NORD gratefully acknowledges Ann-Marie Nazzaro, PhD, Executive Director, Foundation for Women & Girls with Blood Disorders; Claire S. Philipp, MD, Professor of Medicine, Associate Director, Division of Hematology, Chief, Division of Hematology, Robert Wood Johnson Medical School; Andra H. James, MD, MPH, Consulting Professor, Obstetrics & Gynecology, Duke University, for assistance in the preparation of this report.
Von Willebrand disease (VWD) is a common inherited bleeding disorder in the general population affecting males and females equally, but women may be disproportionately impacted due to the bleeding challenges of menstruation and childbirth. There are three main types of VWD (VWD type 1, VWD type 2, and VWD type 3) each with differing degrees of severity and inheritance patterns. Unlike hemophilia which is characterized by joint bleeding, VWD is typically characterized by mucocutaneous bleeding. VWD is caused by a defect or deficiency in von Willebrand Factor (VWF), a large protein made up of multiple subunits. VWF binds to clotting factor VIII in the circulation and protects it from being broken down. VWF also helps platelets bind to the inside of injured blood vessels. This leads to the formation of a stable blood clot which plugs an injured blood vessel and stops bleeding. If there is an insufficient quantity of VWF or if it is defective, an individual may have difficulty forming a blood clot. Most affected individuals have the relatively mild form of the disease, VWD type 1, and are not diagnosed until adulthood. A small percentage of these individuals may have prolonged bleeding during infancy or early childhood. Symptoms can include nosebleeds, bleeding from the gums, and easy bruising. In women with VWD, heavy menses frequently occurs. Affected individuals may bleed easily after injury, childbirth, and/or surgery. Bleeding from the stomach and intestines can occur but is less common.
VWD was first described in the medical literature in 1926 by Dr. Erik von Willebrand, who differentiated the disorder from classic hemophilia. In addition to the genetic form, VWD can be acquired during life, often in relation to a separate underlying condition. This report deals specifically with the genetic forms. VWD types 1 and 3 may also be referred to as partial quantitative deficiency or total quantitative deficiency, respectively, because they are associated with low levels or near complete absence of VWF. VWD type 2 may also be referred to as qualitative VWD because VWF is present in normal or near normal levels, but doesn’t function properly. In recent years, the understanding of the genetic factors and biochemistry associated with VWD has advanced considerably, especially for types 2 and 3. However, many questions and controversies still remain regarding the diagnosis and definition of VWD type 1 (see Causes section below).
The specific symptoms and severity of VWD can vary greatly from one person to another, even among individuals with the same subtype or members of the same family. Some individuals may not have any symptoms (asymptomatic) or only mild manifestations or symptoms of the disorder; other individuals may have moderate to severe bleeding complications. Some individuals may not develop symptoms until adulthood; others may be affected during infancy. Most individuals have a mild form of the disorder. VWD type 1 is the predominant form in the general population. Severe symptoms are most likely to occur with VWD type 3 and in some cases of VWD type 2.
To better understand VWD, it is important to understand how the body forms clots to stop bleeding. Clotting is the process by which blood clumps together to plug the site of a wound to stop bleeding. Clotting requires a series of reactions among clotting proteins to ultimately form a clot. Clotting factors such as VWF are specialized proteins that play an essential role in enabling the blood to clot. VWF has two primary roles, promoting the adhesion of platelets to the injured blood vessel and stabilizing, protecting, and carrying factor VIII to the site of injury. Defects in the levels of or improper function of VWF hamper the clotting process. Consequently, affected individuals have difficulty stopping the flow of blood from a wound.
Mild symptoms associated with VWD include mild bleeding from the mucous membranes and the skin (mucocutaneous sites) including chronic nosebleeds (epistaxis) and bleeding from the gums. Easy bruising and prolonged bleeding from minor cuts may also occur. Bruising can extend to large areas of the body. Women may experience heavy and prolonged bleeding during their menstrual period (menorrhagia) or during and following childbirth. If left untreated, heavy menstrual bleeding may lead to anemia and iron deficiency. Some individuals may experience heavy, prolonged bleeding following trauma, dental procedures or surgery.
More serious, but uncommon complications can include gastrointestinal bleeding, solid swellings of congealed blood (hematomas), and bleeding into the muscle and joints (hemarthrosis), which can cause progressive joint damage and degeneration. Eventually, in these cases, VWD may limit the range of motion of an affected joint.
