What is acquired von Willebrand's disease and how is it treated?

Acquired von Willebrand Syndrome: Diagnosis and Treatment

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder characterized by structural or functional defects of von Willebrand factor (VWF) that occurs secondary to various underlying conditions, with treatment primarily focused on addressing the underlying disorder and managing bleeding episodes with desmopressin or VWF concentrates. 1

Definition and Pathophysiology

Acquired von Willebrand syndrome differs from hereditary von Willebrand disease (VWD) in several key aspects:

• Occurs in individuals without previous bleeding history or family history of bleeding disorders
• Typically presents at an older age than hereditary VWD
• Develops secondary to underlying medical conditions

The pathophysiologic mechanisms of AVWS include:

1. Antibody-mediated clearance or functional interference - autoantibodies against VWF causing rapid clearance or functional inhibition 1
2. Adsorption to transformed cells - binding of VWF to malignant cells or platelets 1, 2
3. Increased shear stress and proteolysis - mechanical destruction of VWF multimers 1
4. Decreased synthesis or release of VWF from storage sites 3

Associated Conditions

AVWS occurs in association with various disorders:

• Lymphoproliferative disorders (most common) 4
• Myeloproliferative disorders including polycythemia vera (occurs in more than a third of PV patients) 5
• Cardiovascular disorders including mechanical circulatory support devices and aortic stenosis 6
• Autoimmune disorders 1
• Solid tumors 2
• Drug-induced cases 2
• Extracorporeal membrane oxygenation (ECMO) 5

Clinical Presentation

AVWS typically presents with:

• Mucocutaneous bleeding (most common) 4
• Easy bruising
• Prolonged bleeding from small wounds
• Epistaxis
• Gingival bleeding
• Menorrhagia in women

Diagnostic Approach

Diagnosis of AVWS can be challenging as no single test is sufficient to prove or exclude the condition 1. Laboratory evaluation should include:

• VWF antigen (VWF:Ag) - often decreased
• VWF activity (VWF:RCo) - decreased
• VWF:RCo/VWF:Ag ratio - ratio <0.7 suggests qualitative defects 5
• Factor VIII coagulant activity - may be normal or reduced
• VWF multimer analysis - often shows decreased large VWF multimers 5
• Bleeding time - typically prolonged
• Platelet Function Analyzer (PFA) - prolonged closure times 5
• Complete blood count and coagulation profile 6

In myeloproliferative disorders like polycythemia vera, AVWS is characterized by decreased large VWF multimers and increased cleavage products, suggesting proteolysis. The abnormality is often associated with extreme thrombocytosis and corrects with platelet count normalization 5.

Treatment Approach

Treatment of AVWS follows a two-pronged approach:

1. Treatment of Underlying Condition

Addressing the primary disorder is the most effective strategy for achieving remission of AVWS. Options include:

• Chemotherapy/radiotherapy for malignancies
• Surgery for appropriate conditions
• Immunosuppressants for autoimmune disorders
• Normalization of platelet counts in myeloproliferative disorders 5

2. Management of Bleeding Episodes

For acute bleeding or prophylaxis during invasive procedures:

First-line options:

• Desmopressin (DDAVP) - 0.3 mcg/kg (maximum 20 mcg) IV over 15-30 minutes 7
  • If used preoperatively, administer 30 minutes before procedure
  • May repeat after 8-12 hours and once daily thereafter if needed
  • Monitor for tachyphylaxis with frequent administration (less than every 48 hours)
  • Most effective in Type 1 VWD-like presentations

Second-line options:

• VWF-containing concentrates - plasma-derived or recombinant
  • Recombinant VWF (rVWF) has shown superior efficacy compared to plasma-derived VWF in correcting pathologic PFA closure times in ECMO-induced AVWS 5
  • Dosing of 40 IU/kg has been reported to increase VWF levels and improve VWF:RCo/VWF:Ag ratios 5
  • Monitor for thrombotic risk, which has been reported in some cases 5

Additional options:

• Intravenous immunoglobulin (IVIG) - particularly effective in antibody-mediated cases 1, 2
• Plasmapheresis or extracorporeal immunoadsorption - for antibody removal in refractory cases 2, 3
• Recombinant factor VIIa - for patients unresponsive to standard therapy 1, 4
• Antifibrinolytic agents (e.g., tranexamic acid) - as adjunctive therapy 2

Monitoring and Follow-up

During treatment:

• Monitor serum sodium levels (risk of hyponatremia with desmopressin) 7
• Assess VWF:Ag, VWF:RCo, factor VIII levels, and bleeding time to ensure adequate response 5, 7
• Restrict free water intake during desmopressin treatment 7
• Monitor for thrombotic complications, particularly in patients with myeloproliferative disorders who have both bleeding and thrombotic risks 5

Special Considerations

• ECMO patients may require higher doses of VWF to normalize hemostatic parameters compared to patients with hereditary VWD 5
• Mechanical circulatory support devices can cause AVWS through shear stress-induced destruction of VWF multimers 6
• Polycythemia vera patients with AVWS often show improvement with normalization of platelet counts 5

Prognosis

Prognosis depends largely on the underlying condition. Successful treatment of the primary disorder often leads to resolution of AVWS. However, in chronic conditions, long-term management of bleeding risk may be necessary.