Von Willebrand factor

Von Willebrand factor (vWF) is a is_associated_with::blood is_associated_with::glycoprotein involved in is_associated_with::hemostasis. It is deficient or defective in is_associated_with::von Willebrand disease and is involved in a large number of other diseases, including is_associated_with::thrombotic thrombocytopenic purpura, is_associated_with::Heyde's syndrome, and possibly is_associated_with::hemolytic-uremic syndrome. Increased plasma levels in a large number of cardiovascular, neoplastic, and connective tissue diseases are presumed to arise from adverse changes to the is_associated_with::endothelium, and may contribute to an increased risk of is_associated_with::thrombosis.

Synthesis
vWF is a large multimeric is_associated_with::glycoprotein present in is_associated_with::blood plasma and produced constitutively as ultra-large vWF in is_associated_with::endothelium (in the Weibel-Palade bodies), is_associated_with::megakaryocytes (α-granules of is_associated_with::platelets), and subendothelial is_associated_with::connective tissue.

Structure
The basic vWF is_associated_with::monomer is a 2050-is_associated_with::amino acid protein. Every monomer contains a number of specific domains with a specific function; elements of note are: Monomers are subsequently N-glycosylated, arranged into dimers in the is_associated_with::endoplasmic reticulum and into multimers in the is_associated_with::Golgi apparatus by crosslinking of is_associated_with::cysteine residues via is_associated_with::disulfide bonds. With respect to the glycosylation, vWF is one of only a few proteins that carry is_associated_with::ABO blood group system antigens.
 * the D'/D3 domain, which binds to is_associated_with::factor VIII, (is_associated_with::Von Willebrand factor type D domain)
 * the A1 domain, which binds to:
 * is_associated_with::platelet GPIb-receptor
 * is_associated_with::heparin
 * possibly is_associated_with::collagen
 * the A3 domain, which binds to collagen (is_associated_with::Von Willebrand factor type A domain)
 * the C1 domain, in which the RGD domain binds to platelet is_associated_with::integrin αIIbβ3 when this is activated
 * the "cysteine knot" domain (at the C-terminal end of the protein), which vWF shares with is_associated_with::platelet-derived growth factor (PDGF), is_associated_with::transforming growth factor-β (TGFβ) and β-is_associated_with::human chorionic gonadotropin (βHCG, of is_associated_with::pregnancy test fame). (is_associated_with::Von Willebrand factor type C domain)

Multimers of vWF can be extremely large, &gt;20,000 is_associated_with::kDa, and consist of over 80 subunits of 250 kDa each. Only the large multimers are functional. Some cleavage products that result from vWF production are also secreted but probably serve no function.

Function
Von Willebrand factor's primary function is binding to other proteins, in particular is_associated_with::factor VIII, and it is important in platelet adhesion to wound sites. It is not an is_associated_with::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 degrades rapidly when not bound to vWF. Factor VIII is released from vWF by the action of is_associated_with::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 platelet is_associated_with::gpIb when it forms a complex with is_associated_with::gpIX and is_associated_with::gpV; this binding occurs under all circumstances, but is most efficient under high is_associated_with::shear stress (i.e., rapid blood flow in narrow blood vessels, see below).
 * vWF binds to other platelet receptors when they are activated, e.g., by is_associated_with::thrombin (i.e., when coagulation has been stimulated).

vWF plays a major role in blood coagulation. Therefore, vWF deficiency or dysfunction (von Willebrand disease) leads to a bleeding tendency, which is most apparent in tissues having high blood flow shear in narrow vessels. From studies it appears that vWF uncoils under these circumstances, decelerating passing platelets. Calcium enhances the refolding rate of vWF A2 domain, allowing the protein to act as a shear force sensor.

Catabolism
The biological breakdown (is_associated_with::catabolism) of vWF is largely mediated by the enzyme is_associated_with::ADAMTS13 (acronym of "a disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13"). It is a is_associated_with::metalloproteinase that cleaves vWF between is_associated_with::tyrosine at position 842 and is_associated_with::methionine at position 843 (or 1605–1606 of the gene) in the A2 domain. This breaks down the multimers into smaller units, which are degraded by other is_associated_with::peptidases.

Role in disease
Hereditary or acquired defects of vWF lead to is_associated_with::von Willebrand disease (vWD), a is_associated_with::bleeding diathesis of the skin and mucous membranes, causing is_associated_with::nosebleeds, is_associated_with::menorrhagia, and is_associated_with::gastrointestinal bleeding. The point at which the is_associated_with::mutation occurs determines the severity of the bleeding diathesis. There are three types (I, II and III), and type II is further divided in several subtypes. Treatment depends on the nature of the abnormality and the severity of the symptoms. Most cases of vWD are hereditary, but abnormalities of vWF may be acquired; is_associated_with::aortic valve stenosis, for instance, has been linked to vWD type IIA, causing is_associated_with::gastrointestinal bleeding - an association known as is_associated_with::Heyde's syndrome.

In is_associated_with::thrombotic thrombocytopenic purpura (TTP) and is_associated_with::hemolytic uremic syndrome (HUS), 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 is_associated_with::microangiopathic hemolytic anemia with deposition of fibrin and platelets in small vessels, and capillary necrosis. In TTP, the organ most obviously affected is the brain; in HUS, the kidney.

Higher levels of vWF are more common among people that have had ischemic stroke (from blood-clotting) for the first time. Occurrence is not affected by ADAMTS13, and the only significant genetic factor is the person's blood group.

History
vWF is named after Dr. is_associated_with::Erik von Willebrand (1870–1949), a Finnish doctor who in 1924 first described a hereditary bleeding disorder in families from the Åland islands, who had a tendency for cutaneous and mucosal bleeding, including is_associated_with::menorrhagia. Although von Willebrand could not identify the definite cause, he distinguished von Willebrand disease (vWD) from is_associated_with::hemophilia and other forms of is_associated_with::bleeding diathesis.

In the 1950s, vWD was shown to be caused by a plasma factor deficiency (instead of being caused by platelet disorders), and, in the 1970s, the vWF protein was purified.

Interactions
Von Willebrand factor has been shown to interact with is_associated_with::Collagen, type I, alpha 1.