VWD is generally broken down into three subtypes. VWD type 1 is the mildest form of the disorder and accounts for approximately 70%-80 of cases. Affected individuals may have low levels of VWF in the blood. In some cases, factor VIII may also be reduced. Generally, affected individuals develop mild mucocutaneous bleeding; in rare cases, affected individuals will develop more severe symptoms. Nosebleeds and bruising are common findings for affected children; heavy menstrual bleeding is a common finding for women of childbearing age.
VWD type 2 accounts for approximately 20% of cases. In these individuals, VWF can be present in the blood in normal or near normal levels, but doesn’t function properly. VWD type 2 is further subdivided depending upon the specific, underlying defect involving VWF. These subtypes are known as VWD type 2a, 2b, 2m, and 2n.
VWD type 2A is characterized by reduced VWF that fails to bind to platelets, reducing the ability of platelets to clump together to form a clot. Affected individuals often have mild to moderate mucocutaneous bleeding.
VWD type 2B is characterized by platelets that have an increased ability to clump together, causing platelets to clump together prematurely in the bloodstream rather than at the site of blood vessel injury. Individuals experience mild to moderate mucocutaneous bleeding and are at a risk of developing reduced levels of platelets in the blood (thrombocytopenia). Thrombocytopenia is worsened by stressful situations such as infection, undergoing surgery, or pregnancy.
VWD type 2M is characterized by decreased activity of VWF and its failure to interact with platelets. This form is generally associated with mild or moderate mucocutaneous bleeding. In some cases, more severe bleeding episodes will develop.
VWD type 2N is characterized by the failure of VWF to transport factor VIII to the site of injury and reduced levels of factor VIII in the blood. Individuals develop excessive bleeding following surgery. This form of VWD can resemble the mild form of classic hemophilia (hemophilia A).
VWD type 3 is the most severe form of the disorder. It accounts for approximately 5% of cases. Affected individuals have an almost complete absence of VWF in their blood. Affected individuals can experience severe mucocutaneous bleeding, bleeding into the muscles and joints, joint damage, and the development of multiple hematomas.
For women with the more severe forms of VWD, monitoring for serious, even life-threatening, reproductive tract bleeding and postpartum hemorrhage is very important.
Most cases of VWD are caused by mutations of the VWF gene. In VWD type 1 and most forms of type 2, the mutation is inherited as an autosomal dominant trait. In some cases, the mutation occurs randomly without cause (spontaneously) with no previous family history (i.e., new mutation). VWF type 3 and some cases of VWF type 2 are inherited as an autosomal recessive trait.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
Investigators have determined that the VWF gene is located on the short arm (p) of chromosome 12 (12p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 12p13” refers to band 13 on the short arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The VWF gene is the only gene that has been identified to cause VWD. The VWF gene regulates (encodes) VWF. Mutations to this gene result in low levels of VWF, or in VWF that is defective and doesn’t function properly. As mentioned above, VWF has two primary roles in the body. It carries and protects factor VIII, preventing it from being broken down (metabolized) before reaching the site of injury and it helps platelets stick to blood vessels. Deficient or defective VWF fails to act as a glue to hold platelets together at the site of injury to a blood vessel. Consequently, the platelets do not stick to the wall of the blood vessel and a blood clot breaks down prematurely. In some cases, deficient or defective VWF leads to low levels of factor VIII in the blood, which results in blood clots taking an abnormally long time to form.
Despite the advances in recent years regarding VWD, the underlying mechanisms and genetics of VWD type 1 are not fully understood. VWD type 1 is associated with variable expressivity and reduced penetrance among family members. Variable expressivity refers to disorders in which the severity from one person to another can vary dramatically even among members of the same family. Reduced penetrance refers to how some individuals who inherited a defective gene for a disorder will not develop all of the symptoms.
In addition, only approximately 50-60% of individuals with VWD type 1 have an identifiable mutation of the VWF gene. Even in cases where a gene mutation is identified, confusion still exists because the exact relationship among VWF gene mutations, residual VWF levels, and the overall risk of bleeding in individuals with VWD type 1 is unclear.
Some of the confusion around VWD type 1 stems from the fact that individuals in the general population have varying levels of VWF in the blood. In general, in many disorders, the amount of residual protein activity often correlates with the severity of the disease (e.g. little to no residual protein activity results in severe disease). However, researchers have noted that many individuals in the general population have moderately low levels of VWF, but do not develop symptoms of VWD. This suggests that additional genetic and environmental factors likely play a role in the development and severity of VWD. For example, individuals with blood type O have lower levels of VWF than people with other blood types.
