von Willebrand disease and modern laboratory diagnostics

von Willebrand disease is an inherited blood clotting disorder. It can go unnoticed for years because the symptoms often look "everyday": frequent bruising, prolonged nosebleeds, heavy menstruation, bleeding after tooth extraction, or slow healing of small cuts. It is because of this invisibility that people sometimes get used to bleeding and do not associate it with the disease.

In von Willebrand disease, the blood doesn't clot properly because there's a lack of von Willebrand factor or because the protein doesn't work properly. The CDC explains that von Willebrand factor helps blood clot and also works with factor VIII, which is needed for normal clotting. If there's not enough von Willebrand factor or it doesn't work properly, bleeding can take longer.

This disease cannot be confirmed by a single general blood test or coagulogram alone. Modern diagnosis is based on a combination of bleeding history, basic coagulation tests, and specific tests for von Willebrand factor.

What is von Willebrand disease and when should you think about it?

Suspicion does not arise after one accidental bruise or one nosebleed. More indicative is the recurrence: bleeding has occurred since childhood, is present in the family, or appears after situations where other people's bleeding stops quickly.

Signs of von Willebrand disease may include:

• nosebleeds that occur frequently or do not stop for a long time;
• slight bruising without significant trauma;
• bleeding gums;
• prolonged bleeding after tooth extraction;
• heavy or long menstruation;
• anemia due to chronic blood loss;
• bleeding after surgery;
• postpartum bleeding;
• relatives with similar symptoms;
• the need to take iron supplements frequently due to blood loss.

The CDC notes that in women, heavy menstrual periods, anemia, and light or frequent bleeding can be signs of a blood clotting disorder; symptoms also include nosebleeds without an obvious cause and bruising without significant trauma.

If a person notices frequent bruising, it is worth noting that it is «thin skin» or «just got caught.» In the material about bruises for no reason discussed in more detail when bruising may be related to platelets, blood clotting, medications, or blood diseases.

Why conventional tests may not be enough

For many patients, the first step is a complete blood count or baseline coagulogram. This is logical, but such studies are often not enough to confirm or rule out von Willebrand disease.

A complete blood count may show anemia or platelet count. A coagulation profile can assess individual clotting factors. However, in mild forms of von Willebrand disease, baseline values may remain unchanged. This is why a normal complete blood count or standard coagulation profile does not always resolve the issue if bleeding is recurring.

The CDC emphasizes that a combination of blood tests is needed to diagnose von Willebrand disease, and screening tests can only indicate a possible clotting disorder. Specific diagnostic tests are needed to determine the type of disorder.

Diagnostic card for suspected von Willebrand disease

This chart does not mean that every patient needs all the tests at once. The doctor selects the tests based on symptoms, family history, age, comorbid conditions, and previous results.

Basic special analyses

Modern laboratory diagnostics of von Willebrand disease should assess not only the amount of the protein, but also how it works. That is why three groups of tests are key: VWF antigen, VWF activity, and factor VIII.

In the international guidelines of ASH, ISTH, NHF and WFH, specific testing for von Willebrand disease includes VWF antigen, platelet-dependent VWF activity and factor VIII coagulation activity.

VWF antigen

This test shows how much von Willebrand factor is in the blood. If it is low, it may support the suspicion of a quantitative deficiency. But the antigen level alone does not always indicate whether the protein is functioning normally.

VWF activity

This is a group of tests that assess the function of von Willebrand factor, particularly its ability to interact with platelets. Current guidelines favor newer tests that measure the platelet-binding activity of VWF, such as VWF GPIbM or VWF GPIbR, over the classic ristocetin cofactor test VWF RCo, when such methods are available.

Factor VIII

von Willebrand factor helps maintain normal levels of factor VIII in the blood. If factor VIII is low, it may be part of the picture of von Willebrand disease or need to be differentiated from other clotting disorders.

Why is it necessary to clarify the type of disease?

There are different types of von Willebrand disease. In some cases, there is simply less von Willebrand factor than needed. In others, the amount may be close to normal, but the structure or function is impaired. There are also rare severe forms, where the factor is almost absent.

The CDC describes three main types of von Willebrand disease: type 1, in which VWF levels are lower than normal; type 2, in which VWF does not work properly; and type 3, the most severe and rare, in which there is very little or no VWF.

Clarifying the type is important not only for the name of the diagnosis. It affects the tactics before surgeries, dental interventions, childbirth, treatment of heavy menstruation, and the choice of medications to control bleeding.

Coagulogram as a first step, but not the final answer

A coagulogram can be a useful part of the initial evaluation, especially if there is bleeding after procedures, bruising, bleeding gums, or in preparation for surgery. It helps assess baseline clotting parameters but does not always detect von Willebrand disease.

That is why, with recurrent bleeding and a normal coagulogram, the doctor may still prescribe special VWF tests. In the material about coagulogram explains why baseline clotting parameters should be interpreted in conjunction with symptoms, medications, and clinical situation.

Why tests sometimes need to be repeated

The results of von Willebrand factor tests can vary. VWF levels can increase during stress, infection, inflammation, pregnancy, after exercise, or in the presence of estrogen. This can make the test results temporarily less suspicious in someone with a true deficiency.

The CDC notes that repeat tests may be needed for an accurate diagnosis because levels of clotting factors change over time and can respond to stress, pregnancy, and infections.

