Von Willebrand Disease: Diagnosis, Treatment Advances, and Acquired Forms

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• Diagnosing Von Willebrand Disease
• Treatment Options: Desmopressin
• Treatment Options: Plasma Products
• New VWF Concentrates
• Acquired Von Willebrand Disease
• MGUS and Bleeding
• Thrombocythemia and VWD
• Full Transcript

Diagnosing Von Willebrand Disease

Von Willebrand disease is the most common inherited bleeding disorder. Dr. Pier Mannucci, MD, emphasizes that its diagnosis is complex and requires sophisticated laboratory techniques. He advises that patients with a suspected bleeding disorder should be referred to a specialist center for evaluation.

Accurate diagnosis involves measuring von Willebrand factor antigen, assessing platelet-associated von Willebrand factor properties, and crucially, measuring coagulation Factor VIII levels. Dr. Mannucci, MD, explains that a secondary deficiency of Factor VIII occurs in von Willebrand disease because von Willebrand factor acts as its chaperone in circulation.

Treatment Options: Desmopressin

Desmopressin is a key non-plasma-based treatment for von Willebrand disease. Dr. Pier Mannucci, MD, notes that this synthetic drug stimulates the release of endogenous von Willebrand factor and Factor VIII from cellular stores.

This treatment is highly effective but has specific limitations. Dr. Mannucci, MD, clarifies that desmopressin can only be used in patients who produce some functional von Willebrand factor and is not suitable for very severe forms of the disease.

Treatment Options: Plasma Products

Plasma-derived products remain a mainstay of treatment for von Willebrand disease. These medications contain both von Willebrand factor and Factor VIII, effectively replacing both deficient proteins.

Dr. Pier Mannucci, MD, describes these products as representing the state of the art in therapy. They are particularly essential for patients with severe disease who cannot use desmopressin, providing a reliable method for controlling and preventing bleeding episodes.

New VWF Concentrates

The most recent advancement is the development of recombinant von Willebrand factor concentrates. Dr. Pier Mannucci, MD, explains that these products replace only the primary deficient protein, von Willebrand factor.

This is a significant advantage. Fortunately, as Dr. Mannucci, MD, tells Dr. Anton Titov, MD, endogenous Factor VIII levels rise a few hours after infusion because its production is genetically normal in von Willebrand disease patients.

Acquired Von Willebrand Disease

Acquired von Willebrand disease is not caused by a genetic defect. Instead, Dr. Pier Mannucci, MD, describes it as a condition where something removes or destroys von Willebrand factor in the circulation during a patient's life.

This form is always secondary to another underlying disorder. Dr. Mannucci, MD, identifies monoclonal gammopathy of uncertain significance (MGUS) and essential thrombocythemia as two of the most frequent causes of this acquired bleeding disorder.

MGUS and Bleeding

Monoclonal gammopathy of uncertain significance (MGUS) can lead to acquired von Willebrand disease. Dr. Pier Mannucci, MD, explains that the abnormal immunoglobulin protein produced in MGUS can absorb von Willebrand factor from the blood.

This absorption mechanism removes the crucial clotting factor from circulation. Consequently, a patient with otherwise benign MGUS may present with a significant bleeding problem as their primary symptom.

Thrombocythemia and VWD

Essential thrombocythemia is another major cause of acquired von Willebrand disease. In this myeloproliferative disorder, platelet counts can soar above one million, a state Dr. Pier Mannucci, MD, refers to as "platelet billionaires".

This extreme number of platelets absorbs the available von Willebrand factor. Dr. Mannucci, MD, notes that treatment focuses on reducing the platelet count to normal levels, which subsequently corrects the von Willebrand factor deficiency and stops the bleeding.

Full Transcript

Dr. Anton Titov, MD: Von Willebrand disease is the most common inherited bleeding disorder. What is new in the diagnosis and treatment of von Willebrand disease?

Dr. Pier Mannucci, MD: Von Willebrand disease generates a lot of interest for its frequency, but it is certainly less severe than hemophilia A and hemophilia B. However, it is much more frequent, so that's why such high interest is generated. It is also because the phenotype of von Willebrand disease is rather complex. It is not easy to diagnose von Willebrand disease.

These patients, when there is a suspicion, should be referred to a specialist center. The average laboratory and also the average hematology unit are usually not particularly conversant with the sophisticated techniques that are needed for the diagnosis of von Willebrand disease.

The tests have improved, but they are still based on the measurement of von Willebrand factor antigen and also the platelet-associated von Willebrand factor properties. There are several tests that can be used; they are all more or less useful.

