Clinical characteristics: Von Willebrand disease (VWD), a congenital bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF), may only become apparent on hemostatic challenge, and bleeding history may become more apparent with increasing age.
Recent guidelines on VWD have recommended taking a VWF level of 30 or 40 IU/dL as a cutoff for those diagnosed with the disorder. Individuals with VWF levels greater than 30 IU/dL and lower than 50 IU/dL can be described as having a risk factor for bleeding. This change in guidelines significantly alters the proportion of individuals with each disease type.
Type 1 VWD (~30% of VWD) typically manifests as mild mucocutaneous bleeding.
Type 2 VWD accounts for approximately 60% of VWD. Type 2 subtypes include:
Type 2A, which usually manifests as mild-to-moderate mucocutaneous bleeding;
Type 2B, which typically manifests as mild-to-moderate mucocutaneous bleeding that can include thrombocytopenia that worsens in certain circumstances;
Type 2M, which typically manifests as mild-moderate mucocutaneous bleeding;
Type 2N, which can manifest as excessive bleeding with surgery and mimics mild hemophilia A.
Type 3 VWD (<10% of VWD) manifests with severe mucocutaneous and musculoskeletal bleeding.
Diagnosis: The diagnosis of VWD typically requires characteristic results of assays of hemostasis factors specific for VWD and/or identification of a heterozygous, homozygous, or compound heterozygous pathogenic variant(s) in VWF by molecular genetic testing. In addition, the diagnosis requires (in most cases) a positive family history. In those with a risk factor for bleeding (VWF levels >30 and <50 IU/dL), family history may not be positive because of incomplete penetrance and variable expressivity.
Management: Treatment of manifestations: Affected individuals benefit from care in a comprehensive bleeding disorders program. The two main treatments are desmopressin (1-deamino-8-D-arginine vasopressin [DDAVP]) and clotting factor concentrates (recombinant and plasma-derived) containing both VWF and FVIII (VWF/FVIII concentrate). Indirect hemostatic treatments that can reduce symptoms include fibrinolytic inhibitors; hormones for menorrhagia are also beneficial. Individuals with VWD should receive prompt treatment for severe bleeding episodes. Pregnant women with VWD are at increased risk for bleeding complications at or following childbirth.
Prevention of primary manifestations: Prophylactic infusions of VWF/FVIII concentrates in individuals with type 3 VWD to prevent musculoskeletal bleeding and subsequent joint damage.
Prevention of secondary complications: Cautious use of desmopressin (particularly in those age <2 years because of the potential difficulty in restricting fluids in this age group). Vaccination for hepatitis A and B.
Surveillance: Follow up in centers experienced in the management of bleeding disorders. Periodic evaluation by a physiotherapist of those with type 3 VWD to monitor joint mobility.
Agents/circumstances to avoid: Activities involving a high risk of trauma, particularly head injury; medications with effects on platelet function (ASA, clopidogrel, or NSAIDS). Circumcision in infant males should only be considered following consultation with a hematologist.
Evaluation of relatives at risk: If the familial pathogenic variant(s) are known, molecular genetic testing for at-risk relatives to allow early diagnosis and treatment, if needed.
Pregnancy management: As VWF levels increase throughout pregnancy, women with baseline VWF and FVIII levels greater than 30 IU/dL are likely to achieve normal levels by the time of delivery. However, those with a basal level lower than 20 IU/dL and those with baseline VWF:RCo or other VWF activity measurement/VWF:Ag ratio <0.6 are likely to require replacement therapy. Desmopressin has been successfully used to cover delivery in women with type 1 VWD and a proportion of pregnant women with type 2 VWD; delayed, secondary postpartum bleeding may be a problem.
Genetic counseling: VWD types 2B and 2M are inherited in an autosomal dominant manner. VWD types 1 and 2A are typically inherited in an autosomal dominant manner but may also be inherited in an autosomal recessive manner. VWD types 2N and 3 are inherited in an autosomal recessive manner.
AD inheritance. Most affected individuals have an affected parent. The proportion of cases caused by de novo pathogenic variants is unknown. Each child of an individual with AD VWD has a 50% chance of inheriting the pathogenic variant.
AR inheritance. At conception, each sib of an individual with AR VWD has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for family members at risk for AR VWD is possible once the pathogenic variants have been identified in the family.
Prenatal and preimplantation genetic testing are possible if the pathogenic variant(s) in the family are known.
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