eMedicine Specialties > Hematology > Coagulation, Hemostasis, and Disorders

von Willebrand Disease

Author: Eleanor S Pollak, MD, Associate Director of Special Coagulation, Associate Professor, Department of Pathology and Laboratory Medicine, Section of Hematology and Coagulation, University of Pennsylvania
Contributor Information and Disclosures

Updated: Aug 13, 2009

Introduction

Background

In 1926, Erik von Willebrand first reported an autosomally inherited mucocutaneous bleeding disorder in a large family from the Aland Islands off the coast of Finland. The disease was termed von Willebrand disease (vWD), named after this original report. vWD is a common, inherited, genetically and clinically heterogeneous hemorrhagic disorder caused by a deficiency or dysfunction of the protein termed von Willebrand factor (vWF). Consequently, primary hemostasis is impaired because of defective interaction between platelets and the vessel wall.

vWF is a large multimeric glycoprotein that circulates in blood plasma at concentrations of approximately 10 mg/mL. In response to numerous stimuli, vWF is released from storage granules in platelets and endothelial cells. It performs 2 major roles in hemostasis. First, it mediates the adhesion of platelets to sites of vascular injury. Second, it binds and stabilizes the procoagulant protein factor VIII (FVIII).

vWD is divided into 3 major categories: (1) partial quantitative deficiency (type I), (2) qualitative deficiency (type II), and (3) total deficiency (type III). Qualitative vWD type II is further divided into 4 variants, ie, IIA, IIB, IIN, and IIM, based on the characteristics of the dysfunctional vWF. These categories correspond to distinct molecular mechanisms, with corresponding clinical features and therapeutic requirements.

Pathophysiology

vWF exists as a series of multimers, varying in molecular weight between 0.5 (dimer) and 20 million kd (multimer). The building block of multimers is a dimer, held together by disulfide bonds located near the C-terminal end of each subunit.

vWD type I causes a mild-to-moderate quantitative deficiency in vWF (ie, ~20-50% of normal levels).

Type II vWD is due to qualitative abnormalities of vWF and is subdivided into types IIA, IIB, IIN, and IIM. vWD type IIA is the most common qualitative abnormality of vWF and is associated with the selective loss of large- and medium-sized multimers.

vWD type IIB is characterized by the loss of large multimers through a mechanism distinct from that of type IIA. Observations to date have identified a critical region of vWF involved in the binding of vWF to the platelet receptor glycoprotein Ib (GpIb). Each of these single amino acid substitutions is thought to result in a gain of function, leading to spontaneous binding of vWF to platelets. Normally, plasma vWF is inert in its interaction towards platelets until it encounters an exposed subendothelial surface. vWF binding to collagen or other ligands within the injured vessel wall presumably results in a secondary conformational change, which then facilitates binding to the GpIb receptor.

In vWD type IIB, the mutant vWF is capable of spontaneously binding GpIb in the absence of subendothelial contact. The large multimers have the highest affinity for GpIb and are rapidly cleared from the plasma along with the bound platelets, resulting in thrombocytopenia and the characteristic loss of large multimers.

vWD type IIN, sometimes referred to as vWD Normandy (after the province of origin of one of the first families identified with the disease), is characterized by a defect residing within the patient's plasma vWF that interferes with its ability to bind FVIII. This has important implications in the differential diagnosis of hemophilia. vWD type IIM (for multimer) refers to qualitative variants with decreased platelet-dependent function that is not due to the absence of high molecular weight multimers.

Patients with vWD type III, a severe quantitative deficiency associated with very little or no detectable plasma or platelet vWF, have a profound bleeding disorder. vWD type III appears to result from the inheritance of a mutant vWF gene from both parents. In the most straightforward model, vWD type I would simply represent the heterozygous form of type III vWD; however, inheritance patterns indicate greater complexity. vWD type III is much more rare than the predicted frequency of 1 case per 40,000 persons based on this model and is closer to 1 case per 1 million persons. Although few mutations have been identified in families with pure vWD type I, some vWD type I cases have been suggested to be due to a mutant vWF subunit that interferes in a dominant negative way with the normal allele, accounting for the autosomal dominant inheritance.

The discovery of a deletion of vWF (c.221-977_532 + 7059del [p.Asp75_Gly178del]) in 7 of 12 white type 3 vWD patients from 6 unrelated families and its absence in 9 Asian patients led Sutherland et al to develop a genomic DNA-based assay for the deletion of vWF exons 4 and 5.¹³ This deletion was also found in 12 of 34 type 1 vWD families and associated with a specific vWF haplotype, which the investigators noted may indicate a possible founder origin. Additional studies demonstrated the presence of the mutation in other type 1 vWD patients and a family that expressed both type 1 and type 3 vWD.¹³

Sutherland et al report the c.221-977_532 + 7059del mutation as a novel cause of both type 1 and type 3 vWD and suggest that screening for this mutation in other type 1 and type 3 vWD patient populations may clarify its contribution to vWD that arises from quantitative vWF deficiencies.¹³

Frequency

United States

Prevalence is not different from that observed internationally.

International

Clinically significant vWD affects approximately 125 persons per million population, with severe disease affecting approximately 0.5-5 persons per million population. Reports from screening unselected individuals indicate a higher prevalence of vWD abnormalities, ie, close to 1% of the population.

Mortality/Morbidity

For most affected individuals, vWD is a mild manageable bleeding disorder in which clinically severe hemorrhage manifests only in the face of trauma or invasive procedures. However, significant variability of symptomatology exists between family members.

• In individuals with types II and III, bleeding episodes may be severe and potentially life threatening.
• Individuals with type III disease who have correspondingly low FVIII levels may develop arthropathies, as is more common in patients with FVIII deficiency, with comparable FVIII levels.

Race

• No racial predilection exists for vWD.

Sex

• Males and females are affected equally; however, the phenotype may be more pronounced in females because of menorrhagia and the visibility of easy bruising.
• During pregnancy, the vWF level increases in most patients with non–type III disease. Thus, in patients with functionally normal vWF, labor and delivery usually proceed normally. However, patients with type II disease may experience hemorrhagic problems. In particular, patients with type IIB may experience thrombocytopenia due to the increased plasma levels associated with abnormal vWF. All patients should be monitored for excessive bleeding, particularly during the first week postpartum.

Age

• This is an inherited condition. Bleeding-related symptoms may occur at a young age, even just after or during birth.
• Females often present with heavy periods at menarche.
• Some reports suggest a decreased bleeding tendency as patients age.

Clinical

History

The most common symptoms include nosebleeds, skin bruises, and hematomas. Prolonged bleeding from trivial wounds, oral cavity bleeding, and excessive menstrual bleeding are common. Gastrointestinal bleeding is rare.

• A common but nonspecific symptom is easy bruising.
• Prolonged bleeding after minor trauma to skin or mucous membranes is characteristic of vWD.
• Severe hemorrhage after major surgery is less common, but delayed bleeding may occur up to several weeks after surgery.
• Heavy bleeding is common after tooth extraction or other oral surgery, such as tonsillectomy and adenoidectomy.
• Menorrhagia is a common presenting complaint in women.
• Bleeding symptoms are often exacerbated by the ingestion of aspirin and are ameliorated by the use of oral contraceptives.

Physical

Physical examination findings are usually normal. However, patients may have physical sequelae, such as bleeding or bruises.

Causes

See Pathophysiology for a discussion of the inherited nature of the condition (congenital vWD). A rare acquired form of vWD exists and is due to antibodies to vWF (acquired vWD).

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