What is the appropriate management for an adult patient with no significant past medical history and low haptoglobin (a protein that binds free hemoglobin) levels?

Management of Low Haptoglobin in Adults

Low haptoglobin in an adult with no significant past medical history indicates hemolysis until proven otherwise, and you must immediately evaluate for the underlying cause of red blood cell destruction through targeted laboratory testing and clinical assessment. 1

Understanding Haptoglobin Physiology

Haptoglobin is a liver-synthesized protein that binds free hemoglobin released from lysed red blood cells, preventing hemoglobin's toxic oxidative effects and renal damage. 1, 2 When significant hemolysis occurs—either intravascular or extravascular—haptoglobin becomes depleted as it binds the excess free hemoglobin, making low haptoglobin (<32 mg/dL) a sensitive marker for hemolytic processes. 1, 3

Immediate Diagnostic Workup

Order the following tests immediately to characterize the hemolysis:

• Complete blood count with peripheral blood smear review - Look specifically for schistocytes (microangiopathic hemolysis), spherocytes (autoimmune or hereditary spherocytosis), bite cells or Heinz bodies (G6PD deficiency), or sickle cells. 4

• Reticulocyte count - Should be elevated (>2%) in hemolysis as the bone marrow compensates for red cell destruction. 1

• Lactate dehydrogenase (LDH) - Elevated in hemolysis as LDH is released from lysed red cells. 4, 1

• Indirect (unconjugated) bilirubin - Elevated as hemoglobin breakdown produces bilirubin. 1

• Direct antiglobulin test (Coombs test) - Essential to identify autoimmune hemolytic anemia, particularly in patients with chronic lymphocytic leukemia, non-Hodgkin's lymphoma, or autoimmune disease history. 4, 3

Differential Diagnosis Algorithm

Work through this systematic approach:

1. Rule Out Intravascular Hemolysis

• Check for hemoglobinuria (tea-colored urine, positive urine hemoglobin without RBCs on microscopy). 1
• Consider paroxysmal nocturnal hemoglobinuria (PNH) if unexplained intravascular hemolysis—order flow cytometry for CD55/CD59 deficiency. 3
• Evaluate for mechanical hemolysis: prosthetic heart valves, severe valvular disease, or microangiopathic hemolytic anemia (TTP/HUS). 1

2. Assess for Autoimmune Hemolytic Anemia

• If Coombs test is positive, this confirms immune-mediated hemolysis. 4, 3
• Review medication history for drug-induced hemolytic anemia. 4
• Screen for underlying lymphoproliferative disorders or autoimmune conditions. 4

3. Consider Hereditary Hemolytic Anemias

• G6PD deficiency: Review recent oxidant drug exposure (antimalarials, sulfonamides, dapsone); order G6PD enzyme level. 4
• Hereditary spherocytosis: Family history, spherocytes on smear, osmotic fragility testing. 4
• Unstable hemoglobins: Heinz bodies on smear, isopropanol or heat stability testing, hemoglobin electrophoresis, or targeted globin gene sequencing. 4

4. Evaluate for Myeloproliferative Disorders

• Low haptoglobin occurs in 33% of myelofibrosis patients, particularly those with high JAK2 allele burden or on JAK inhibitor therapy. 3
• Consider checking JAK2V617F mutation if other features suggest myeloproliferative neoplasm. 5, 3

Important Pitfalls and False Results

Be aware of these confounding factors:

• False positives (inappropriately low haptoglobin without hemolysis): Cirrhosis, elevated estrogen states (pregnancy, oral contraceptives), hemodilution, hypersplenism. 1

• False negatives (normal haptoglobin despite hemolysis): Haptoglobin is an acute phase reactant that increases with inflammation, potentially masking hemolysis in patients with concurrent infection, malignancy, or inflammatory conditions. 1, 6 Corticosteroids and androgens also elevate haptoglobin levels. 1

• Recent transfusion: Multiple studies confirm that packed red blood cell transfusion does NOT significantly affect haptoglobin levels, so low haptoglobin remains interpretable even in recently transfused patients. 7

When Hemolysis is Excluded

If comprehensive workup excludes hemolysis, consider:

• Liver disease: Check liver function tests, as cirrhosis impairs haptoglobin synthesis. 1, 3
• Genetic haptoglobin variants: Some individuals have naturally low or absent haptoglobin due to genetic polymorphism (Hp phenotypes), though this is rare and a diagnosis of exclusion. 2, 6

Clinical Context Matters

The absence of anemia does NOT exclude hemolysis—compensated hemolysis with adequate bone marrow response can maintain normal hemoglobin despite ongoing red cell destruction. 1 Conversely, the presence of inflammation may mask hemolysis by elevating haptoglobin into the "normal" range despite active hemolysis. 1, 6