DEFINITION
von Willebrand Disease is the most common hereditary coagulation abnormality described in humans, although it can also be acquired as a result of other medical conditions. It arises from a qualitative or quantitative deficiency of von Willebrand factor (vWF), a multimeric protein that is required for platelet adhesion
von Willebrand
EPIDEMIOLOGY
The prevalence of vWD is about 1 in 100 individuals. However the majority of these people do not have symptoms.
SYMPTOMS
DIAGNOSIS
histopathology
radiology
NMR
laboratory tests
PATHOGENESIS
PATIENT RISK FACTORS
Vascular
Genetic
Acquired
Hormonal
Genetic
Acquired
TISSUE SPECIFIC RISK FACTORS
anatomical (due its structure)
vascular (due to the local circulation)
physiopathological (due to tissue function and activity)
COMPLICATIONS
THERAPY
DESCRIPTION
The Finnish hematologist Erik von Willebrand,who lived in the early part of the last century, was the first to describe this disease in 1926.
He noticed that many male and female members of a large family the Aland Island had increased brusing and prolonged episodes of bleeding.
Von Willebrand named this disorders “Hereditary Pseudohemophilia”.
What diferentiated this bleedding disorderfrom classical hemophilia was that it appared not to associated with muscle and joint bleeding and affect people of either sex.
This disease occurs when the body does not produce ,or produced abnormal, enough of a protein called von willebran factor (vWF ),that is one of the proteins in the blood that helps to make blood clot.
Blood clotting is necessary to heal an injury to a blood vessel.When a blood vessel is injured,vWF enables platelets to bind to the injured area and form a temporary plug to seal the hope and stop the bleeding. vWF is secreded by platelets and by the endothelian cells.the platelets release other chemical called factors in response to a blood vessel injured that are involved in forming the permanent clot.
A deficients or abnormal in vwf can interfere with the formation of the temporary pletelet plugand also affect the normal survival of factor VIII, which can indirectly interfere with the production of the permanent clot.
Von willebrand disease affects males and females in approximately equal proportions and is present in up to 1% of the U.S. population.
The genetics of VWD are complex and involve a gene that produces vWF and is found on the short arm of chromosome 12. Since humans inherit two of each type of chromosome, they inherit two vWF genes. There are different types of changes (mutations) in the vWF gene that can affect the production of vWF. Some types of changes can cause the vWF gene to produce decreased amounts of normal vWF, while other changes can cause the gene to produce abnormal vWF. Most of the gene changes are significant enough that a change in only one vWF gene is sufficient to cause VWD. Some gene mutations cause VWD only if both genes are changed, which often leads to more severe symptoms.
TYPES
This disease is divided into types according to whether someone has a low amount of von Willebrand factor but the vonWillebrand factor that does not work propely , or both.
VWD is classified into three basic types: type 1, type 2, and type 3. The definitions of each type are based on the amount and type of vWF that is produced
Type 1. Signs may be mild in type 1, the most common form, and tend to occur in people with only modest declines in the blood levels of both von Willebrand factor and factor VIII, a substance that’s carried in your blood by von Willebrand factor and that IIB,IIM andIIN), signs tend to be more intense. In these people, the von Willebrand factor that is helps stimulate clotting.
Type 2. In this type, which has several four subtypes(IIA,present doesn’t function properly.
Type IIA: is the most common type.People affect have von Willbrand factor which does not work properly.This type of vW is classed as moderate.
Type IIB: is classed moderate to severe and can be characterised by thrombocytopaenia
Type IIM :can cause mild to moderate bleeding episodes. It can be difficult to diagnose and is very like type 1 vW.
Type IIN:caused reduced levels of factor VIII because the vWf cannot bind factor VIII properly. It is likened to haemophilia A and only correct investiugations will distinguish between the two.Bleeding is classed as mild to moderate.
Type 3. People with type 3 disease, which is rare, lack von Willebrand factor altogether and have low levels of factor VIII. Bleeding may occur into the joints and muscles, and signs and symptoms may be severe in intensity.
CAUSES
The causes of von Willebrand disease is a difect in the gene that controls von Willebrand factors.
The genetics of VWD are complex and involve a gene that produces vWF and is found on the short arm of chromosome 12. Since humans inherit two of each type of chromosome, they inherit two vWF genes. There are different types of changes (mutations) in the vWF gene that can affect the production of vWF. Some types of changes can cause the vWF gene to produce decreased amounts of normal vWF, while other changes can cause the gene to produce abnormal vWF. Most of the gene changes are significant enough that a change in only one vWF gene is sufficient to cause VWD. Some gene mutations cause VWD only if both genes are changed, which often leads to more severe symptoms.
DIAGNOSIS
Diagnostic testing:
Because many people with von Willebrand disease have very mild signs, the condition can be
difficult to diagnose. Some people live for years with the disease before it’s identified.
