Von Willebrand disease

Definition

Von Willebrand disease is caused by a deficiency or an abnormality in a protein called von Willebrand factor and is characterized by prolonged bleeding.

Description

The Finnish physician Erik von Willebrand was the first to describe von Willebrand disease (VWD). In 1926, von Willebrand noticed that many male and female members of a large family from the Aland Islands had increased bruising (bleeding into the skin) and prolonged episodes of bleeding. The severity of the bleeding varied among family members and ranged from mild to severe and typically involved the mouth, nose, genital and urinary tracts, and occasionally the intestinal tract. Some women in the family also experienced excessive menstrual bleeding. What differentiated this bleeding disorder from classical hemophilia was that it appeared not to be associated with muscle and joint bleeding and affected women and men rather than just men. Dr. von Willebrand named this disorder hereditary pseudohemophilia.

Pseudohemophilia, or von Willebrand disease (VWD) as it is called in the twenty-first century, occurs when the body does not produce enough of a protein, called von Willebrand factor(vWF), or produces abnormal vWF. vWF is involved in the process of blood clotting (coagulation). Blood clotting is necessary to heal an injury to a blood vessel. When a blood vessel is injured, vWF enables blood cells called platelets to bind to the injured area and form a temporary plug to seal the hole and stop the bleeding. vWF is secreted by platelets and by the cells that line the inner wall of the blood vessels (endothelial cells). The platelets stimulate the release other chemicals, called factors, which help form a strong permanent clot. vWF binds to and stabilizes factor VIII, one of the factors involved in forming the permanent clot.

A deficiency or abnormality in vWF can interfere with the formation of the temporary platelet plug and affect the normal survival of factor VIII. This indirectly interferes with the production of the permanent clot. Individuals with VWD, therefore, have difficulty in forming blood clots, and as a result, they may bleed for a longer time. In most cases the bleeding is due to an obvious injury, although it sometimes occurs spontaneously.

VWD is classified into three basic types: type 1, 2, and 3 based on the amount and type of vWF that is produced. Type 1 is the most common and mildest form and results when the body produces slightly decreased amounts of normal vWF. Type 2 can be classified into four subtypes (A, B, M, N) and results when the body produces an abnormal type of vWF. Type 3 is the rarest and most severe form and results when the body does not produce any detectable vWF.

Demographics

Approximately one out of 100 people are affected with VWD, making it the most common inherited bleeding disorder. VWD affects people of all ethnic backgrounds. Approximately 70 to 80 percent of people with VWD have type 1, and close to 20 to 30 percent have type 2. Type 3 is very rare and occurs in less than 1 percent of people with VWD. Type 3 occurs in about one out of every million people.

Causes and symptoms

The complex genetics of VWD involve a gene found on chromosome 12. Different types of changes in the vWF gene can affect the production of vWF. Some changes cause the vWF gene to produce decreased amounts of normal vWF, while other changes cause the gene to produce abnormal vWF. Each individual inherits two copies of each gene, one from the mother and one from the father. Most of the vWF gene changes are significant enough that a change in only one vWF gene is sufficient to cause VWD. However, some types of gene changes only cause VWD if both genes are changed, which often leads to more severe symptoms.

Type 1 VWD is called an autosomal dominant condition since it is caused by a change in only one vWF gene. Since type 1 VWD results in only a slight decrease in the amount of vWF produced, the symptoms are often mild and not apparent in some individuals. Most cases of type 2 VWD are autosomal dominant since a change in only one vWF gene results in the production of an abnormal form of vWF. An autosomal dominant form of VWD can be inherited from either parent or can occur as a spontaneous gene mutation (change) in the embryo that is formed when the egg and sperm cells come together during fertilization.

Some cases of type 2 VWD and all cases of type 3 VWD are autosomal recessive, since they are caused only by changes in both vWF genes. A person with an autosomal recessive form of VWD has inherited both a changed gene from the mother and a changed gene from the father. Parents who have a child with an autosomal recessive form of VWD are called carriers, since they each possess at least one changed vWF gene. Many carriers for the autosomal recessive forms of type 2 VWD and type 3 VWD do not have any symptoms. Each child born to parents who both have one changed gene has a 25 percent chance of having VWD, a 50 percent chance of being a carrier, and a 25 percent chance of not being and not having VWD disease. A person with an autosomal dominant form of VWD has a 50 percent chance of passing the changed gene on to his or her children who may or may not have symptoms.

