Disease relevance of VWF

• Alterations in the intrinsic properties of the GPIbalpha-VWF tether bond define the kinetics of the platelet-type von Willebrand disease mutation, Gly233Val [1].
• Furthermore, it could provide a tool to investigate the role of VWF in the development of thrombocytopenia in various diseases [2].
• The level of VWF-cleaving protease activity in the patient was remarkably low (<5%) throughout her disease, even after she entered complete remission [3].
• The patient was deficient in plasma high molecular weight (HMW)-VWF multimers during acute disease but had increased amounts of the HMW-VWF multimers during periods of remission [3].
• In fact, VWF level also correlates with thrombosis risk and inversely with bleeding risk within the apparently healthy population [4].
• Anti-beta(2) GPI antibodies isolated from a subset of antiphospholipid syndrome patients neutralized the beta(2) GPI-VWF interactions and thus the inhibitory activity of beta(2) GPI [5].
• There were no thrombotic complications and none of the 18 patients with type 3 VWD developed anti-VWF or anti-FVIII antibodies [6].

Psychiatry related information on VWF

• Release of both t-PA and VWF from the same storage pool likely accounts for the coordinate increase in the plasma level of the 2 proteins in response to numerous stimuli, such as physical activity, beta-adrenergic agents, and 1-deamino-8d-arginine vasopressin (DDAVP) among others [7].
• We recently identified ABO(H) blood group structures in Asn-linked sugar chains of human von Willebrand factor (vWF) purified from factor VIII concentrates (J Biol Chem 267:8723, 1992) [8].
• The superfamily of proteins with von Willebrand factor type A-like domains: one theme common to components of extracellular matrix, hemostasis, cellular adhesion, and defense mechanisms [9].
• Relationship between human development and disappearance of unusually large von Willebrand factor multimers from plasma [10].
• Age, psychosocial stress, unhealthful life style, atherogenic biochemical factors, and hypertension mediated the association of low educational level with elevated levels of fibrinogen and vWF [11].

High impact information on VWF

• VWF also is a carrier protein for blood clotting factor VIII, and this interaction is required for normal factor VIII survival in the circulation [12].
• VWF mediates the adhesion of platelets to sites of vascular damage by binding to specific platelet membrane glycoproteins and to constituents of exposed connective tissue [12].
• Other VWD mutations impair the survival of VWF in plasma or the function of specific ligand binding sites [12].
• Biochemistry and genetics of von Willebrand factor [12].
• In addition, ion channels may be involved in the regulation of the traffic of macromolecules by endocytosis, transcytosis, the biosynthetic-secretory pathway, and exocytosis, e.g., tissue factor pathway inhibitor, von Willebrand factor, and tissue plasminogen activator [13].

Chemical compound and disease context of VWF

• A novel mutation, R1308L (3923G > T) was present in the heterozygous state in five members of a family with type 2B von Willebrand disease (VWD) characterized by a full set of von Willebrand factor (VWF) multimers in plasma and by the absence of thrombocytopenia before and after desmopressin (DDAVP) [14].
• The interaction of the glycoprotein (GP) Ib-IX-V complex with von Willebrand factor (vWF) is critical in initiation of haemostasis and thrombosis through platelet adhesion to damaged endothelium [15].
• Functional characteristics, including vWF release upon histamine stimulation and upregulated expression of VEGF and VEGF type 1 receptor in response to hypoxia, were indistinguishable between the MOMC-derived endothelial-like cells and cultured mature endothelial cells [16].
• We analyzed the association of bleeding severity with candidate gene haplotypes within pedigrees of 11 index cases of von Willebrand disease (VWD) type 2 (two type 2A, three type 2B and six type 2M), using the QTL Association model (MENDEL 5.5) [17].
• When expressed in a baculovirus system, recombinant VWF CK domains (residues 1957-2050) were secreted as dimers that were converted to monomers by selective reduction and alkylation of three unconserved cysteine residues: Cys(2008), Cys(2010), and Cys(2048) [18].

