Von Willebrand factor

A large multimeric glycoprotein that performs two critical functions in hemostasis: it acts as a bridging molecule at sites of vascular injury for normal platelet adhesion, and under high shear conditions, it promotes platelet aggregation.

VWF also acts as a carrier for factor VIII in the circulation, maintaining the normal level of factor VIII by increasing the half-life of factor VIII fivefold.

The WF stabilizes factor VIII by binding, and therefore the natural half-life of factor VIII is limited by the ceiling effect to approximately 18 hours.

von Willebrand disease (VWD) a bleeding disorder occurs when VWF is deficient or qualitatively abnormal.

Normally, when von Willebrand factor changes conformation into its active state, it is degraded by its natural catabolic enzyme ADAMTS13, rendering it incapable of binding the collagen at an injury site.

As the quantity of von Willebrand factor in the blood decreases, the rate of bleeding dramatically increases.

VWD is the most common of the inherited bleeding disorders, with an estimated prevalence in the general population of 1 percent by laboratory testing.

Symptomatic VWD is less common, approximately 0.01 percent.

Although it is primarily a congenital disorder, there are also acquired forms of the disease.

The gene for VWF is located on the short arm of chromosome 12 and is composed of 178 kilobases (kb) and 52 exons

Von Willebrand factor is synthesized in endothelial cells and megakaryocytes as a primary translation product of 2813 amino acids.

Von Willebrand factor is synthesized in the walls of the blood vessels and circulates freely in the blood in a folded form. 

When it encounters damage to the wall of a blood vessel, particularly in situations of high velocity blood flow, it binds to the collagen beneath the damaged endothelium and uncoils into its active form. 

After synthesis, endothelial cells store von Willebrand factor is ultralarge multimers and Weibel-Palade bodies.

ABO antigens  are expressed on the von Willebrand factor (vWF) glycoprotein.

On stimulation of endothelial cells by sheer stress, catecholamines, cytokines, or histamine, ultralarge von Willebrand factor multimeter are secreted and either remain attached to the end endothelial surface or released into the circulation.

Shear conditions of flowing blood unfold freshly released ultralarge von Willebrand factor multimers, exposing the otherwise cryptic platelet binding sites in the von Willebrand factor A1 domains and the ADAMTS13 cleavage sites in the von Willebrand factor A2 domains.

Cleavage of von Willebrand factor to smaller sizes by ADAMTS 13 decreases its capacity of supporting platelet adhesion for hemostasis.

In the absence of ADAMTS 13, shear stress increases the activity of von Willebrand factor instead, presumably by exposing its binding site in the A1 domain to platelet receptor 1b.

It subsequently undergoes dimerization and multimerization to very large forms.

Plasma VWF levels are known to vary significantly over time,

It is recommended repeat testing to demonstrate consistency in levels prior to making a diagnosis.

Plasma VWF levels are 25% lower in blood group O individuals compared with non-O individuals.

Higher levels of vWF are more common amongst people who have had ischemic stroke for the first time.

Plasma VWF levels vary according to the menstrual cycle and can be affected by use of the combined oral contraceptives

Interestingly, plasma VWF levels also exhibit diurnal rhythm, with peak levels at midday and an amplitude of 22%.

The normal range for plasma VWF:Ag levels is 50 to 200 IU/dL, by definition, 2.5% of the normal population will also have VWF levels < 50 IU/dL.

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