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The condition known as von Willebrand disease is the result of reduction in the plasma levels of, or the production of a defective form of, the coagulation factor known as von Willebrand factor (vWF). This is a large glycoprotein made up of many monomers.
Its main function is to bind plasma proteins, and in particular factor VIII. When unbound, factor VIII rapidly catabolizes. vWF binds to exposed endothelium as well as to activated platelet receptors, uncoiling and slowing down the platelets to begin forming a platelet clot, which is the initial step in the coagulation process.
There are two categories of the disease, inherited and acquired. The inherited forms comprise types 1 to 3, and type 2 is subdivided further into 2A, 2B, 2M and 2N. Each type varies according to the type and intensity of defect in vWF.
Since vWF is activated only under conditions of high blood flow and shear stress, organs that have many small vessels, and therefore slow flow, do not have adequate levels of this factor.
Type 1
Genetically, vWF is altered such that the level of the factor is low. The mutations interfere with the intracellular transport of the subunits of this glycoprotein, in the dominant severe type 1.
Another mechanism is the rapid clearance of the factor from the plasma, leading to a shorter cleavage time of the multimer in circulation by ADAMTS-13. As a result, the distribution pattern of the multimer changes. The end result is a fall in vWF activity.
Type 2
Here the plasma vWF level is normal but it is structurally and functionally defective. The type of defect is the basis for further subclassification:
Type 2A
This type shows decreased platelet adhesion mediated by deficiency of high molecular weight vWF multimers in circulation. This reduction may be due to either a defect in the assembly of the multimers or increase in the rate of multimer cleavage. The former is caused by mutations, either homozygous or heterozygous, which prevent multimer formation in the Golgi apparatus.
Type 2B
Here large multimers are markedly reduced in circulation, while the rate of catabolism is high. This is due to a mutation that allows normal multimerization to occur in the Golgi apparatus, but results in the binding of the secreted multimers to the platelets where they are cleaved by ADAMTS-3.
This causes failure of effective platelet adhesion by the abnormally small multimers, with subsequent failure to bind to connective tissue.
Type 2M
In this type, vWF-dependent platelet adhesion is reduced despite a normal level of high molecular weight multimers in plasma. This is due to normal secretion and assembly of multimers, but mutation-dependent loss of function which prevents normal binding of vWF to the platelets.
This exposes less of the multimer to the cleaving enzyme ADAMTS-13, leading to a persistence of large multimers in a distribution that is almost identical to that when they were originally secreted by endothelial cells.
Type 2N
This type is characterized by a very low binding affinity of vWF for factor VIII. Both homozygous and heterozygous mutations responsible for this defect have been recognized. Both alleles may be affected in some cases, but this is rare. The failure to bind factor VIII leads to its rapid catabolism, so that plasma levels of factor VIII are very low.
Type 3
This form is caused by a recessive mutation which results in an almost total absence of vWF, which is why it is often termed severe vWD.
This is due to rapid clearance of von Willebrand factor from the plasma after it forms a complex with its antibody. This may be due to its adhesion to tumor cells, or due to the presence of vWF antibodies which disrupt the multimer, or even slow digestion of the protein, and is also seen in patients with aortic stenosis.