Von Willebrand disease: what is it, types, symptoms, treatment, prognosis

What is von Willebrand disease?

Von Willebrand disease (BV) is a common inherited bleeding disorder affecting men and women in equally, but can disproportionately affect women due to menstrual problems and childbirth.

There are three main types of BV (BV type 1, BV type 2, and BV type 3), each with varying degrees of severity and inheritance patterns. Unlike hemophiliawhich is characterized by bleeding in the joints, von Willebrand disease is usually characterized by mucocutaneous bleeding. BV is caused by a defect or deficiency of von Willebrand factor (eng. von Willebrand factor, VWF), a large protein composed of several subunits.

VWF binds to coagulation factor VIII in the circulation and protects it from destruction. VWF also helps platelets to bind to the inside of damaged blood vessels. This leads to the formation of a stable blood clot that clogs the damaged blood vessel and stops the bleeding. If the VWF is not enough or is defective, the person may have problems with the formation of a blood clot.

Most sick people have a relatively mild form of the disease, type 1 BV, and are not diagnosed until adulthood. A small percentage of these people may have prolonged bleeding during infancy or early childhood. Symptoms may include nosebleeds, bleeding from the gums, and easy bruising. Women with BV often have heavy periods. Affected women bleed easily after injury, childbirth, and / or surgery. Bleeding from the stomach and intestines may occur, but is less common.

BV was first described in the medical literature in 1926 by Dr. Erik Adolph von Willebrand, who differentiated the disorder from classic hemophilia. In addition to the genetic form, von Willebrand disease can be acquired throughout life, often in association with a separate underlying disease.

Signs and symptoms

The specific symptoms and severity of BV can vary greatly from one person to another, even among people of the same subtype or family members. Some people may have no symptoms or only mild manifestations of the disorder; other people can have mild symptoms to severe bleeding complications. Some people may not experience symptoms until adulthood; others may be affected in infancy.

Most people have a mild form of the disorder. Type 1 disease is the predominant form in the general population. Severe symptoms most often occur with type 3 BV and, in some cases, type 2 BV.

To better understand von Willebrand disease, it is important to understand how the body forms clots (blood clots) to stop bleeding. Clotting is the process by which blood gathers together to close an area of ​​a wound and stop bleeding. Clotting requires a series of reactions between the clotting proteins to eventually form a clot. Clotting factors such as VWF are specialized proteins that play an important role in blood clotting. VWF has two main functions: it promotes platelet adhesion to the damaged blood vessel and stabilizes, protects and transports factor VIII to the site of injury. Defects in levels or improper VWF function make clotting difficult. Consequently, it is difficult for affected people to stop the bleeding from the wound.

Mild symptoms associated with von Willebrand disease include mild bleeding of the mucous membranes and skin (mucocutaneous areas), including chronic nosebleeds and bleeding from the gums. Minor bruising and prolonged bleeding may also occur due to minor cuts. Bruising may spread over large areas of the body. Women may experience heavy and prolonged bleeding during menstrual cycle (menorrhagia) or during and after childbirth. If left untreated, heavy menstrual bleeding can lead to anemia and iron deficiency. Some people may experience heavy, prolonged bleeding after injury, dental procedures, or surgery.

More serious but unusual complications may include gastrointestinal bleeding, hard swelling of congealed blood (hematomas) and bleeding in muscles and joints (hemarthrosis), causing progressive damage and degeneration joints. Ultimately, in these cases, BV can limit the range of motion of the affected joint.

- Subtypes of von Willebrand disease.

BVs are usually categorized into three subtypes.

