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:[5]
the A2 domain, which must partially unfold to expose the buried cleavage site for the specific ADAMTS13 protease that inactivates VWF by making much smaller multimers. 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.[8][9]
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.[5]
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 vasculature. The VWF A1 domain (yellow) interacts with the extracellular domain of GP1ba (blue).
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.[5] 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:[5]
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. In the absence of VWF, factor VIII has a half-life of 1–2 hours; when carried by intact VWF, factor VIII has a half-life of 8–12 hours.
VWF binds to collagen, e.g., when collagen is exposed beneath endothelial cells due to damage occurring to the blood vessel. Endothelium also releases VWF which forms additional links between the platelets' glycoprotein Ib/IX/V and the collagen fibrils
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 (i.e., rapid blood flow in narrow blood vessels, see below).
VWF binds to other platelet receptors when they are activated, e.g., by 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.[5] Recent research also suggests that von Willebrand Factor is involved in the formation of blood vessels themselves, which would explain why some people with von Willebrand disease develop vascular malformations (predominantly in the digestive tract) that can bleed excessively.[11]
The biological breakdown (catabolism) of VWF is largely mediated by the enzyme ADAMTS13 (acronym of "adisintegrin-like andmetalloprotease with thrombospondin type 1 motif no. 13"). It is a metalloproteinase that cleaves VWF between tyrosine at position 842 and 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 peptidases.[12]
The half-life of vWF in human plasma is around 16 hours; glycosylation variation on vWF molecules from different individuals result in a larger range of 4.2 to 26 hours. Liver cells as well as macrophages take up vWF for clearance via ASGPRs and LRP1. SIGLEC5 and CLEC4M also recognize vWF.[10]
Higher levels of VWF are more common among people that have had ischemic stroke (from blood-clotting) for the first time.[16] Occurrence is not affected by ADAMTS13, and the only significant genetic factor is the person's blood group. High plasma VWF levels were found to be an independent predictor of major bleeding in anticoagulated atrial fibrillation patients.[17] VWF is a marker of endothelial dysfunction, and is consistently elevated in atrial fibrillation, associated with adverse outcomes.[18]
VWF is named after Erik Adolf von Willebrand, a Finnish physician who in 1926 first described a hereditary bleeding disorder in families from Åland. Although von Willebrand did not identify the definite cause, he distinguished von Willebrand disease (vWD) from hemophilia and other forms of bleeding diathesis.[19]
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.[5]Harvey J. Weiss[20] and coworkers developed a quantitative assay for VWF function that remains a mainstay of laboratory
evaluation for VWD to this day.[21]
Recently, It has been reported that the cooperation and interactions within the von Willebrand Factors enhances the adsorption probability in the primary haemostasis. Such cooperation is proven by calculating the adsorption probability of flowing VWF once it crosses another adsorbed one. Such cooperation is held within a wide range of shear rates.[23]
^Shahidi M (2017). "Thrombosis and von Willebrand Factor". Thrombosis and Embolism: From Research to Clinical Practice. Advances in Experimental Medicine and Biology. Vol. 906. pp. 285–306. doi:10.1007/5584_2016_122. ISBN978-3-319-22107-6. PMID27628010.
^Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, Holmberg L, et al. (October 2006). "Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor". Journal of Thrombosis and Haemostasis. 4 (10): 2103–2114. doi:10.1111/j.1538-7836.2006.02146.x. PMID16889557. S2CID23875096.
^Denorme F, De Meyer SF (September 2016). "The VWF-GPIb axis in ischaemic stroke: lessons from animal models". Thrombosis and Haemostasis. 116 (4): 597–604. doi:10.1160/TH16-01-0036. PMID27029413. S2CID4964177.
