von Willebrand disease (VWD; 2019 ICD-10-CM: D68.0) is an inherited bleeding disorder caused by low concentration of or functionally impaired von Willebrand factor (VWF), with an estimated prevalence of approximately 1% of the population.1,2 VWD affects men and women at the same rate, but women are more often diagnosed because of heavy menstruation, bleeding during pregnancy or bleeding following delivery. Diagnosis and treatment of VWD at haemostasis centres tends to be much lower than the actual prevalence. Patients with VWD that present with medically significant symptoms are estimated to be about 0.1% of the population.1-3
Dr Erik von Willebrand, a physician living in Helsinki, Finland, first described VWD in 1926. By assessing 66 members of a single patient’s family, he deduced the patient had an as-yet undescribed bleeding disorder shared in an autosomal inheritance pattern. Researchers began to elucidate the underlying mechanisms of prolonged bleeding, including VWF, in the 1950s.1
VWF is a large, complex protein assembled from multimers comprising identical subunits encoded by the VWF gene, located on chromosome 12. VWF regulates platelet adhesion via interaction with glycoprotein Ib alpha, a membrane protein located on the platelet surface. VWF is also involved in the binding and stabilisation of factor VIII (FVIII).1,4,5
Normal ranges of VWF levels are 50–150%, however patients with blood type O sometimes have lower mean levels. Less than 50% of normal VWF activity is considered low. VWD is classified into three distinct types based on clinical presentation (summarised below in Table 1). Type 1 and 3 VWD are characterised by low or absent concentrations (quantitative defects) of VWF. Type 2 VWD is characterized by decreased activity (qualitative defects) of VWF and is divided into four separate categories depending on the specific reason for the loss of VWF activity.1,4,5
Table 1. Classification of VWD by functional deficiency
|Type 1|| |
Represents about 50–75% of cases
Abnormally low levels of VWF
Normal to mild decreases in FVIII due to lack of stabilisation
|Type 2|| |
Prevalence of classifications varies by region
25–50% of all cases
|Qualitative||Caused by mutations that alter VWF function|
|2A||A scarcity of large VWF multimers causing decreased platelet adhesion|
Gain-of-function mutation in the A1 domain of VWF
High glycoprotein Ib alpha affinity
Spontaneous binding to the platelet surface
Increased clearance of platelets and VWF
|2M||Normal VWF multimers, but decreased VWF-dependent platelet adhesion|
Mutations that impede VWF binding to FVIII
Decreased FVIII levels
Can be misdiagnosed as haemophilia
|Type 3|| |
Approximate prevalence of 1:1,000,000
Higher where consanguinity is more common
Immeasurable VWF in plasma
Caused by nonsense or frameshift mutation
Low levels of FVIII
Current classification of VWD shows multiple types of heritability. Type 1 VWD is autosomal dominant, type 2 VWD is mostly autosomal dominant (types 2A and M can also be autosomal recessive) and type 3 VWD is autosomal recessive.1
Many variants of VWD have been described. However, the use of genetics for diagnostic confirmation is limited and dependent on classification. Mutations that cause VWD type 3, often frameshifts and nonsense mutations, are mostly unique to related individuals. Less than two thirds of patients with type 1 VWD have an identifiable genetic variant. Type 2 VWD variants, however, are better characterised, and genetic analysis by sequencing the VWF gene may confirm the diagnosis. Furthermore, prenatal sequencing of the VWF gene in cases in which the child may have inherited VWD type 3 may help in planning during and after birth.1,5,6
Many factors such as stress, ABO blood group and inflammation can influence VWF levels in plasma. For example, individuals with blood group AB have the highest mean baseline VWF levels and persons with blood group O have the lowest levels. Menstrual cycle as well as oral contraceptives can also affect VWF levels. During pregnancy, women with VWD have an increased risk of bleeding complications and postpartum haemorrhage.1,4,7
Due to similar mechanisms of action, a number of bleeding disorders such as acquired von Willebrand syndrome (AVWS) and platelet-type VWD (PLT-VWD) have clinical symptoms similar to VWD. AVWS is a disorder characterised by deficient or abnormal VWF function that is non-heritable and secondary to other medical disorders. PLT-VWD is attributable to a gain-of-function defect in glycoprotein Ib alpha that causes enhanced binding to VWF. PLT-VWD is often misdiagnosed as VWD type 2B.1,8
Symptoms in individuals presenting with VWD depend on a number of factors and can range from mild to very severe. Bleeding in persons with VWD is often mucocutaneous and common symptoms include epistaxis, menorrhagia, bleeding after dental extraction, ecchymosis, bleeding after minor cuts and abrasions, gingival and postoperative bleeding. As the most common form of VWD is type 1, these symptoms are often of mild to moderate severity. As many of the mild symptoms can occur at similar rates in normal individuals, VWD can be difficult to diagnose during the clinical evaluation. Patients with type 3 and forms of type 2 VWD, however, can present with frequent spontaneous bleeding, severe bleeding and life-threating symptoms such as haemarthrosis and gastrointestinal bleeding due to vascular malformations.1,4,9
Menorrhagia is common in women with VWD. However, similar to mild bleeding episodes, menorrhagia occurs at a comparable rate in healthy women and is only considered to have low predictive value. Medications such as nonsteroidal anti-inflammatory drugs and aspirin can increase the severity of VWD symptoms (by inhibiting platelet function and further impairing primary haemostasis), and queries about medication, symptom history (frequency, severity and duration of bleeding episodes) and family history can help to elucidate symptoms during a clinical evaluation.1,5,10-12
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3. MASAC Recommendations Regarding the Treatment of von Willebrand
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6. Lillicrap D. von Willebrand disease: advances in pathogenetic understanding, diagnosis, and therapy. Blood 2013;122:3735-40.
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11. Bowman M, Riddel J, Rand ML, Tosetto A, Silva M, James PD. Evaluation of the diagnostic utility for von Willebrand disease of a pediatric bleeding questionnaire. J Thromb Haemost 2009;7:1418-21.
12. Casey LJ, Tuttle A, Grabell J, et al. Generation and optimization of the self-administered pediatric bleeding questionnaire and its validation as a screening tool for von Willebrand disease. Pediatr Blood Cancer 2017;64.