1. BV type 1 is the mildest form of the disorder and accounts for approximately 70-80% of cases. Affected people may have low blood levels of VWF. In some cases, factor VIII can also be reduced. Typically, affected people develop mild mucocutaneous bleeding; in rare cases, affected people will develop more severe symptoms. Nosebleeds and bruising are common signs of illness in children; Heavy menstrual bleeding is common in women of childbearing age.
2. BV type 2 accounts for approximately 20% of cases. In these people, VWF may be present in the blood at normal or near-normal levels, but does not function properly. Type 2 BV is further subdivided depending on the specific underlying VWF defect. These subtypes are known as BV types 2a, 2b, 2m, and 2n.
   1. BV 2A type characterized by decreased VWF that does not bind to platelets, decreasing the ability of platelets to clump together to form a clot. Patients often have mild to moderate mucocutaneous bleeding.
   2. BV 2B type characterized by platelets that have an increased clumping ability, causing premature clumping of platelets in the bloodstream rather than at the site of damage to the blood vessel. People experience mild to moderate mucosal bleeding and are at risk of developing low platelet levels in the blood (thrombocytopenia). Thrombocytopenia is exacerbated by stressful situations such as infection, surgery, or pregnancy.
   3. BV 2M type characterized by reduced VWF activity and its inability to interact with platelets. This form is usually associated with mild to moderate mucocutaneous bleeding. In some cases, more serious bleeding may develop.
   4. BV 2N type characterized by the inability of VWF to transport factor VIII to the site of injury and a reduced level of factor VIII in the blood. People develop excessive bleeding after surgery. This form of von Willebrand disease may resemble a mild form of classic hemophilia (hemophilia A).
3. BV type 3 is the most severe form of the disorder. It accounts for approximately 5% of cases. Affected people have an almost complete absence of VWF in their blood. Patients may experience severe mucocutaneous bleeding, bleeding in muscles and joints, joint damage, and the development of multiple hematomas.

For women with more severe BV, monitoring for serious, life-threatening bleeding in the reproductive tract and postpartum hemorrhage is very important.

Causes of von Willebrand disease

Most cases of von Willebrand disease are caused by mutations in the VWF gene. In type 1 BV and most forms of type 2, the mutation is inherited as an autosomal dominant trait. In some cases, the mutation occurs randomly for no reason (spontaneously) with no previous family history (i.e., a new mutation). BV type 3 and some cases of BV type 2 are inherited as an autosomal recessive trait.

Genetic diseases are defined by a combination of genes for a specific trait, which are found on chromosomes received from the father and mother. Dominant genetic disorders occur when only one copy of an abnormal gene is needed for a disease to appear. An abnormal gene can be inherited from either parent or be the result of a new mutation (gene change) in a patient. The risk of passing the abnormal gene from a sick parent to offspring is 50% with every pregnancy, regardless of the sex of the child.

Recessive genetic disorders occur when a person inherits the same abnormal gene for one trait from each parent. If a person receives one normal gene and one gene for the disease, the person will carry the disease but usually show no symptoms. The risk for two carrier parents passing on both defective genes and therefore conceiving a sick child is 25% with each pregnancy. The risk of conceiving a carrier child, 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 this particular trait is 25%. The risk is the same for men and women.

Scientists have determined that the VWF gene is located on the short arm (p) of chromosome 12 (12p13). Chromosomes are present in the nucleus of cells and carry the genetic information of every person. The cells of the human body usually have 46 chromosomes. Pairs of human chromosomes are numbered 1 through 22, and the sex chromosomes are labeled X and Y. Men have one X and one Y chromosome, while women have two X chromosomes. Each chromosome has a short arm, labeled "p", and a long arm, labeled "q". Chromosomes are further subdivided into many numbered bands. For example, "chromosome 12p13" refers to lane 13 on the short arm of chromosome 12. The numbered stripes indicate the location of the thousands of genes present on each chromosome.

The VWF gene is the only gene identified as causing von Willebrand disease (VWD). The VWF gene regulates (encodes) the von Willebrand factor. Mutations in this gene result in low levels of VWF, which is defective and does not function properly. As mentioned above, von Willebrand factor has two main functions in the body. It carries and protects factor VIII, preventing it from being broken down (metabolized) to the site of injury, and helps platelets to adhere to blood vessels. Defective VWF cannot act as an adhesive to hold platelets at the site of damage to the blood vessel. Consequently, platelets do not adhere to the blood vessel wall and the blood clot breaks down prematurely. In some cases, a deficiency or defect in von Willebrand factor results in low levels of factor VIII in the blood, resulting in abnormal blood clots.

Despite the successes achieved in recent years with regard to BV, the main mechanisms and genetics of BV type 1 are not fully understood. Type 1 BV is associated with variable expressivity and decreased penetrance among family members. Variable expressiveness refers to disorders in which the severity from one person to another can vary significantly, even among members of the same family. Reduced penetrance means that some people who have inherited the defective gene for the disorder will not develop all of the symptoms.

