von Willebrand Disease 

Von Willebrand disease (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, defective vWF interaction between platelets and the vessel wall impairs primary hemostasis. (See Etiology and Workup.)

vWF, a large, multimeric glycoprotein, circulates in blood plasma at concentrations of approximately 10mg/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). (See Etiology.)

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

Patient education

Patients should be instructed about their coagulation disorder and be aware of the conditions in which prophylactic therapy is highly recommended. For patient education information, see the Skin Conditions and Beauty Center, as well as Bruises.

With the exception of a rare, acquired form of vWD, caused by antibodies to vWF, vWD is an inherited condition. The vWF gene is located near the tip of the short arm of chromosome 12. The gene is composed of 52 exons and spans a total of 180kb of the human genome; therefore, it is similar in size to the FVIII gene. Expression of the vWF gene is restricted to megakaryocytes, endothelial cells, and, possibly, placental syncytiotrophoblasts. A partial, nonfunctional duplication (pseudogene) is present on chromosome 22.

vWF exists as a series of multimers varying in molecular weight between 0.5-kd (dimer) and 20 million kd (multimer). The building blocks of multimers are dimers, which are held together by disulfide bonds located near the C-terminal end of each subunit.^[1]

vWD type I

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

vWD type II

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

vWD type IIB characterized by the loss of large multimers occurs 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 the identified 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 and/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 spontaneously binds to 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) involves qualitative variants with decreased platelet-dependent function not resulting from absence of high–molecular weight multimers.

vWD type III

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 vWD type III; however, inheritance patterns indicate greater complexity.

vWD type III is much rarer than the predicted frequency of 1 case per 40,000 persons based on this model, instead having a frequency 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 patients with vWD type III from 6 unrelated families, and its absence in 9 Asian patients, led Sutherland et al to develop a genomic deoxyribonucleic acid (DNA) ̶ based assay for the deletion of vWF exons 4 and 5.^[2] This deletion was also found in 12 of 34 vWD type I families and was 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 patients with type I vWD and in a family that expressed both type I and type III vWD.^[2]

Sutherland et al reported the c.221-977_532 + 7059del mutation as a novel cause of type I and type III vWD and suggested that screening for this mutation in other type I and type III vWD patient populations may clarify its contribution to vWD that arises from quantitative vWF deficiencies.^[2]

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

Sex- and age-related demographics

Males and females are affected equally by vWD. However, the phenotype may be more pronounced in females, because of menorrhagia and the greater visibility of bruises.^[3]

vWD is an inherited condition. Bleeding-related symptoms may occur at a young age, even just after or during birth. Some reports have suggested a decreased bleeding tendency as patients age.

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 among family members.

In individuals with vWD 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 more commonly seen in hemophilia A patients with comparably decreased FVIII levels.