eMedicine Specialties > Pediatrics: General Medicine > Hematology

Von Willebrand Disease

Author: John D Geil, MD, Associate Professor of Pediatrics, Division of Hematology/Oncology, University of Kentucky College of Medicine; Consulting Staff, Department of Pediatric Hematology/Oncology, University of Kentucky Children's Hospital
Contributor Information and Disclosures

Updated: May 21, 2009

Introduction

Background

Although referred to as a single disease, von Willebrand disease (VWD) is in fact a family of bleeding disorders caused by an abnormality of the von Willebrand factor (VWF). von Willebrand disease is the most common hereditary bleeding disorder.

First described by Erik Adolf von Willebrand in 1926, von Willebrand disease is a congenital bleeding disorder characterized by a lifelong tendency toward easy bruising, frequent epistaxis, and menorrhagia.

Pathophysiology

von Willebrand disease is due to an abnormality, either quantitative or qualitative, of the von Willebrand factor, which is a large multimeric glycoprotein that functions as the carrier protein for factor VIII (FVIII). von Willebrand factor is also required for normal platelet adhesion. As such, von Willebrand factor functions in both primary (involving platelet adhesion) and secondary (involving FVIII) hemostasis. In primary hemostasis, von Willebrand factor attaches to platelets by its specific receptor to glycoprotein Ib on the platelet surface and acts as an adhesive bridge between the platelets and damaged subendothelium at the site of vascular injury. In secondary hemostasis, von Willebrand factor protects FVIII from degradation and delivers it to the site of injury.

von Willebrand factor is composed of dimeric subunits that are linked by disulfide bonds to form complex multimers of low, intermediate, and high molecular weights. The small multimers function mainly as carriers for FVIII.

High–molecular weight multimers have higher numbers of platelet-binding sites and greater adhesive properties. Each multimeric subunit has binding sites for the receptor glycoprotein Ib on nonactivated platelets and the receptor glycoprotein IIb/IIIa on activated platelets. This facilitates both platelet adhesion and platelet aggregation, making high molecular weight multimers most important for normal platelet function.

von Willebrand disease can be classified into 3 main types.

• Type 1 von Willebrand disease, which accounts for 70-80% of cases, is characterized by a partial quantitative decrease of qualitatively normal von Willebrand factor and FVIII. An individual with type 1 von Willebrand disease generally has mild clinical symptoms, and this type is usually inherited as an autosomal dominant trait; however, penetrance may widely vary in a single family. In addition, clinical and laboratory findings may vary in the same patient on different occasions. Typically, a proportional reduction in von Willebrand factor activity, von Willebrand factor antigen, and FVIII is observed in type 1 von Willebrand disease.
• Type 2 disease accounts for 15-20% of von Willebrand disease cases. Type 2 von Willebrand disease is a variant of the disease with primarily qualitative defects of von Willebrand factor. Type 2 von Willebrand disease can be either autosomal dominant or autosomal recessive. Of the 4 described type 2 von Willebrand disease subtypes (ie, 2A, 2B, 2M, 2N), type 2A von Willebrand disease is by far the most common.
  • Type 2A von Willebrand disease is inherited as an autosomal dominant trait and is characterized by normal-to-reduced plasma levels of factor VIIIc (FVIIIc) and von Willebrand factor. Analysis of von Willebrand factor multimers reveals a relative reduction in intermediate and high molecular weight multimer complexes. The multimeric abnormalities are commonly the result of in vivo proteolytic degradation of the von Willebrand factor. The ristocetin cofactor activity is greatly reduced, and the platelet von Willebrand factor reveals multimeric abnormalities similar to those found in plasma.
  • Type 2B von Willebrand disease is also an autosomal dominant trait. This type is characterized by a reduction in the proportion of high molecular weight von Willebrand factor multimers, whereas the proportion of low–molecular weight fragments are increased. Patients with type 2B von Willebrand disease have a hemostatic defect caused by a qualitatively abnormal von Willebrand factor and intermittent thrombocytopenia. The abnormal von Willebrand factor has an increased affinity for platelet glycoprotein Ib.
  • The platelet count may fall further during pregnancy, in association with surgical procedures, or after the administration of desmopressin acetate (DDAVP). Although some investigators found DDAVP to be clinically useful in persons with type 2B von Willebrand disease , studies directed at excluding the 2B variant should be completed before DDAVP is used. Measurements of FVIIIc and von Willebrand factor in plasma vary; however, studies involving the use of titered doses of ristocetin reveal that aggregation of normal platelets is enhanced and induced by unusually small amounts of the drug.
  • In patients with the rare type 2M von Willebrand disease, laboratory results are similar to those of certain patients with type 2A von Willebrand disease. Type 2M von Willebrand disease is characterized by a decreased platelet-directed function that is not due to a decrease of high–molecular weight multimers. Laboratory findings show decreased von Willebrand factor activity, but von Willebrand factor antigen, FVIII, and multimer analysis are found to be within reference range.
  • Type 2N von Willebrand disease is also rare and is characterized by a markedly decreased affinity of von Willebrand factor for FVIII, resulting in FVIII levels reduced to usually around 5% of the reference range. Other von Willebrand factor laboratory parameters (ie, von Willebrand factor antigen [VWF:Ag], ristocetin cofactor activity) are usually normal. The FVIII-binding defect in these patients is inherited in an autosomal recessive manner. Evaluate patients with FVIII deficiency and a bleeding disorder that is not clearly transmitted as an X-linked disorder or those who respond incompletely to hemophilia A therapy for type 2N von Willebrand disease. Unfortunately, the confirmatory test for type 2N von Willebrand disease is not routinely available, likely resulting in an underestimate of the true frequency of this subtype.
• Type 3 is the most severe form of von Willebrand disease. In the homozygous patient, type 3 von Willebrand disease is characterized by marked deficiencies of both von Willebrand factor and FVIIIc in the plasma, the absence of von Willebrand factor from both platelets and endothelial cells, and a lack of response to DDAVP. Type 3 von Willebrand disease is characterized by severe clinical bleeding and is inherited as an autosomal recessive trait. Consanguinity is common in kindreds with this variant. Less severe clinical abnormalities and laboratory abnormalities may be identified in occasional heterozygotes; however, such cases are difficult to identify. Multimeric analysis of the small amount of von Willebrand factor present yields variable results, in some cases revealing only small multimers.

