Description

• von Willebrand disease (vWD) is an inherited bleeding disorder resulting from either a quantitative or qualitative defect in von Willebrand factor (vWF) protein.
• vWF plays an essential role in primary hemostasis, which facilitates the adherence of platelets to the injured blood vessel; it also serves as a carrier for factor VIII (FVIII) in the circulation.
• The most common clinical consequences of vWD are mucocutaneous bleeding, bleeding during childbirth and dental procedures, easy bruising, and menorrhagia (signs of platelet type bleeding).
• vWD is most commonly diagnosed as an autosomal inherited condition but rarely can also be acquired (AvWD).

Epidemiology

Prevalence

• vWD is the most common inherited bleeding disorder.
• 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 (1).

Etiology and Pathophysiology

• vWF is a large, multimeric glycoprotein that is released from endothelial cells and stored within the α-granules of platelets (2).
• vWF binds to subendothelial collagen at sites of vascular injury and facilitates platelet adhesion to these sites via its interaction with the platelet GP1b receptor. A platelet plug is formed, allowing for the initial arrest of bleeding (primary hemostasis). The formation of a fibrin clot follows the creating of the platelet plug, which requires normal amounts of and function of coagulation factors (secondary hemostasis).
• vWF acts as a carrier for FVIII in the circulation, protecting it from degradation. A deficiency in vWF may result in decreased FVIII levels.
• When vWF is deficient or dysfunctional, primary hemostasis is compromised, resulting in the clinical symptoms described above.
• There are three distinct types of inherited vWD. Within this classification scheme, type 2 vWD has several subtypes, described below (2). Whereas type 1 and type 3 are associated with quantitative deficiencies in vWF (decreased in type 1, absent in type 3), type 2 vWD results from functional defects in the glycoprotein.
  • Type 1, the most common and mildest form, represents 70–80% of cases.
  • Type 2, caused by qualitative defects in vWF, accounts for 10–15% of cases. The various subtypes are described below:
    • Type 2A results from the absence of high- and intermediate-molecular weight multimers of vWF.
    • Type 2B occurs due to a gain-of-function mutation in vWF, which increases its affinity for the platelet GP1b receptor. Complexes of platelet and vWF form as result and are subsequently removed from the circulation. Removal of these aggregates results in loss of the high-molecular-weight multimers on vWF as well as thrombocytopenia.
    • Type 2M results from a defect in the platelet binding domain of vWF; however, in contrast to types 2A and 2B, the entire vWF multimer remains intact.
    • Type 2N results from a mutation in the FVIII binding domain of vWF, resulting in low FVIII levels with an intact multimer.
  • Type 3 represents 1–5% of cases, the least common and most severe form.
    • Most severe form with markedly decreased-to-undetectable levels of vWF and FVIII
  • Platelet-type vWD (PT-vWD), also known as pseudo vWD, results from a hyperaffinity mutation in the platelet GP1b receptor, causing increased binding to vWF. Consequently, many platelet-vWF complexes form, which are then cleared from the circulation. Similar to vWD type 2B, these patients will demonstrate loss of high-molecular-weight multimers of vWF in addition to thrombocytopenia.
  • 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.

Genetics

• 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 follows both autosomal dominant and autosomal recessive inheritance patterns.
• Type 3 follows an autosomal recessive inheritance pattern.

Risk Factors

• Inherited (vWD): Risk factors include personal and/or family history of bleeding disorders.
• Acquired (AvWD): Risk factors include lymphoproliferative disorders, myeloproliferative disorders, autoimmune disorders, states of high vascular flow (e.g., aortic stenosis, presence of LVAD or ventricular septal defect).

Commonly Associated Conditions

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.