Von Willebrand Disease

The most commonly inherited genetic bleeding disorder is von Willebrand Disease. It is caused by deficiency of the von Willebrand factor, a protein component of Factor VIII that helps platelets stick to the blood vessel wall and to each other, which is necessary for blood clotting. It is a characterized by abnormally slow coagulation of the blood, spontaneous epistaxis and gingival bleeding. It is virtually unknown among the general public. More people are familiar with hemophilia, the second most commonly transmitted bleeding disorder. Normal blood clotting requires a series of reactions among blood factors, proteins, and platelets to form the platelet plug that ultimately creates a fibrin clot that, in turn, stops blood from leaking from the vessels. An interruption in the normal clotting process with the absence or dysfunction of von Willebrand factor causes bleeding episodes. The von Willebrand factor is produced by cells lining vessel walls. It is also a carrier protein for plasma factor VIII (classic hemophilia A factor). Patients with diminished, absent, or ineffective von Willebrand factor may appear to have hemophilia A when they actually have von Willebrand disease. The bleeding tendency is life-long, with hemorrhage especially from the gums, nose, and female genitalia, and following surgical procedures. Characteristically, the bleeding is less severe than other genetically determined bleeding disorders.

Erik von Willebrand, MD, first described an autosomally inherited mucocutaneous bleeding disorder in 1925 after studying a family of women from the Aland Islands off the coast of Finland, who had extremely heavy menstrual bleeding. One member was a twelve-year-old girl who died during her first menstrual period. The disease was named after this original report. Dr. von Willebrand found this common, inherited, genetically and clinically heterogeneous hemorrhagic disorder caused by a deficiency or dysfunction of a particular protein, now termed the von Willebrand factor. Consequently, primary hemostasis is impaired because of defective interaction between platelets and the vessel wall. The disease is characterized by a tendency for bruising, frequent epistaxis (nosebleeds) and menorrhagia (heavy menstrual flow). The hallmark of the disease is defective platelet adhesion to subendothelial components caused by deficiency of von Willebrand factor. This factor is a large protein synthesized, processed and stored in the Weibel-Palade bodies of the endothelial cells. It is secreted following stimulation/injury to the vessel.

Von Willebrand disease occurs in one to two percent of the United States population, not different from that observed internationally. It is the most common bleeding disorder present at birth. Unlike hemophilia, it affects both sexes approximately equally. The phenotype may be more pronounced in females because of menorrhagia and the visibility of easy bruising. White women are more likely than black women to have von Willebrand Disease. Many people are unaware of the true cause of their symptoms or that treatment is available. Without proper diagnosis, people with the disorder can die unnecessarily during surgery, trauma, or menses. Most cases are mild, and bleeding episodes may only occur after a surgical procedure or tooth extraction (as opposed to episodes of spontaneous nose bleeds etc.) The disease is worsened by the use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs). A family history of a bleeding disorder is the primary risk factor. There is no cure, but von Willebrand can be treated.

Nearly all cases are transmitted as a genetic mutation by a non-sex-linked chromosome. Patients with von Willebrand disease have a 50 percent chance of passing on a mutation for von Willebrand disease to each of their children. Although extremely rare, von Willebrand can also be acquired at, or after, birth from drug therapy, autoimmune disorders, such as lupus and rheumatoid arthritis, kidney failure and cancer.

Acquired forms of von Willebrand Disease can be observed in the following conditions:

• Wilm’s tumor
• Systemic lupus erythematosus
• Congenital heart disease
• Angiodysplasia
• Seizure disorders treated with valproic acid
• Hypothyroidism

Blood clotting normally occurs when there is damage to a blood vessel. Clotting factors are proteins and other substances, numbered I to XIII, that form a fibrin matrix at sites of blood vessel or tissue injury. Common factors include:

• Wilm’s tumor
• Factor I – fibrinogen
• Factor II – prothrombin
• Factor III – tissue thromboplastin or tissue factor
• Factor IV – calcium
• Factor VIII – antihemophilic factor

Platelets, which come from white blood cell fragments, immediately begin to adhere to the cut edges of the vessel and release chemicals to attract even more platelets. Platelets then degranulate, releasing serotonin, von Willebrand factor, adenosine diphosphate (ADP), fibrinogen, and thromboxane from cell vesicles into the surrounding environment constricting the blood vessel to minimize blood loss and recruiting more platelets and clotting factors to the area. A glue-like platelet plug is formed, and the external bleeding stops.

