Can hydroxyurea cause unexplained bleeding in patients with chronic myeloid leukemia, polycythemia vera, sickle‑cell disease, or other myeloproliferative disorders?

Can Hydroxyurea Cause Bleeding of Unknown Origin?

Yes, hydroxyurea can cause unexplained bleeding in patients with myeloproliferative disorders through multiple mechanisms: bone marrow suppression leading to thrombocytopenia, acquired von Willebrand disease (AVWS) in the setting of extreme thrombocytosis, and direct mucocutaneous toxicity including ulcerations that may bleed.

Primary Mechanisms of Hydroxyurea-Related Bleeding

Thrombocytopenia from Bone Marrow Suppression

• Hydroxyurea causes dose-dependent bone marrow suppression affecting all cell lines, including platelets. 1
• Platelet counts falling below 100 × 10⁹/L at any dose represent a criterion for hydroxyurea intolerance and mandate immediate dose reduction or discontinuation. 1, 2
• The NCCN guidelines explicitly state that hydroxyurea therapy must be stopped immediately if platelet count falls below 100 × 10⁹/L due to severe bleeding risk. 2

Acquired von Willebrand Disease (AVWS)

• In patients with essential thrombocythemia or polycythemia vera presenting with high platelet counts, bleeding may occur despite normal or elevated platelet counts due to AVWS. 3
• This paradoxical bleeding occurs when extreme thrombocytosis (often >1,000 × 10⁹/L) leads to consumption of von Willebrand factor multimers. 3
• NCCN guidelines recommend that aspirin should be used with extreme caution in patients with acquired VWD due to increased bleeding risk. 3
• Coagulation tests to evaluate for acquired VWD should be performed when bleeding occurs in the setting of elevated platelet counts. 3

Direct Mucocutaneous Toxicity

• Hydroxyurea causes a spectrum of mucocutaneous changes in approximately 13% of patients on long-term therapy, including ulcerations that can bleed. 4
• Ulcers develop primarily on the lower extremities (particularly near the malleoli), genitalia, and oral mucosa after prolonged therapy (median 36 months, range 7-96 months). 5, 4
• These ulcers represent a poorly recognized but clinically significant side effect that requires discontinuation of hydroxyurea. 5

Clinical Presentation and Diagnosis

When to Suspect Hydroxyurea-Related Bleeding

• Twenty percent of children with chronic myeloid leukemia present with bleeding manifestations despite normal or elevated platelet counts. 3
• Bleeding can manifest as mucosal bleeding (epistaxis, gingival bleeding, gastrointestinal bleeding), cutaneous bleeding (petechiae, ecchymoses), or bleeding from ulcerated skin lesions. 3, 4
• The NCCN guidelines specifically instruct clinicians to "rule out other potential causes and treat coexisting causes as necessary" when bleeding occurs. 3

Diagnostic Workup

• Obtain complete blood count with differential to assess for thrombocytopenia (target: platelet count >100 × 10⁹/L). 1, 2
• Perform coagulation studies including PT, aPTT, and specific testing for acquired von Willebrand disease (VWF antigen, VWF activity, ristocetin cofactor activity). 3
• Examine skin carefully for ulcerations, particularly on lower extremities, genitalia, and sun-exposed areas. 5, 4
• Assess oral mucosa for stomatitis, glossitis, and ulcerations. 4

Management Algorithm

Immediate Actions When Bleeding Occurs

1. Discontinue aspirin immediately until bleeding is controlled. 3
2. If platelet count is <100 × 10⁹/L, stop hydroxyurea immediately. 2, 6
3. If bleeding occurs with normal/elevated platelets, test for acquired VWD and consider cytoreductive therapy to normalize platelet counts. 3
4. For bleeding from cutaneous ulcers, discontinue hydroxyurea; ulcers typically heal within 1-4 months after stopping the drug. 5

Hemolytic Anemia as a Confounding Factor

• Hydroxyurea can rarely cause hemolytic anemia, which may present with anemia disproportionate to the degree of bone marrow suppression. 7
• When hemoglobin falls below 10 g/dL, systematically evaluate for hemolysis (LDH, haptoglobin, reticulocyte count, bilirubin, Coombs test) in addition to bone marrow suppression. 6
• Hemolysis persists until hydroxyurea is discontinued and may require transfusion support. 7

Restarting Therapy After Bleeding Resolution

• After bleeding has resolved and platelet count has recovered above 100 × 10⁹/L, hydroxyurea may be restarted at 25-50% lower dose than the dose that caused suppression. 6
• If bleeding recurs or if the patient meets criteria for hydroxyurea resistance/intolerance, switch to alternative cytoreductive therapy. 2, 6
• For polycythemia vera, consider interferon-alpha or ruxolitinib as second-line agents. 2, 6
• For essential thrombocythemia, consider anagrelide or interferon-alpha. 2

Critical Caveats and Pitfalls

Common Pitfalls to Avoid

• Do not assume all anemia in hydroxyurea-treated patients is due to bone marrow suppression; actively exclude hemolysis and bleeding. 7
• Do not continue aspirin in patients with acquired VWD or active bleeding; the NCCN guidelines explicitly warn against this. 3
• Do not overlook cutaneous ulcers as a source of occult blood loss; these develop insidiously after prolonged therapy. 5, 4
• Do not restart hydroxyurea at the same dose after a bleeding episode; dose reduction of 25-50% is mandatory. 6

Special Populations

• In children with chronic myeloid leukemia, bleeding at diagnosis can occur despite normal platelet counts due to AVWS, which resolves within 2-4 weeks of starting tyrosine kinase inhibitor therapy. 3
• Young patients (<40 years) should use hydroxyurea with particular caution due to long-term leukemogenic risk, making bleeding complications particularly problematic as they may necessitate prolonged therapy. 2, 6

Monitoring Requirements

• Monitor complete blood counts every 4-8 weeks once stabilized on hydroxyurea therapy. 2
• Examine skin and mucous membranes at each visit for early signs of ulceration. 5, 4
• Maintain platelet count <400 × 10⁹/L to reduce thrombotic risk while keeping it >100 × 10⁹/L to minimize bleeding risk. 2