What is Haptoglobin
Haptoglobin is a plasma glycoprotein synthesized primarily in the liver that binds free hemoglobin released during red blood cell destruction, forming a complex that is rapidly cleared from circulation to prevent hemoglobin toxicity and iron loss. 1, 2
Primary Function and Mechanism
Haptoglobin's main role is to bind free hemoglobin with high affinity, preventing the toxic effects of extracellular hemoglobin including oxidative tissue damage, iron loss through the kidneys, and renal injury. 1, 3
The hemoglobin-haptoglobin complex binds to CD163 receptors on monocytes and macrophages, leading to cellular internalization and subsequent metabolism of both globin and heme components. 1
Normal red blood cell turnover occurs at approximately 2 × 10⁶ RBCs/second, with a small fraction of hemoglobin released into plasma being efficiently sequestered by haptoglobin within the physiologic range. 1
Clinical Significance as a Hemolysis Marker
Decreased haptoglobin is a specific marker of hemolysis because haptoglobin becomes depleted when large amounts of free hemoglobin are present in circulation. 2
The diagnostic triad of elevated LDH, decreased haptoglobin, and elevated indirect bilirubin is specific for hemolysis, as recommended by consensus guidelines. 4
Haptoglobin is listed as a mandatory marker of hemolysis alongside reticulocyte count, LDH, and unconjugated bilirubin in the diagnostic workup of conditions like pyruvate kinase deficiency and other hemolytic anemias. 5
Additional Biological Functions
Haptoglobin functions as an antioxidant by binding free hemoglobin and preventing oxidative stress and peroxidative reactions in tissues. 1, 3, 6
It acts as a positive acute phase protein, with levels increasing during inflammation, which can complicate interpretation in patients with concurrent inflammatory conditions. 7, 2
Haptoglobin has immunomodulatory properties, functioning as a potent immunosuppressor of lymphocyte function and modulating the Th1/Th2 balance. 3, 6
Haptoglobin Phenotypes
Three major phenotypes exist: Hp 1-1, Hp 2-1, and Hp 2-2, with Hp 1-1 being biologically most effective at binding free hemoglobin and suppressing inflammatory responses, while Hp 2-2 is least active. 7, 3, 6
These phenotypes can be separated by capillary electrophoresis, with Hp1-1 and Hp2-1 inducing an important and moderate split of the α2-globulin zone respectively, whereas Hp2-2 does not. 7
Testing Considerations and Pitfalls
False positive results (inappropriately low haptoglobin without hemolysis) can occur in improper specimen preparation, cirrhosis, elevated estrogen states, hemodilution, and mechanical heart valves without clinically relevant hemolysis. 4, 2
False negative results (normal haptoglobin despite hemolysis) can occur with hypersplenism, androgen or corticosteroid use, and during acute phase responses when haptoglobin production is increased. 2
Interpretation is particularly difficult in inflammatory states because haptoglobin is an acute phase reactant that increases during inflammation, potentially masking hemolysis. 2
Role in Chronic Hemolytic Conditions
When hemolysis exceeds the physiologic range or becomes chronic, haptoglobin is depleted, allowing hemoglobin to distribute to tissues where oxidative conditions can release heme, accelerating tissue damage. 1
Hemopexin serves as a backup system, binding free heme with high affinity when haptoglobin is depleted and transporting it to the liver for catabolism. 1