Von Willebrand factor is a blood glycoprotein involved in hemostasis. VWF is a large multimeric glycoprotein present in plasma and produced constitutively as ultra-large vWF in endothelium, megakaryocytes. The basic vWF monomer is a 2050-amino acid protein, the partial unfolding is affected by shear flow in the blood, by calcium binding, and by the lump of a sequence-adjacent vicinal disulfide at the A2-domain C-terminus. Monomers are subsequently N-glycosylated, arranged into dimers in the endoplasmic reticulum, with respect to the glycosylation, vWF is one of only a few proteins that carry ABO blood group system antigens. Multimers of vWF can be large, >20,000 kDa. Only the large multimers are functional, some cleavage products that result from vWF production are also secreted but probably serve no function. Von Willebrand factors primary function is binding to proteins, in particular factor VIII. It is not an enzyme and, thus, has no catalytic activity, VWF binds to a number of cells and molecules. The most important ones are, Factor VIII is bound to vWF while inactive in circulation, Factor VIII is released from vWF by the action of thrombin. VWF binds to collagen, e. g. when it is exposed in endothelial cells due to damage occurring to the blood vessel, VWF binds to other platelet receptors when they are activated, e. g. by thrombin. VWF plays a role in blood coagulation. Therefore, vWF deficiency or dysfunction leads to a bleeding tendency, from studies it appears that vWF uncoils under these circumstances, decelerating passing platelets. The biological breakdown of vWF is largely mediated by the enzyme ADAMTS13 and it is a metalloproteinase that cleaves vWF between tyrosine at position 842 and methionine at position 843 in the A2 domain. This breaks down the multimers into smaller units, which are degraded by other peptidases, hereditary or acquired defects of vWF lead to von Willebrand disease, a bleeding diathesis of the skin and mucous membranes, causing nosebleeds, menorrhagia, and gastrointestinal bleeding. The point at which the mutation occurs determines the severity of the bleeding diathesis, there are three types, and type II is further divided in several subtypes. Treatment depends on the nature of the abnormality and the severity of the symptoms, in thrombotic thrombocytopenic purpura and hemolytic uremic syndrome, ADAMTS13 either is deficient or has been inhibited by antibodies directed at the enzyme. This leads to decreased breakdown of the ultra-large multimers of vWF and microangiopathic hemolytic anemia with deposition of fibrin and platelets in small vessels, in TTP, the organ most obviously affected is the brain, in HUS, the kidney. Higher levels of vWF are more common people that have had ischemic stroke for the first time
VWF monomer and multimers
The interaction of vWF and GP1b alpha. The GP1b receptor on the surface of platelets allows the platelet to bind to vWF, which is exposed upon damage to vasulature. The vWF A1 domain (yellow) interacts with the extracellular domain of GP1ba (blue).