How to manage von Willebrand disease with leukocytosis?

Management of Von Willebrand Disease with Leukocytosis

In patients with von Willebrand disease (VWD) and leukocytosis, screening for acquired von Willebrand syndrome (AvWS) is essential, particularly when leukocytosis is associated with myeloproliferative disorders, and treatment should be tailored to the underlying cause with appropriate VWF replacement therapy and cytoreduction as needed.

Diagnostic Evaluation

• Leukocytosis in VWD patients should prompt evaluation for underlying myeloproliferative neoplasms (MPNs), particularly essential thrombocythemia (ET) or polycythemia vera (PV), which can cause acquired von Willebrand syndrome 1
• Complete VWD workup should include VWF:Ag, VWF:RCo, and the ratio of VWF:RCo/VWF:Ag to properly classify the type of VWD 2
• Ristocetin co-factor and multimer analysis should be performed to rule out acquired von Willebrand syndrome, especially in patients with extreme thrombocytosis (platelet count >1 million/μL) 1
• Sample collection and processing conditions significantly affect test results - ensure proper handling at room temperature and prompt processing to avoid false results 2

Underlying Causes of Leukocytosis in VWD

• Waldenström's macroglobulinemia can present with leukocytosis and may be associated with acquired von Willebrand disease 3
• Myeloproliferative neoplasms (MPNs) like polycythemia vera and essential thrombocythemia can cause leukocytosis and are associated with acquired von Willebrand syndrome 3, 1
• Inflammatory conditions can cause both leukocytosis and elevated VWF levels, potentially masking underlying VWD 2, 4

Treatment Approach

For VWD with Myeloproliferative Neoplasm-Related Leukocytosis:

• In patients with extreme thrombocytosis (>1 million/μL) and acquired VWD, cytoreductive therapy is indicated to reduce platelet count and improve VWF function 1
• Hydroxyurea is the first-line cytoreductive agent of choice for patients with MPNs requiring treatment 1
• Interferon-α and busulfan are second-line options for cytoreduction when hydroxyurea is not tolerated or ineffective 1
• Aspirin should be avoided in patients with extreme thrombocytosis and confirmed AvWS due to increased bleeding risk 3, 1

For VWD with Waldenström's Macroglobulinemia-Related Leukocytosis:

• Bortezomib-based therapy is recommended for patients with Waldenström's macroglobulinemia who have high IgM levels, symptomatic hyperviscosity, or acquired VWD 3
• Rituximab-based regimens remain a recommended primary therapy for most patients with Waldenström's macroglobulinemia 3
• In patients with high IgM levels (≥4000 mg/dL), prophylactic plasmapheresis should be considered before rituximab administration 3

VWD-Specific Management:

• For Type 1 VWD (approximately 80% of cases), desmopressin is the treatment of choice 5, 6
• In Type 3 and most Type 2 VWD patients, plasma concentrates containing factor VIII and von Willebrand factor are necessary 5
• Target VWF activity level should be ≥50 IU/dL for most procedures 2
• Desmopressin should not be used to treat patients with Type 2B VWD since it may induce platelet aggregation 7

Special Considerations and Pitfalls

• Leukocytosis is an independent risk factor for thrombosis in MPNs, creating a complex balance between bleeding risk from VWD and thrombotic risk from the MPN 1
• Acquired von Willebrand syndrome in MPNs is associated with decreased large von Willebrand factor multimers, which can be corrected with cytoreduction 3, 1
• Relying solely on FVIII levels for treatment decisions is a common pitfall - VWF activity is the critical parameter 2
• Desmopressin can cause hyponatremia; fluid restriction is recommended, especially in pediatric and geriatric patients 7
• For women with VWD and leukocytosis planning pregnancy, a multidisciplinary approach with early involvement of high-risk obstetrics is strongly recommended 3

Monitoring and Follow-up

• For surgical patients, monitor VWF:RCo, VWF:Ag, and FVIII levels pre-treatment, post-treatment, and periodically during treatment 2
• In patients with MPNs, regular monitoring of complete blood counts is essential to assess response to cytoreductive therapy 1
• For persistent mucosal bleeding despite adequate FVIII levels, consider adjunctive treatments like tranexamic acid 2
• In patients with Waldenström's macroglobulinemia, regular monitoring of IgM levels and fundoscopic examination for signs of hyperviscosity are recommended 3