Biological context of VWF

• Shear-induced platelet aggregation (SIPA) involves the sequential interaction of von Willebrand factor (VWF) with both glycoprotein Ib (GPIb) and alphaIIbbeta3 receptors [19].
• Bombay phenotype is associated with reduced plasma-VWF levels and an increased susceptibility to ADAMTS13 proteolysis [20].
• An inverse correlation between activated VWF levels and platelet count was observed (R2 = 0.74; P < .003) [2].
• Monoclonal antibodies (MoAbs) 6D1 (anti-GPIb) and 328 (anti-VWF A1 domain), completely abolished SIPA and p125FAK phosphorylation mediated by 2B-rVWF [19].
• A prospective study of 200 individuals yielded 2 Tyr/Cys1584 heterozygotes; for both, plasma VWF showed increased susceptibility to proteolysis [21].

Anatomical context of VWF

• Second, an anti-VWF antibody coimmunoprecipitates P-selectin from the histamine-activated endothelial cells [22].
• von Willebrand factor (VWF) released from endothelium is ultralarge (UL) and hyperreactive [22].
• Immunolocalization showed VWF not only associated with platelets, but already on the megakaryocyte surface and within internal channels [23].
• These observations indicate that VWF plays an active role in sequestering IL-8 into Weibel-Palade bodies [24].
• This cell line has retained the typical phenotypic characteristics of primary endothelial cells but has lost the capacity to produce VWF in appreciable amounts [24].

Associations of VWF with chemical compounds

• Integrin activation (inside-out signaling) in platelets can be initiated by agonists such as von Willebrand factor (VWF) and thrombin [25].
• This mutation, which was present in the proband and his father, predicts the substitution of Cys for Arg at position 760 of pre-pro-VWF, 4 residues before the propeptide cleavage site belonging to a consensus sequence for substrate recognition by the processing enzyme paired dibasic amino acid-cleaving enzyme (PACE)/furin [26].
• Raised levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate, as well as membrane-permeable calcium chelators, inhibited these [Ca(++)](i) oscillations and prevented stable adhesion without affecting the dynamic characteristics of the typical platelet translocation on VWF mediated by GPIbalpha [27].
• We conclude that reduction in the number of terminal sugars on N-linked glycan increases susceptibility of globular VWF to ADAMTS13 proteolysis and is associated with reduced plasma VWF:Ag and VWF:CB levels [20].
• The specific inhibitory effect of anions was due to their binding to VWF, which caused a conformational change responsible for quenching the intrinsic fluorescence of the protein and reducing tyrosine exposition to bulk solvent [28].
• VWF collagen binding activity (VWF:CB) and ristocetin cofactor activity (VWF:RCo) were significantly lower for Y/C1584 heterozygotes than for Y/Y1584 homozygotes, and a qualitative difference in Y/C1584 plasma VWF multimer profile was observed compared with that for Y/Y1584 VWF [29].
• We demonstrate that some of the plasma VWF multimers contain surface-exposed free thiols [30].
• We detected a marked decrease in PNA binding in post-DDAVP (1-deamino-8-D-arginine vasopressin) samples from various patients, indicating that the O-linked glycosylation profile of VWF stored in endothelial storage organelles may differ from circulating VWF [31].
• Mutation of N1574 increased the susceptibility of VWF to ADAMTS13 proteolysis and allowed cleavage in the absence of urea [32].
• The data indicate that in vivo C1584 and blood group O are associated with increased VWF clearance, and that clearance contributes to differing VWF level within a given blood group [33].

Physical interactions of VWF

• Independent modulation of von Willebrand factor and fibrinogen binding to the platelet membrane glycoprotein IIb/IIIa complex as demonstrated by monoclonal antibody [34].
• While the roles that leucine tandem repeats may normally play within the GPIb/IX complex are not yet known, the perturbation of such a repeat in GPIb alpha may impair interaction with other components of the complex and/or with the binding of vWF [35].
• Therefore, the spacer domain is required for ADAMTS13 binding to von Willebrand factor [36].
• Furthermore, vWF binding to GPIb-IX induces phosphorylation of Thr-202/Tyr-204 of extracellular signal-regulated kinase 2 (ERK2) [37].
• Reciprocal immunoprecipitation experiments revealed that while not associated with P-Selectin, OPG is physically complexed with vWF both within the WPB and following secretion from endothelial cells [38].
• Our findings demonstrate that FVIII trafficking to WPBs is independent of Tyr1680 and high-affinity binding to VWF [39].