Because of the varying levels of VWF in the general population, it is difficult to establish what constitutes “low” and what constitutes “normal.” The normal range of VWF in the blood is generally considered to be between 50-200 IU/dL. Individuals with very low levels (e.g. <20 IU/dL) are very likely to have an identifiable mutation of the VWF gene, severe bleeding symptoms and a positive family history of the disorder. These individuals can be diagnosed with VWD type 1. However, individuals with VWF levels between 30-50 IU/dL, which is technically below normal, pose a significant problem in regards to diagnosis and definition. Several million people in the United States are estimated to have VWF levels within this range. In a large European study of individuals with more than > 30 IU/dL, less than 50% of individuals had an identifiable mutation of the VWF gene. In addition, in cases with a VWF gene mutation, the bleeding symptoms did not correlate significantly to the gene mutation.
In many cases, VWD type 1 can be considered a complex genetic disorder in which multiple factors, both genetic and environmental, all play a role in the development of the disorder. Genetic factors associated with VWD type 1 may include ones that are unrelated to VWF. More research is necessary to fully understand the complex, underlying mechanisms that ultimately cause VWD type 1 and to help establish a clear, universal definition of the disorder. Until that time, disagreement may remain in the medical literature as to whether individuals with moderately low levels of VWF and no symptoms should be classified as having VWD or having a risk factor for developing VWD or having no disease at all.
VWD is a common inherited bleeding disorder. It affects males and females in equal numbers, although it is diagnosed more often in women because women have more associated symptoms (i.e. heavy menstrual bleeding and bleeding after childbirth). VWD can be diagnosed at any age and in individuals of any race or ethnicity.
The disease is often estimated to affect 1% of the population in the United States. However, the prevalence of symptomatic VWD is estimated to be in between 23-110 per 1,000,000 in the general population. The prevalence of VWD in the medical literature varies because different criteria are used to define individuals who have the disorder. For example as stated above, some medical sources equate low levels of VWF as having VWD, while other sources consider this a risk factor for developing the disorder. In addition some cases of VWD can go undiagnosed or misdiagnosed. Consequently, it is difficult to determine the true frequency of VWD in the general population. Regardless, all forms of VWD type 2 are uncommon disorders. VWD type 3 is extremely rare, estimated to occur in approximately 1 in 250,000-1,000,000 people in the general population.
A diagnosis of VWD is based upon identification of characteristic symptoms (e.g. evidence of mucocutaneous bleeding), a detailed patient and family history, a thorough clinical evaluation, and a variety of specialized tests. Such tests may measure the amount of VWF, how well it functions, the amount of factor VIII, and the ability of the blood to clot.
Individuals with severe cases of VWD may be diagnosed during infancy. Mild cases of VWD may be difficult to identify and may not be diagnosed until adulthood. An accurate diagnosis is extremely important for women in order to avoid unnecessary and/or invasive treatments, such as hysterectomy, for abnormal menstrual blood flow; these treatments often occurring before they might be warranted.
Because of the disagreement and confusion in the medical community regarding the specific definition of VWD type 1 (see Causes section above), obtaining a diagnosis can be difficult. Differentiating true VWD type 1 from individuals who have low levels of VWF, but do not have the disorder can be challenging.
Clinical Testing and Workup
Individuals may undergo standard blood screening tests including a complete blood count (CBC), which may be normal or may show microcytic anemia or low platelet count, especially in individuals with VWD type 2B. Screening coagulation tests that measure how long it takes the blood to clot may also be used. Two of these tests are known as activated partial thromboplastin time (aPTT) or promthrombin time (PT). APTT may be normal in individuals with VWD or can be prolonged if deficiency of factor VIII is present. PT is normal in individuals with VWD.
Even if the above screening tests are normal, individuals suspected of having VWD should undergo specific assays. An assay is a test that can measure the activity of certain substances in the blood. Such tests include the VWF antigen test, which measures the amount of VWF in the blood; the ristocetin cofactor activity test, which measures how well VWF works to stop bleeding; and factor VIII clotting activity test; which measures how well factor VIII is working.
If the above tests are positive, affected individuals will undergo specialized VWD testing to determine the specific subtype of VWD present. Such tests include the von Willebrand factor multimer test, which examines the structure of VWF and can help to determine the specific type of VWD present and platelet function tests, which determine how well platelets function.
A diagnosis of VWD can be confirmed in some cases by molecular genetic testing, which can identify the characteristic VWF gene mutation that causes the disorder. Molecular genetic testing is available through commercial and academic research laboratories. Failure to identify a mutation of the VWF gene does not necessarily rule out a diagnosis of VWD in all cases.
