von Willebrand Disease

Key Features

Essentials of Diagnosis

• The most common inherited bleeding disorder

• von Willebrand factor (vWF) binds platelets to subendothelial surfaces, aggregates platelets, and prolongs the half-life of factor VIII

General Considerations

• vWF is an unusually large multimeric glycoprotein that binds to subendothelial collagen and its platelet receptor, glycoprotein Ib, bridging platelets to the subendothelial matrix at the site of vascular injury, and contributing to linking them together in the platelet plug

• vWF also has a binding site for factor VIII, prolonging its half-life in the circulation

• Type 1 von Willebrand disease (vWD)

  • Seen in 75–80% of patients with vWD

  • It is a quantitative abnormality of the vWF molecule that usually does not feature an identifiable causal mutation in the vWF gene

• Type 2 vWD

  • Seen in 15–20% of patients with vWD

  • In type 2A or 2B, a qualitative defect in the vWF molecule is causative

  • Types 2N and 2M are due to defects in vWF that decrease binding to factor VIII or to platelets, respectively; importantly, type 2N can clinically resemble hemophilia A because factor VIII activity levels are decreased and vWF activity and antigen (Ag) are normal

  • Type 2M features a normal multimer pattern

• Type 3 vWD

  • Rare

  • Quantitative defect

  • Mutational homozygosity or compound heterozygosity yielding very low levels of vWF

  • Due to its factor VIII carrier function, a severely low vWF level leads to low factor VIII activity and prolonged aPTT

Demographics

• Common disorder affecting both men and women

Clinical Findings

Symptoms and Signs

• Type 1 vWD: patients usually have mild or moderate platelet-type bleeding (mucocutaneous)

• Type 2 vWD: patients usually have moderate to severe bleeding that presents in childhood or adolescence

• Type 3 vWD: patients have severe bleeding in infancy or childhood

Differential Diagnosis

• Other qualitative platelet disorders, eg, uremia, aspirin use, Glanzmann thrombasthenia

• Thrombocytopenia

• Hemophilia

• Waldenström macroglobulinemia

Diagnosis

Laboratory Tests

• See Table 14–9

• In type 1 vWD, the vWF activity (by ristocetin co-factor assay) and the vWF Ag are mildly depressed, whereas the vWF multimer pattern is normal

• In type 2A or 2B vWD, the ratio of vWF Ag:vWF activity is typically approximately 2:1 and there is a multimer pattern that lacks the highest molecular weight multimers

• In type 2B vWD, thrombocytopenia is common due to a gain-of-function mutation of the vWF molecule; a ristocetin-induced platelet aggregation (RIPA) study shows an increase in platelet aggregation in response to low concentrations of ristocetin

• aPTT and PT are most commonly normal, except in the more severe forms of vWD that feature a significantly decreased factor VIII activity