Von Willebrand factor is a blood glycoprotein involved in hemostasis.
It is deficient or defective in von Willebrand disease and is involved in a large number
of other diseases, including thrombotic thrombocytopenic purpura, Heyde's syndrome, and possibly 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 endothelium, and may
contribute to an increased risk of thrombosis.
Biochemistry Synthesis
vWF is a large multimeric glycoprotein present in blood plasma and produced constitutively
as ultra-large vWF in endothelium, megakaryocytes, and subendothelial connective tissue.
Structure The basic vWF monomer is a 2050-amino acid
protein.
Every monomer contains a number of specific domains with a specific function; elements
of note are: the D'/D3 domain, which binds to factor VIII,
the A1 domain, which binds to: platelet GPIb-receptor
heparin possibly collagen
the A3 domain, which binds to collagen the C1 domain, in which the RGD domain binds
to platelet integrin αIIbβ3 when this is activated
the "cysteine knot" domain, which vWF shares with platelet-derived growth factor, transforming
growth factor-β and β-human chorionic gonadotropin.
Monomers are subsequently N-glycosylated, arranged into dimers in the endoplasmic reticulum
and into multimers in the Golgi apparatus by crosslinking of cysteine residues via disulfide
bonds.
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 extremely large, >20,000 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 factor VIII, and it is important in platelet adhesion
to wound sites.
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 degrades rapidly when not bound to vWF.
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 platelet gpIb when it forms a complex with gpIX and gpV; this binding occurs
under all circumstances, but is most efficient under high shear stress.
vWF binds to other platelet receptors when they are activated, e.g., by thrombin.
vWF plays a major role in blood coagulation.
Therefore, vWF deficiency or dysfunction 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 of vWF is largely
mediated by the enzyme ADAMTS13.
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.
Role in disease
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.
Most cases of vWD are hereditary, but abnormalities of vWF may be acquired; aortic valve stenosis,
for instance, has been linked to vWD type IIA, causing gastrointestinal bleeding - an
association known as Heyde's syndrome.
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, 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 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. Erik von Willebrand,
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
menorrhagia.
Although von Willebrand could not identify the definite cause, he distinguished von Willebrand
disease from hemophilia and other forms of bleeding diathesis.
In the 1950s, vWD was shown to be caused by a plasma factor deficiency, and, in the 1970s,
the vWF protein was purified.
Interactions Von Willebrand factor has been shown to interact
with Collagen, type I, alpha 1.
See also Von Willebrand disease
Bernard-Soulier syndrome References
External links GeneReviewsNIH/UW entry on von Willebrand
Factor Deficiency.
Includes: Type 1 von Willebrand Disease, Type 2A von Willebrand Disease, Type 2B von Willebrand
Disease, Type 2M von Willebrand Disease, Type 2N von Willebrand Disease, Type 3 von Willebrand
Disease