What non‑genetic causes can explain a severe von Willebrand factor (VWF) deficiency with VWF antigen approximately 19 % and ristocetin‑cofactor activity approximately 17 %?

Non-Genetic Causes of Severe VWF Deficiency

The most likely non-genetic cause of severe VWF deficiency with VWF antigen ~19% and ristocetin cofactor activity ~17% is Acquired von Willebrand Syndrome (AVWS), which can develop from mechanical circulatory support devices (ECMO, ventricular assist devices), high shear stress conditions (severe aortic stenosis, other cardiac conditions), lymphoproliferative disorders, autoimmune diseases, or certain malignancies.

Understanding the Laboratory Pattern

The laboratory values presented (VWF:Ag ~19%, VWF:RCo ~17%) show:

• Proportional reduction in both antigen and activity levels, with a VWF:RCo/VWF:Ag ratio of approximately 0.89 1
• This ratio is above the typical threshold of <0.7 that would suggest qualitative VWF defects (Type 2 variants) 1
• The pattern resembles quantitative VWF deficiency rather than qualitative dysfunction 1

Primary Non-Genetic Causes to Investigate

1. Mechanical Circulatory Support (Most Common in Critical Care)

ECMO (Extracorporeal Membrane Oxygenation) causes AVWS in 70-100% of patients within hours of initiation 1:

• Loss of high-molecular-weight (HMW) VWF multimers occurs within 6-24 hours of ECMO implantation 1
• VWF:RCo/VWF:Ag ratios typically drop to 0.60-0.63 during ECMO support 1
• Reversibility is key: VWF parameters return to baseline within 24 hours of ECMO decannulation 1
• Both VA-ECMO and VV-ECMO cause AVWS with similar frequency 1

Ventricular Assist Devices (VADs) also cause AVWS in 95% of patients 1:

• Similar mechanism involving shear stress-induced proteolysis of VWF 1
• Loss of HMW multimers with decreased VWF:RCo/VWF:Ag ratios (median 0.56) 1

2. High Shear Stress Cardiac Conditions

Severe aortic stenosis causes acquired VWF deficiency through mechanical destruction 1:

• High-velocity blood flow across stenotic valves causes shear-induced VWF proteolysis 1
• VWF large multimer index significantly reduced compared to normal (31.8% vs 75.0%) 1
• Resolves after valve replacement

Other cardiac conditions with turbulent flow can produce similar effects 1

3. Lymphoproliferative and Plasma Cell Disorders

• Monoclonal gammopathy of undetermined significance (MGUS)
• Multiple myeloma
• Waldenström macroglobulinemia
• Chronic lymphocytic leukemia

Mechanism: Antibodies against VWF or increased VWF clearance

4. Autoimmune Diseases

• Systemic lupus erythematosus
• Antiphospholipid syndrome
• Other autoimmune conditions with anti-VWF antibodies

5. Hypothyroidism

• Decreased VWF synthesis
• Usually causes milder reductions than observed in this case

6. Certain Malignancies

• Wilms tumor
• Other solid tumors with increased VWF clearance

Diagnostic Algorithm

Step 1: Assess Clinical Context

Immediate questions to answer:

• Is the patient on ECMO, VAD, or other mechanical circulatory support? 1
• Does the patient have severe aortic stenosis or other valvular disease? 1
• Is there a recent history showing normal VWF levels before acute illness?

Step 2: Perform VWF Multimer Analysis

This is the definitive test to distinguish acquired from inherited VWD 1:

• Loss of HMW multimers indicates AVWS, particularly if associated with mechanical support 1
• Normal multimer distribution with proportional reduction suggests Type 1 VWD (genetic)
• Semiautomated methods (Hydragel, Sebia) provide standardized results within 1 day 1

Step 3: Evaluate for Underlying Conditions

Laboratory workup:

• Serum protein electrophoresis and immunofixation (monoclonal proteins)
• Complete blood count with differential (lymphoproliferative disorders)
• Thyroid function tests (TSH, free T4)
• Autoimmune serologies if clinically indicated

Imaging:

• Echocardiography to assess for valvular disease and cardiac function
• CT chest/abdomen/pelvis if malignancy suspected

Step 4: Assess Temporal Relationship

Key distinguishing feature of AVWS:

• Rapid onset (hours to days) in previously normal individuals 1
• Reversibility when underlying cause removed (e.g., ECMO decannulation) 1
• Inherited VWD would show lifelong bleeding history

Critical Pitfalls to Avoid

Testing-Related Pitfalls

• Do not rely solely on VWF:Ag and VWF:RCo without multimer analysis in suspected AVWS 1
• VWF:Ag levels may be elevated in critically ill patients due to acute phase response, masking the functional defect 1
• Blood type O individuals have VWF levels 25% lower than other blood groups—this alone does not explain severe deficiency 1

Clinical Pitfalls

• AVWS during ECMO does not correlate with bleeding risk in all studies 1
• Some patients with documented AVWS do not bleed, while others without AVWS may have major bleeding 1
• Do not assume genetic VWD without family history and lifelong bleeding symptoms 1

Prognosis and Reversibility

For ECMO-associated AVWS 1:

• VWF parameters normalize within 6-24 hours of device removal
• This rapid reversibility confirms the acquired nature
• Bleeding complications occur in 60-94% during support but resolve after decannulation

For other causes:

• Treatment of underlying condition (valve replacement, treating lymphoproliferative disorder) typically resolves AVWS
• Autoimmune AVWS may require immunosuppression

When Genetic Testing is Indicated

Consider VWF gene sequencing if:

• Lifelong bleeding history present
• Family history of bleeding disorder
• VWF deficiency persists after resolution of acute illness
• No identifiable acquired cause after comprehensive workup
• Multimer analysis shows patterns consistent with inherited Type 2 variants