In addition, only about 50-60% of people with type 1 BV have an identifiable VWF gene mutation. Even in cases where a gene mutation has been identified, confusion still exists because the exact link between mutations in the VWF gene, residual VWF levels, and an overall risk of bleeding in people with type 1 disease unclear.

Some of the confusion surrounding type 1 von Willebrand disease stems from the fact that people in the general population have different levels of VWF in their blood. In general, in many disorders, the amount of residual protein activity is often correlated with the severity of the disease (for example, little or no protein activity leads to severe disease). However, the researchers noted that many people in the general population have moderately low VWF levels but do not develop BV symptoms. This suggests that additional genetic and environmental factors are likely to play a role in the development and severity of BV. For example, people with blood type 0 have lower levels of VWF than people with other blood types.

Due to the differences in VWF levels among the population, it is difficult to establish what is “low” and what is “normal”. The normal blood VWF range is generally considered to be 50-200 IU / dL. People with very low levels (eg, <20 IU / dL) are very likely to have an identifiable VWF gene mutation, severe bleeding symptoms, and a positive family history of the disorder. These people may be diagnosed with type 1 BV. However, people with VWF levels between 30-50 IU / dL, which is technically below normal, present a significant problem in terms of diagnosis and determination.

In many cases, type 1 BV can be considered a complex genetic disorder in which many factors, both genetic and environmental, play a role in the development diseases. Genetic factors associated with type 1 BV may include factors not associated with VWF. More research is needed to fully understand the complex underlying mechanisms that which ultimately cause type 1 BV, and help establish a clear, universal definition of disorders. Until that time, there may be controversy in the medical literature as to whether individuals with moderate low levels of VWF and no symptoms as having disease or having a risk factor for developing BV or not having disease at all.

Affected populations

Von Willebrand disease (VWD) is a common inherited bleeding disorder. It affects men and women in equal numbers, although it is more commonly diagnosed in women because women are more likely to experience symptoms (for example, heavy menstrual bleeding and bleeding after childbirth). BV can be diagnosed at any age and in people of any race or ethnicity.

The disease is estimated to affect 1% of the population. However, the prevalence of symptomatic BV is estimated to be 23-110 per 1,000,000 in the general population. The prevalence of BV in the medical literature varies because different criteria are used to define individuals with the disorder. For example, as noted above, some medical sources equate low VWF levels with BV, while others consider this to be a risk factor for the disorder. In addition, some cases of von Willebrand disease go undiagnosed or misdiagnosed. Consequently, it is difficult to determine the true incidence of BV in the general population. Despite this, all forms of BV type 2 are rare disorders. BV type 3 is extremely rare, with an estimated 1 in 250,000-1,000,000 people in the general population.

Diagnostics

The diagnosis of BV is based on the identification of characteristic symptoms (for example, the presence of mucocutaneous bleeding), detailed medical history of the patient and family, careful clinical evaluation and various specialized tests. Such tests can measure the amount of VWF, how well it is functioning, the amount of factor VIII, and the blood's ability to clot.

People with severe cases of von Willebrand disease can be diagnosed during infancy. Mild cases of BV are difficult to identify and cannot be diagnosed until adulthood. An accurate diagnosis is extremely important for women to avoid unnecessary and / or invasive treatments such as hysterectomy for abnormal menstrual flow.

Due to controversy and confusion in the medical community regarding the specific definition of type 1 BV (see. (See Causes section above), diagnosis can be difficult. Differentiating true type 1 BV from people who have low levels of VWF but do not have the disorder can be challenging.

People may have routine blood tests, including a complete blood count (CBC), which may be normal or show microcytic anemia or low platelet counts, especially in people with BV type 2B. Screening coagulation tests can also be used, which measure how long it takes for blood to clot. Two of these tests are known as activated partial thromboplastin time (APTT) or prothrombin time (PTT). APTT may be normal in people with BV, or it may be prolonged if factor VIII is deficient. PTV is usually normal in people with BV.

Even if the aforementioned screening tests are normal, people suspected of having BV should undergo special tests. An analysis 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 a factor VIII clotting activity test; which measures how well factor VIII works.