VWD is usually a relatively mild disorder characterized by easy bruising, recurrent nosebleeds, heavy menstrual periods, and extended bleeding after surgeries and invasive dental work. There is a great deal of variability in the severity of symptoms, which can range from clinically insignificant to life threatening. Even children within the same family who are affected with the same type of VWD may exhibit different symptoms. A child with VWD may exhibit a range of symptoms over the course of his or her lifetime and may experience an improvement in symptoms with age. The severity of the disease is partially related to the amount and type of vWF that the body produces, but it is also influenced by other genetic and non-genetic factors.

Type 1

Type 1, the mildest form of VWD, is usually associated with easy bruising, recurrent nosebleeds, heavy menstrual periods, and prolonged bleeding after surgeries and invasive work. Many people with type 1 VWD do not have any noticeable symptoms or only have prolonged bleeding after surgery or significant trauma. The amount of vWF produced by the body increases during pregnancy, so prolonged bleeding during delivery is uncommon in people with type 1 VWD.

Type 2

Children with type 2 VWD usually have symptoms from early childhood. Symptoms may even be present at birth. These children usually experience prolonged bleeding from cuts, easy bruising, nosebleeds, skin hematomas, and prolonged bleeding from the gums following tooth extraction and minor trauma. Gastrointestinal bleeding is rare but can be life-threatening. More than 50 percent of women with type 2 VWD experience heavy menstrual periods that may require a blood transfusion. Some women with type 2 VWD exhibit prolonged bleeding during delivery.

Type 3

Type 3 VWD can be quite severe and is associated with bruising and bleeding from the mouth, nose, and from the intestinal, genital, and urinary tracts. Type 3 is also associated with spontaneous bleeding into the muscles and joints, which can result in joint deformities. Some women with type 3 VWD experience prolonged bleeding during delivery.

When to call the doctor

If a child frequently experiences significant bleeding, takes longer than normal to stop bleeding, or experiences easy bruising, then the doctor should be consulted.

Diagnosis

Many children with VWD have mild symptoms or symptoms that can be confused with other bleeding disorders, making it difficult for a doctor to diagnose VWD based on clinical symptoms. VWD should be suspected in any child with a normal number of platelets in the blood and bleeding from the mucous membranes such as the nose, gums, and gastrointestinal tract. Testing for a child with suspected VWD often includes the measurement of the following:

how long it takes for the bleeding to stop after a tiny cut is made in the skin (bleeding time)
the amount of vWF (vWF antigen measurement)
the activity of vWF (ristocetin co-factor activity)
the amount of factor VIII (factor VIII antigen measurement)
activity of factor VIII

Children with type 1 VWD usually have an increased bleeding time, but they may have an intermittently normal time. They also have a decreased amount of vWF and decreased vWF activity and usually have slightly decreased factor VIII levels and activity. Children with type 2 VWD have a prolonged bleeding time and decreased activity of vWF; they may also have decreased amounts of vWF and factor VIII and decreased factor VIII activity. Type 3 children have undetectable amounts of vWF, negligible vWF activity, factor VIII levels of less than 5 to 10 percent, and significantly reduced factor VIII activity. The activity of vWF is reduced for all types of VWD, making it the most sensitive means of identifying all three types. Individuals with borderline results should be tested two to three times over a three-month period.

Once a person is diagnosed with VWD, further testing such as vWF multimer analysis and ristocetin-induced platelet aggregation (RIPA) should be performed to determine the subtype. Multimer analysis evaluates the structure of the vWF, and RIPA measures how much ristocetin is required to cause the clumping of platelets in a blood sample. The vWF multimer analysis is able to differentiate children with a structurally normal vWF (Type 1) from children with a structurally abnormal vWF (Type 2) and is often able to identify the subtype of patients with Type 2 VWD. Children with type 1 VWD usually have normal to decreased RIPA concentrations. Depending on the subtype, patients with type 2 VWD either have increased or decreased RIPA. RIPA is usually absent and the multimer analysis shows undetectable vWF in children with type 3 VWD.

