What is Von Willebrand Disease?
Von Willebrand Factor is a sort of protein, known as a glycoprotein, that plays a key role in blood clotting. It’s made in specific cells lining our blood vessels and huge cells known as megakaryocytes. Once it’s made, this protein (called pro-vWF at this stage) sticks together to make pairs, inside a part of the cell called the endoplasmic reticulum. From here, bigger pairs of proteins form in another area of the cell, the Golgi complex and secretory granules. Then, the pro-von Willebrand factor propeptide— a specific part of the protein— is cut off. Both this cut-off piece and the mature von Willebrand factor are then released into the blood vessels.
Its major role is to act as a transporter for another protein called Factor VIII, which helps maintain its levels in the body and also assists in the stickiness of platelets—tiny blood cells that help in clotting—and binds to parts of blood vessels when there’s an injury. If there are any issues with the quality or quantity of the pro-von Willebrand factor, it can lead to more bleeding than normal. This condition is known as Von Willebrand disease.
What Causes Von Willebrand Disease?
Von Willebrand disease (VWD) can be either inherited, meaning it is passed down from parents to their children, or acquired, meaning it develops due to certain conditions or factors during a person’s life.[4][5]
The inherited types of Von Willebrand disease are:
Type 1: This type is passed down from parents to their children and involves a partial shortage of a protein called von Willebrand factor. This protein helps blood to clot.
Type 2: This type, which is also passed down from parents, is caused by various defects in the von Willebrand factor. There are four specific varieties of Type 2, with 2A being the most common.
Type 3: This type is caused by a complete lack of the von Willebrand factor. It is passed down from parents to their children and is often characterized by severe bleeding, as von Willebrand factor levels are undetectable.
The gene that influences the von Willebrand factor can vary significantly from person to person, leading to a range of von Willebrand factor levels and a wide spectrum of disease presentations and severity.
Acquired Von Willebrand disease happens when certain conditions or factors interfere with the von Willebrand factor, decreasing its quantity or disrupting its role in blood clotting. Conditions that might lead to acquired Von Willebrand disease include various types of cancers, blood disorders, lupus, metabolic disorders like hypothyroidism, side effects of certain medications, and high-vascular flow conditions, which involve rapid blood flow. In these high flow states, the von Willebrand factor, a large complex protein, is particularly vulnerable to damage.
The way von Willebrand disease presents itself can vary a lot in autoimmune conditions, as the von Willebrand factor appears in various sizes and certain sizes might escape the immune system’s defense mechanisms. In cases of cancer, the disease can occur due to the formation of unspecific antibodies that bind to the von Willebrand factor, leading to increased clearance by the body’s defense system. Additionally, the von Willebrand factor can be absorbed on the surface of cancer cells – as often seen in multiple myeloma or solid tumors – or be broken down, which is common in certain blood disorders.
Risk Factors and Frequency for Von Willebrand Disease
Von Willebrand disease is a condition that affects about 1% of the population. However, the prevalence of severe forms of the disease is much lower, affecting about 125 people in every one million, with the most serious forms affecting up to five in a million.
Both men and women are equally likely to have this disease. A variant of the disease, known as acquired von Willebrand disease, could account for about 1% to 5% of all cases. But it’s not clear exactly how many people have this type because the incidence rate can vary widely in certain groups. For example, up to 20% of people with cancer and 100% of people with specific high flow states such as those on a type of life support known as ECMO (extracorporeal membrane oxygenation) or people with metallic heart valves might have this variant of the disease.
Signs and Symptoms of Von Willebrand Disease
Having a low von Willebrand factor, which helps with blood clotting, is quite common in people. However, not everyone with this condition experiences significant bleeding problems, so many could remain undiagnosed. Usually, it is identified when someone has major bleeding problems. These can include often having excessive bruising, bleeding for a long time from minor skin wounds, and prolonged bleeding from mucus-producing areas such as nosebleeds, dental extractions, and menstruation.
A doctor’s examination may often appear standard. But sometimes, signs of bleeding or bruising like small, round spots appearing on the skin (petechiae), or blood pooling in the skin (hematomas) may be visible.
When there’s an issue with the quality of von Willebrand factor, this could be mistaken for hemophilia due to similar symptoms such as bleeding into soft tissues, joints, and the presence of blood in urine. It’s also important to note that sometimes, type 2N von Willebrand disease can be misdiagnosed as hemophilia.
Testing for Von Willebrand Disease
If your doctor thinks you may have von Willebrand disease, a condition that affects your blood’s ability to clot, they will likely perform several tests. These tests help them understand more about what’s happening in your blood.
Firstly, a Complete Blood Count (CBC) is done to check the number of different cells in your blood. In von Willebrand disease, you typically have a normal number of clot-forming cells, called platelets.
Next, they look at your coagulation profile, which measures how fast your blood clots. In von Willebrand disease, a test called aPTT may show a longer than usual clotting time due to increased breakdown of a protein called factor VIII. Another test in this profile, PT, should show a normal result.
