von Willebrand Disease

von Willebrand disease or vWD is thought to be the most common bleeding disorder among the general population. The National Hemophilia Foundation (NHF) estimates that 1 – 2 in 100 people have vWD. Both men and women are affected. vWD is an under–recognized and under–diagnosed disorder, in that many people with the disorder are unaware of their condition. The knowledge of having vWD is vitally important, as it leads to:

1. A decreased risk of complications such as excessive bleeding with injury or medical interventions; and
2. Better control of bleeding symptoms with decreased risk for prolonged or complicated bleeding events.

vWD Defined

von Willebrand disease is an inherited blood clotting disorder. In 1926, Finnish internist Dr. Erik von Willebrand first described vWD after evaluating a large family from the Aland Islands (located in the Baltic Sea between Sweden and Finland) whose bleeding disorder inheritance pattern was dominant and not related to sex unlike classical hemophilia (factor VIII deficiency). The family’s bleeding symptoms ranged from mild to severe, and males and females were equally affected. The bleeding symptoms were also distinct from hemophilia, with abnormal bleeding from the skin and mucous membranes. The first identified person in the family died at 14 years of age from bleeding during her fourth menstrual cycle.

von Willebrand protein or factor (vWF) is part of the blood clotting mechanism. vWF is a large protein made of building blocks called multimers. Multimers are assembled and stored in cells lining the blood vessels. vWF is released into the circulation where it binds to factor VIII, the clotting factor that, when deficient, is associated with hemophilia. For many years it was difficult to study or recognize patients with vWD because of this close association between the von Willebrand factor and factor VIII. Factor VIII needs to be bound to vWF to protect it from being degraded in the blood.

Besides binding and protecting factor VIII, another important role of vWF in coagulation is helping platelets (cells in the body that are important in forming the primary plug to stop bleeding, called a hemostatic plug) bind to an injured area. Therefore, defects in vWF may lead to what is commonly called “platelet–like” bleeding such as bleeding from mucosal surfaces (the mouth, gastrointestinal tract and urogenital tract), development of easy bruising and petechiae (small red dots caused by the rupture of small blood vessels).

In affected people, the von Willebrand factor isn’t normal, either in amount (i.e., an insufficient quantity) or structure. Either mechanism may lead to impaired function and therefore an increased risk of bleeding. vWD is classified into subtypes. Affected individuals with the same subtype may manifest a variable range of severity, from mild to moderate to severe. Levels of severity are categorized as:

Type 1 = mild
Types 2A and 2B = moderate
Type 3 = severe

Rarer forms of vWD exist, such as 2M and 2N. (Type 2M vWD is a rare subtype of vWD type 2. Type 2M affects approximately 0.5–2% of people with vWD.)

The majority of persons with vWD fall in the mild to moderate range (approximately 80% of all cases). Yet even those who are mildly affected should become knowledgeable about their bleeding disorder, as surgery or an injury may lead to excessive bleeding without appropriate therapeutic interventions. Type 3, the most severe form of vWD, is also the least common form, affecting 1 or 2 people per million. Persons with type 3 vWD have an almost complete lack of von Willebrand factor, as well as decreased factor VIII and ristocetin cofactor activity levels.

Similar to hemophilia patients, individuals affected with vWD do not bleed faster than normal, but rather, take longer to stop bleeding. It should be noted that bleeding may occur without injury or trauma in people with vWD, especially internal bleeding. This is usually seen in patients with moderate to severe von Willebrand disease, and may be associated with other medical problems such as ulcers.

Symptoms

The symptoms of von Willebrand disease include:

Menorrhagia – unusually heavy or prolonged menstrual bleeding
Metrorrhagia – increased and abnormal bleeding between menstrual cycles
Epistaxis – excessive nose bleeds
Easy bruising
Abnormal bleeding in the mouth and gums
Abnormal bleeding following surgery, particularly surgery involving mucous membranes (e.g., tonsillectomy), childbirth or dental procedures

Diagnosis

vWD is most often diagnosed by hematologists, physicians specializing in blood disorders. As a federally recognized comprehensive hemophilia treatment center (HTC), the IHTC is the leading medical facility in Indiana in the diagnosis and treatment of vWD. If you need to locate a hemophilia treatment center outside of Indiana, please refer to the listing of federally recognized HTCs at the Centers for Disease Control and Prevention’s (CDC) National Center for Infectious Diseases web site, www.ncid.cdc.gov, or call the National Hemophilia Foundation at (800) 42–HANDI.

