What is Von Willebrand Disease: Types, Symptoms, Causes, Treatment, Pathophysiology, Prognosis

Von Willebrand Disease is the most common hereditary bleeding disorder. It is named after Dr. Erik Willebrand, who first discovered it in the year 1926. It is an autosomal recessive disorder and is found to occur in 1% of the world’s population.

Von Willebrand Disease occurs due to the defect in the gene coding for protein known as von Willebrand. This protein is an important factor for clotting of blood and prevents blood loss. When blood vessel gets injured, blood oozes out from it and then stops, since it gets clotted. Von willebrand factor protein helps platelets to form a clot which stops bleeding. However, due to the defective gene, people with Von Willebrand Disease either lack or have insufficient levels of this protein. When they get injured, it takes long time for their blood to clot and to stop bleeding. Von Willebrand factor (von willebrand factor) also carries another substance, known as factor VIII which stimulates the clotting process. It is observed that people with Von Willebrand Disease (vWD) also suffers from lower levels of factor VIII.

Generally, the syndrome is inherited and occasionally acquired. Von Willebrand Disease is inherited through either of the parents and is seen in both males and females in equal proportion from all racial backgrounds. This disorder is less severe than other bleeding disorders. Most people with Von Willebrand Disease show mild symptoms and are not aware that they have this disorder.

• Inherited Type of Von Willebrand Disease: It has three main sub-types. The symptoms and treatment is different for each type:
  • Type1: It is the most common type of Von Willebrand Disease affecting 80% of all people with the disease. The von willebrand factor works in normal manner, however, it is present in low levels. Although, the symptoms can be mild yet, bleeding can be severe.
  • Type2: It involves a defect in the von willebrand factor protein structure due to which the protein cannot function properly. Symptoms are usually moderate. Type 2 is divided into subtypes as 2A, 2B, 2M and 2N.
  • Type3: It is a serious form of Von Willebrand Disease. People with Type3 Von Willebrand Disease have little or no von willebrand factor. Symptoms are very severe and there can be bleeding in the muscles or joints.
• Acquired Type Von Willebrand Disease: It is a very rare type and occurs due to spontaneous mutation after the child’s birth.

The symptoms differ depending on the type of Von Willebrand Disease. In most of the Von Willebrand Disease cases, very mild symptoms are observed. While serious Von Willebrand Disease cases show excessive bleeding problems. The common symptoms observed in all types of Von Willebrand Disease are:

• Easy bruising
• Excessive nose bleeding
• Bleeding from gums
• Women face problems of abnormally heavy or prolonged bleeding during menstruation.

Less commonly observed symptoms of Von Willebrand Disease, which occur in older people include

• Blood in feces due to bleeding in the intestine
• Blood in urine samples due to bleeding in the kidneys

People with type3 lack von willebrand factor and experience bleeding which is difficult to control. It also raises risk of internal bleeding in the joints and gastrointestinal system.

Women with Von Willebrand Disease show more symptoms than men during menstruation and childbirth. In case of women with heavy periods, there is more blood loss which results in anemia. It also depends on the blood type; as observed, it is more severe in people with blood type O.

These symptoms of Von Willebrand Disease can change over lifetime as some people have bleeding problems in childhood and may not show such symptoms in their adulthood. However, the type of Von Willebrand Disease persists.

Most people with type 1 Von Willebrand Disease live normal lives with only mild bleeding problems. In case of type 2 Von Willebrand Disease there is always mild to moderate bleeding. There may be problems in case in infection, surgery and pregnancy. While in case of type 3 Von Willebrand Disease, there is high risk of severe bleeding and internal bleeding too.

A genetic mutation causes Von Willebrand Disease. The exact reason as to why this genetic defect takes place is not yet known. It may be an autoimmune disease or due to hypothyroidism. It also occurs in case of certain anti-seizure medications like valproic acid or the antibiotic ciprofloxacin.

Von Willebrand Disease is caused due genetic defect and is an inherited disorder. Either the less quantity or deficiency of von willebrand factor affects the clotting process during injury. The platelets do not clump together to form a meshwork due to which blood clotting does not take place and results in excess blood loss.