The von Willebrand factor is a high-molecular-weight protein necessary for the platelet adhesion and formation of the platelet plug; as such, this factor functions in both primary (involving platelet adhesion) and secondary (FVIII) hemostasis. In von Willebrand disease there is an abnormality, either quantitative or qualitative of the von Willebrand factor multimeric glycoprotein that functions as the carrier protein (FVIII). In primary hemostasis, von Willebrand factor binds on platelets to its specific receptor glycoprotein as an adhesive bridge between platelets and damaged subendothelium at the site of vascular hemostasis, von Willebrand factor protects FVIII from degradation and delivers it to the site of injury.

Von Willebrand Disease can be classified into 3 main types:

• Type I: A shortage of von Willebrand Factor (mild). This type is the mildest form and can result in mild to moderate bleeding episodes, depending on how much von Willebrand factor is missing. It is characterized by a quantitative decrease of quantitatively normal von Willebrand’s factor. There is insufficient amount for effective or complete clotting in the time interval during a bleeding event. Between 70 percent and 80 percent of all cases of von Willebrand disease is type I. Some people with type I disease do not need treatment and may not be aware that they have a blood disorder. Type I is inherited in an autosomal dominant pattern from one parent.
• Type II: A flawed von Willebrand Factor. Although the body produces normal amounts of the von Willebrand factor, it does not work properly. Type II is further classified (such IIa or IIb) based on the characteristics of the dysfunctional von Willebrand factor.
  • Type IIA is a common variant and results from functionally defective von Willebrand factor. It is a moderate to severe form of the disease. The factor VIII level may be normal.
  • Type IIB is another variant in which the protein has heightened interaction with platelets even in the absence of stimulation. This leads to a deficiency of von Willebrand protein in the plasma. Increased affinity for von Willebrand protein in the resting stage leads to the deletion of plasma von Willebrand protein. This disease is sometimes referred to as pseudo von Willebrand disease or platelet-type von Willebrand disease.
• Type III: A complete lack of von Willebrand factor (more severe). Type III is the rarest and most severe form of the disease. It occurs because little or no von Willebrand factor proteins are produced. When the body does not produce von Willebrand factor, the cells (platelets) needed to form a clot do not work properly and clotting factor VIII levels are low, both of which can lead to severe bleeding. People with type III disease are in more danger of anemia and excessive bleeding after an accident or during surgery. Clinical features are similar to hemophilia A, but with autosomal dominant inheritance pattern from both parents. Type III patients are typically diagnosed after major bleeding episodes, trauma, or the onset of menses, if they don’t die first after misdiagnosis. Diagnosis can be complicated because people who carry the von Willebrand disease gene mutation may have symptoms, yet test negative or their symptoms may not be clinically significant.

The severity of symptoms varies widely even within the same family – most cases are mild, with episodes of excessive bleeding presenting a risk only after surgery. Over half of all women with von Willebrand disease have very heavy menstrual bleeding. Unlike hemophilia, most people with von Willebrand disease need not limit their level of physical activity. The severity of the bleeding tendency is described as very mild, mild, moderate, or severe. To say severity is very mild means that the patient has only one or two symptoms, which are unclear. Mild indicates one or two obvious symptoms that do not usually require treatment. Moderate means that the patient has two or more symptoms and has needed a transfusion because of abnormal bleeding after an operation or after a tooth extraction. Characteristics of a severe bleeding tendency are rare but include hemarthritis. Other symptoms include:

• Frequent nosebleeds
• Occasional bleeding from the gums
• Excessive bleeding after dental extractions
• Heavy menstrual periods in women (menorrhagia)
• Bruising easily
• Gastrointestinal/genitourinary bleeding
  • Black, tarry or blood stools
  • Blood in the urine
• Bleeding into the joints, resulting in stiffness, pain, swelling
• Bleeding in the muscles
• Bleeding after intramuscular medication administration
• Intracerebral bleeding

The familial nature of the disease complicates diagnosis. Information relating to the menstrual cycle may have been relayed from a mother, grandmother, or other female relative with undiagnosed von Willebrand disease. This information may falsely convey to a woman that she should expect heavy and/or long periods because this was the experience of other women in her family. In addition, menstruation may not be openly discussed due to embarrassment or cultural variations. When women do complain of menstrual irregularities, they may be misdiagnosed as having only a gynecological condition. In the case of von Willebrand disease, the clinician may treat the symptom, not the underlying disorder.

