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Chapter 56: von Willebrand Disease

Pier M. Mannucci

INTRODUCTION

von Willebrand disease (VWD)

  • A congenital bleeding disorder resulting from a quantitative or qualitative deficiency of von Willebrand factor (VWF)

  • VWF is a plasma glycoprotein with essential platelet-dependent function in primary hemostasis and a carrier for factor VIII (FVIII) in the circulation

  • Acquired von Willebrand syndrome presents as a similar bleeding disorder

Epidemiology

Prevalence:

Inherited: 0.01–1%

  • 0.01% of population using the number of patients seen at specialized hemostasis centers

  • 1% of population using population-based screening (the most common inherited bleeding disorder)

Acquired: 0.04–0.13%

Male to female ratio: 1:1

 

Rodeghiero F et al. Blood 1987;69:454–459

Sadler JE et al. Thromb Haemost 2000;84:160–174

Werner EJ et al. J Pediatr 1993;123:893–898

Classification of Inherited VWD

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Classification of Inherited VWD
  Percent of Cases Defect Inheritance
Type 1 (classic) 70–80% Quantitative deficiency of VWF AD
Type 2 (variant) 15–30% Qualitative defect of VWF AD or AR
Type 2A 10–20% Decreased platelet-dependent VWF function, with lack of high-molecular-weight VWF multimers

AD

Rarely AR
 Type 2B 5–10% Increased VWF affinity for platelet receptor (leading to decreased plasma levels of VWF). Patients may or may not lack high-molecular-weight VWF multimers. They may have thrombocytopenia from clearance of platelet aggregates formed by the heightened binding of VWF to platelets AD
 Type 2M Uncommon Decreased platelet-dependent VWF function, with normal high-molecular-weight VWF multimers AD
 Type 2N Uncommon Decreased affinity for FVIII. Lack of protection of FVIII by VWF leads to rapid clearance and low levels of FVIII, with normal or low borderline levels of VWF AR
Type 3 Rare (1–5/106) Complete (quantitative) deficiency of VWF AR

VWF, von Willebrand factor; AD, autosomal dominant; AR, autosomal recessive

Sadler JE et al. J Thromb Haemost 2006;4:2103–2114

Work-up

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Work-up
Diagnostic Test Role/Comment
Abbreviation Name
aPTT Activated partial thromboplastin time Not a sensitive measure for VWD
VWF:Ag Plasma VWF antigen
VWF:RCo Plasma VWF activity (ristocetin cofactor activity and collagen binding activity ELISA; limited availability
FVIII✫ Factor VIII activity✫
Bleeding time Bleeding time Not sensitive or specific measures for VWF function
PFA-100 Automated platelet function analyzer testing

Perform tests below:

  1. To determine the VWD subtype after the diagnosis is established

  2. If there is a high index of suspicion for VWD, and some of the tests above are normal
VWF multimers VWF multimers Gel electrophoresis for size distribution of plasma multimers
RIPA

Ristocetin-induced platelet aggregation

 Use to determine if a patient's VWF has an abnormally high affinity for platelet receptors; it is a necessary and specific for the diagnosis of type 2B VWD

VWF, von Willebrand factor; VWD, von Willebrand disease

✫Note: FVIIIC is the coagulant component of FVIII, which, in normal people, circulates in the plasma complexed with von Willebrand factor
Type VWF:Ag VWF:RCo RIPA Plasma Multimer Distribution Factor VIII:C✫...

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