What types of anemia can hydroxyurea cause?

Types of Anemia Caused by Hydroxyurea

Hydroxyurea causes two distinct types of anemia: macrocytic anemia from bone marrow suppression (the most common mechanism) and, rarely, hemolytic anemia. 1, 2, 3

Macrocytic Anemia from Bone Marrow Suppression

This is the primary and expected mechanism of hydroxyurea-induced anemia, occurring through direct myelosuppression:

• Megaloblastic changes develop in the bone marrow as hydroxyurea inhibits DNA synthesis, leading to macrocytic red blood cells with elevated mean corpuscular volume (MCV). 3

• Dose-dependent erythroid suppression is the intended pharmacologic effect in myeloproliferative neoplasms but becomes a dose-limiting toxicity when hemoglobin falls below 10 g/dL. 1, 2

• NCCN and European LeukemiaNet guidelines mandate immediate discontinuation or dose reduction when hemoglobin drops below 10 g/dL at any dose, as this threshold defines hydroxyurea intolerance. 1, 2

• The anemia is reversible within 2 weeks after temporary discontinuation of hydroxyurea, as demonstrated in multicenter sickle cell disease trials. 1

Clinical Context in Sickle Cell Disease

The hematologic picture differs substantially in sickle cell anemia:

• Hydroxyurea paradoxically increases hemoglobin by a mean of +2.54 g/dL through reduced hemolysis, mediated by elevated fetal hemoglobin (HbF) levels that inhibit sickling. 1, 4

• Treatment produces decreased hemolysis markers (lower bilirubin, LDH) and prolonged red cell survival, offsetting any mild marrow suppressive effects. 4

• The net effect is improved anemia rather than worsening, making hydroxyurea first-line disease-modifying therapy in sickle cell disease. 5

Hemolytic Anemia (Rare)

A case report documents hydroxyurea-induced hemolytic anemia requiring multiple transfusions in an 80-year-old man with essential thrombocythemia, with hemolysis persisting until drug discontinuation. 3

• This represents a non-dose-dependent idiosyncratic reaction distinct from the expected bone marrow suppression. 3

• The case emphasizes that not all hydroxyurea-induced anemia is secondary to erythropoiesis depression, requiring clinicians to actively monitor for hemolysis markers. 3

Monitoring for Hemolytic Anemia

When hemoglobin falls below 10 g/dL during hydroxyurea therapy, systematically evaluate:

• Peripheral blood smear for schistocytes or spherocytes 1
• Hemolysis markers: LDH, haptoglobin, reticulocyte count, indirect bilirubin 1
• Direct Coombs test to exclude immune-mediated hemolysis 1
• Iron, folate, and vitamin B12 status 1
• Occult gastrointestinal blood loss 1

Management Algorithm

For hemoglobin <10 g/dL at any dose:

1. Discontinue hydroxyurea immediately per NCCN mandatory discontinuation criteria. 1, 2

2. Assess for hemolysis using the markers listed above to distinguish bone marrow suppression from hemolytic anemia. 1, 3

3. After recovery (hemoglobin >10 g/dL and resolution of other cytopenias), restart at 25–50% dose reduction if bone marrow suppression was the cause. 1

4. For myeloproliferative neoplasms meeting intolerance criteria, switch to second-line therapy with ruxolitinib or interferon-alpha rather than attempting dose re-escalation. 1, 5

Critical Monitoring Parameters

• CBC with reticulocyte count every 2–4 weeks during dose titration, then every 1–3 months on stable dosing. 2, 5

• Weekly CBC until stable dose achieved initially. 2

• Hemoglobin <10 g/dL, ANC <1.0 × 10⁹/L, or platelets <100 × 10⁹/L are absolute discontinuation thresholds. 1, 2

Common Pitfall

Inadequate monitoring of blood counts can lead to severe, unrecognized myelosuppression or failure to detect rare hemolytic reactions, both of which require prompt intervention. 2, 5