Von Willebrand’s Disease

Posted by • November 24th, 2016


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Von Willebrand’s disease is an inherited bleeding disorder characterized by defective platelet adhesion and aggregation. It is the most common inherited bleeding disorder and is generally transmitted as an autosomal dominant trait. It is mainly associated with mucosal bleeding and excessive bleeding after trauma or surgery. A variety of effective treatments are available and research is summarized in a new Review Article.

Clinical Pearl

What are the different types of von Willebrand’s disease?

Von Willebrand’s disease is subdivided into types 1, 2, and 3. Type 1, which accounts for 70 to 80% of cases, is characterized by a quantitative deficiency of von Willebrand factor. Type 2, accounting for approximately 20% of cases, is caused by dysfunctional von Willebrand factor, resulting in a normal or reduced von Willebrand factor antigen concentration but a large reduction in von Willebrand factor function. Type 2 is further subdivided on the basis of specific phenotypic characteristics. Type 3 von Willebrand’s disease is rare (accounting for <5% of cases), is the most severe form, and is caused by the absence of circulating von Willebrand factor.

Clinical Pearl

What are some of the clinical features of von Willebrand’s disease?

The symptoms of von Willebrand’s disease vary among patients, depending on the level of residual von Willebrand factor activity, the disease subtype, and to some extent, age and sex. In children with von Willebrand’s disease, the most frequent presenting symptoms are bruising and epistaxis. In adults, the most common symptoms are hematomas, menorrhagia, and bleeding from minor wounds. The majority of patients (60 to 80%) have bleeding after surgery or dental extractions. A well-known, serious, and possibly life-threatening bleeding complication is gastrointestinal bleeding from angiodysplasia. It is most common in elderly patients with type 2 or 3 von Willebrand’s disease. Intraarticular (joint) bleeding is a frequent complication in patients with hemophilia but has not been reported as a major problem in patients with von Willebrand’s disease, although it may be a presenting symptom in those with type 2N (type 2 subtype Normandy) or type 3 disease. It is now known that joint bleeding occurs in a considerable number of severely affected patients, potentially leading to arthropathy and reduced joint function.

Morning Report Questions

Q: Does the progressive physiological rise in von Willebrand factor levels throughout life reduce bleeding episodes in older patients with von Willebrand’s disease?

A: As a result of the physiologic rise in von Willebrand factor levels throughout life, patients with type 1 von Willebrand’s disease may have levels within the normal range when they become older. It is still not known whether this rise results in fewer bleeding episodes. A recent study showed that among patients with type 1 disease, bleeding symptoms occurred as frequently in patients who were older than 65 years of age as in those who were 18 to 65 years of age, which suggests that the age-dependent rise in von Willebrand factor levels does not lead to a mitigation of bleeding symptoms. Even though von Willebrand factor antigen levels also rise with age in patients with type 2 disease, von Willebrand factor activity remains low because of the functional defect in the protein. In these patients, an increase in bleeding symptoms is observed with increasing age. These observations should be confirmed in larger prospective studies.

Q: What are some of the factors other than mutations in the VWF gene that may play a role in reducing von Willebrand factor levels? 

A: Even though many mutations causing type 1 von Willebrand’s disease have been identified, no mutations are found in approximately 30% of patients. Genetic modifiers outside the VWF gene and physiological factors probably play a role in reducing von Willebrand factor levels. One of the major genetic determinants of von Willebrand factor levels outside the VWF gene is the ABO blood group, with 25% lower von Willebrand factor levels in persons with type O blood than in those with other types. Genomewide association studies have identified several other genetic loci that are associated with von Willebrand factor levels in healthy persons. Studies have confirmed that these genetic loci lead to variability in von Willebrand factor levels in patients with von Willebrand’s disease, as well as in healthy persons. The newly recognized genetic loci may contribute to the variability in the von Willebrand’s disease phenotype and may explain low levels of von Willebrand factor in affected patients who do not have a mutation in the VWF gene. Apart from genetic modifiers, physiological factors such as age and the response to exercise and the acute-phase response, as well as the menstrual cycle and pregnancy in women, also play a role in the variability of von Willebrand factor levels.

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