Skip Navigation LinksHome > January 2012 - Volume 23 - Issue 1 > Structure and function of von Willebrand factor
Blood Coagulation & Fibrinolysis:
doi: 10.1097/MBC.0b013e32834cb35d
Reviews

Structure and function of von Willebrand factor

Hassan, Md. Imtaiyaz; Saxena, Aditya; Ahmad, Faizan

Free Access
Article Outline
Collapse Box

Author Information

Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India

Correspondence to Md. Imtaiyaz Hassan, PhD, Assistant Professor, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110 025, India Tel: +91 11 2698 1733; fax: +91 11 2698 3409; e-mail: mihassan@jmi.ac.in

Received 5 April, 2011

Revised 2 June, 2011

Accepted 1 September, 2011

Collapse Box

Abstract

von Willebrand factor (VWF) is a long plasma protein that contains many domains and each domain has its own function. VWF exists in a multimeric form and performs varieties of functions in the human body, including thrombus formation and blood coagulation. The crystal structures of three subdomains are known, and, interestingly, all three domains share identical three-dimensional fold with α−β−α sandwiched model. VWF is directly associated with different types of von Willebrand disease. In this review, our aim is to gather recent developments on structure and functions of VWF and its clinical relevance.

Back to Top | Article Outline

Introduction

von Willebrand factor (VWF is a long polypeptide chain having a molecular mass of ∼270 kDa. This multimeric plasma protein is present in blood plasma and platelets, and is produced constitutively in endothelium, megakaryocytic, and subendothelial tissues [1]. Each monomer of VWF is composed of identical repeated domains designated as A, B, C, D, and E [2,3]. The arrangement of the domains appears like a mosaic protein [4]. The basic features of each domain are given in detail (Table 1). The multimeric size of VWF is important for its function [5]. VWF in the circulating blood is found as a series of multimers ranging in size from about 500 to 20 000 kDa, the larger ones being hemostatically more effective [6].

Table 1
Table 1
Image Tools

An increase in VWF concentration in the blood is thought to be an indicator of endothelial injury [7,8]. VWF facilitates hemostasis via two separate pathways by stabilizing coagulation factor VIII and recruiting platelets to injured vessel wall or thrombi through the interaction with GPIb-α [9]. At the site of a wound or injury VWF helps platelets to adhere together to the walls of blood vessels and eventually lead to the healing process [10]. VWF carries another blood clotting protein called coagulation factor VIII to the site of clot formation [11]. This coagulation factor helps in platelet adhesion. At high shear rates the binding of VWF to collagen types I and III intercede platelet adhesion [12].

Recently, the crystal structure of A2 domain has been determined, and it shows high structural similarity with A1 and A3 domains and reflect that it adapts to shear sensor function [13]. Many reviews on VWF are available [14–16]. In this review our aim is to collect the recent information on VWF with special attention to A1, A2 and A3 subdomains for structure, function, metabolic network, and possible role in various diseases.

Back to Top | Article Outline
Biosynthesis of von Willebrand factor

The biosynthesis of VWF is completed through a complex process, including several posttranslational modifications [17,18]. A 350-kDa polypeptide encoded by 9 kb VWF mRNA contains 2050 amino acid residue long mature polypeptide, 22 amino acids long signal peptide and propeptide of 741 amino acid residues. This pro-VWF rapidly dimerizes in the endoplasmic reticulum by disulfide formation [16,19]. VWF is synthesized in the endothelial cells and megakaryocytes [18]. The precursor undergoes multimerization after processing in the endoplasmic reticulum and the Golgi apparatus of the endothelial cell and is cleaved into two components; one is the mature protein, whereas the other is a propeptide of 97 kDa [20]. This mature protein mediates the interaction between platelets and components of the subendothelium at sites of vascular injury, and as a result these interactions lead to protection of the coagulation factor VIII from the proteolytic degradation. VWF is initially synthesized as a prepro-polypeptide. The pro-polypeptide can be cleaved and also be secreted. Free pro-polypeptide is identified as von Willebrand antigen II, a plasma glycoprotein of unknown function [10]. Plasma VWF consists of a heterogeneous series of multimers that are composed of an apparently single-type glycoprotein subunit, linked together by disulfide bonds [16,21].

Yamamoto et al.[22] observed that VWF is frequently used as a universal marker for endothelial cells and found that different levels of VWF antigen were detected in veins and arteries in mice. mRNA of VWF is present at elevated levels in lungs, spleen, aorta, and brain, and at low levels in liver, gut, skeletal muscle, and kidney [23]. In animals such as mouse, pig, the VWF expression is heterogeneous and varying in size, location, and type of vessel [24]. The liver is an important site of factor VIII synthesis. Factor VIII circulates in complex with VWF, and this interaction appears to prevent premature proteolytic cleavage and clearance of factor VIII [14,25]. High expression of VWF in the lung could promote homeostatic process that would help to protect against bleeding after injury through adhesion of cells at the alveolar capillary level in the lung [26].

