VWF is synthesized as a prepropeptide comprising 2813 amino acids inendothelial cells andmegakaryocytes. The prepropeptide includes a 22-amino acid signal peptide (SP), a 741-amino acid propeptide (VWFpp), and a 2050-amino acid mature VWF monomer. The signal peptide directs the prepropeptide to the endoplasmic reticulum, where it is cleaved, resulting in the formation of pro-VWF. Pro-VWF undergoes glycosylation, forms disulfide bonds, and dimerizes under neutral pH and the influence of Protein Disulfide Isomerase A1 (PDIA1).
Dimerized pro-VWF is then transported to the Golgi apparatus, where it forms "dimeric bouquets" and undergoes further glycosylation. The propeptide is cleaved byfurin, but remains associated with the mature VWF in a non-covalent manner. This association persists until the propeptide dissociates, yielding mature VWF monomers, which subsequently dimerize and multimerize. Although the fundamental structure of mature VWF is monomeric, the smallest form detectable in blood plasma is a VWF dimer.
The basic monomer of VWF, a 2050-amino acid protein, contains several key domains with specific functions:
The D'/D3 domain: Binds tofactor VIII, heparin, and P-selectin.
The A2 domain: Unfolds to expose the cleavage site forADAMTS13 protease, which cleaves VWF into smaller multimers. Unfolding is influenced by blood shear flow, calcium binding, and a "vicinal disulfide" at the A2-domain’s C-terminus.
The A3 domain: Acts as the primary collagen binding site for VWF, binding to collagen types I and III.
The CK (cystine knot) domain at the protein’s C-terminal end: Involved in VWF dimerization.
VWF is one of the few proteins carrying ABO blood group antigens. After glycosylation in the Golgi apparatus, VWF is packaged into storage granules, Weibel-Palade bodies (WPBs) in endothelial cells, and α-granules in platelets.[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 particularfactor VIII, and it is important inplatelet adhesion to wound sites.[5] It is not anenzyme 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 ofthrombin. 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 beneathendothelial 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 plateletGpIb when it forms a complex withgpIX andgpV; this binding occurs under all circumstances, but is most efficient under highshear stress (i.e., rapid blood flow in narrow blood vessels, see below).
VWF binds to other platelet receptors when they are activated, e.g., bythrombin (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 flowshear 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 theformation of blood vessels themselves, which would explain why some people with von Willebrand disease develop vascular malformations (predominantly in thedigestive tract) that canbleed excessively.[7]
The biological breakdown (catabolism) of VWF is largely mediated by the enzymeADAMTS13 (acronym of "adisintegrin-likeandmetalloprotease withthrombospondin type 1 motif no.13"). It is ametalloproteinase thatcleaves VWF betweentyrosine at position 842 andmethionine 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 otherpeptidases.[8]
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 asmacrophages take up vWF for clearance viaASGPRs andLRP1.SIGLEC5 andCLEC4M also recognize vWF.[9]
Higher levels of VWF are more common among people that have hadischemic stroke (from blood-clotting) for the first time.[13] Occurrence is not affected by ADAMTS13, and the only significant genetic factor is the person'sblood group. High plasma VWF levels were found to be an independent predictor of major bleeding in anticoagulatedatrial fibrillation patients.[14] VWF is a marker ofendothelial dysfunction, and is consistently elevated in atrial fibrillation, associated with adverse outcomes.[15]
VWF is named afterErik Adolf von Willebrand, a Finnish physician who in 1926 first described a hereditary bleeding disorder in families fromÅland. Although von Willebrand did not identify the definite cause, he distinguished von Willebrand disease (vWD) fromhemophilia and other forms ofbleeding diathesis.[16]
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[17] and coworkers developed a quantitative assay for VWF function that remains a mainstay of laboratoryevaluation for VWD to this day.[18]
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.[20]
^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.
