Von Willebrand Disease

What Is Von Willebrand Disease? What Causes Von Willebrand Disease?

Von Willebrand disease, also known as vWD, is the most common hereditary blood clotting (coagulation) abnormality described in humans - in other words, it is the most common inherited bleeding condition. Von Willebrand disease, however, can also result from other medical conditions. The patient suffers from extended or excessive bleeding. The bleeding may sometimes damage internal organs, and even cause death, although this is rare.

VWD may arise from a quantitative or qualitative deficiency of vWF (von Willebrand factor), a multimeric protein that is required for platelet adhesion - i.e., patients either have low levels of that protein in their blood, or the protein does not work properly. VWF is a vital component in the blood clotting process. Patients take longer to form blood clots; when they are cut it takes longer for them to stop bleeding.

When a blood vessel is injured, small blood cell fragments called platelets will normally clump together to plug the hole in the blood vessel and stem the bleeding. VWF is a glue-like substance that helps the platelets stick together and form a blood clot. VWF also carries clotting factor VIII, a vital protein in the blood clotting process. Clotting factor VIII is either missing or faulty in patients who have hemophilia, or some other clotting disorder.

Although von Willebrand disease is much more common than hemophilia, it is usually milder.

According to the NIH (National Institutes of Health), USA, 1 in every 100 to 1,000 people in the USA is affected. While hemophilia affects males, VWD affects both sexes.

The condition is known to affect humans and dogs (especially Doberman Pinschers), and in very rare cases swine, cattle, horses and cats.

Other factors, including ABO blood groups may also influence the severity of the condition.

Von Willebrand disease treatment focuses on preventing or stopping bleeding episodes, mainly with medications. With proper treatment patients can lead normal and healthy lives.

According to Medilexicon's medical dictionary:

Von Willebrand disease is "a hemorrhagic diathesis characterized by tendency to bleed primarily from mucous membranes, prolonged bleeding time, normal platelet count, normal clot retraction, partial and variable deficiency of factor VIIIR, and possibly a morphologic defect of platelets; autosomal dominant inheritance with reduced penetrance and variable expressivity, caused by mutation in the von Willebrand factor gene (VWF) on 12p. Type III von Willebrand disease is a more severe disorder with markedly reduced factor VIIIR levels. There is a recessive version of this disease [MIM*277480], which has the remarkable property that it represents a mutation at the same locus as the dominant form."

There are three main types of vWD:

• vWD type 1 - the patient has low levels of von Willebrand factor (vWF), and possibly low levels of factor VIII. This is the most common and mildest form. About three-quarters of vWD patients have this type.
• vWD type 2 - von Willebrand factor (vWF) is faulty, it does not work the way it should. vWD type 2 is divided into the following types - 2B, 2M, and 2N. Each type is caused by varying gene mutations, and receives different medical treatment. Hence, knowing what subtype of vWD type 2 the patient has is crucial.
• vWD type 3 - the patient typically has low levels of factor VIII and no von Willebrand factor. This is the rarest and most severe form of vWD.

What are the signs and symptoms of von Willebrand disease?

A symptom is something the patient senses and describes, while a sign is something other people, such as the doctor notice. For example, drowsiness may be a symptom while dilated pupils may be a sign.
In many cases signs and symptoms may be very mild, or seemingly not present at all. When symptoms do occur, they may do so in varying ways. Doctors commonly do not spot milder forms of vWD.

The most common sign or symptom is abnormal bleeding, and may include:

• Nosebleeds, which may be prolonged and/or recurring
• Bleeding from the gums
• In females, their menstrual periods may be longer and/or heavier
• Excessive bleeding from a cut
• Excessive bleeding after a tooth extraction or some dental work
• Patients may also bruise easily. The bruises may sometimes have lumps which form under the skin.

In some cases, the bleeding disorder is only discovered after the patient has undergone a surgical procedure, had some dental work done, or had serious trauma.

Females - the main sign is heavy menstrual bleeding. However, a significant number of women with prolonged or heavy menstrual bleeding will not seek medical help. Doctors may consequently overlook this sign. The following signs may be linked to von Willebrand disease:

• Blood clots at least 2.5cms (1inch) in diameter in the menstrual flow
• Having to replace the tampon or sanitary towel more than once per hour
• Having to use double sanitary protection to control bleeding
• The period continues for longer than one week
• Anemia signs and symptoms, including fatigue, panting, and drowsiness

What are the risk factors for von Willebrand disease?

A risk factor is something which increases the likelihood of developing a condition or disease. For example, obesity significantly raises the risk of developing diabetes type 2. Therefore, obesity is a risk factor for diabetes type 2.

Family history - a child can inherit the abnormal gene from one of the parents. A person who has the gene has a 50% chance of passing it on to his/her offspring. If both parents have the defective gene there is a risk their offspring may have vWD type 3 (the severest and rarest form).

According to the Mayo Clinic, race or ethnic origin does not appear to be a risk factor in vWD.

What are the causes of von Willebrand disease?

A protein, called vWF (von Willebrand factor) is either missing or does not work properly. This protein works like a glue that helps blood platelets clump together, forming blood clots which block bleeding. If it is not present or does not work properly clumps cannot be formed (properly) and bleeding continues.

Some patients have non-existent or faulty vWF as well as a problem with another clotting substance called factor VIII.

Some individuals may develop a form of vWD later in life as a result of other medical conditions. In such cases, the vWD is known as acquired vWD.