It is also very important to see the level of factor VIII because in von Willebrand disease, there is not only a deficiency of von Willebrand factor, but there's also a secondary deficiency of coagulation factor VIII. It is as in hemophilia, but it is for a reason different from hemophilia because the factor VIII gene functions very well and the production of the protein is normal.

The only problem is that in von Willebrand disease, the chaperone of factor VIII is in the circulation. When the von Willebrand factor is deficient or dysfunctional, factor VIII decreases. So patients with von Willebrand disease are also deficient in factor VIII.

In diagnosing von Willebrand disease, you should also measure factor VIII. As far as the treatment is concerned, one should consider a few factors. Von Willebrand factor is important, but also the associated concomitant factors, albeit they are secondary, also factor VIII.

Patients with von Willebrand disease enjoy excellent treatment. There are medications that contain plasma-derived products; they contain both factor VIII and von Willebrand factor to replace both deficient factors. Those medications have been used for many years. They represent the state of the art, and probably still, these drugs are the mainstay of treatment.

There is also desmopressin. It was actually first described by us in Italy. Desmopressin is a synthetic drug that is released into circulation. It is endogenous factor VIII; von Willebrand factor is contained in cellular stores. So desmopressin can be used to treat von Willebrand disease without resorting to the use of plasma products.

But desmopressin can be used only in patients that produce some small amount of von Willebrand factor and also factor VIII. So desmopressin cannot be used in a very severe form of von Willebrand disease. Then you have to use the replacement therapy with a plasma-derived product containing both von Willebrand factor and factor VIII, which are deficient.

The most recent novelty is the advent of the von Willebrand replacement product that replaces the von Willebrand factor and not factor VIII. This is an advantage because, of course, von Willebrand disease is the primary deficiency of the von Willebrand factor. But you have to take into account that factor VIII is also deficient.

Fortunately enough, if you infuse into these patients von Willebrand factor, after three or four hours, factor VIII is produced endogenously by the individual. Because, as I said, in von Willebrand disease, there is no defect in factor VIII protein. So von Willebrand factor-only concentrates are the last resource in the armamentarium for treatment of von Willebrand disease.

They have some indications, but on the whole, we have a broad number of products that can be used as a treatment of von Willebrand disease. It is a very satisfactory treatment in the congenital form of von Willebrand disease.

Dr. Anton Titov, MD: As you mentioned, most von Willebrand disease cases are inherited. But there is also an acquired form of von Willebrand disease. What is an acquired form of von Willebrand disease?

Dr. Pier Mannucci, MD: An acquired form of von Willebrand disease is because there is no defect in the von Willebrand gene as it is in inherited congenital von Willebrand disease. But there is something that happens during the life of a patient with acquired von Willebrand disease. Something removes the von Willebrand factor from the blood circulation, or something destroys it.

A typical example is two hematological diseases that are rather frequent. One is monoclonal gammopathy of uncertain significance, MGUS. These individuals usually are happy; they have no special problems. The abnormal protein that they produce may pick up; it may absorb the von Willebrand factor and remove it from the circulation.

In a sense, the monoclonal protein is an immunoglobulin. It captures the von Willebrand factor from the circulation, and that's how the patient with these abnormalities (MGUS) develops acquired von Willebrand disease. This situation usually is quite benign. Once upon a time, it was called benign monoclonal gammopathy; now it is called monoclonal gammopathy of uncertain significance (MGUS).

So that's why they become deficient in von Willebrand factor, and they bleed. Patients who have MGUS sometimes have no problem except the problem of bleeding because the abnormal protein is absorbing the von Willebrand factor.

Another typical example is when platelets are in the myeloproliferative disorder, particularly essential thrombocythemia. In this disease, you can become a millionaire of platelets. Platelets can go above 1 million in blood circulation. Platelets can cause, on one side, thrombosis, but also platelets can cause bleeding because a huge number of platelets tend to absorb the von Willebrand factor in the blood circulation.

So patients with essential thrombocythemia or myeloproliferative disorder become secondarily deficient in available von Willebrand factor. The treatment is to decrease the platelet count within the normal limits. In this way, also the abnormality of the von Willebrand factor is corrected because it is strictly related to the number of platelets. It is a problem of platelet billionaires, as I call them.

There are other causes of acquired von Willebrand disease, but these causes are probably the most frequent. In general, acquired von Willebrand disease is secondary to another disease. There are cardiac diseases; a patient could be carrying abnormal mechanical valves in the heart. But I think the mechanism is the absorption or destruction of available von Willebrand factor on other proteins or on other cells.

So the defect in the von Willebrand factor is not impaired at the gene level, but it does appear deficient in the circulation.