Von Willebrand disease and genetics
Von Willebrand disease (vWD) is the most common hereditary bleeding disorder, affecting approximately 1% of the global population. It results from mutations in the VWF gene located on chromosome 12, which is essential for the production of von Willebrand factor (vWF), a protein crucial for blood clotting. The severity of vWD varies, with three main types: Type 1 involves reduced levels of vWF, Type 2 involves dysfunctional vWF, and Type 3 features a complete lack of functional vWF. Symptoms can range from mild to severe and may include easy bruising, prolonged nosebleeds, and excessive bleeding during menstruation or after injuries.
Inheritance patterns differ among types; Type 1 and some Type 2 cases are typically autosomal dominant, while Type 3 and most Type 2 cases are autosomal recessive. Diagnosis involves assessing symptoms, medical history, and blood tests to evaluate clotting function and vWF levels. Treatment varies based on severity and may include medications such as desmopressin or antifibrinolytics, and in some cases, genetic counseling is recommended to understand familial risk. Advances in treatment options have emerged in recent years, enhancing management for those affected by vWD.
Von Willebrand disease and genetics
ALSO KNOWN AS: vWD
DEFINITION Von Willebrand disease (vWD) is an inherited blood disorder. It decreases the blood’s ability to clot, causing bleeding to last an unusually long time.
Von Willebrand disease is the most common hereditary bleeding disorder, affecting about 1 percent of the population. It affects both sexes approximately equally.
Risk Factors
The only risk factor for vWD is having family members with this disease.
Etiology and Genetics
Von Willebrand disease is caused by mutations in a gene called VWF, which is found on the short arm of chromosome 12 at position 12p13.3. This gene encodes a protein known as the von Willebrand factor (vWF), which plays an important role in the formation of blood clots. It is the von Willebrand factor that causes platelets to aggregate together and to help plug the holes in damaged blood vessel walls, a critical first step in clot formation. Some mutations in the gene cause a reduced amount of von Willebrand factor to be produced, and these result in the mildest (type 1) form of the disease. Type 2 disease usually results from different mutations that do not reduce the amount of protein but instead compromise the ability of the protein to perform its normal function. In the severest form (type 3), mutations typically result in an abnormally short protein that is completely nonfunctional.
All cases of type 1 vWD and a minority of type 2 cases are inherited in an autosomal dominant fashion, meaning that a single copy of the mutation is sufficient to cause full expression. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children. Some of these cases, however, result from a spontaneous new mutation, so in these instances, affected individuals will have unaffected parents. All cases of type 3 disease and most instances of type 2 disease are inherited in an autosomal recessive manner, which means that both copies of the gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers is 75 percent unaffected and 25 percent affected.
Symptoms
Many people with the vWD gene have very mild symptoms or none at all. When symptoms do occur, the severity varies from person to person. Many people only notice symptoms after taking aspirin or similar medications that interfere with clotting. Symptoms usually begin in childhood and fluctuate throughout life.
Common symptoms include easy bruising, frequent or prolonged nosebleeds, prolonged bleeding from the gums and minor cuts, heavy or prolonged bleeding during menstrual periods, and bleeding in the digestive system. Another symptom is prolonged bleeding after injury, childbirth, surgery, or invasive dental procedures.
Screening and Diagnosis
The doctor will ask about a patient’s symptoms and medical history and will perform a physical exam. Blood tests may be done to check for bleeding time, which in vWD will be prolonged, particularly after the administration of aspirin. Blood tests can also check for the factor VIII antigen. This indirectly measures levels of vWF in the blood; in vWD, it will be reduced. Ristocetin cofactor activity can also be checked by a blood test. This shows how well a patient’s vWF works; in vWD, it will be decreased. In addition, a blood test can check the von Willebrand factor multimer. This examines the different structural types of vWF in the blood; in vWD, it will be reduced.
Treatment and Therapy
Many people with vWD do not need treatment. For patients who do, their treatment will depend on the type and severity of their vWD. In many cases, treatment is only necessary for patients who are having a surgical or dental procedure that is likely to cause bleeding.
Treatment may include desmopressin. This medicine usually controls bleeding in mild cases of type I vWD by raising the level of vWF in the blood. It can be taken as a nasal spray (Stimate) or an injection (DDAVP). Intravenous infusions control a patient’s bleeding. These infusions are concentrates that contain factor VIII and the von Willebrand factor. Birth control pills may be used to control heavy menstrual periods in women with type 1 vWD. Antifibrinolytic medicine (often Amicar) can be used for bleeding in the nose or mouth. It helps keep a clot that has already formed from being dissolved.
Several treatment options for vWD were developed in the 2010s and 2020s. The drug Recombinant VWF showed promising results in clinical trials for on-demand bleed control. Emicizumab is a bispecific monoclonal antibody that can be administered subcutaneously weekly, biweekly, or monthly.
Prevention and Outcomes
There are no guidelines for preventing vWD. Genetic counseling can be helpful to review a detailed family history and discuss risks and tests available for von Willebrand disease.
Bibliography
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