Frequency

United States

von Willebrand disease is estimated to affect about 1% of the population.

International

Prevalence worldwide is estimated at 0.9-1.3%.

Mortality/Morbidity

The morbidity in individuals with von Willebrand disease varies. Many children with von Willebrand disease are asymptomatic. Some of these children have cutaneous and/or mucus membrane bleeding (eg, easy bruising, epistaxis).

Menorrhagia is a common symptom in females with von Willebrand disease . It occurs in more than 50% of women with von Willebrand disease and may be the only clinical manifestation of the disease.

The rare type 3 von Willebrand disease can manifest with severe bleeding symptoms similar to severe hemophilia (eg, hemarthrosis, intramuscular bleeding).

Race

No influence of ethnicity on the prevalence of von Willebrand disease has been reported.

Sex

von Willebrand disease affects males and females in equal numbers.

Age

von Willebrand disease is a congenital bleeding disorder and can be diagnosed at any age.

Clinical

History

• Many children with von Willebrand disease (VWD) are asymptomatic and are diagnosed as a result of a positive family history or during routine preoperative screening (eg, prolonged bleeding time). Importantly, remember that a wide variation in clinical manifestations is observed, even for members of the same family. 
• The diagnosis of von Willebrand disease can be challenging and depends on an accurate personal and family bleeding history, as well as demonstration of a low von Willebrand factor (VWF) level.¹
• The history may reveal the following:
  • Increased or easy bruising
  • Recurrent epistaxis
  • Menorrhagia
  • Postoperative bleeding (particularly after tonsillectomy or dental extractions)
  • Family history of a bleeding diathesis
    • Bleeding from wounds
    • Gingival bleeding
    • Postpartum bleeding

Physical

• The physical examination findings may be normal, but the following may be present:
  • Increased bruises
  • Mucosal bleeding

Causes

• von Willebrand disease is caused by an inherited defect that results in a deficiency or dysfunction of von Willebrand factor. The gene for von Willebrand factor is on the short arm of chromosome 12. It spans approximately 180 kilobases (kb) and is composed of 52 exons. Exons range in size from 40 base pairs (bp) to 1.4 kb. Various point mutations, insertions, and deletions at the von Willebrand factor locus have been described.
• In some cases, von Willebrand disease is believed to result from other pathologic processes; however, because of the relatively high prevalence of von Willebrand disease, its concomitant occurrence with other disease states may be coincidental.
• Nevertheless, acquired forms of von Willebrand disease can be observed in the following conditions:
  • Wilms tumor
  • Congenital heart disease
  • Systemic lupus erythematosus
  • Angiodysplasia
  • Seizure disorders treated with valproic acid
  • Hypothyroidism

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