Clinical characteristics: Von Willebrand disease (VWD) is characterized by mucocutaneous bleeding and excessive bleeding with trauma and procedures. Individuals with more severe forms of VWD are also at-risk for musculoskeletal bleeding. Mucocutaneous bleeding can include easy bruising, prolonged bleeding from minor wounds, epistaxis, oral cavity bleeding, heavy menstrual bleeding, gastrointestinal bleeding, and bleeding with hemostatic challenges such as dental work, childbirth, and surgery. Bleeding severity can vary widely in VWD, even between affected individuals within the same family. For some with VWD the bleeding phenotype may only become apparent upon hemostatic challenge, while others may have frequent spontaneous bleeding.

Diagnosis: The diagnosis of VWD is established in a proband with excessive bleeding by identification of a quantitative or qualitative deficiency in von Willebrand factor (VWF) and/or identification of a VWD-causative variant(s) in VWF by molecular genetic testing.

Management: Targeted therapy: VWF replacement; desmopressin.

Supportive care: People with VWD benefit from care in a comprehensive bleeding disorders program. Treatment is often given on demand for active bleeding episodes or for prevention of bleeding with hemostatic challenges. Prophylaxis should be considered in those with more severe bleeding. Useful adjunctive hemostatic treatments include antifibrinolytics, hormonal therapies for female reproductive tract bleeding, and local anatomic measures. Antifibrinolytic treatment (e.g., tranexamic acid) can be used alone for some hemostatic challenges or in combination with VWF-increasing treatment. Hormonal treatments can be useful in managing female reproductive tract bleeding either alone or in combination with antifibrinolytics and/or VWD-specific treatment.

Surveillance: Assessment in a center experienced in the comprehensive management of bleeding disorders to determine bleeding frequency and severity, treatment efficacy and tolerability, CBC, iron levels, VWF levels, and VWF inhibitors in those at risk (type 3 VWD) annually in those receiving treatment or every two to three years in those without bleeding and not requiring treatment. Evaluation by a physiotherapist, including consideration of musculoskeletal ultrasound evaluation for those with more severe VWD and/or low factor VIII levels, to monitor joint health (as in individuals with hemophilia A). Gynecology evaluation as needed for females with heavy bleeding. Gastroenterology evaluation with any suspected gastrointestinal bleeding or per gastroenterologist. Infectious disease assessment as needed in those exposed to blood products prior to 1985 or with other risk factors.

Agents/circumstances to avoid: Activities with a high risk of trauma; high contact sports with risk of head injury; medications with effects on platelet function (e.g., aspirin, clopidogrel); nutritional supplements that may impair hemostasis (e.g., fish oil, turmeric); invasive procedures without prior consultation with a hematologist (e.g., circumcision, dental, dermatologic, piercings). NSAIDs can increase bleeding risk and should be used cautiously and only for brief periods.

Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic at-risk relatives of an affected individual to allow early diagnosis and treatment as needed. In newborns, assess cord blood for low VWF and factor VIII levels to inform neonatal treatment. Molecular genetic testing of cord blood can be informative, particularly if the familial VWD-causing variant(s) are known.

Pregnancy management: Monitor VWF and factor VIII levels throughout pregnancy; postpartum hemorrhage prophylaxis with antifibrinolytics unless contraindicated; VWF replacement can be used to increase VWF levels.

Genetic counseling: Type 1, type 2A, and type 2M VWD are typically caused by a heterozygous VWF variant and inherited in an autosomal dominant manner; rarely, these VWD types are associated with biallelic VWF variants. Type 2B VWD is typically caused by a heterozygous VWF variant and inherited in an autosomal dominant manner. Type 2N and type 3 VWD are caused by biallelic VWF variants and inherited in an autosomal recessive manner.

Autosomal dominant inheritance: Many individuals diagnosed with autosomal dominant VWD have an affected parent. Each child of an individual with autosomal dominant VWD has a 50% chance of inheriting the VWD-causing variant. VWD often exhibits variable penetrance and expressivity.

Autosomal recessive inheritance: If both parents are known to be heterozygous for a VWD-causing variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial VWD-causing variants. Heterozygous sibs of an individual with type 2N VWD are often asymptomatic; however, a small proportion of these heterozygous individuals may have some mild bleeding symptoms and lower factor VIII levels and may be diagnosed with VWD. Heterozygous sibs of an individual with type 3 VWD may be asymptomatic or may have bleeding symptoms and low VWF levels and may be diagnosed with type 1 VWD. Molecular genetic testing for at-risk relatives is most informative if the VWD-causing variant(s) have been identified in an affected family member.

Once the familial VWD-causing variant(s) have been identified, prenatal and preimplantation genetic testing for VWD are possible.