What to do when hydroxyurea (Hydrea) 500 mg reduces Red Cell Count (RCC) but increases platelet count?

Management of Hydroxyurea-Induced Red Cell Suppression with Paradoxical Thrombocytosis

When hydroxyurea 500 mg reduces red blood cell count but increases platelet count, this represents an atypical response requiring immediate dose adjustment or discontinuation, as hydroxyurea typically suppresses all cell lines uniformly—this paradoxical pattern suggests either inadequate dosing for the underlying myeloproliferative disorder or an unusual drug response. 1

Understanding the Paradoxical Response

This clinical scenario is unusual because hydroxyurea is a cytoreductive agent that causes bone marrow suppression affecting all cell lines, including both red cells and platelets. 2 The typical expectation is that hydroxyurea would reduce both RBC and platelet counts simultaneously. 1

Your patient's rising platelet count despite treatment suggests:

• The 500 mg dose is insufficient to control the underlying myeloproliferative disorder (likely essential thrombocythemia or polycythemia vera) 3, 4
• The red cell suppression may indicate selective sensitivity to hydroxyurea or concurrent anemia from another cause 1

Immediate Assessment Required

Check the following parameters urgently:

• Complete blood count with differential, including absolute neutrophil count, hemoglobin level, and platelet count 1
• Baseline hemoglobin: if <10 g/dL, this meets criteria for hydroxyurea intolerance 5, 4
• Platelet count: if >400 × 10⁹/L, the disease remains uncontrolled 5, 3
• Absolute neutrophil count: if <1.0 × 10⁹/L, immediate dose reduction or discontinuation is mandatory 4, 1

Management Algorithm

If Hemoglobin <10 g/dL at Current Dose:

This meets NCCN/European LeukemiaNet criteria for hydroxyurea intolerance. 5, 4 You must:

1. Discontinue hydroxyurea immediately 5, 4
2. Switch to second-line therapy:
   • For essential thrombocythemia: anagrelide is the recommended second-line agent 3, 6
   • For polycythemia vera: interferon-alpha or ruxolitinib 5, 3

If Hemoglobin ≥10 g/dL but Platelets Remain Elevated:

The 500 mg dose is inadequate. 3, 4 The target platelet count should be <400 × 10⁹/L. 3

1. Increase hydroxyurea dose progressively:

   • Standard dosing for myeloproliferative neoplasms starts at 15 mg/kg/day (approximately 1000-1500 mg/day for average adults) 1, 7
   • Your current 500 mg dose is substantially below therapeutic range 4
   • Maximum dose is 2 g/day (or 2.5 g/day if patient weighs >80 kg) 4

2. Monitor weekly during dose escalation:

   • Complete blood counts must be checked at least weekly 1
   • Watch for hemoglobin dropping below 10 g/dL, platelets <100 × 10⁹/L, or ANC <1.0 × 10⁹/L 4, 1

3. Assess response after 3 months:

   • If platelets remain >400 × 10⁹/L after 3 months at ≥2 g/day, this defines hydroxyurea resistance 5, 3, 4
   • Switch to second-line therapy at that point 3

Critical Monitoring Parameters

During any dose adjustment, monitor for these mandatory discontinuation criteria: 4, 1

• Hemoglobin <10 g/dL 5, 4
• Platelet count <100 × 10⁹/L 5, 4
• Absolute neutrophil count <1.0 × 10⁹/L 4, 1
• Development of leg ulcers or mucocutaneous toxicity 5, 3

Important Caveats

The FDA label explicitly states that severe anemia must be corrected before initiating or continuing hydroxyurea therapy. 1 If your patient's red cell reduction represents true anemia (hemoglobin <10 g/dL), you cannot safely continue or escalate hydroxyurea. 1

Consider alternative causes of anemia:

• Hemolytic anemia can occur with hydroxyurea in myeloproliferative disorders 1
• Check LDH, haptoglobin, reticulocyte count, indirect bilirubin, and Coombs test if anemia is present 1
• If hemolysis is confirmed, discontinue hydroxyurea immediately 1

For patients <40 years old, use hydroxyurea with particular caution due to long-term leukemogenic risk. 4 Consider interferon-alpha as first-line therapy in younger patients. 3