- Von Willebrand factor
Von Willebrand factor (vWF) is a
blood glycoprotein involved inhemostasis . It is deficient or defective invon Willebrand disease and is involved in a large number of other diseases, includingthrombotic thrombocytopenic purpura ,Heyde's syndrome , and possiblyhemolytic-uremic syndrome .cite journal |author=Sadler JE |title=Biochemistry and genetics of von Willebrand factor |journal=Annu. Rev. Biochem. |volume=67 |issue= |pages=395–424 |year=1998 |pmid=9759493 |doi=10.1146/annurev.biochem.67.1.395]Biochemistry
Synthesis
vWF is a large multimeric
glycoprotein present inblood plasma and produced constitutively inendothelium (in the Weibel-Palade bodies),megakaryocyte s (α-granules ofplatelet s), and subendothelialconnective 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 toFactor VIII
* the A1 domain, which binds to:
**platelet GPIb-receptor
**heparin
** possiblycollagen
* the A3 domain, which binds to collagen
* the C1 domain, in which the RGD domain binds to plateletintegrin αIIbβ3 when this is activated
* the "cysteine knot" domain (at the C-terminal end of the protein), which vWF shares withplatelet-derived growth factor (PDGF),transforming growth factor -β (TGFβ) and β-human chorionic gonadotropin (βHCG, ofpregnancy test fame).Monomers are subsequently N-glycosylated, arranged into dimers in the
endoplasmic reticulum and into multimers in theGolgi apparatus by crosslinking ofcysteine residues viadisulfide bond s. With respect to the glycosylation, vWF is one of the few proteins that carryABO 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 is not an
enzyme and therefore has no catalytic activity. Its primary function is binding to other proteins, particularly Factor VIII and it is important in platelet adhesion to wound sites.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 ofthrombin .
* 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 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 appears to play a major role in blood coagulation. vWF deficiency or dysfunction (von Willebrand disease) therefore 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.
Catabolism
The biological breakdown (
catabolism ) of vWF is largely mediated by the proteinADAMTS13 (acronym of "a" "d"isintegrin-like "a"nd "m"etalloprotease with "t"hrombo"s"pondin type 1 motif no. "13"). It is ametalloproteinase which cleaves 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 otherpeptidase s. [cite journal |author=Levy GG, Motto DG, Ginsburg D |title=ADAMTS13 turns 3 |journal=Blood |volume=106 |issue=1 |pages=11–7 |year=2005 |pmid=15774620 |doi=10.1182/blood-2004-10-4097| url=http://bloodjournal.hematologylibrary.org/cgi/content/full/106/1/11]Role in disease
Hereditary or acquired defects of vWF lead to von Willebrand disease (vWD), a
bleeding diathesis of the skin and mucous membranes, causingnosebleed s,menorrhagia , andgastrointestinal bleed ing. The point at which themutation 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. [cite journal |author=Sadler JE, Budde U, Eikenboom JC, "et al" |title=Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor |journal=J. Thromb. Haemost. |volume=4 |issue=10 |pages=2103–14 |year=2006 |pmid=16889557 |doi=10.1111/j.1538-7836.2006.02146.x |url=http://www.blackwell-synergy.com/doi/full/10.1111/j.1538-7836.2005.01681.x] Most cases of vWD are hereditary, but abnormalities to vWF may be acquired;aortic valve stenosis , for instance, has been linked to vWD type IIA, causinggastrointestinal bleeding - an association known asHeyde's syndrome . [cite journal |author=Vincentelli A, Susen S, Le Tourneau T, "et al" |title=Acquired von Willebrand syndrome in aortic stenosis |journal=N. Engl. J. Med. |volume=349 |issue=4 |pages=343–9 |year=2003 |pmid=12878741 |doi=10.1056/NEJMoa022831|url=http://content.nejm.org/cgi/content/full/349/4/343]In
thrombotic thrombocytopenic purpura (TTP) andhemolytic 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 andmicroangiopathic 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. [cite journal |author=Moake JL |title=von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura |journal=Semin. Hematol. |volume=41 |issue=1 |pages=4–14 |year=2004 |pmid=14727254|doi=10.1053/j.seminhematol.2003.10.003]Higher levels of vWF are more common among people that have had ischaemic 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. [cite journal | author = Bongers T, de Maat M, van Goor M, et. al | title = High von Willebrand factor levels increase the risk of first ischemic stroke: influence of ADAMTS13, inflammation, and genetic variability | journal = Stroke | volume = 37 | issue = 11 | pages = 2672–7 | year = 2006|url=http://stroke.ahajournals.org/cgi/content/full/37/11/2672 | doi = 10.1161/01.STR.0000244767.39962.f7 | pmid = 16990571]
History
vWF is named after Dr.
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, includingmenorrhagia . Although von Willebrand could not identify the definite cause, he distinguished von Willebrand disease (vWD) fromhaemophilia and other forms ofbleeding diathesis . [cite journal|author=von Willebrand EA|title=Hereditär pseudohemofili|journal=Fin Läkaresällsk Handl|year=1926|volume=68|pages=87–112 Reproduced in cite journal |author=Von Willebrand EA |title=Hereditary pseudohaemophilia |journal=Haemophilia |volume=5 |issue=3 |pages=223–31; discussion 222 |year=1999 |pmid=10444294 |doi=10.1046/j.1365-2516.1999.00302.x]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.
References
ee also
*
von Willebrand disease
*Bernard-Soulier syndrome PBB_Controls
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