Can hydroxyurea cause a decrease in red blood cell count (anemia)?

Does Hydroxyurea Cause Decreased RBC (Anemia)?

Yes, hydroxyurea causes anemia through multiple mechanisms: bone marrow suppression leading to decreased red blood cell production, and less commonly, hemolytic anemia. 1

Mechanisms of Hydroxyurea-Induced Anemia

Bone Marrow Suppression (Primary Mechanism)

Hydroxyurea causes severe myelosuppression affecting all cell lines, with anemia being a well-established dose-limiting toxicity. 1 The FDA label explicitly states that bone marrow suppression may occur, and while leukopenia is typically the first manifestation, anemia occurs less frequently but is clinically significant. 1

• Mandatory discontinuation threshold: Hemoglobin <10 g/dL at any dose requires immediate dose reduction or discontinuation. 2, 3, 4, 1
• The anemia develops through direct suppression of erythropoiesis, creating a megaloblastic pattern with increased mean corpuscular volume (MCV). 5
• Bone marrow examination shows megaloblastic changes, increased iron stores, and increased sideroblasts—all consistent with ineffective erythropoiesis. 5

Hemolytic Anemia (Less Common but Important)

Hydroxyurea can cause hemolytic anemia, particularly in patients with myeloproliferative disorders. 1, 6 This is a critical diagnostic pitfall because clinicians may incorrectly attribute all anemia to marrow suppression alone.

• The FDA label specifically warns about hemolytic anemia cases in patients treated for myeloproliferative diseases. 1
• Patients developing acute jaundice or hematuria with worsening anemia should be evaluated for hemolysis with: LDH, haptoglobin, reticulocyte count, unconjugated bilirubin, urinalysis, and direct/indirect Coombs tests. 1
• If hemolytic anemia is confirmed and no other cause is identified, discontinue hydroxyurea immediately. 1

Clinical Context: Disease-Specific Patterns

Sickle Cell Disease

In sickle cell anemia, hydroxyurea's effect on RBC count is more nuanced:

• The Multicenter Study of Hydroxyurea demonstrated that while mild marrow suppression occurs, hemoglobin levels actually increased by a mean of +2.54 g/dL due to decreased hemolysis from elevated fetal hemoglobin. 2, 7
• Bone marrow suppression occurred in most patients but resolved within 2 weeks of temporary discontinuation. 2
• The therapeutic goal is mild marrow suppression with reticulocyte count decline signaling approach to maximum tolerated dose. 3

Myeloproliferative Neoplasms

In polycythemia vera and essential thrombocythemia, anemia is a recognized intolerance criterion:

• Hemoglobin <10 g/dL (or <100 g/L) at the lowest effective dose defines hydroxyurea intolerance and mandates switching to second-line therapy (ruxolitinib or interferon-alpha). 2, 3
• The paradox: some patients develop anemia while platelets remain uncontrolled (>400 × 10⁹/L), indicating selective suppression of the erythroid line. 3

Monitoring Requirements

CBC monitoring is mandatory to detect anemia early:

• During dose titration: CBC every 2–4 weeks, or weekly until stable dose achieved. 3, 4
• On stable dose: CBC every 1–3 months for sickle cell disease; every 4–8 weeks for myeloproliferative neoplasms. 3, 8, 4
• Reticulocyte count should be monitored every 1–3 months during dose escalation in sickle cell disease. 3

Critical Diagnostic Pitfall

Do not assume all hydroxyurea-associated anemia is due to marrow suppression. 3, 8 When hemoglobin falls:

1. Review peripheral smear for hemolysis markers 3
2. Check iron, folate, and B12 status 3
3. Evaluate for occult GI bleeding 3
4. Measure hemolysis markers: LDH, haptoglobin, reticulocyte count, bilirubin, Coombs test 3, 1

This systematic approach prevents missing hemolytic anemia or other treatable causes that would not improve with simple dose reduction.

Management Algorithm

When hemoglobin drops below 10 g/dL:

1. Discontinue hydroxyurea immediately (meets FDA and guideline discontinuation criteria). 2, 3, 4, 1
2. Perform systematic evaluation for alternative/contributing causes (see above). 3
3. After hemoglobin rises above 10 g/dL and other cytopenias resolve, restart at 25–50% lower dose than the dose that caused suppression. 3
4. If hemolytic anemia is confirmed, do not restart hydroxyurea—switch to alternative therapy. 1

Additional Considerations

• Patients with prior radiotherapy or chemotherapy have higher risk of marrow suppression and require cautious dosing. 1
• In myeloproliferative disorders, anemia may also result from acquired von Willebrand disease causing occult bleeding when platelet counts are extremely elevated (>1,000 × 10⁹/L). 8
• Megaloblastic changes from hydroxyurea can cause diagnostic confusion; serum folate and B12 remain normal, distinguishing this from nutritional deficiency. 5