Diagnosing von Willebrand disease is also difficult because symptoms that suggest a blood clotting disorder, such as frequent nosebleeds or heavy menstrual periods, indicate the need for initial bleeding studies, such as prothrombin time (PT), partial thromboplastin time (PTT) or international normalized ratio (INR) which may not give useful information. The significance of a detailed history is important to identify the most common presenting problem - menorrhagia (heavy uterine bleeding). Additional expensive, time-consuming workups may be necessary to exclude other potential conditions, such as autoimmune disorders, hormonal imbalance, renal or liver disease and hypothyroidism.

When von Willebrand disease is the sole cause of bleeding problems, the PT is always normal (150,000 to 400,000/mm3), the PTT is occasionally prolonged and the bleeding time may be normal (1 to 9 min) or prolonged. Diagnosis is established starting with thorough clinical history from the patient and family and through a complete physical examination. Additional blood tests to measure blood levels of von Willebrand factor and Factor VIII are then required. These diagnostic tests for von Willebrand disease examine the amount, structure and functioning of von Willebrand factor. Specifically:

• Von Willebrand factor activity (ristocetin cofactor)
• Von Willebrand factor antigen
• Von Willebrand factor multimetric analysis
• Factor VII activity
• Prothrombin time
• Activated thromboplastin time

In the presence of von Willebrand disease there will be reduced Willebrand factor, reduced platelet aggregation and reduced ristocetin co-factor. Lower levels of von Willebrand factors correlate with ABO blood type. Individuals with type O blood normally have the lowest level of von Willebrand factor. A history of excessive bleeding and genetic testing confirms the diagnosis. It is recommended to repeat these highly sensitive tests because results can be affected by:

• Recent stress
• Blood transfusion
• Menstrual cycle timing
• Hormone, acetylsalicylic acid or nonsteroidal anti-inflammatory drug use
• Pregnancy and breastfeeding
• Exercise
• Crying
• Cold environment

Many children with von Willebrand disease are asymptomatic and are diagnosed as a result of routine preoperative screening (prolonged bleeding time). It is important to remember that clinical manifestations vary even for members of the same family. Female patients may also experience metorrhagia or bleeding between periods. With women, diagnosis may depend on an accurate assessment of the menstrual period, replacing terms such as “heavy” or “long” with the exact number of days of the menstrual cycle and the pattern of use for sanitary supplies. When interviewing the patient the questions should address:

• A typical period (length, flow and bleeding in between) and the age of menarche (initial menses)
• Pads/tampons, including type (e.g. regular, super absorbent), number used simultaneously and how frequently changed
• Overflow staining of sheets or clothing
• Presence of excessive pain or discomfort
• Pain before period (ovulation time)
• Loss of time from work or school
• Increased or easy bruising
• Recurrent epistaxis
• Postoperative bleeding (particularly after tonsillectomy or dental extractions)
• Family history of bleeding diathesis
  • Bleeding from wounds
  • Gingival bleeding
  • Postpartum bleeding

Bleeding episodes may decrease during pregnancy as a result of a “protective effect” as von Willebrand factor increases with pregnancy-related hormonal changes in most patients with non-type III disease. Thus, in patients with functionally normal von Willebrand factor, labor and delivery usually proceed normally. Some patients with type II disease may experience hemorrhagic problems. Patients with type IIB may experience thrombocytopenia due to the increased plasma levels associated with abnormal von Willebrand factor. The temporary protection extends into the postpartum period if the woman breastfeeds. After delivery, the surplus von Willebrand factor subsides as pregnancy hormonal balance returns, along with previous bleeding risk. All patients should be monitored for excessive bleeding, particularly during the first week postpartum. Prophylactic medications are available to help avoid bleeding episodes in women with von Willebrand disease that enable them to become pregnant and carry the pregnancy to term.

Treatment for von Willebrand is directed at prevention and prompt treating of bleeding episodes throughout life. The course of von Willebrand is difficult to predict because it may stay at the same level of activity or get better or worse as the patient gets older. Minor bleeding problems, such as bruising or a brief nose bleed, may not require specific treatment since minor bleeding in von Willebrand disease is often self-limiting and effectively treated with direct pressure or ice. For more serious bleeding medications that can raise the von Willebrand factor level and thereby limit bleeding are available. The goal of therapy is to correct the defect in platelet adhesiveness (by raising the level of effective von Willebrand factor) and the defect in coagulation (by raising the factor VIII level).