Enzymatic interactions of VWF

• ADAMTS-13 specifically cleaves a peptidyl bond between Y1605 and M1606 in the A2 domain of VWF [40].
• VWF-cleaving protease activity (VWF:CP) and protein S (PS) levels (total and free antigen and activity) were within the conventional FFP reference range for test and control CSP [41].
• The VWF-cleaving proteinase activity of the truncated enzyme was comparable to that of the wild-type enzyme but its secretion from transfected COS-7 cells was about 14% of the wild type [42].
• In previous reports, plasmin was shown in vitro to inactivate FVIII and cleave the vWF subunit extensively, but to cause only a modest decrease in vWF platelet-agglutinating activity [43].
• The inability of PC2 and PC3 to cleave vWF was apparently not due to the absence of a transmembrane domain, since deletion of the transmembrane domain from PACE resulted in a secreted form which retained its propeptide processing activity within the secretory apparatus [44].

Co-localisations of VWF

• In HUVEC, OPG co-localizes with P-selectin and von Willebrand factor (vWF), within the Weibel-Palade bodies (WPB) [38].

Regulatory relationships of VWF

• The results of the present study demonstrate that independent modulation of vWF and fibrinogen binding to stimulated platelets can be attained with monoclonal antibodies directed against distinct epitopes of GPIIb/IIIa [34].
• Vasopressin-induced vWF secretion is mimicked by DDAVP and inhibited by the selective V2R antagonist SR121463B [45].
• The finding that an amino acid polymorphism in VWF may influence susceptibility to ADAMTS13 has potentially significant implications in diverse areas [21].
• These results establish that genetic differences in the adhesion receptor subunits alpha(2), alpha(IIb,) and GPVI can influence the phenotype of VWD type 1 [46].
• The proportion of TM-positive microvessels was expressed relative to total vWF-staining vessels, according to vessel caliber and regional distribution within the nerve [47].

Other interactions of VWF

• We report that DDAVP stimulates vWF secretion in a cAMP-dependent manner in HUVECs after transfection of the V2R [45].
• Thus, binding of vWF to its major physiological ligands may promote the feedback inhibition of platelet adhesion by stimulating the cleavage of domain A2 by ADAMTS13 independent of fluid shear stress [48].
• For tPA but not for PAI-1 and vWF, this association is independent of established risk factors [49].
• The results suggest that vWF domain A1 inhibits the cleavage of domain A2, and that inhibition can be relieved by interaction of domain A1 with platelet GPIbalpha or certain glycosaminoglycans [48].
• CD9 and PECAM-1 were found lining the membrane of the same granules that contained fibrinogen and vWF in their matrix [50].

Analytical, diagnostic and therapeutic context of VWF

• Blood was drawn on admission (baseline) and 48 hours later for plasma VWF, IL-6 (both enzyme-linked immunosorbent assay [ELISA]), and CECs (CD146 immunomagnetic separation) [51].
• Sequence analysis of VWF exon 28 indicated that increased susceptibility to proteolysis tracked with the "G" allele of the A/G polymorphism at position 24/1282, encoding the amino acid polymorphism Tyr/Cys1584 ("G" = Cys1584) [21].
• Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) documented the presence of both processed and unprocessed VWF in the patient's plasma, with unprocessed VWF relatively less represented [26].
• Treatment of multimer but not protomer VWF with random homobifunctional linker BS(3) prior to reduction of intermonomer disulfide linkages and Western blotting reveals a pattern of dimer and trimer units that indicate the presence of stable intermonomer non-covalent interactions within the multimer [52].
• However, despite no improvement in the level of VWF-cleaving protease activity, this patient had complete resolution of disease following splenectomy and commencing hemodialysis, without need for ongoing plasma therapy [3].

References