Willebrand disease

Definition

Von Willebrand's disease is an inherited blood disorder characterized by prolonged bleeding time. It is the most common hereditary bleeding disorder in humans.

Description

The disease was first described by the Finnish physician Erik von Willebrand in 1926, when he noticed that many members of a large family from the Aland Islands in the Gulf of Bothnia had a bleeding disorder with a distinct inherited pattern. Von Willebrand's disease affects about 1-3% of the world's population, including about 1% of people in the United States.

Von Willebrand's disease is classified into three basic types. The mildest form, type 1, occurs in approximately 70-80% of patients. The moderate form of von Willebrand's disease is called type 2 and affects about 20-30% of people with the disease. The most severe form is called type 3. Type 3 disease is very rare, occurring in about one person per million.

The classification system for von Willebrand's disease was revised in 1994. The three major types were subdivided into types 1, 2A, 2B, 2M, 2N, and 3. This revision was necessary because of the many different genetic mutations that cause the disorder.

Causes & symptoms

Von Willebrand factor (vWF)

In order to understand the symptoms of von Willebrand's disease, it is helpful to have some basic information about the process of blood clotting. When a person is bleeding from a cut, blood cells called platelets form a clump or plug at the site of the injury in order to stop the bleeding. If healing is progressing normally, the platelets release different chemicals as they are forming the plug at the site of the bleeding. A complex protein in the blood called von Willebrand factor (vWF) is released by the platelets to strengthen the plug in order to stop the bleeding completely. When there is not enough vWF in the body, the affected individual has von Willebrand's disease. In addition to the platelets, the cells that line the inner wall of the blood vessels (endothelial cells) also release vWF.

Von Willebrand factor is a complex chemical compound made up of sugars and proteins. This factor exists in the body as a mass of sugars and proteins that can vary in size. The larger masses of vWF are important in helping to maintain proper blood clotting functions as well as maintaining a necessary amount of von Willebrand factor in the body.

Genetic transmission

Von Willebrand's disease is passed from one generation to another in a well-defined pattern. This disease occurs in differing degrees of severity in people who have inherited either one or two mutant copies of the gene that produces von Willebrand factor. Humans have two copies of each gene. When both are abnormal, the person is said to be homozygous for the disease. A person who has one normal and one mutant gene is said to be heterozygous for the disease. Most people affected by von Willebrand's disease are heterozygous and have milder forms of the disorder. Only in the rarest cases--type 3 disease--will both genes be abnormal. These patients are homozygous for von Willebrand's disease.

Because the majority of people affected with von Willebrand's disease have one healthy gene for vWF, their blood has some clotting ability. People who are heterozygous for the disorder have some von Willebrand factor in their bodies.

Patients with the milder forms of von Willebrand's disease have abnormal bleeding only after surgery or trauma. Patients with the more severe form may suffer from spontaneous nose bleeds, bleeding from the mouth, the stomach and intestines, or the urinary system.

Diagnosis

Because most persons with von Willebrand's disease have some level of vWF in their blood, the symptoms of abnormal bleeding tendencies may be difficult to recognize. Von Willebrand's disease is characterized by having reduced vWF levels or by a nearly normal level of vWF that functions at reduced capacity. It is possible for someone with a very mild reduction in either the level or function of their von Willebrand factor to have no outward signs of disease.

A definitive diagnosis of von Willebrand's disease requires four different laboratory measurements. The diagnosis is made if all of the following are present:

• An increased bleeding time.
• Lower than normal level of VWF.
• Reduced level of vWF functioning.
• Lower than normal level of function of another blood clotting factor (factor VIII).

Treatment

Von Willebrand's disease can only be treated properly following accurate diagnosis and clear identification of the specific subtype of the disorder. There are two types of therapy currently available: replacement therapy, in which prepared doses of concentrated vWF or factor VIII are given; and nonreplacement therapy, in which other drugs are used that are not clotting factors.

Replacement therapies

Patients who may not be able to tolerate drug-based treatments may be given concentrated vWF or factor VIII preparations. The factors are taken from normal blood, concentrated, and heated to very high temperatures or treated with a detergent to kill any viruses that may be present. It is important that the prepared mixture contain both factor VIII and vWF, in order to restore normal clotting function. In addition, the vWF in the concentrate must be in large-sized masses as described earlier. Replacement therapy is very safe and is the currently preferred mode of treatment.

Nonreplacement therapies

A synthetic drug named desmopressin (DDAVP, 1-deamino-8-D-arginine vasopressin) is also used to help restore clotting function in persons with von Willebrand's disease. This drug is similar to the naturally occurring hormone vasopressin. It has become the first choice for treatment of type 1 von Willebrand's disease.

It is not known exactly how desmopressin works. The drug does, however, increase the activity of factor VIII. It also stimulates the body to produce more vWF. Desmopressin is usually given intravenously, but a new form of it can now be used with a nasal inhaler. The effects of this form of the drug last for six to 12 hours.

Desmopressin has some side effects, including facial flushing, tingling sensations, and headaches. It is most effective in patients with type 1 disease. About 80% of people with this type of von Willebrand's disease respond to treatment with desmopressin.

Prognosis

Therapy for von Willebrand's disease is usually based on the individual's previous responses to therapy. Depending on the severity of bleeding, treatments may need to be given more than once a day. Although the available therapies are useful, this disease has a very complicated genetic foundation. As more information about the underlying genetic mutations becomes available, additional treatment options will likely be developed.

Prevention

There is no known prevention or cure for von Willebrand's disease. Prenatal screening for the disorder, however, may allow for more accurate identification of the disease based on the genetic information gathered.

Key Terms

Desmopressin (DDAVP)

A synthetic drug that resembles vasopressin. It used in nonreplacement treatment of von Willebrand's disease.

Endothelial cells

The cells in the tissue layer that lines the blood vessels. Endothelial cells also produce vWF.

Factor VIII

Another clotting factor in human blood that can be measured to help diagnose von Willebrand's disease.

Genetic mutation

Any abnormal change in the makeup of a gene.

Heterozygous

Having one normal and one abnormal gene for a hereditary disorder.

Homozygous

Having a pair of identical genes for any hereditary characteristic.

Hormone

A substance produced in an organ that is released into the bloodstream to have its effects at a different site in the body.

Platelets

Small plate-shaped blood cells that are involved in the formation of blood clots.

Von Willebrand factor (vWF)

A complex of protein and sugars in the blood that helps platelets clump together.

Vasopressin

A hormone produced by the brain that elevates blood pressure and decreases the amount of urination.

Further Reading

For Your Information

Books

• Handin, Robert I. "Disorders of the Platelet and Vessel Wall." In Harrison's Principles of Internal Medicine edited by Anthony S. Fauci, et al. New York: McGraw-Hill, 1998.

  Periodicals

• Nichols, William C., and David Ginsburg. "Von Willebrand's Disease." Medicine 76(Jan. 1997): 1.
• Voelker, Rebecca. "New Focus on von Willebrand's Disease." Journal of the American Medical Association 278(Oct. 8, 1997): 1137.

  Organizations

• American Heart Association. 7272 Greenville Ave., Dallas, TX 75231-4596. (800)787-8984. http://www.americanheart.org/.

Gale Encyclopedia of Medicine. Gale Research, 1999.