What causes Willebrand's disease?

It has now been established that von Willebrand disease is not a single disease, but a group of related hemorrhagic diatheses caused by a disruption in the synthesis or qualitative anomalies of von Willebrand factor.

Hereditary von Willebrand disease

The cause of hereditary von Willebrand disease is polymorphism of the gene encoding the synthesis of the von Willebrand factor. Hereditary von Willebrand disease is the most common hemorrhagic disease. The frequency of carriage of the defective von Willebrand factor gene in the population reaches 1 in 100 people, but only 10-30% of them have clinical manifestations. It is transmitted by an autosomal dominant or recessive type and occurs in both girls and boys.

Von Willebrand factor is expressed in endothelial cells and megakaryocytes. It is contained in alpha granules of platelets, endothelial cells, plasma and subendothelial matrix. Von Willebrand factor consists of polymers of progressively increasing molecular weight. Light, medium, heavy and superheavy multimers are distinguished with molecular weights from approximately 540 kDa for dimers to several thousand kilodaltons for the largest multimers. The greater the molecular weight of the von Willebrand factor, the greater its thrombogenic potential.

In hemostasis, von Willebrand factor plays a dual role: it mediates the adhesion of platelets to subendothelial structures and mutual adhesion of platelets during thrombus formation, and serves as a “carrier” of factor VIII in plasma, significantly prolonging its circulation time.

Acquired von Willebrand disease

Acquired von Willebrand disease is a hemorrhagic condition that is laboratory and clinically similar to the disorders characteristic of congenital von Willebrand disease. In total, about 300 cases of acquired von Willebrand disease have been described. In children, acquired von Willebrand disease develops against the background of diseases of the heart, blood vessels, connective tissue, systemic and oncological processes.

Pathogenetic mechanisms of formation of von Willebrand factor deficiency:

• specific antibodies to factor VIII/von Willebrand factor;
• non-specific antibodies that form immune complexes and activate the clearance of von Willebrand factor;
• absorption of von Willebrand factor by malignant tumor cells;
• increased proteolytic degradation of von Willebrand factor;
• loss of heavy von Willebrand factor molecules under high shear stress in conditions of active blood flow;
• decreased synthesis or release of von Willebrand factor.

Classification and pathogenesis of von Willebrand disease

There are three types of von Willebrand disease:

1. Type 1 - characterized by a quantitative decrease in the content of von Willebrand factor in the blood of varying severity;
2. Type 2 - characterized by qualitative changes in the von Willebrand factor. There are four subtypes: 2A, 2B, 2M, 2N;
3. Type 3 - almost complete absence of von Willebrand factor in the blood.

Pseudo von Willebrand disease (platelet type) occurs due to increased binding of von Willebrand factor to glycoprotein Ib-IX-V, which is associated with changes in the structure of the latter. This leads to accelerated elimination, first of all, of the most high-molecular complexes of von Willebrand factor from plasma and a disproportionate decrease in its activity compared to the antigen. Moderate thrombocytopenia is possible with the disease. Pseudo von Willebrand disease is phenotypically similar to type 2B von Willebrand disease, but differs from it in the localization of the disorder. For differential diagnosis, it is necessary to perform RIPA with low concentrations of ristomycin. In this test with plasma of a healthy donor and platelets of the patient, aggregation will be observed in a patient with pseudo von Willebrand disease, and in the study with platelets of a healthy donor and plasma of the patient, aggregation will be observed in a patient with von Willebrand disease (type 2B).