In some cases, DNA testing can be a valuable adjunct to biochemical testing. The detection of gene alteration(s) can confirm a diagnosis and can determine the type and subtype of VWD. It can also help to facilitate prenatal testing and testing of other family members. Unfortunately many people with VWD possess DNA changes that are not detectable through DNA testing. A child who has a mother, father, or sibling diagnosed with VWD should undergo biochemical testing for VWD. If the relative with VWD possesses a detectable gene change, then DNA testing should be considered.

Prenatal testing

If one parent has been diagnosed with an autosomal dominant form of VWD or both parents are carriers for an autosomal recessive form of VWD, then prenatal testing should be considered. DNA testing can be performed through amniocentesis or chorionic villus sampling. If the DNA change in the parent(s) is unknown, then prenatal testing can sometimes be performed through biochemical testing of blood obtained from the umbilical cord. However this procedure is less accurate and is associated with a higher risk of pregnancy loss.

Treatment

VWD is most commonly treated by replacement of vWF through the administration of blood products that contain vWF or through treatment with desmopressin (DDAVP, 1-deamino-8-D-arginine vasopressin). DDAVP functions by increasing the amount of factor VIII and vWF in the circulating blood. Treatment with blood products or DDAVP may be started in response to uncontrollable bleeding or may be administered before procedures such as surgeries or dental work. The type of treatment chosen depends on the type of VWD and a patient's response to a preliminary treatment trial.

Treatment with desmopressin (DDAVP)

DDAVP is the most common treatment for people with type 1 VWD. About 80 percent of people with type 1 VWD respond to DDAVP therapy. Treatment with DDAVP can also be used to treat some people with type 2 VWD. Patients with type 2B VWD should not be treated with this medication, since DDAVP can induce dangerous platelet clumping. Type 3 VWD should not be treated with DDAVP, since this medication does not increase the level of vWF in type 3 patients. DDAVP should only be used in people who have been shown to be responsive through a pre-treatment trial transfusion with this medication.

DDAVP can be administered intravenously or through a nasal inhaler. DDAVP has relatively few side effects although some people may experience facial flushing, tingling sensations, and headaches after treatment with this medication. Often treatment with this medication is only required prior to invasive surgeries or dental procedures.

Treatment with blood products

Patients who are unable to tolerate or are unresponsive to drug-based treatments are treated with concentrated factor VIII obtained from blood products. Not all factor VIII concentrates can be used, since some do not contain enough vWF. The concentrate is treated to kill most viruses, although caution should be used since not all types of viruses are destroyed. If the factor VIII concentrates are unable to manage a severe bleeding episode, then blood products called cryoprecipitates, which contain concentrated amounts of vWF, or platelet concentrates should be considered. Caution should be used when treating with these blood products since they are not treated to kill viruses.

Other treatments and precautions

Medications called fibrinolytic inhibitors can be helpful in controlling intestinal, mouth, and nose bleeding. Estrogens, such as are found in oral contraceptives , increase the synthesis of vWF and can sometimes be used in the long-term treatment of women with mild to moderate VWD. Estrogens are also sometimes used before surgery in women with type 1 VWD. Some topical agents are available to treat nose and mouth bleeds. Patients with VWD should avoid taking aspirin, which can increase their susceptibility to bleeding. Children with severe forms of VWD should avoid activities that increase their risk of injury such as contact sports .

Prognosis

The prognosis for VWD is generally good, and most individuals have a normal lifespan. The prognosis can depend, however, on accurate diagnosis and appropriate medical treatment.

Prevention

There is no known way to prevent VWD. If an individual planning to become a parent believes he or she may be a carrier of VWD, genetic counseling is suggested so that options may be explored.

Parental concerns

VWD is usually very mild and does not cause unusual bleeding except after trauma or surgery. Children with moderate or severe VWD may need to be discouraged from playing contact sports or participating in other activities where injury is likely. Special care should be taken before surgical or dental procedures to ensure that severe bleeding does not occur.