In recent years, desmopressin (1-deamine-8-D-arginine vasopressin, DDAVP) has become the mainstay of therapy for most patients with mild von Willebrand disease. It is a synthetic hormone which mimics the action of the natural antiduretic hormone vasopressin. At appropriate doses, DDAVP causes a two- to five-fold increase in plasma von Willebrand factor and factor VIII concentrations in individuals who are healthy and patients who are responsive. DDAVP can be used to treat bleeding complications or to prepare patients with von Willebrand disease for surgery. Until recently it was only available as intravenous injection. It is now available as a nasal spray – Stimate Nasal Spray – a prescription product that patients can take at the onset of menses, after a minor injury, or before undergoing dental procedures. DDAVP should not be used to treat:

• A person with type IIb or type III von Willebrand disease
• An infant younger than three months of age
• A person with serious injuries
• A person diagnosed with advanced (atherosclerosis) hardening of the arteries

Side effects include: fluid retention, mild increase in pulse or blood pressure, redness of face and neck, headache, nausea, and rarely, thrombosis.

Therapies to replace the clotting factors in the blood are used for patients who do not respond to DDAVP and those with type IIb or type III von Willebrand disease. Antifibrinolytic agents that help prevent the breakdown of blood clots can be used alone or in combination with DDAVP or replacement therapy. Hormone therapy (oral contraceptives or estrogen therapy) can be used to control heavy menstrual periods in women.

Topical medications used to stop bleeding from mucous membranes include silver nitrate, cautery, nasal or oral packing, topical thrombin (Thrombinar), microfibrillar collagen (Avitene), collagen sponges (Instat) and gel foam. Oral contraceptives, which raise the levels of clotting factor VIII and von Willebrand factor can control uterine bleeding; hormone replacement therapy is used in older women.

The goal of patient education is directed at preventing bleeding episodes. Patients need to avoid all medications with anti-platelet activity:

• Nonsteroidal anti-inflammatory drugs (NSAIDs)
  • Aspirin
  • Ibuprofen (Advil or Motrin)
  • Naproxen (Aleve or Naprosyn)
  • Ketoprofen (Actron or Orudis)
• Medications that contain the ingredient salicylate, which is closely related to aspirin
  • Alka-Seltzer
  • Pepto-Bismol
  • Many cough medicines
  • Antihistamines
• Antimicrobials
  • High dose penicillins
  • Cephalosporins
  • Nitrofurantoin
  • Hydroxychloroquine
• Cardiovascular medications
  • Propramolol
  • Furosemide
  • Calcium channel blockers
  • Quinidine
• Others
  • Caffeine
  • Tricyclic antidepressants
  • Phenothiazines
  • Valproate
  • Heparin

No evidence suggests that extensive activity restrictions are necessary for most patients with mild type I von Willebrand. Patients with more severe forms should follow guidelines developed for patients with severe hemophilia.

Characterized by abnormally slow coagulation of the blood and spontaneous epistaxis and gingival bleeding caused by a deficiency of a component of factor VIII, von Willebrand Disease is the most common inherited blood coagulation disorder. Excessive bleeding is common during menstruation, post operatively, or after injury. It is also called angiohemophilia. It is caused by a deficiency or dysfunction in a blood clotting factor known as von Willebrand factor. This factor promotes clotting in two ways: first, it is an essential component in the mechanism that causes platelets to gather and adhere to one another at the site of an injury; second, it acts as a carrier for factor VIII (the antihemophilic factor) a crucial protein in the process of clot formation. A deficiency in von Willebrand factor thus results in uncontrolled bleeding due to inadequate platelet activity and decreased level of active factor VIII. The disease affects both men and women and the severity of symptoms varies widely.

Cooke, Kerry V. von Willebrand Disease, Healthwise.net. Jan. 2005

Dilley A, Drews C, Miller C, et al. von Willebrand Disease and Other Inherited bleeding disorders in Women With Diagnosed Menorrhagia. Am J Obstet Gynecol. 2000: 183:1271-1277.

Feiden KL. Von Willebrand Disease: A Huge Undiagnosed Problem. Hemalog. 1999;7:10-13.

Geil, John D, von Willebrand Disease, emedicine.com Aug. 2004.

Geil, John D, von Willebrand Disease, J. Intern Med, 1997; 740:121.

Pavolivch-Danis, Susanne J., von Willebrand Disease – The Commonly Inherited Bleeding Disorder, Nursing Spectrum, 2004.

Pollak, Eleanor S, von Willebrand Disease, eMedicine.com, Aug. 2004.

Thiagarajan, Perumal, Disorders of Platelet Function – von Willebrand disease, eMedicine.com, Sept. 2004.