haptoglobin

**Function:** Haptoglobin is an alpha-2 glycoprotein synthesized by the liver. It binds free plasma hemoglobin (Hb alpha-beta dimers) with very high affinity. This prevents renal filtration of Hb, limits Hb-mediated oxidative injury, and conserves iron. The haptoglobin-Hb complex is taken up by monocytes/macrophages through CD163 and degraded. The complex is cleared rapidly, so haptoglobin is depleted when hemolysis occurs.

**Pathophysiology and lab interpretation:** - **Intravascular hemolysis** (e.g., G6PD deficiency crisis, mismatched transfusion reaction, PNH, microangiopathic hemolytic anemias such as TTP/HUS/DIC, mechanical heart valve hemolysis, autoimmune hemolytic anemia with complement activation): haptoglobin is markedly decreased or undetectable. Other findings are increased LDH, increased indirect bilirubin, free plasma Hb, hemoglobinemia, hemoglobinuria, hemosiderinuria (a later finding), and a high reticulocyte count. Peripheral smear may show schistocytes. - **Extravascular hemolysis** (e.g., hereditary spherocytosis, warm AIHA, sickle cell disease): haptoglobin is normal or mildly decreased, because most Hb is catabolized within macrophages. Sickle cell disease is a mixed picture, so haptoglobin is often low. - **Decreased haptoglobin without hemolysis:** severe liver disease (decreased synthesis) and congenital anhaptoglobinemia. - **Increased haptoglobin:** it is a positive acute-phase reactant, so it rises with inflammation, infection, malignancy, tissue injury, and steroid use. This can mask hemolysis by pushing a low level back into the normal range. Elevation is also seen in biliary obstruction and nephrotic syndrome.

**Clinical pearls:** - Low haptoglobin is sensitive and fairly specific for hemolysis, especially intravascular. Specificity falls in liver disease. - Haptoglobin works with **hemopexin**, which binds free heme. When haptoglobin is saturated, free Hb is filtered by the kidney, causing hemoglobinuria. Hb in the proximal tubule can cause acute tubular necrosis and hemosiderinuria. - Free Hb scavenges nitric oxide, causing smooth muscle dystonia, esophageal spasm, abdominal pain, erectile dysfunction, and pulmonary hypertension. This is prominent in PNH. - Haptoglobin has phenotypes (Hp 1-1, 2-1, 2-2). Hp 2-2 has been associated with higher cardiovascular risk in diabetics, though this is less high-yield for boards. - **Hemolysis workup:** CBC with high reticulocytes, high LDH, high indirect bilirubin, low haptoglobin, then Coombs (direct antiglobulin) test to distinguish immune from non-immune causes.

**Board pattern:** A patient with anemia, jaundice, dark urine, elevated LDH, and **low haptoglobin** indicates hemolysis. A positive direct Coombs test indicates autoimmune hemolytic anemia. A negative Coombs test with schistocytes suggests microangiopathic hemolysis.