How is acquired von Willebrand syndrome (AvWS) managed and treated?

Management and Treatment of Acquired von Willebrand Syndrome (AvWS)

Acquired von Willebrand syndrome requires a multidisciplinary approach with treatment focused on addressing the underlying condition while managing acute bleeding with desmopressin, VWF concentrates, or other hemostatic agents based on the specific pathophysiologic mechanism involved. 1

Diagnosis and Pathophysiology

Acquired von Willebrand syndrome (AvWS) is characterized by structural or functional defects of von Willebrand factor (VWF) that develop secondary to various underlying conditions. Unlike congenital von Willebrand disease, AvWS has no family history of bleeding disorders and typically presents later in life.

The pathophysiologic mechanisms include:

• Antibody-mediated clearance or functional interference
• Adsorption to surfaces of transformed cells or platelets
• Increased shear stress leading to proteolysis of high molecular weight (HMW) VWF multimers 2

Common underlying conditions associated with AvWS:

• Lymphoproliferative disorders (47%)
• Myeloproliferative disorders (19%)
• Cardiovascular diseases (especially with mechanical circulatory support)
• Autoimmune disorders
• Solid tumors (7%)
• Other miscellaneous conditions (14%) 3

Treatment Approach

1. Treatment of the Underlying Condition

Treating the primary disorder should always be the first consideration as it can lead to complete remission of AvWS 4:

• Chemotherapy/radiotherapy for lymphoproliferative disorders
• Surgery for cardiovascular conditions
• Immunosuppressants for autoimmune disorders

2. Management of Acute Bleeding

For active bleeding episodes, a stepwise approach is recommended 1:

First-line therapy:

• Desmopressin (DDAVP): 0.3 μg/kg intravenously
  • Mechanism: Releases stored VWF from endothelial cells
  • Effectiveness: Increases VWF levels 3-6 fold within 30-90 minutes
  • Limitations: Tachyphylaxis may occur after 3-5 doses; less effective in patients with depleted endothelial VWF stores
  • Dosing: May be repeated at 12-24 hour intervals 1

Second-line therapy (if bleeding persists or desmopressin is ineffective):

• VWF-containing concentrates:

  • Plasma-derived VWF concentrates (pdVWF):

    • Dosage: 15-30 U/kg for minor bleeding; 40 IU/kg for major bleeding
    • Examples: Humate P, Wilate
    • Consideration: Contains FVIII which may increase thrombotic risk with repeated dosing 1, 5

  • Recombinant VWF (rVWF):

    • Advantages: Contains more HMW VWF multimers, lacks FVIII, higher platelet binding activity, longer half-life
    • More effective in correcting platelet function in in vitro studies of AvWS 1

Additional options for refractory bleeding:

• Intravenous immunoglobulin (IVIG):

  • Particularly effective in antibody-mediated AvWS
  • Dosage: 1g/kg/day for 2 days 2, 6

• Plasmapheresis: For rapid removal of antibodies or paraproteins 3

• Tranexamic acid: As adjunctive therapy for mucosal bleeding 4

• Recombinant Factor VIIa: For severe bleeding unresponsive to other treatments 2

3. Perioperative Management

For patients requiring surgery:

• Preoperative assessment of VWF function is essential
• For major procedures, consider:
  • VWF concentrate prophylaxis
  • IVIG (particularly effective for monoclonal gammopathy-associated AvWS)
  • Close monitoring of VWF levels 6

Special Considerations for AvWS in ECMO Patients

AvWS is nearly universal in patients on extracorporeal membrane oxygenation (ECMO) due to high shear stress causing proteolysis of HMW VWF multimers 1:

• Diagnosis requires specialized testing as routine coagulation tests are insensitive
• VWF multimer analysis is the gold standard but has limited availability
• A low VWF:Act/Ag ratio (<0.7) may serve as a surrogate marker 1

Management in ECMO patients:

1. Minimize or hold anticoagulation when bleeding occurs
2. Consider desmopressin (though may be less effective in COVID-19 ECMO patients)
3. VWF concentrates have shown promise in small studies:
   • In one study, Humate P (40 IU/kg) resolved bleeding in all patients, though 3/10 developed thrombotic complications 1

Pitfalls and Caveats

1. Diagnostic challenges: No single test is sufficient to diagnose AvWS; multimer analysis is the gold standard but has limited availability 1

2. Balancing thrombosis and bleeding risk: Many patients with AvWS have underlying conditions that predispose to thrombosis (e.g., myeloproliferative disorders) 4

3. Treatment response monitoring: The effectiveness of treatment can be difficult to assess, particularly in emergency situations 2

4. Tachyphylaxis with desmopressin: Effectiveness decreases after repeated doses due to depletion of VWF stores 1

5. Thrombotic risk with VWF concentrates: Particularly with repeated dosing of FVIII-containing products 1

6. Limited evidence base: Most recommendations are based on small studies or case series rather than randomized controlled trials 3

7. Recurrence after treatment: AvWS will recur unless the underlying condition is successfully treated 4

By addressing both the underlying condition and providing appropriate hemostatic support, most patients with AvWS can be effectively managed, though the approach must be tailored to the specific pathophysiologic mechanism and clinical scenario.