Haptoglobin

Haptoglobin is an acute-phase reactant whose principal clinical utility is in defining conditions of hemolysis. Its levels can also become elevated in infection and inflammation.

The reference ranges for haptoglobin are as follows ^[1] :

• Adults: 50-220 mg/dL or 0.5-2.2 g/L (SI units)
• Newborns: 0-10 mg/dL or 0-0.1 g/L (SI units)

Possible critical value: < 40 mg/dL ^[1]

Haptoglobin is used as an acute-phase marker of red blood cell (RBC) destruction. Its value decreases and may even be absent when RBCs are destroyed at twice the normal rate.

Haptoglobin values above 40 mg/dL are used to show signs of successful splenectomy. A value above 40 mg/dL is also used as an indicator in chronic hemolysis to show that splenectomy is not indicated. ^[2]

Increased haptoglobin levels are seen in the following conditions ^{[2, 3]} :

• Diseases associated with elevated erythrocyte sedimentation rate (acute-phase reactants) such as rheumatic disease, myocardial infarction, ^[1] infection, trauma, inflammation, hepatitis, Amyloidosis, collagen diseases, or lymphoma and leukemia
• Obstructive or biliary diseases
• Peptic ulcer ^[1]
• Ulcerative colitis ^[1]
• Steroid use
• Aplastic Anemia
• Neoplasia ^[1]
• Diabetes mellitus
• Smoking
• Nephrotic Syndrome
• Pyelonephritis ^[1]
• Increased estrogen level
• Inflammatory vasculitides (e.g., immunoglobulin A vasculitis) ^[4]

Studies show in sepsis and acute respiratory distress syndrome patients undergoing veno-venous extracorporeal membrane oxygenation, mean haptoglobin ≤ 0.39 g/L (39 mg/dL) correlates with significantly increased intensive care unit mortality (OR 0.29). ^[5]

Decreased or absent haptoglobin levels are seen in the following conditions ^{[2, 3]} :

• Intravascular hemolysis (Hereditary Spherocytosis, Pyruvate Kinase Deficiency, autoimmune hemolytic anemia, Transfusion Reactions)
• Extravascular hemolysis (intraperitoneal hemorrhage)
• Intramedullary hemolysis (thalassemias, Sideroblastic Anemias, Megaloblastic Anemia)
• Hematoma ^[1]
• Genetics (haptoglobin is absent in 1% of White and 4-10% of Black individuals)
• Cirrhosis
• Primary liver disease not associated with hemolytic anemia ^[1]
• Infancy
• Pregnancy
• Burns
• Prosthetic heart valves ^[1]
• Severe malnutrition ^[1]
• Systemic lupus erythematosus ^[1]
• Transfusion reactions ^[1]

Specimen: Plasma

Condition: Fasting preferred (but not strictly required for haptoglobin measurement) ^[1]

Container: Red top tube ^[1] ; plasma separator tube or serum separator tube; also acceptable: green (sodium, lithium, or heparin), lavender (ethylenediaminetetraacetic acid [EDTA]), or pink (K₂ EDTA) tube

Collection method: Routine venipuncture

Processing: Allow specimen to clot completely at room temperature. Separate sample from plasma or serum within 2 h of collection. Minimum required sample is around 0.5 mL. Results are typically reported within 24 h.

Unacceptable conditions: Hemolyzed

Storage: Refrigerated

Length of storage: Ambient, refrigerated, or frozen (up to 3 months)

Description

Haptoglobin is a colorless protein of the alpha-globulin fraction of human serum. It transports "freed" hemoglobin released from destroyed RBCs to the reticuloendothelial system.

Haptoglobin is produced by the liver and collects the hemoglobin from destroyed RBCs, then transports it back to the liver, where heme is converted to bilirubin. ^[2] In the setting of increased RBC destruction, haptoglobin becomes depleted, and the free hemoglobin dimmers are filtered by the kidney, ultimately producing hemosiderin. ^[3] Macrophages destroy the hemoglobin-haptoglobin complex. ^[6] The hemoglobin-haptoglobin complex is removed from the bloodstream within minutes. ^[7]

The kidneys can filter about 5 g of hemoglobin per day; the unprocessed and unbound hemoglobin is oxidized and then becomes methemoglobin. ^[3] Unbound haptoglobin has a half-life of 5 days in the serum. ^[7]

Haptoglobin does not reach adult values in the serum until around age 4 months.

The three phenotypes of haptoglobin include haptoglobin 1-1 (Hp 1-1), haptoglobin 2-1 (Hp 2-1), and haptoglobin 2-2 (Hp 2-2). No diseases are associated with specific variations, but there are genetic familiarities that make the genotyping useful in paternity testing and forensic medicine. ^[3] Genotype-specific range interval as per Z-test includes ^[8] :

• Hp 1-1: 0.37-2.19 g/L
• Hp 2-1: 0.38-2.12 g/L
• Hp 2-2: 0.12-1.51 g/L

Elevated haptoglobin is also observed in various cancers and may serve as an independent prognostic marker in several solid tumors. ^[9]

Indications/Applications

Haptoglobin is an acute-phase reactant whose principal clinical utility is in defining conditions of hemolysis. Its levels can also become elevated in infection and inflammation.

In hemolytic anemia, lactic dehydrogenase (LDH) levels typically increase while haptoglobin levels decrease. In a retrospective study from 1980, the sensitivity and specificity of haptoglobin in the diagnosis of hemolytic anemia was 83% and 96%, respectively. Overall, a serum haptoglobin level below 25 mg/dL equated to an 87% probability of predicting hemolytic disease. ^[10]

Haptoglobin is being recognized as a modulator of immune responses, influencing the activity of macrophages, neutrophils, and dendritic cells, with implications for autoimmune diseases, chronic inflammation, and cancer. Its genotype-specific effects are being explored as biomarkers for cardiovascular risk and diabetes complications. ^[11]

Recombinant haptoglobin and phenotype-specific preparations (e.g., Hp 1-1, Hp 2-2) are being investigated as therapeutics to attenuate hemoglobin toxicity in conditions such as sickle cell disease, transfusion-related hemolysis, and acute kidney injury. ^[12] In Japan, haptoglobin is approved for hemolysis in trauma, burns, and massive transfusion. ^[13]

False-positive and false-negative results can occur in patients with comorbid conditions; for example, hypersplenism plus hemolytic anemia may result in a false-normal overall serum value.

Other tests used in combination with haptoglobin to confirm hemolysis include peripheral smear, LDH, indirect bilirubin, reticulocyte count, complete blood count, and Coombs' test.

Zhao et al developed a nomogram that efficiently identifies the severe influenza early on based on haptoglobin and myeloperoxidase level in addition to the duration of illness. ^[14]