KEY TERMS

Amniocentesis —A procedure performed at 16–18 weeks of pregnancy in which a needle is inserted through a woman's abdomen into her uterus to draw out a small sample of the amniotic fluid from around the baby for analysis. Either the fluid itself or cells from the fluid can be used for a variety of tests to obtain information about genetic disorders and other medical conditions in the fetus.

Autosomal dominant —A pattern of inheritance in which only one of the two copies of an autosomal gene must be abnormal for a genetic condition or disease to occur. An autosomal gene is a gene that is located on one of the autosomes or non-sex chromosomes. A person with an autosomal dominant disorder has a 50% chance of passing it to each of their offspring.

Autosomal recessive —A pattern of inheritance in which both copies of an autosomal gene must be abnormal for a genetic condition or disease to occur. An autosomal gene is a gene that is located on one of the autosomes or non-sex chromosomes. When both parents have one abnormal copy of the same gene, they have a 25% chance with each pregnancy that their offspring will have the disorder.

Biochemical testing —Measuring the amount or activity of a particular enzyme or protein in a sample of blood or urine or other tissue from the body.

Carrier —A person who possesses a gene for an abnormal trait without showing signs of the disorder. The person may pass the abnormal gene on to offspring. Also refers to a person who has a particular disease agent present within his/her body, and can pass this agent on to others, but who displays no symptoms of infection.

Chorionic villus sampling —A procedure used for prenatal diagnosis at 10–12 weeks gestation. Under ultrasound guidance a needle is inserted either through the mother's vagina or abdominal wall and a sample of the chorionic membrane. These cells are then tested for chromosome abnormalities or other genetic diseases.

Chromosome —A microscopic thread-like structure found within each cell of the human body and consisting of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Chromosomes contain the genetic information necessary to direct the development and functioning of all cells and systems in the body. They pass on hereditary traits from parents to child (like eye color) and determine whether the child will be male or female.

Desmopressin acetate (DDAVP) —A drug used to regulate urine production.

DNA —Deoxyribonucleic acid; the genetic material in cells that holds the inherited instructions for growth, development, and cellular functioning.

DNA testing —Analysis of DNA (the genetic component of cells) in order to determine changes in genes that may indicate a specific disorder.

Endothelial cells —The cells lining the inner walls of a body cavity or the cardiovascular system. Also known as endothelium.

Factor VIII —A protein involved in blood clotting that requires von Willebrand factor for stability and long-term survival in the bloodstream.

Gene —A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.

Mutation —A permanent change in the genetic material that may alter a trait or characteristic of an individual, or manifest as disease. This change can be transmitted to offspring.

Platelet —A cell-like particle in the blood that plays an important role in blood clotting. Platelets are activated when an injury causes a blood vessel to break. They change shape from round to spiny, "sticking" to the broken vessel wall and to each other to begin the clotting process. In addition to physically plugging breaks in blood vessel walls, platelets also release chemicals that promote clotting.

Prenatal testing —Testing for a disease, such as a genetic condition, in an unborn baby.

Protein —An important building blocks of the body, a protein is a large, complex organic molecule composed of amino acids. It is involved in the formation of body structures and in controlling the basic functions of the human body.

Skin hematoma —Blood from a broken blood vessel that has accumulated under the skin.

von Willebrand factor (vWF) —A protein found in the blood that is involved in the process of blood clotting.

Resources

BOOKS

Berntorp, Erik, et al. Textbook on Hemophilia. Oxford, UK: Blackwell Publishing, 2005.

Cannon, Christopher P., et al. Platelet Function: Assessment, Diagnosis, Treatment. Totowa, NJ: Humana Press, 2004.

PERIODICALS

Renee Paper. "Can You Recognize and Respond to von Willebrand Disease?" Nursing 33 (July 2003): 54–6.

Society for the Advancement of Education. "Diagnosis Key to Treating von Willebrand Disease." USA Today 131 (February 2003): 546–9.

ORGANIZATIONS

National Hemophilia Foundation. 116 West 32nd Street, 11th Floor, New York, NY 10001. Web site: http://www.hemophilia.org.

Tish Davidson, A.M. Lisa Maria Andres, MS, CGC