The type of Von Willebrand Disease one gets depends on, if one mutated gene (from a parent) or two mutated genes (one each from both parents) have been passed to the offspring. Type 1 or type 2 is caused when only single gene has been inherited and the severity of bleeding is less. Type 3 is caused when mutated genes are inherited from both the parents.

The risk factor includes a genetic inheritance. The complications associated with Von Willebrand Disease include:

• Anemia as a Complication of Von Willebrand Disease: Women with heavy menstrual bleeding can develop anemia and iron deficiency.
• Swelling and Pain due to Von Willebrand Disease: When abnormal bleeding occurs in the joints or soft tissue, it can lead to severe pain.
• Von Willebrand Disease Complication Associated with Drug Intake: Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) can make this condition worse. Hence, these drugs are to be taken only under doctor’s advice and observation.
• Death due to Von Willebrand Disease: It results when abnormal bleeding is not controlled in people with Von Willebrand Disease.

It is difficult to diagnose Von Willebrand Disease and it may require repeated tests to confirm the presence of the disorder. Diagnosis procedure includes:

• Personal history to know the extent of bleeding on injury or trauma.
• Family history to know if the same episodes of this disorder existed in the family or it is acquired.
• Conducting laboratory blood tests
• Since the von willebrand factor protein has more than one function, more than one lab test should be used to diagnose Von Willebrand Disease. These includes:
  • Quantitative analysis of von willebrand factor antigen to know the amounts in which it is produced.
  • Qualitative analysis of von willebrand factor multimers to reveal the structure of this protein. This test enables to know the type of Von Willebrand Disease.
  • Ristocetin cofactor (Functional Von Willebrand factor) activity reveals whether this protein performs its function of clotting or not.
  • Factor VIII activity measures the binding capacity of von willebrand factor to factor VIII and whether it maintains the levels of factor VIII in the blood.
  • Platelet function tests to measure if the person’s platelets are functioning normally.

Some factors such as stress, exercise, pregnancy, hormonal therapy can give wrong results hence the tests are repeated to obtain confirmed results. Since results of these tests are complex, it needs to be interpreted by an experienced Haematologist who has efficiently treated Von Willebrand Disease.

Once the type of Von Willebrand Disease is diagnosed, the treatment plan is made by a team consisting of haematologists, haemophilia nurses, counselors, physiotherapists and other healthcare professionals. The type of treatment depends on the type of Von Willebrand Disease.

• Desmopressin (DDAVP) to Treat Von Willebrand Disease: This is a synthetic drug which contains a clotting factor concentrate or drugs that control bleeding. It is important in treating type 2 Von Willebrand Disease. It controls bleeding during surgeries. This drug stimulates the release of von willebrand factor from endothelial cells and increases levels of von willebrand factor three to five folds. However, treatment with Desmopressin does not work for everyone. The doctor administers a small dose to evaluate its response in the patient.
• Factor Concentrates for Treating Von Willebrand Disease: It contains von willebrand factor and Factor VIII. It is used when desmopressin is not very effective. It is preferred for treatment of type 3 and most forms of type 2. It is used for controlling serious bleeding during surgery in all types of Von Willebrand Disease.
• Tranexania and Aminocaproic Acid to Treat Von Willebrand Disease: These drugs are used for controlling bleeding from mucous membranes. They help to maintain the clot and do not actually form a clot.
• Treating Von Willebrand Disease with Fibrin Glue: It is made of protein fibrinogen and thrombin which participate in the clotting process. It is a medical gel applied directly to the wounds.
• Hormone Treatment for Von Willebrand Disease: It is administered by means of oral contraceptives to control heavy menstrual bleeding in a woman. Iron supplements are advised to women who may suffer from anemia.
• Biological Therapy for Treating Von Willebrand Disease: This therapy incorporates use of Humate-P or Alphanate Solvent Detergent/Heat treated biologics or genetically engineered proteins. They are developed from human plasma and replace the von willebrand factor that is deficient or non-functional in the body. These are used for treatment of Type 2 and type 3 Von Willebrand Diseases. However, there are certain side effects such as chest tightness, rash and swelling.

The help from genetic counselors may enable prospective parents to understand the risk to their children. Through increased research efforts, it is important to understand the cause and elucidate pathogenesis of Von Willebrand Disease. This approach will enable better therapeutics and effective treatment for patients with Von Willebrand Disease in future.