ACOG also points out that the results of specific tests for suspected von Willebrand disease can be affected by stress, systemic inflammation, anemia, pregnancy, oral contraceptives, phase of the menstrual cycle, sample processing, and laboratory quality. Because of this, repeat testing is sometimes necessary to make a definitive diagnosis.

Heavy menstruation as a frequent route to diagnosis

In women, von Willebrand disease is often first suspected due to heavy menstrual bleeding. The problem is that many patients consider this blood loss «their norm» for years, even though it can lead to iron deficiency, anemia, weakness, and a reduced quality of life.

The CDC notes that von Willebrand disease occurs in men and women with equal frequency, but women are more likely to notice symptoms due to bleeding during menstruation, pregnancy, and after childbirth.

You should consider a possible clotting disorder if your period lasts more than seven days, you have to change pads or tampons very often, you have large clots, you have weakness, dizziness, low ferritin or anemia. In such cases, the examination should not be limited to gynecological reasons.

Preparation for surgery, dentistry, and childbirth

Von Willebrand disease is especially important before procedures where bleeding is possible. A person may not have daily symptoms but may experience a problem after a tooth extraction, surgery, injury, or childbirth.

Before planned interventions, you should inform your doctor if you have previously had:

• prolonged bleeding after dental procedures;
• bleeding after operations;
• severe bruising after injections or injuries;
• heavy menstruation with anemia;
• bleeding after childbirth;
• relatives with von Willebrand disease or other clotting disorders.

The CDC recommends that women with von Willebrand disease during pregnancy undergo testing in the third trimester to measure VWF and factor VIII levels to help plan delivery.

When is a hematologist consultation needed?

A family doctor, pediatrician, gynecologist, or dentist may be the first to suspect a clotting disorder. However, confirming von Willebrand disease and determining its type usually requires the involvement of a hematologist or hemostasis specialist.

You may be referred to a hematologist if:

• there is recurrent bleeding without an obvious cause;
• there are heavy menstruations with anemia;
• basic tests do not explain the symptoms;
• there is a family history of bleeding;
• preparation for surgery is required;
• pregnancy or childbirth is planned;
• special VWF tests gave borderline or conflicting results;
• von Willebrand disease must be distinguished from platelet disorders or hemophilia.

The specialist evaluates not only the numbers on the form. Past bleeding, family history, medications, hormonal status, concomitant diseases, results of repeated tests, and risks of future interventions are also important.

What can distort the diagnostic picture?

Sometimes a patient has typical bleeding, but the results of the first test do not confirm the disease. This does not always mean that there is no problem. The level of von Willebrand factor can be affected by physiological and technical factors.

It is important to inform your doctor about:

• acute infection or inflammation;
• recent surgery or injury;
• pregnancy;
• taking hormonal contraceptives;
• severe stress before the analysis;
• intense physical activity;
• taking medications that affect bleeding;
• anemia;
• previous blood transfusions or treatment with clotting drugs;
• familial cases of bleeding.

The NHLBI notes that stress, surgery, exercise, anxiety, systemic inflammation, pregnancy, or estrogens can increase plasma VWF levels and mask lower baseline values.

What not to do yourself

If you suspect von Willebrand disease, it is dangerous to draw conclusions based on one test or, conversely, ignore symptoms due to a normal coagulogram.

It is not worth it:

• take blood-thinning medications on your own;
• cancel prescribed medications without a doctor;
• take aspirin or anti-inflammatory drugs without consulting a doctor if you have a tendency to bleed;
• ignore heavy menstruation and anemia;
• to plan surgery without a history of bleeding;
• consider a normal coagulogram to be a complete exclusion of the disease;
• interpret borderline results without a hematologist;
• postpone retesting if recommended by a doctor.

Laboratory diagnosis of von Willebrand disease requires accuracy, timing, quality of the sample, and correct interpretation. This is not a case where a single random reading is sufficient.

What does the modern approach to confirming a diagnosis look like?

The modern approach can be described as a combination of three levels.

The first level is the clinical history. The doctor finds out whether there is indeed recurrent bleeding that goes beyond the normal response to trauma.

The second level is a basic laboratory evaluation. It helps to see anemia, platelets, general coagulation parameters and possible alternative causes of bleeding.

The third level is special tests for von Willebrand factor. They allow you to assess the amount of VWF, its activity, its relationship with factor VIII, and, if necessary, to clarify the type of disease.

ASH, ISTH, NHF, and WFH in their recommendations emphasize the use of specific testing, including VWF antigen, platelet-dependent VWF activity, and factor VIII activity, as well as additional tests to clarify the type of disease when necessary.

Von Willebrand disease can be mild, but it is important to detect it before serious bleeding, surgery, childbirth, or repeated complications occur. If a person has frequent bruising, nosebleeds, heavy menstruation, anemia, or bleeding after procedures, it is worth noting that superficial explanations are not enough. Properly selected tests can help to see if there is a deficiency or dysfunction of von Willebrand factor and create a safe plan of action for future medical situations.

Author: Ulyana Anatolyivna Dzyuba

Director of Medi Lab Plus LLC, a doctor of the highest category. Has over 45 years of practical experience in medicine and laboratory diagnostics. Founder and head of the laboratory since 2007. More details…