The condition known as von Willebrand disease (vWD) is the result of a 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.
What is vWF?
The main function of vWF is to bind plasma proteins and, in particular, factor VIII. When unbound, factor VIII rapidly catabolizes. vWF binds to both exposed endothelium and activated platelet receptors, which uncoils and slows down the platelets that are beginning to form a platelet clot, which is the initial step in the coagulation process.
Types of vWD
There are two categories of vWD, which include inherited vWD and acquired vWD. The inherited forms comprise types 1 to 3, with type 2 vWD being subdivided further into 2A, 2B, 2M, and 2N. Each type of inherited vWD varies according to the type and intensity of the 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 typically have a slow blood flow, do not have adequate levels of this factor.
Pathophysiology of inherited forms of vWD
Type 1 vWD
Genetically, vWF is altered such that the level of the factor is low. In the dominant severe type 1 vWD, genetic mutations interfere with the intracellular transport of the subunits of this glycoprotein.
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, which leads to a fall in vWF activity.
Type 2 vWD
In type 2 vWD, the plasma vWF level is normal but is structurally and functionally defective. The type of defect is the basis for further subclassification.
Type 2A vWD
Type 2A vWD causes decreased platelet adhesion that is mediated by a 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 an 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 vWD
In type 2 vWD, 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 vWD
In type 2M vWD, 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 a mutation-dependent loss of function that prevents the normal binding of vWF to the platelets.
This inability of vWF to bind to platelets exposes less of the multimer to the cleaving enzyme ADAMTS-13, which leads to the persistence of large multimers in distribution that is almost identical to that when they were originally secreted by endothelial cells.
Type 2N vWD
Type 2N vWD 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, thereby causing plasma levels of factor VIII to be very low.
Type 3 vWD
Type 3 vWD form is caused by a recessive mutation which results in an almost total absence of vWF, which is why this type is often termed severe vWD.
Acquired vWD
Acquired vWD is due to the rapid clearance of vWF from the plasma after it forms a complex with its antibody. This may be due to its adhesion to tumor cells, the presence of vWF antibodies that disrupt the multimer, or even slow digestion of the protein. Notably, acquired vWD can be seen in patients with aortic stenosis.
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