What is the management approach for acquired von Willebrand factor disease?

Management of Acquired von Willebrand Syndrome

Manage acquired von Willebrand syndrome (AVWS) with a stepwise approach: first treat the underlying disorder when feasible, then use targeted hemostatic therapies including VWF-containing concentrates, desmopressin (with caution regarding its limitations), or IVIG depending on the pathogenic mechanism and clinical context. 1

Diagnostic Confirmation

Before initiating treatment, confirm AVWS diagnosis through specialized testing, as routine coagulation tests are insensitive:

• VWF multimer analysis remains the gold standard for detecting loss of high-molecular-weight (HMW) multimers, though it has limited availability and slow turnaround time 1
• Measure VWF antigen (VWF:Ag), VWF activity (VWF:Act), and VWF collagen binding (VWF:CB) assays, though these do not always detect impaired VWF function 1
• Calculate the VWF:RCo/VWF:Ag ratio to assess functional deficiency 1
• Consider newer semi-automated methods (Hydragel von Willebrand multimers test) that provide results within one day with excellent agreement to traditional methods 1

Critical pitfall: Elevated VWF:Ag levels may mask underlying AVWS in inflammatory conditions, myeloproliferative disorders, or critical illness—complete VWF testing including multimer analysis is essential 2

Primary Management: Treat the Underlying Disorder

Treatment of the causative condition should always be attempted first, as this can lead to remission of AVWS: 3, 4

• For lymphoproliferative/myeloproliferative disorders: chemotherapy or radiotherapy 3, 5
• For monoclonal gammopathies: immunosuppressants or high-dose IVIG 6, 5
• For cardiovascular causes (aortic stenosis): valve replacement may normalize coagulation parameters 2
• For autoimmune disorders: immunosuppressive therapy 5

Acute Bleeding Management: Stepwise Approach

When bleeding occurs, implement the following hierarchy: 1

Step 1: Minimize Anticoagulation

• Hold or reduce anticoagulation and antiplatelet therapy immediately 1
• Provide blood product replacement based on clinical guidelines 1

Step 2: VWF-Containing Concentrates (First-Line for Severe Bleeding)

VWF concentrates are the preferred targeted therapy for restoring HMW multimers in refractory bleeding: 1, 3

• Use plasma-derived VWF (pdVWF) or recombinant human VWF (rVWF) concentrates 1
• These directly replace deficient HMW multimers regardless of pathogenic mechanism 3, 4
• Particularly effective when AVWS results from antibody-mediated clearance, adsorption to malignant cells, or increased proteolysis 3
• Evidence is limited to in vitro and small in vivo studies in ECMO patients, but clinical experience supports use 1

Step 3: Desmopressin (DDAVP) - Use with Significant Caveats

Desmopressin has major limitations in AVWS and should be used cautiously: 1, 7

• FDA-approved dose: 0.3 mcg/kg IV administered 30 minutes prior to procedures 7
• Releases stored VWF from endothelial Weibel-Palade bodies, increasing VWF and Factor VIII levels 3- to 6-fold within 30-90 minutes 1

Critical limitations specific to AVWS:

• Ineffective in COVID-19 ARDS patients on ECMO due to depleted endothelial VWF stores—desmopressin did not significantly increase VWF:Ag, VWF:Act, or VWF:Act/VWF:Ag ratio 1
• Tachyphylaxis occurs after 3-5 doses due to exhaustion of endothelial VWF storage 1
• Released VWF undergoes rapid shear-induced proteolysis by ADAMTS-13, contributing to transient effect 1
• Contraindicated in Type IIB von Willebrand disease as it may induce platelet aggregation 7

Mandatory precautions when using desmopressin:

• Fluid restriction is required to prevent water intoxication and hyponatremia, which can be fatal 7
• Monitor for hyponatremia symptoms: headache, nausea, weight gain, confusion, seizures, or coma 7
• Use extreme caution in elderly and pediatric patients 7
• Avoid in patients with psychogenic polydipsia 7

Step 4: High-Dose Intravenous Immunoglobulin (IVIG)

For antibody-mediated AVWS refractory to VWF replacement: 6, 5

• High-dose IVIG can successfully treat bleeding when classical VWF replacement fails 6
• Particularly effective when autoantibodies cause rapid VWF clearance or functional interference 3, 5
• Consider in monoclonal gammopathies and autoimmune disorders 5

Step 5: Additional Therapies for Refractory Cases

• Tranexamic acid as adjunctive antifibrinolytic therapy 4
• Plasmapheresis or extracorporeal immunoadsorption for cases with anti-VWF antibodies 5
• Recombinant Factor VIIa as rescue therapy for life-threatening bleeding unresponsive to other measures 3

Prophylaxis for Invasive Procedures

Test for AVWS prior to any surgery or high-bleeding-risk intervention in patients with associated disorders: 4

• Administer VWF-containing concentrates or desmopressin 30 minutes before scheduled procedures 7, 3
• Have multiple therapeutic options available, as heterogeneous mechanisms often require more than one approach 3
• For patients with elevated VWF:Ag but normal VWF activity (>50 IU/dL), standard perioperative management is appropriate 2

Special Populations

ECMO Patients

Bleeding during ECMO results from multiple mechanisms—AVWS is only one contributor: 1

• Over-anticoagulation, thrombocytopenia, platelet dysfunction, decreased coagulation factors, and liver failure all contribute 1
• VWF:CB/Ag ratio may be higher in patients who experience major bleeding 1
• Multidisciplinary approach involving intensivists, hematologists, and perfusionists is mandatory 1

Myeloproliferative Disorders

• AVWS occurs in >33% of polycythemia vera patients, associated with extreme thrombocytosis 1
• Pathogenesis involves abnormal adsorption of large VWF multimers to clonal platelets, enhancing proteolysis 1
• Use aspirin with extreme caution due to potentially increased bleeding risk despite elevated VWF:Ag 2
• Corrects with platelet count normalization 1

Monitoring Treatment Response

• Recheck bleeding time, Factor VIII coagulant activity, ristocetin cofactor activity, and VWF antigen during treatment to ensure adequate levels 7
• Monitor for signs of hyponatremia if using desmopressin 7
• Assess for remission of AVWS after treating underlying disorder 4