Laboratory testing for vWD requires a specialized laboratory skilled in this area. To accurately diagnose vWD, a panel of tests must be performed. These tests may include:

Factor VIII activity
Ristocetin cofactor – performed to evaluate von Willebrand factor activity
von Willebrand factor antigen – evaluates the amount of vWF present (it does not indicate how well the factor works)
Multimer analysis – looks at the structure of the protein
Platelet function

Other testing may be performed as necessary, such as blood typing. Some uncommon testing may be performed in specific clinical situations.

Diagnosing vWD can be challenging. A host of factors can confound vWD testing results, making the tests difficult to interpret and leading to misdiagnosis. These include but are not limited to physical/emotional stress, exercise just prior to the patient’s blood being drawn for testing, and hormone changes including pregnancy and taking oral contraceptives. Testing may need to be repeated to reach a conclusive diagnosis.

Inheritance

If you are diagnosed with vWD, it is recommended that your family be evaluated for the disease, as vWD is an inherited disorder. The abnormal gene present in vWD parents is known as an autosomal chromosome or autosome, which is not a sex–linked chromosome. As a result, both men and women can pass the defective vWD gene onto their children. Affected parents have a 50% chance of passing the defective gene to each of their children.

vWD can also occur as the result of a spontaneous genetic mutation. As in those affected with vWD by birth, individuals who are affected by a mutation can pass the defective gene onto their children.

Treatment

There is no cure for von Willebrand disease. However, the disorder can often be successfully managed. The patient’s age, symptoms and the subtype and severity of the vWD will determine the proper treatment regimen. Treatment includes the use of:

Clotting factor concentrate that contains and replaces the abnormal vWF such as Humate–P®, which may be utilized in managing type 2A, 2B and type 3 vWD as well as used for severe bleeding in other types.
Stimate® nasal spray, which causes the release of stores of vWF into the circulation. Stimate® is usually used in type 1 patients. Stimate® is a medication, not a blood product. It may be associated with some symptoms and these should be discussed in detail with your physician before it is used as a therapeutic agent.
Oral birth control pills in women whose primary symptom is menorrhagia or metrorrhagia and who are not responsive to other therapies.
Adjunctive therapies such as local fibrin glue, microfibular collagen and antifibrinolytic therapies are commonly employed to control bleeding episodes in this patient population.

Healthy Advice

If you have been diagnosed with a bleeding disorder, it is critical that you become well educated about the disease. Your local hemophilia treatment center is the best educational resource to provide you all the information you need to know about von Willebrand disease.

It is also very important that you inform all your healthcare providers that you have vWD, especially your primary care physician and dentist (and, if you are female, be sure to notify your obstetrician/gynecologist). Your healthcare providers are encouraged to contact your HTC to provide them the proper medical guidance in delivering optimal medical management. For Indiana patients, the IHTC is happy to provide educational seminars on bleeding disorders to your primary care and other medical and dental providers. For more information on arranging such a session, contact the IHTC toll free at (877) CLOTTER.

To manage vWD, patients should…

Be seen regularly by a hematologist who specializes in the diagnosis and treatment of vWD; optimum treatment by a team of multidisciplinary medical care providers is available at your local federally recognized HTC
Adhere to the treatment regimen provided by your hematologist
Exercise and/or engage in regular physical activity
Become an advocate for your own healthcare and wellness
Contact your HTC prior to having any type of surgery or other invasive procedure; this includes dental work involving heavy gingival manipulation and/or block injections (numbed cheeks)

References

What You Should Know About Bleeding Disorders, National Hemophilia Foundation, 1997 For You and Your Doctor, National Hemophilia Foundation, 2001 von Willebrand Disease (vWD): A Patient’s Guide to Understanding, Aventis Behring L.L.C., 2000
Indiana Hemophilia & Thrombosis Center Inc. 2001