Von Willebrand disease (VWD) is a genetic bleeding disorder characterized by low levels or reduced activity of von Willebrand factor (VWF). It is a highly heterogeneous condition, presenting with a wide range of clinical and laboratory phenotypes. The diagnosis of VWD is based on three main criteria: a positive bleeding history, low levels of circulating VWF, and autosomal inheritance patterns. VWD is classified into three main types: Type 1, Type 2, and Type 3, each with distinct characteristics and inheritance patterns. The prevalence of VWD has been estimated to be around 1%, but accurate diagnosis can be challenging due to various confounding factors affecting plasma VWF levels, especially in mild cases. The prevalence of clinically relevant VWD could range from 1/1,000 to 10,000 inhabitants based on patients referred to tertiary care centers. Recent genetic data suggests that pathogenic VWF variants or putative disease alleles may be more common than previously thought.
The classification of VWD includes Type 1 (60-70% of cases), Type 2 (20-25% of cases), and Type 3 (5% of cases). Type 1 VWD is characterized by partial quantitative VWF deficiency (10-30 U/dL) and normal or slightly reduced levels of factor VIII (FVIII). The ratio between VWF activity and its concentration is typically >0.7, and inheritance is autosomal dominant. Type 2 VWD is further divided into four variants (Type 2A, 2B, 2M, and 2N) based on distinct pathophysiological mechanisms and laboratory features. Type 3 VWD is characterized by the absence of VWF and very low FVIII levels, with autosomal recessive inheritance. The remaining patients with Type 2 VWD have distinct clinical phenotypes and inheritance patterns.
The clinical presentation of VWD includes excessive mucocutaneous bleeding, such as epistaxis, gum bleeding, heavy menstrual bleeding, and gastrointestinal bleeding. Bleeding after tooth extraction and surgery is also common. The bleeding tendency varies across different types of VWD. Type 1 VWD typically presents with mild clinical expression, especially in females, due to menstruation and childbirth. However, women with VWD often have a lower quality of life due to increased bleeding during childbearing and chronic anemia. Infants and toddlers with VWD may also experience bleeding complications, such as circumcision-related bleeding and oropharyngeal bleeding.
The severity of bleeding in VWD correlates with the degree of VWF and FVIII reduction, particularly for joint bleeding and surgical complications. Some mucocutaneous bleeding, like epistaxis during childhood and menorrhagia, can be frequent and impact quality of life. However, the rate of spontaneous bleeding can vary, even in patients with significant VWF deficiency. Post-operative bleeding is a common concern, especially after dental extraction, and hemostatic prophylaxis is often required to prevent delayed bleeding.
The prevalence of VWD in the general population is estimated to be around 1%, but accurate diagnosis can be challenging due to various confounding factors. The prevalence of clinically significant VWD cases is uncertain, and estimates are influenced by clinical criteria, populations studied, and laboratory methods. The assessment of bleeding history is also more difficult in epidemiological studies compared to clinical settings. Stringent clinical criteria and standardized questionnaires are essential for accurate assessment.
VWD is classified into three main types based on VWF abnormalities: Type 1 (quantitative deficiencies), Type 2 (qualitative defects), and Type 3 (absence of VWF). The prevalence of Type 3 VWD is very low, ranging from 0.1 to 5.3 per million in the population. The prevalence of clinically moderate to severe VWD is higher in recessive Type 1 cases and Type 1 and Type 2 with high penetrance and expressivity. The prevalence of clinically intermediate VWD is similar to the cumulative prevalence of hemophilia A and B, while the prevalence of mild VWD is still uncertain.
The classification of VWD based on clinical phenotypes includes three distinct groups: Group A (severe to moderate bleeding symptoms), Group B (milder bleeding phenotype), and Group C (mild hemorrhagic phenotype). The prevalence of severe VWD (Group A) is estimated to be around 1.53 to 1.38 cases per million in Europe and North America. The prevalence of intermediate VWD (Group B) is estimated to range from 40 to 100 cases per million, while the prevalence of mild VWD (Group C) is uncertain but possibly one case per 1,000 to 10,000 subjects.
The prevalence of VWD varies globally, with higher rates in high-income countries (60.3 per million) compared to low-income countries (1.1 per million). The prevalence of Type 3 VWD is higher in low-income countries due to diagnostic limitations and restricted access to treatment. The global prevalence of VWD is estimated to be 25.6 per million people, with the lowest registration rate in South Asia (0.6 per million) and the highest in Europe/Central Asia (50.9 per million).
The prevalence of mutant VWF genes in the general population is also uncertain, but some heterozygous variants are highly penetrant and cause severe reduction of VWF levels. The prevalence of heterozygous p.Arg854Gln may be as high as 1%, but bleeding occurs only in a homozygous or compound heterozygous state. Heterozygous Type 3 VWD carriers or patients with recessive Type 1 VWD are usually asymptomatic but carry variants that produce significant bleeding in a compound heterozygous or homozygous state.
Recent genetic studies have provided valuable insights into the prevalence and mutational landscape of VWD. By analyzing exome and genome data from large populations, researchers have identified a total of 4,313 variants, with 505 predicted to be pathogenic or associated with VWD. The global prevalence of dominant VWD was estimated at 7.4% for Type 1, 0.3% for Type 2A, 0.3% for Type 2B, and 0.6% for Type 2M. The prevalence of recessive Type 3 VWD was estimated at 0.03%, and Type 2N at 0.07%. These estimates varied across different ancestral populations, highlighting the functional diversity of VWF gene variants.
In summary, VWD is a heterogeneous bleeding disorder caused by reduced VWF activity. The classification and epidemiology of VWD provide valuable insights into its clinical presentation and global prevalence. However, accurate diagnosis and understanding of the disease's genetic basis are essential for proper management and treatment.
