contribute to hemolysis 2

Diagnostic Approach to Differentiate Causes

Initial Laboratory Confirmation of Hemolysis

• Reticulocytosis: Elevated reticulocyte index (>2.0) indicates appropriate marrow response to hemolysis 5
• Increased lactate dehydrogenase (LDH): Marker of red cell destruction 2
• Decreased haptoglobin: Binds free hemoglobin released during hemolysis 2
• Elevated unconjugated bilirubin: Product of heme catabolism 2

Critical Differentiating Tests

The direct antiglobulin (Coombs) test is the pivotal test that separates immune-mediated from non-immune causes of hemolysis. 5

• Positive Coombs test: Indicates immune-mediated hemolysis requiring evaluation for autoimmune disease, drugs, or transfusion reactions 5
• Negative Coombs test: Points toward hereditary causes (enzymopathies, membranopathies, hemoglobinopathies) or non-immune extrinsic factors 4

Peripheral Blood Smear Morphology

A peripheral blood smear is mandatory when hemolysis is suspected to identify characteristic red cell morphologies. 5

• Spherocytes: Hereditary spherocytosis or immune hemolysis 4
• Schistocytes: Microangiopathic hemolytic anemia 1
• Echinocytes: May suggest pyruvate kinase deficiency, especially post-splenectomy 2
• Bite cells or blister cells: G6PD deficiency with oxidative stress 1
• Sickle cells: Sickle cell disease 4

Specialized Testing Based on Initial Results

For negative Coombs test with unremarkable morphology, proceed to:

• Red cell enzyme assays: Spectrophotometric measurement of pyruvate kinase and G6PD activity 2
• Hemoglobin analysis: Electrophoresis or HPLC for hemoglobinopathies 4
• Osmotic fragility testing: Though not specific, may support membrane disorders 2

For positive Coombs test, evaluate:

• Medication history: Review all drugs for immune-mediated hemolysis 1
• Underlying malignancy or autoimmune disease: Screen for secondary causes 2

Critical Clinical Pitfalls

• Delay enzyme testing at least 50 days after transfusion to minimize interference from donor red cells with normal enzyme activity 3
• Establish diagnosis before splenectomy in hereditary hemolytic anemias, as splenectomy is contraindicated in hereditary stomatocytosis due to thrombophilic risk 2
• Consider family studies in suspected hereditary cases to confirm heterozygous carrier states in parents, particularly valuable in transfusion-dependent patients 2
• Recognize that reticulocytosis may be inappropriately low in pyruvate kinase deficiency despite hemolysis, due to splenic sequestration of young red cells and improved oxygen delivery from elevated 2,3-DPG 2
• Do not assume normal red cell morphology excludes enzymopathies, as pyruvate kinase deficiency typically shows unremarkable morphology unlike membrane disorders 2