Description

• von Willebrand disease (vWD) is a lifelong bleeding disorder resulting from either a quantitative or qualitative (e.g., structural or functional) defect in von Willebrand factor (vWF).
• vWF is a large glycoprotein that 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) circulating in the blood.
• The most common clinical consequences mucocutaneous bleeding, bleeding during childbirth, dental procedures, easy bruising, and menorrhagia.
• vWD is most commonly diagnosed as an autosomal-dominant condition but can also be autosomal recessive. In rare cases, this condition can also be acquired (AvWD).
• vWD can be broken down into three different types:
  • Type 1: mildest type—associated with a mild-to-moderate quantitative vWF deficiency
  • Type 2: qualitative defect in vWF (e.g., issues with the protein folding, binding, polypeptide chain structure)
  • Type 3: most severe type—associated with a complete deficiency in vWF

Epidemiology

Prevalence

• vWD is the most common inherited bleeding disorder.
• Prevalence of the inherited forms of vWD is about 109 to 2,200 per 100,000 of the general population with men and women acquiring the disorder at equal frequency.
• Women are diagnosed more often due to the increased bleeding that is seen during menstrual periods, during pregnancy, and after childbirth.
• Exact prevalence of the 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.
• 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. This process forms a platelet plug, allowing for the initial arrest of bleeding (i.e., primary hemostasis). The formation of a fibrin clot follows the creation of a platelet plug, which requires normal amounts of and function of coagulation factors (i.e., 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. Whereas types 1 and 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 vWF multimers.
    • Type 2B occurs due to a gain-of-function mutation in vWF, which increases its affinity for the platelet GP1b receptor. Complexes of platelets and vWF form as a result and are subsequently removed from circulation. Removal of these aggregates results in loss of the high-molecular-weight vWF multimers 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 (PLT-vWD), also known as pseudo-vWD, results from a hyperaffinity mutation in the platelet GP1b receptor gene, causing increased binding to vWF. Consequently, many platelet-vWF complexes form, which are then cleared from circulation. Similar to vWD type 2B, these patients demonstrate loss of high-molecular-weight vWF multimers 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 underlying quantitative and/or qualitative changes in vWF 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 178-kb gene for vWF is located on the short arm of chromosome 12.
• Most cases of type 1 vWD follow an autosomal-dominant inheritance pattern, with variable expressivity. Rarer occurrences of type 1 are inherited in an autosomal-recessive manner.
• Types 2A, 2B, and 2M are inherited in an autosomal-dominant manner, whereas 2N is inherited in an autosomal-recessive manner.
• Type 3 follows an autosomal-recessive inheritance pattern.

Risk Factors

• Inherited vWD: personal and/or family history of bleeding disorders.
• 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. Therefore, type 1 disease is diagnosed more frequently in individuals with type O blood.