Von Willebrand disease (VWD) is the most common congenital bleeding disorder. It is estimated to occur at a frequency of one in 100 individuals, but is symptomatic in only about one in 10,000. Von Willebrand disease is caused by mutations in von Willebrand factor (VWF). The gene for von Willebrand Factor is located on chromosome 12, and the disease is inherited in an autosomal manner, affecting both males and females. Von Willebrand factor is a glycoprotein consisting of disulfide-linked high molecular weight multimeric FVIII proteins (multimers), and is synthesized in megakaryocytes and endothelial cells, and stored in platelets and endothelial cells. Von Willebrand factor serves as a carrier protein for FVIII and promotes platelet aggregation after vessel injury.

Von Willebrand disease is a clinically heterogeneous disease with a number of disease variants, each characterized by different quantitative and/or qualitative defects in von Willebrand factor. It is import to determine the specific von Willebrand disease variant in order to establish the best and safest treatment for each patient.

Mutations in von Willebrand factor result in deficient or defective von Willebrand factor antigen and von Willebrand factor activity (ristocetin cofactor). These are usually accompanied by a decrease in FVIII coagulant activity (FVIII:C), because normal expression of FVIII:C in the circulation is dependent on FVIII:C complexing with its carrier protein, von Willebrand factor. The coagulation screening tests typically associated with the defects in von Willebrand factor and FVIII:C include a prolonged activated partial thromboplastin time (APTT) and a long bleeding time.

In some von Willebrand disease variants (see below) the von Willebrand multimers are qualitatively normal but quantitatively decreased, while in other variants the von Willebrand multimers are both qualitatively and quantitatively abnormal. Because there is temporal variability in these coagulation tests, the clinical history is very important in diagnosis of von Willebrand disease.

Von Willebrand disease was first recognized by Erik von Willebrand in 1926 in related kindreds living in the isolated Aaland Islands in the North Sea near Finland. Von Willebrand disease was first termed 'pseudohemophilia', because it differed from hemophilia in its primarily mucosal (rather than joint and muscle) bleeding, the prolonged bleeding time (not found in hemophilia), and the fact that it affected females (hemophilia is X-linked and affects primarily males).

Symptoms in individuals with von Willebrand disease include easy bruising, epistaxis, postoperative or post-traumatic bleeding, and mucosal bleeding, primarily in the gastrointestinal and genitourinary tracts. Females with severe disease may also suffer menorrhagia. The clinical bleeding in von Willebrand disease occurs because the defective von Willebrand factor results in defective platelet aggregation and platelet plug formation following vessel injury.

The type of mutation affecting the von Willebrand factor locus forms the basis for classification of von Willebrand disease. By convention, there are three major types; Type II is subdivided into four different subtypes.

Von Willebrand factor is encoded by an autosomal gene on chromosome 12. Quantitative deficiency of von Willebrand factor, such as which occurs in Type 1 and 3 von Willebrand disease, has been associated with promoter, nonsense, and frameshift mutations, with large deletions. Qualitative deficiency of von Willebrand factor, such as occurs in Type 2 von Willebrand disease, has been associated with missense mutations and small deletions or insertions.

It is anticipated that as mutations in von Willebrand factor continue to be identified, newer approaches to prevention of postoperative vascular occlusion and atherosclerotic plaques may be developed, taking advantage of the interference in primary hemostasis afforded by mutations in von Willebrand factor.

Cryoprecipitate contains the high molecular weight von Willebrand factor multimers missing in von Willebrand disease, and could theoretically be the treatment for all types of von Willebrand disease. However, it is not the preferred treatment for von Willebrand disease, because cryoprecipitate (as a cold precipitate of plasma) cannot be inactivated or purified without destroying the activity, and thus transmission of HIV and/or hepatitis viruses cannot be prevented with this product, other than by standard antibody screening.

The recommended treatment for Type I von Willebrand disease or other clinically mild disease is DDAVP, an arginine vasopressin analogue. DDAVP serves to release von Willebrand factor from storage in Weibel Palade bodies in endothelial cells and alpha granules of platelet. The standard dose is 0.3 m g per kilogram body weight, and DDAVP may be given once daily. DDAVP is not helpful for individuals with severe disease, as there is little or no von Willebrand factor in storage sites. In general, DDAVP is well-tolerated, with occasional flushing during infusion. The greatest drawback to its use is the development of tachyphylaxis after two or three treatments. As mentioned above, DDAVP is contraindicated for individuals with 2B disease, because it may further increase platelet aggregation and thrombocytopenia.

For individuals with moderate to severe von Willebrand disease, such as those with Type 3 von Willebrand disease or severe Type 2A variants, the blood product of choice is factor VIII concentrate containing high-molecular weight von Willebrand factor multimers, e.g. Humate P. This clotting factor concentrate is virally-inactivated by pasteurization and highly purified by the use of monoclonal antibody purification. The standard dose for a hemorrhage is 25 to 40 units per kilogram of body weight, administered once or twice daily, depending on the severity of the hemorrhage. There is no evidence for transmission of hepatitis or HIV virus with this product, and the only drawback to its use is the potential transmission of non-lipid-enveloped viruses, such as hepatitis A or parvovirus.

As with other congenital coagulation disorders, the use of hepatitis B vaccine for prophylaxis against potential hepatitis B transmission, and oral antifibrinolytic agents, such as Amicar, for oral bleeding or tooth extraction, are recommended.

Von Willebrand disease is a heterogeneous bleeding disorder, characterized by deficiency in a glycoprotein, von Willebrand factor, VWF, which is important in platelet plug and fibrin clot formation when injury occurs. Coagulation findings include a prolonged bleeding time and decreased FVIII activity, von Willebrand factor, and ristocetin platelet aggregation. Mucosal bleeding is the most typical clinical symptom, occurring primarily in the oral, gastrointestinal, and genitourinary tracts. Treatment of von Willebrand disease is with DDAVP for mild or moderate disease, and with Humate P for severe disease or Type 2B variants. Current research on mutations in von Willebrand factor and its regulatory sequences may lead to new approaches to the prevention of vascular occlusion and atherosclerotic vascular disease.