There is no cure for VWD, but there are safe and effective treatments for all types of the disorder. The specific treatment of VWD varies depending on the subtype and severity of the disorder. Minor bleeds such as nosebleeds, small bruises, and minor cuts may not require therapy. In mild cases, individuals may only require treatment before undergoing surgery or a dental procedure or following trauma or injury. Individuals with VWD should receive prompt treatment during severe bleeding episodes.
Individuals with factor VWD will benefit from referral to a federally-funded hemophilia treatment center. These specialized centers can provide comprehensive care for individuals with hemophilia and related disorders including the development of specific treatment plans, monitoring and follow up of affected individuals, and state-of-the-art medical care. Treatment at a hemophilia treatment center ensures that individuals and their family members will be cared for by a professional healthcare team (physicians, nurses, physical therapist, social worker and genetic counselor) experienced at treating individuals with inherited bleeding disorders. Genetic counseling can be of benefit for affected individuals and their families.
Individuals with mild or moderate VWD, trauma-induced or spontaneous bleeding episodes may be managed with the drug desmopressin acetate, which stimulates the release of VWF stored in blood vessel walls. The drug, which is a synthetic agent that is a derivative of the natural hormone vasopressin (antidiuretic hormone), may also increase the activity of factor VIII, enabling blood to clot properly and thereby reducing bleeding time. Parenteral use of desmopressin may also be used to control bleeding (hemostatis) during and after surgical procedures in those with mild to moderate disease. Some women may use the drug at the start of their menstrual cycle. Desmopressin can be injected intravenously, underneath the skin (subcutaneous) or delivered via a nasal spray.
Desmopressin is the first-line therapy for individuals with VWD type 1 and some individuals with VWD type 2. Therapy with desmopressin is not indicated for individuals with most types of type 2 VWD and severe VWD. In individuals with VWD type 2B, desmopressin can potentially cause a drop in platelet count and should only be used after testing is done before therapeutic use to determine an individual’s response to the drug. In most individuals with VWD type 2M, response to desmopressin is poor. Desmopressin is generally ineffective in VWD type 3 as well.
Individuals who do not respond to treatment with desmopressin or who have more severe complications may require treatment with concentrated forms of VWF and factor VIII. This is referred to as replacement therapy because it replaces the proteins that are defective or missing from the blood. Concentrated forms of VWF and factor VIII are created from the plasma of thousands of different blood donors. These products undergo a viral inactivation process that kills any viruses or similar pathogens that can potentially be present in the blood. When treatment is required, replacement therapy is used for individuals with severe VWD or individuals with mild or moderate disease who cannot use or do not respond to treatment with desmopressin. Replacement therapy is the treatment of choice in VWD types 2M and type 3 and for some individuals with VWD type 2B. Individuals with VWD type 3 may require repeated infusions of factor VWF/FVIII concentrates. Individuals with VWD type 3 often receive VWF/FVIII concentrates as a preventive (prophylactic) therapy against the development of musculoskeletal bleeding and joint damage.
The U.S. Food and Drug Administration (FDA) has approved the VWF/FVIII replacement therapies Humate-P®, Alphanate®, and Wilate® for the treatment of individuals with VWD. Replacement therapy is usually administered through intravenous infusion.
In 2016, Vonvendi was approved for use in patients 18 years and older. It is the first FDA approved drug, and is approved on a as needed-base to treat and control VWD. It is made by Bazalta U.S. Inc.
Some individuals with superficial bleeding may be treated with fibrin glue (sealants). Fibrin glue is applied directly to the site of bleeding. Fibrin is a protein that is essential to the formation of a blood clot. Fibrin glue is manufactured from various clotting factors obtained from donated plasma. Fibrin glue acts to hold platelets together to strengthen a clot. Fibrin glue is often used for surgery or dental procedures in affected individuals.
Additional therapies for VWD include hormonal contraceptives such as birth control pills, which can boost levels of VWF in the blood, helping to control heavy bleeding during a woman’s menstrual period. Drugs known as antifibrinolytics, which slow the breakdown of clotting factors in the blood, can also be used to treat individuals with VWD. Such drugs include aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron, Lysteda) and can be given for the prevention or treatment of bleeding episodes.
Individuals with VWD should avoid drugs that affect blood clotting including aspirin, drugs that contain aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), and blood thinners such as warfarin and heparin.
Researchers are studying the effectiveness of genetically engineered (recombinant) forms of von Willebrand factor for the treatment of individuals with VWD. Because it is artificially created in a lab, recombinant VWF does not contain human blood or plasma… More research is necessary to determine the long-term effectiveness and safety of such therapies for the treatment of individuals with VWD.
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