How is von Willebrand disease diagnosed?

Early diagnosis and treatment significantly increase the chances that the patient can lead a normal and active life. As some patients with vWD type 1 or type 2 may not have major bleeding problems, they may not be diagnosed until some event occurs, such as surgery or a serious injury.

Patients with vWD type 3 are usually diagnosed early on because major bleeding will occur during infancy and childhood.

A doctor will review the patient's medical history and check the result of diagnostic tests and a physical exam.

Medical history - the doctor most likely will ask the patients the following questions:

• Did bleeding return within 7 days of a small wound?
• Did bleeding from a small wound persist for over 15 minutes?
• Did excessive bleeding ever occur after surgery or a dental procedure - bleeding that required medical attention?
• Has there been any unexpected bruising?
• Has there been any bruising with a lump under it?
• Has there been any unexpected blood in feces (stools)?
• Has there ever been any bleeding of the joints or muscles?
• Have any medications, such as aspiring, NSAIDs (non-steroidal anti-inflammatory drugs), or blood thinners caused bleeding?
• Have there been abnormal blood platelet counts?
• Have there been any unexpected or unexplainable nosebleeds that have persisted for over 10 minutes, despite placing pressure on the nose?
• Is menstrual bleeding heavy? Does it include clots? Does it last longer than a week?
• Is there a history of kidney, liver, blood or bone marrow disease?

Physical exam - the doctor will check for any peculiar bruising and signs of recent bleeding.

Blood tests - the following blood tests may be ordered:

• vWF (von Willebrand factor) antigen - the vWF protein (antigen) is measured to determine the levels of von Willebrand factor (vWF).
• Ristocetin cofactor activity - this test determines how well vWF works; whether its role in the blood clotting process is adequate. Ristocetin is an antibiotic used in lab testing; it causes a blood reaction which may help doctors identify vWD.
• Factor VIII clotting activity - to determine what the levels of factor VIII are. Factor VIII is carried by vWF and plays a role in the blood clotting process (coagulation).
• Von Willebrand factor multimers - looks at the structure of vWF factor, its multimers (protein complexes) and how its molecules break down. Doctors use this test to determine what type of vWD the patient has.
• PFA-100 test (platelet function test) - determines how well or badly the platelets are functioning.
• Bleeding time - determines how long it takes for a small wound to stop bleeding.

Test results may take two to three weeks to come back. The patient may have to repeat some of the tests to confirm a diagnosis. The doctor, if he/she is not a specialist, may refer the patient to a hematologist (a doctor specialized in blood diseases) to confirm the diagnosis and also for follow-up care.

What are the treatment options for von Willebrand disease?

vWD is incurable, however it is treatable. Treatment depends on several factors, including what type it is, how severe signs and symptoms are, and how well the patient responds to therapy and medications.

In most cases, vWD symptoms are mild and treatment is only needed when the patient has to undergo surgery, dental work, or has experienced trauma (an accident or injury).

Medications are prescribed to:

• Control heavy menstruation
• Increase the release of vWF and factor VIII into the bloodstream
• Prevent the breakdown of blood clots
• Replace vWF

Desmopressin (DDAVP) - this synthetic hormone is administered by injection or through a nasal spray (Stimate). It is similar to vasopressin, a natural hormone that controls bleeding by making the body release more vWF already stored in the lining of the blood vessels, which in turn raises factor VIII levels. This medication is usually prescribed for individuals with vWD types 1 and 2. It may also be used, in nasal spray form by females at the beginning of a menstrual period. It may sometimes be used by doctors before minor surgery.

Replacement therapies - doses of concentrated blood clotting factors containing vWF and factor VIII. May be prescribed if DDAVP was not effective enough, or if signs and symptoms are severe. Replacement therapies may be used for all three types of vWD.

Contraceptives - for women with heavy periods. Birth control pills contain estrogen, which can raise levels of vWF and factor VIII activity. The doctor may recommend placing a progesterone-containing contraceptive device in the uterus (womb).

Clot-stabilizing medications (antifibrinolytic medications) - the slow down the breakdown of clotting factors, helping keep a clot in place once it is formed. They are prescribed before or after a surgical procedure or dental work. Examples include aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron).

Fibrin sealants - this glue-like substance is applied directly onto a wound (cut) to stop bleeding.

Prevention of bleeding episodes for patients with vWD

• Avoid OTC (over-the-counter, no prescription required) medications which may affect blood clotting, such as aspirin, ibuprofen and other NSAIDs (non-steroidal anti-inflammatory drugs).
• Check with a qualified health care professional, such as your doctor or a pharmacist before taking any medications.
• Tell health care professionals you have vWD, for example, a doctor or dentist.
• Tell other relevant people, such as a sports coach or trainer that you have vWD.
• Wear a medical ID necklace or bracelet, especially if your symptoms are severe.
• Exercise regularly. Check with your doctor what type of exercise is best for you.
• Maintain a healthy, well-balanced diet.

Pregnancy

Some women may have bleeding complications during delivery (giving birth), even though vWF and factor VIII levels tend to go up during pregnancy. Bleeding may be heavy and longer lasting after giving birth.

A pregnant woman with vWD should consult a hematologist and specialized obstetrician when she becomes pregnant.

The pregnant woman is likely to have blood tests during the last trimester to check vWF and factor VIII levels.

The pregnant mother should discuss anesthesia options for delivery with an anesthesiologist.