Causes of Intravascular versus Extravascular Hemolysis
Intravascular Hemolysis
Intravascular hemolysis occurs when red blood cells lyse directly within the circulation due to complement fixation, mechanical trauma, or other extrinsic factors that cause immediate membrane disruption. 1
Primary Causes:
Incompatible blood transfusion - acute hemolytic transfusion reactions cause rapid complement-mediated RBC destruction 1
Glucose-6-phosphate dehydrogenase (G6PD) deficiency - oxidative stress triggers hemolysis, particularly with certain medications like quinine 2, 1
Paroxysmal nocturnal hemoglobinuria (PNH) - complement-mediated lysis due to deficiency of GPI-anchored complement regulatory proteins 1, 3
Severe infections - malaria, babesiosis, and other pathogens directly invade and destroy red cells 4
Microangiopathic hemolytic anemia - mechanical shearing of RBCs in damaged vasculature produces schistocytes 4
Severe burns - direct thermal injury to circulating erythrocytes 1
Drug-induced hemolysis - quinine can cause acute intravascular hemolysis (blackwater fever) with hemoglobinuria and hemoglobinemia 2
Diagnostic Features:
- Hemoglobinemia, hemoglobinuria, and hemosiderinuria occur only with severe and rapid intravascular hemolysis 1
- Decreased or absent haptoglobin (binds free hemoglobin) 4
- Elevated plasma free hemoglobin 4, 3
Extravascular Hemolysis
Extravascular hemolysis is the most common mechanism, occurring when red cells are removed from circulation by the mononuclear-phagocytic system in the spleen and liver, either due to intrinsic RBC defects or surface-bound immunoglobulins. 1, 5
Primary Causes:
Autoimmune hemolytic anemia (AIHA) - autoantibodies coat RBCs, leading to splenic/hepatic macrophage destruction 5, 6
- Warm AIHA (IgG antibodies)
- Cold agglutinin disease (IgM antibodies)
Hereditary spherocytosis - membrane defects cause spherocyte formation and splenic sequestration; characterized by spherocytes, family history, and negative direct antiglobulin test 4, 3
Sickle cell disease - abnormal hemoglobin causes chronic hemolysis with splenic trapping 4, 3
Thalassemia - hemoglobinopathy with chronic extravascular hemolysis 4
Hypersplenism - enlarged spleen removes RBCs prematurely 1
Diagnostic Features:
- Absence of hemoglobinemia and hemoglobinuria (hemoglobin remains intracellular until phagocytosed) 1
- Elevated unconjugated bilirubin (from heme catabolism in macrophages) 4
- Elevated lactate dehydrogenase (LDH) 4, 3
- Reticulocytosis 4, 3
- Positive direct antiglobulin test (DAT) in immune-mediated cases 5, 6
Key Distinguishing Features
The critical difference is the site of RBC destruction: intravascular hemolysis releases hemoglobin directly into plasma (causing hemoglobinuria), while extravascular hemolysis processes hemoglobin within macrophages (causing hyperbilirubinemia without hemoglobinuria). 1
Common Pitfalls:
- Do not assume normal haptoglobin excludes hemolysis - it may be falsely normal in liver disease (decreased synthesis) 4
- LDH elevation correlates with platelet adhesion but not necessarily with plasma hemoglobin or reticulocyte counts - it reflects multiple cellular sources beyond just hemolysis 3
- Splenectomy in hereditary spherocytosis reverses many markers including plasma hemoglobin, RBC adhesion, reticulocytosis, and inflammation, demonstrating the extravascular nature 3
- Mixed patterns can occur - some conditions like severe AIHA may have both intravascular (complement-mediated) and extravascular (antibody-mediated splenic) components 5, 6