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USMLE – Von Willebrand Disease

Genetics
The gene for von Willebrand factor (vWF) is located on chromosome 12 and therefore the disorder is inherited in an autosomal fashion. In most families it has the appearance of being inherited in a dominant manner; rarely it appears in a clinically severe form with almost undetectable levels of vWF. In these circumstances the patient usually inherits a different abnormal vWF gene from each parent and is thus a compound heterozygote. Probes are available to trace the gene in a family, although in most instances antenatal diagnosis is not indicated because of the relatively mild nature of the disorder.

The vWF is a protein, synthesized by endothelial cells and megakaryocytes, that performs two principal functions. It acts as carrier protein for factor VIII, to which it is noncovalently bound. A deficiency of vWF therefore results in a secondary reduction in the plasma factor VIII level. Its other function is to form bridges between platelets and subendothelial components-for example, collagen, allowing platelets to adhere to damaged vessel walls. A deficiency of vWF therefore also leads to prolonged primary hemorrhage after trauma.

Clinical features
As vWF participates, along with platelets, in primary hemostasis, patients present with hemorrhagic manifestations which are similar to individuals with reduced platelet function. Superficial bruising, epistaxis, menorrhagia and gastrointestinal hemorrhage are common. Bleeding episodes are usually much less common than in severe hemophilia and excessive hemorrhage may only be observed after trauma or surgery. Within a single family the disease is of very variable expression so that some members may have quite severe and frequent bleeds, whereas others are relatively little troubled.

Investigations
The disorder is characterized by finding a reduced level of vWF, which is often accompanied by a secondary reduction in factor VIII and a prolongation of the bleeding time.

Management
Many episodes of mild hemorrhage can be successfully treated with desmopressin, which raises the vWF level, resulting in a secondary increase in factor VIII. For more serious or persistent bleeds hemostasis can be achieved with some factor VIII concentrates which contain considerable quantities of vWF in addition to factor VIII.

Lillian Thompson By Lillian Thompson

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