The doctors will then examine the levels and functioning of the von Willebrand factor protein. One test measures how much of this protein you have in your blood (a quantitative test), and another test looks at how well the protein works (a qualitative test). For the latter, tests like Ristocetin cofactor activity (vWF:RCo) and collagen binding activity (vWF:CB) are used. If your Ristocetin cofactor activity is below 30 IU/dL, it suggests you have von Willebrand disease. The doctors will also check for the activity of the factor VIII protein.
By comparing the activity of the von Willebrand factor with its levels in your blood, doctors can identify cases with serious deficiencies in the protein’s functioning. A low ratio could suggest that you have type 2 von Willebrand disease, but there is no absolute normal value determined yet.
Finally, if your von Willebrand factor activity and levels are between 30 and 50, you may be categorized as having “low-von Willebrand factor”. If you’re in a situation where bleeding risk is high, your doctors might consider treating you for von Willebrand disease.
Treatment Options for Von Willebrand Disease
When dealing with von Willebrand disease, a genetic disorder that prevents the blood from clotting properly, doctors often first try a medication called desmopressin (DDAVP). This drug is like a synthetic (or man-made) version of a hormone the body naturally makes to help control bleeding. The purpose of giving desmopressin is to see if it can help increase the levels of a specific factor known as the von Willebrand factor which aids in blood clotting. This method is usually attempted when a patient is not actively experiencing bleeding.
Different types of von Willebrand disease respond differently to desmopressin. Type 1 normally has a good response and types 2A, 2M, and 2N typically show a variable or poor response. Unfortunately, type 3 doesn’t usually respond to this treatment because there’s a complete lack of von Willebrand factor. Therefore, a successful use of this drug is often measured by whether it can get the von Willebrand factor levels to rise to at least 30 IU/dL, or ideally 50 IU/dL.
Desmopressin can be delivered in a few ways – subcutaneous (under the skin) injection, intravenous (into a vein) injection, or an intranasal (through the nose) spray. It can help increase the von Willebrand factor and another blood clotting factor called factor VIII, with effects lasting up to 12 hours. This drug is helpful for minor bleeding episodes and minor surgical procedures.
For more severe cases, such as type 3 von Willebrand, or serious forms of types 1 and 2 that do not respond well to desmopressin, doctors may consider von Willebrand factor replacement. Made up of blood clotting concentrates, these replacements are often used in severe bleeding situations or for major surgeries. Short-term use is typical.
In some special cases, doctors may use an medication called tranexamic acid. This drug helps prevent the breakdown of clots that have already formed, proving useful in instances of bleeding from membranes and linings of various passages and cavities in the body, such as the nose or the mouth.
What else can Von Willebrand Disease be?
These are some conditions that could be affecting your blood clotting:
- Factor X deficiency
- Factor XI deficiency
- Hemophilia A
- Hemophilia B
- Bernard-Soulier syndrome
- Platelet function defects
- Consumption of antiplatelet drugs
- Fibrinolytic defects
What to expect with Von Willebrand Disease
For most patients, Von Willebrand Disease (vWD) is a mild and treatable condition that causes bleeding. Generally, severe bleeding only happens when there is an injury or during invasive procedures.
Possible Complications When Diagnosed with Von Willebrand Disease
In people who have type 3 of this disease, around 10 to 15% may develop alloantibodies. This could lead to complications which require careful management, as it increases the risk for severe allergic reactions to some medications. During pregnancy, most women with type 1 and 2 of the disease may see an increase in vWF levels, which usually means they can have a normal delivery. However, those with type 2B can face bleeding problems. If a woman’s vWF levels do not increase to normal during pregnancy, she will need to be monitored by a specialist and a team of health professionals.
Additionally, rare but serious problems linked to this disease can include stomach or bowel bleeding, large bruises (hematomas), and bleeding into the joints that can damage and degrade them over time. This can limit how much a person is able to move an affected joint.
Common Problems with the Disease are:
- Development of alloantibodies in 10 to 15% of patients with Type 3
- Increase in vWF levels in most women with type 1 and 2 during pregnancy
- Bleeding problems in pregnancy in patients with Type 2B
- Woman’s vWF levels not going back to normal during pregnancy
- Bleeding in the stomach or intestines
- Big bruises
- Bleeding into the joints
Preventing Von Willebrand Disease
Doctors need to educate patients about the risk of bleeding. This includes advising patients on certain medications to steer clear of, such as antiplatelet drugs (medicines that stop blood cells from sticking together) and non-steroidal anti-inflammatory drugs (NSAIDs), which are often used for pain relief and can increase bleeding risk. Additionally, patients should know that some high-risk activities, like contact sports, may not be suitable for them.
While it’s important for patients to be aware of these risks, they should also be comforted knowing minor bleeding issues, like nosebleeds or bruises, may not necessarily require any special treatment.
