von Willebrand Disease

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  • von Willebrand disease (vWD) is a bleeding disorder caused by deficiency or a defect of von Willebrand factor (vWF) protein.
  • vWF is critical to the initial stages of blood clotting, acting as a bridge for platelet adhesion; it also acts as a carrier for factor VIII (FVIII).
  • Most common subtypes of vWD manifest as mucocutaneous, perioperative bleeding, or menorrhagia, whereas more serious subtypes may result in joint and soft tissue bleeding.
  • vWD is an inherited condition but rarely can be acquired (AvWD).


  • Prevalence of the inherited forms of vWD is 1 in 100 to 10,000 of the general population with more females being diagnosed than males.
  • Exact prevalence of the acquired forms of vWD (AvWD) is unknown but is estimated to be up to 0.1% of the general population.

Etiology and Pathophysiology

  • vWF is a large, multimeric protein that is released from endothelial cells and is also carried within platelets in α-granules.
  • vWF binds to collagen at sites of vascular injury and creates a surface for platelet adhesion through GP1b receptors. This results in platelet plug formation.
  • vWF is also a carrier for FVIII and stabilizes this factor from degradation. A deficiency in vWF may result in lower levels of FVIII.
  • When vWF is deficient or dysfunctional, primary hemostasis is compromised, resulting in increased mucocutaneous and postprocedural bleeding.
  • Three major inherited types of vWD exist.
    • Type 1, the most common and mildest form, represents 60–80% of cases.
      • Mild to moderate quantitative deficiency of vWF and concordant deficiency of FVIII
      • Generally, a mild bleeding disorder
    • Type 2, caused by qualitative defect in vWF, accounts for 10–30% of cases and is divided into the following multiple subtypes:
      • Type 2A is noted for loss of hemostatically active large multimers with low ristocetin cofactor/vWF activity.
      • Type 2B, noted for increased binding affinity for platelets, is associated with thrombocytopenia, low ristocetin cofactor/vWF activity, abnormal ristocetin-induced platelet aggregation (RIPA), and loss of large multimers.
      • Type 2M is noted for defective platelet or collagen binding without loss of large multimers.
      • Type 2N demonstrates defective binding to FVIII, which results in increased clearance of FVIII and a hemophilia A–like picture.
    • Type 3 represents 1–5% of cases.
      • Most severe form with markedly decreased-to-undetectable levels of vWF and FVIII
      • Manifests as hemophilia A with hemarthroses (1,2,3)
  • AvWD may be due to cardiovascular, hematologic, or autoimmune conditions as well as tumors and medications. The pathophysiology of AvWD is related to the underlying cause and may result from shear-induced cleaving of vWF in cardiovascular conditions, increased adsorption of vWF by certain tumor cells or activated platelets, or presence of anti-vWF autoantibodies in hematologic disorders.
  • Individuals with type O blood have accelerated clearance of vWF leading to vWF levels that are 25–30% lower than other those with blood type A, B, or AB. Type 1 disease is diagnosed more frequently in individuals with type O blood.
  • Platelet-type vWD (PLT-vWD), also called pseudo vWD, is caused by platelet GP1 alpha receptor mutation.

  • The 175-kb gene for vWF is located on short arm of chromosome 12.
  • Type 1 follows an autosomal dominant inheritance pattern, with variable expressivity.
  • Type 2 varies but primarily follows an autosomal dominant inheritance pattern.
  • Type 3 follows an autosomal recessive inheritance pattern (2).

Commonly Associated Conditions

AvWD may be found in patients with hematologic disorders such as MGUS and myeloproliferative neoplasms. Commonly associated cardiovascular conditions include aortic stenosis and left ventricular assist device (LVAD) placement. AvWD is associated with gastrointestinal (GI) bleeding from arteriovenous malformations.

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