What's happening with my relative's Myeloproliferative Neoplasm (MPN) treatment, given their severe thrombocytosis (elevated platelet count), anemia (low hemoglobin), recent Subdural Hematoma (SDH) surgeries, Peripheral Artery Disease (PAD), and discontinued blood thinners, and why is Hydroxyurea (Hydrea) not effective?

Understanding Your Relative's Complex MPN Situation

Your relative's hydroxyurea is likely "not working" because they meet formal criteria for hydroxyurea resistance—specifically, their platelet count remains severely elevated at 1126 × 10⁹/L despite treatment, and they've developed severe anemia (hemoglobin 8.6 g/dL), which represents hydroxyurea intolerance. 1, 2

Why Hydroxyurea Appears Ineffective

Your relative meets two specific European LeukemiaNet criteria for hydroxyurea resistance/intolerance 1:

• Uncontrolled thrombocytosis: Platelet count >600 × 10⁹/L (theirs is 1126 × 10⁹/L) after adequate hydroxyurea therapy 1
• Treatment-limiting anemia: Hemoglobin <10 g/dL (theirs is 8.6 g/dL) at any dose of hydroxyurea—this represents drug intolerance, not disease control 1, 2

The hydroxyurea is actually causing the low hemoglobin through bone marrow suppression, which is a known dose-limiting toxicity 3. The drug cannot be increased to control the platelets because doing so would worsen the dangerous anemia 2.

The Critical Bleeding Risk Paradox

Your relative faces an extremely dangerous situation: severe thrombocytosis (platelet count >1000 × 10⁹/L) paradoxically causes bleeding, not clotting, due to acquired von Willebrand syndrome 4. This explains:

• Why they had subdural hematomas requiring two surgeries 4
• Why blood thinners had to be stopped (they would worsen bleeding risk) 1
• Why urgent platelet reduction is critical despite the anemia 4

At platelet counts >1000 × 10⁹/L, the excessive platelets consume von Willebrand factor, creating a bleeding disorder 4. This is why your relative bled despite having "too many" platelets 4.

Immediate Management Priorities

The treatment team should:

1. Switch cytoreductive therapy immediately 1:

• Ruxolitinib is the FDA/EMA-approved second-line agent for hydroxyurea-resistant/intolerant MPN patients 1
• Interferon-alpha is an alternative non-leukemogenic option, particularly if your relative is younger 1
• The choice depends on age, drug availability, and insurance coverage 1

2. Address the severe anemia 3:

• Blood transfusions may be necessary given hemoglobin 8.6 g/dL and recent surgeries 4
• Severe anemia must be corrected before optimizing new cytoreductive therapy 3

3. Manage perioperative thrombosis risk carefully 1:

• With peripheral artery disease (PAD) and recent neurosurgery, restarting anticoagulation requires careful timing 1
• Aspirin should typically be restarted 24 hours post-surgery when bleeding risk is acceptable 1
• Extended prophylaxis with low-molecular-weight heparin should be considered given the high-risk surgeries 1

Why Blood Thinners Were Stopped

Blood thinners were appropriately discontinued before and after neurosurgery due to catastrophic bleeding risk 1. The subdural hematomas themselves represent life-threatening bleeding complications 1.

However, with PAD and MPN, your relative needs thrombosis prophylaxis once bleeding is controlled 1:

• Aspirin should be restarted when neurosurgical team approves (typically 24 hours post-op if no bleeding) 1
• Cytoreductive therapy must achieve platelet control before considering full anticoagulation 1
• Target platelet count <400 × 10⁹/L before resuming anticoagulation for PAD 1

Critical Next Steps

The medical team should evaluate for second-line therapy using these specific criteria 1:

1. Document hydroxyurea failure formally: Platelet count >600 × 10⁹/L after adequate trial AND hemoglobin <10 g/dL at any dose 1

2. Initiate alternative cytoreductive therapy 1:

   • Ruxolitinib 10 mg twice daily (adjust for blood counts) for patients with proven hydroxyurea resistance 1
   • OR interferon-alpha if ruxolitinib unavailable or patient younger 1

3. Achieve rapid platelet reduction 4:

   • Target platelet count <400 × 10⁹/L to reverse acquired von Willebrand syndrome 1
   • Monitor coagulation studies (PTT, von Willebrand factor) as platelets decrease 4

4. Coordinate with neurosurgery regarding anticoagulation timing 1:

   • Ensure adequate time since last surgery (typically weeks for subdural hematoma) 1
   • Balance PAD thrombosis risk against recurrent intracranial bleeding risk 1

Common Pitfalls to Avoid

Do not simply increase hydroxyurea dose—this will worsen the anemia without adequately controlling platelets, meeting the definition of treatment failure 1, 2.

Do not restart anticoagulation until platelets are controlled—the current severe thrombocytosis with acquired von Willebrand syndrome creates bleeding risk that anticoagulation would catastrophically worsen 4.

Do not delay switching therapy—your relative has already experienced major bleeding complications (subdural hematomas requiring two surgeries), indicating urgent need for effective platelet control 4.