If the above tests are positive, patients will need to undergo specialized BV testing to determine the specific subtype of true BV. Such tests include the von Willebrand factor multimeric test, which examines the structure of VWF and can help determine the specific type of BV present and platelet function tests that determine how well they are functioning platelets.

The diagnosis of von Willebrand disease can be confirmed in some cases by molecular genetic testing that can identify the characteristic VWF gene mutation that causes disorder.

Treatment of von Willebrand disease

There are no cures for von Willebrand disease, but there are safe and effective methods for managing all types of the disorder. Specific treatment for BV varies according to the subtype and severity of the disorder. Minor bleeding, such as nosebleeds, minor bruises, and minor cuts, may not require therapy. In mild cases, patients may need treatment only before surgery or dental procedure, or after an injury or cut. Individuals with BV should receive prompt treatment for severe bleeding.

People with BV can be referred to a hemophilia treatment center. These specialist centers can provide comprehensive care for people with hemophilia and related disorders, including development of specific treatment plans, monitoring and follow-up of sick people, as well as modern medical help. Treatment at a hemophilia center provides care to individuals and their families by a professional team of medical professionals (doctors, nurses, physiotherapists, social workers and genetic counselors) experienced in treating patients with hereditary coagulation disorders blood.

Patients with mild to moderate BV caused by trauma or spontaneous bleeding episodes may be treated with a drug called desmopressin acetate (Desmopressin), which stimulates the release of VWF stored in the walls of the blood vessels. The drug is a synthetic agent derived from the natural hormone vasopressin (antidiuretic hormone), can also increase the activity of factor VIII, allowing blood to clot properly and thereby shortening the time bleeding. Parenteral desmopressin can also be used to control bleeding (hemostasis) during and after surgery in patients with mild to moderate diseases. Some women may use the drug early in their menstrual cycle. Desmopressin can be administered intravenously, subcutaneously, or delivered via a nasal spray.

Desmopressin is the first line therapy for people with von Willebrand disease type 1 and some people with type 2. Desmopressin therapy is not indicated for people with most types of BV type 2 and severe BV. In people with type 2B BV, desmopressin can potentially cause a decrease in platelet count and should be used only after testing before therapeutic use to determine the patient's response to a drug. Most people with BV type 2M have a mild response to desmopressin. Desmopressin is usually also ineffective for type 3 BV.

Individuals who do not respond to desmopressin treatment or have more severe complications may require treatment with concentrated forms of VWF and factor VIII. This is called replacement therapy because it replaces proteins that are defective or not present in the blood. Concentrated forms of VWF and factor VIII are generated from plasma from thousands of different blood donors. These products undergo viral inactivation, which kills any viruses or similar pathogens that could potentially be present in the blood. When treatment is required, replacement therapy is used for people with severe BV or people with mild to moderate illness for whom desmopressin therapy is contraindicated. Replacement therapy is the treatment choice for type 2M and type 3 BV and for some people with type 2B BV. Individuals with type 3 BV may require repeated infusions of VWF / FVIII concentrates. Individuals with type 3 BV often receive VWF / FVIII concentrates as a preventive therapy against the development of musculoskeletal bleeding and joint damage.

Some people with superficial bleeding can be treated with fibrin glue. Fibrin glue is applied directly to the bleeding site. Fibrin is a protein that is essential for the formation of a blood clot. Fibrin glue is made from various clotting factors obtained from donor plasma. The glue holds the platelets together to strengthen the clot. Fibrin glue is often used for surgical or dental procedures on affected individuals.

Additional treatments for BV include hormonal contraceptives, such as birth control pills, which can raise blood VWF levels, helping to control heavy bleeding during the menstrual cycle women. Drugs known as antifibrinolytics, which slow down the breakdown of clotting factors, can also be used to treat people with BV.

People with von Willebrand disease should avoid medications that affect blood clotting, including aspirin, medications that contain aspirin, non-steroidal anti-inflammatory drugs (NSAIDs) and blood thinners such as warfarin and heparin.

Forecast

For patients undergoing treatment in specialized hemophilia clinics, the prognosis is favorable, even for patients with the most severe forms of the disease.