Von Willebrand disease is the most common inherited bleeding disorder. What is new in the diagnosis and treatment of von Willebrand disease?

Von Willebrand disease generates a lot of interest for its frequency. But it is certainly less severe than Haemophilia A and Haemophilia B. But it is much more frequent. So that's why such high interest is generated. But it is also because the phenotype of von Willebrand disease is rather complex. It is not easy to diagnose von Willebrand's disease. So, these patients, when there is a suspicion, should be referred to a specialist center. Because the average laboratory and also the average hematology unit are usually are not particularly conversant with the sophisticated techniques that are needed for the diagnosis of von Willebrand disease. The tests have improved, but that they are still based on the measurement of von Willebrand factor, von Willebrand 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. But also it is 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 for 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 also are deficient in Factor VIII. So, 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 the factor VIII.

Patients with von Willebrand disease enjoy the 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 disease 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 eight 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 disease factor only concentrates the last resource in the armamentarium or 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.

Well, as you mentioned, most of von Willebrand's disease cases are inherited. But there is also an acquired form of von Willebrand disease. What is an acquired form of von Willebrand disease?

An acquired form of von Willebrand disease is because 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. So, 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 a von Willebrand factor, and they bleed. So 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. And 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. They are, 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.