Hydroxyurea-Induced Anemia: Macrocytic with Myelosuppressive Features
Hydroxyurea causes macrocytic anemia through direct bone marrow suppression, resulting in megaloblastic changes and reduced red blood cell production. 1
Primary Mechanism: Myelosuppressive Macrocytosis
The FDA label explicitly identifies myelosuppression as the primary mechanism of hydroxyurea-induced anemia, with bone marrow depression manifesting first as leukopenia, followed by thrombocytopenia and anemia. 1 The anemia is characteristically macrocytic due to:
- Megaloblastic bone marrow changes that develop during continuous low-dose therapy, with mean corpuscular volume (MCV) increasing linearly after treatment initiation 2
- Complete replacement of the normocyte population by abnormally large erythrocytes within 150 days of starting therapy 2
- Increased bone marrow iron stores and sideroblasts, indicating ineffective erythropoiesis 2
The NCCN guidelines classify drugs like hydroxyurea as causes of macrocytic anemia (MCV >100 fL), specifically noting that hydroxyurea can cause macrocytosis alongside other agents. 3
Critical Discontinuation Threshold
Hemoglobin below 10 g/dL at any dose mandates immediate dose reduction or discontinuation of hydroxyurea. 1 This threshold represents:
- A formal FDA-labeled criterion for dose modification 1
- The NCCN definition of hydroxyurea intolerance in myeloproliferative neoplasms, requiring switch to second-line therapy such as ruxolitinib or interferon-alpha 3, 4
Secondary Mechanism: Hemolytic Anemia (Less Common)
While myelosuppression is the dominant mechanism, the FDA label warns that hemolytic anemia can occur in patients treated with hydroxyurea for myeloproliferative diseases. 1 When hemolysis is suspected:
- Evaluate for acute jaundice or hematuria in the presence of worsening anemia 1
- Obtain hemolysis markers: LDH, haptoglobin, reticulocyte count, unconjugated bilirubin, urinalysis, and direct/indirect Coombs tests 1
- Discontinue hydroxyurea if hemolytic anemia is confirmed and no other cause is identified 1
A case report documented severe hemolytic anemia requiring multiple transfusions in an 80-year-old man with essential thrombocythemia, with hemolysis persisting until drug discontinuation. 5
Context-Dependent Hematologic Effects
In Sickle Cell Disease (Paradoxical Improvement)
In sickle cell anemia, hydroxyurea typically increases hemoglobin by a mean of +2.54 g/dL through reduced hemolysis from elevated fetal hemoglobin levels. 4 This represents a therapeutic benefit rather than toxicity in this population. 6
Recovery Timeline
Bone marrow suppression is usually reversible, with recovery occurring rapidly—typically within 2 weeks—after temporary discontinuation. 4, 7 However, recovery may be prolonged in patients with chronic kidney disease due to potentiation of myelosuppressive effects. 7
Common Pitfall to Avoid
Do not assume all hydroxyurea-induced anemia is purely myelosuppressive. 5 The increasing use of hydroxyurea across multiple indications (myeloproliferative disorders, sickle cell disease, psoriasis) necessitates monitoring for hemolysis, particularly when anemia worsens despite dose reduction or when accompanied by jaundice or hematuria. 1, 5