Many people with VWD have mild symptoms or symptoms that can be confused with other bleeding disorders, making it difficult to diagnose VWD on the basis of clinical symptoms. VWD should be suspected in any person with a normal number of platelets in their blood and bleeding from such mucous membranes as the nose, gums and gastrointestinal tract. Testing for an individual with suspected VWD often includes the measurement of:
how long it takes for the bleeding to stop after a tiny cut is made in the skin (the 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
Many doctors routinely screen women with menorrhagia for VWD, as heavy menstrual bleeding is the most common symptom of the disorder in females.
People with type 1 VWD usually have an increased bleeding time but they may have an intermittently normal bleeding time. They also have a decreased amount of vWF, and decreased vWF activity and usually have slightly decreased factor VIII levels and activity. People with type 2 VWD have a prolonged bleeding time, decreased activity of vWF and may have decreased amounts of vWF and factor VIII, and may have decreased factor VIII activity. Type 3 individuals have undetectable amounts of vWF, negligible vWF activity, factor VIII levels of less than 5-10%, 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 of VWD. Patients with borderline results should be tested two to three times over a three month period.
Once a patient is diagnosed with VWD, further testing such as vWF multimer analysis and ristocetin-induced platelet aggregation (RIPA) may need to 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 people with a structurally normal vWF (type 1) from people with a structurally abnormal vWF (type 2) and is often able to identify the subtype of patients with type 2 VWD. People 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 people 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, as of 2001, many people with VWD possess DNA changes that are not detectable through DNA testing. A person 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 also 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 can be considered. If the parent with an autosomal dominant form of VWD possesses a detectable gene change or both parents who are carriers for an autosomal recessive form of VWD possess detectable mutations, then DNA testing of their fetus would be available. 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 fetal umbilical cord, which is less accurate and is associated with a higher risk of pregnancy loss.
SIGNS AND SYMPTOMS
In many people with von Willebrand disease (vWD), signs are mild or they may be absent altogether. When signs occur, their intensity can vary from one person to another. In its milder forms, von Willebrand disease is often missed by doctors in the diagnostic process.
Abnormal bleeding is the most common symptom of von Willebrand disease, although it may be present at only moderate levels. The abnormal bleeding may occur as:
Recurrent and prolonged nosebleeds
Bleeding from the gums
Increased menstrual flow
Excessive bleeding from a cut or following a tooth extraction or other dental procedure
Blood in the stool or urine
People with von Willebrand disease may also experience easy bruising and skin rashes.
Women affected by von Willebrand disease may not be overly concerned by a moderate or even heavy level of increased menstrual bleeding. And doctors may overlook heavy menstrual bleeding as a possible indicator of von Willebrand disease.
Some people may realize that they have a bleeding disorder only after a surgical procedure or serious trauma in which excessive bleeding occurs.
The severity of the bleeding varied between family members and ranged from mild to severe and typically involved the mouth, nose, genital and urinary tracts, and occasionally the intestinal tract. Excessive bleeding during the menstrual period (menorrhagia) was also experienced by some of the women in this family.
RISK FACTORS
A family history of von Willebrand disease is the leading risk factor. A parent can pass the abnormal gene for the disease to his or her child. Most cases are “autosomal dominant inherited” disorders, and if you have the gene for von Willebrand disease, you have a 50 percent chance of transmitting this gene to your offspring. To inherit the most severe form of the condition (type 3), both of your parents have to pass along the gene to you.
Race does not appear to play a role in the disease, except that affected women who have extended and heavy menstrual bleeding are more likely to be Caucasian rather than African-American.
COMPLICATIONS
Complications of von Willebrand disease may include:
Anemia: women who experience heavy menstrual bleeding can develop iron deficiency anemia.
Swelling and pain: if abnormal bleeding flows into the joints or soft tissue, swelling and severe pain can result.
Death from bleeding: when abnormal bleeding cannot be controlled, it can become life-threatening and needs emergency medical attention.
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 bloodstream. Treatment with blood products or DDAVP may be started in response to uncontrollable bleeding or may be administered prior to 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 is the most common treatment for people with type 1 VWD. About 80% 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 the control of 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 prior to surgery in women with type 1 VWD. Some topical agents are available to treat nose and mouth bleeds.
Endometrial ablation, or the removal of the lining of the uterus by means of electrocautery or other thermal methods, is sometimes recommended as a treatment for menorrhagia associated with VWD. This procedure appears to be successful in lowering the amount of bleeding that these women experience during their menstrual periods.
Patients with VWD should avoid taking aspirin, ibuprofen, or other NSAIDs, which can increase their susceptibility to bleeding. They should also inform their dentist of their diagnosis, as many routine dental procedures can cause bleeding from the gums. People with severe forms of VWD should avoid activities that increase their risk of injury such as contact sports.
Patients with type 3 VWD living in the United States may wish to contact one of the 146 federally funded Hemophilia Treatment Centers (HTCs) for advice about prophylactic treatment and general follow up.
PROGNOSIS
The prognosis for VWD disease is generally fairly good and most individuals have a normal lifespan. The prognosis can depend, however on accurate diagnosis and appropriate medical treatment.