Back to Top | Article Outline
Secretion of von Willebrand factor

VWF is secreted as large multimers that are cleaved in the A2 domain by the metalloprotease, a disintegrin and metalloproteinase with a thrombospondin type I motif, member 13 (ADAMTS13), to give smaller multimers [27]. Cleaved VWF is activated by hydrodynamic forces found in arteriolar bleeding to promote hemostasis, whereas uncleaved VWF is activated at lower physiological shear stresses and causes thrombosis. VWF is secreted from endothelial cells through both the luminal and abluminal membranes [15]. Interestingly, through abluminal secretion some VWF is deposited into the vascular subendothelium, where it acts as an extracellular matrix protein to bridge circulating platelets [16]. Secretion of VWF from specialized storage granules of the endothelial cell, called Weibel–Palade bodies, is triggered by several substances [28]. These substances include some of important mediators of thrombosis and inflammation. Moreover, the regulated secretion of mature VWF also causes the release of equimolar amounts of the propeptide [29].

The secretion of VWF is stimulated by a variety of agents such as histamine, thrombin, fibrin β-adregenic agnoists, calcium ionophore A23187, and phorbol myristate acetate [30–32]. However, the magnitude of acute secretory response to epinephrine depends on the intracellular cyclic AMP levels [33]. It has been observed that desmopressin, a vasopressin analogue, induces a rapid, two-fold to three-fold increase in plasma VWF secretion [34]. Desmopressin itself is inactive on endothelial cells in vitro, and it is thought to produce an undefined secondary messenger [35]. The secretion of VWF occurs through two distinct pathways: one is continuous, which occurs without any cellular stimulation, whereas the other is regulated by storage granules [36]. On the contrary, a third pathway has also been described known as the basal secretion [37].

Back to Top | Article Outline
Gene structure

VWF gene is located at the tip of the short arm of chromosome 12 [38]. Mancuso et al.[39] determined the gene structure of VWF and described the importance of various exons. VWF spans approximately 180 kb and contains 52 exons. The length of exons and introns vary from 40 to 1379 base pairs (bp) and 0.97 to 19.9 kb, respectively [39]. Furthermore, they have identified a number of repeats such as 14 Alu and an approximately 670 bp TCTA repeat in intron 40. Moreover, the 5′ flanking region of VWF contains an AT-rich region resembling TATA element and a repetitive sequence (GT)19[40]. The positions of intron–exon boundaries within the repeated amino acid sequence domains of VWF reflect that the evolution of these domains presumably occurs through the gene duplication [15]. The primary translation product predicted from the cloned cDNA of VWF shows a relationship between exons and various domains of VWF-polypeptide, and each relationship is well described earlier [41]. It may be suggested that each domain is encoded by one or many exons.

Back to Top | Article Outline
Primary structure

Over 90% of the VWF precursors consists of four distinct repeated domains present in two to five tandem copies each in the order D1-D2-D′-D3-A1-A2-A3-D4-B1-B2-B3-C1-C2 (Table 1) [39,42]. There are five types of repeated domains that approximately constitute 77% of the sequences. Domain A comprises approximately 180 amino acid residues and is present in three tandem copies between 1277 and 1871. The A domain of VWF is homologous to segments of complement factor B, complement factor C2, cartilage matrix protein, and α1-procollagen type I binding sites. The c domain of VWF is homologous to segments of thrombospondin and α 11-procollagen type I and type III [16]. The gene structure of VWF domain A3 and that of cartilage matrix show considerable variation in the placement of intron–exon boundaries with the exception at the 3′ ends of VWF domain A3 and both cartilage matrix protein [43].

The primary translational product consists of 2813 amino acids including a signal peptide [15]. Among the 2813 amino acids, 234 amino acids are cysteine, which accounts for exactly 8.3% content of cysteine. Cysteine is abundant in all domains except the triplicated A domain, which together contain only six cysteine residues. Interestingly, all the cysteine residues are conserved in mammalian VWFs. The mature subunit of VWF is glycosylated with 12 N-linked and 10 O-linked oligosaccharides, and the propeptide has three potential N-glycosylation sites [44]. Similar to the cysteine, the glycosylation sites are also conserved in all mammalian VWFs. At Asn384 and Asn468 of the mature subunit one or both of the oligosaccharides are sulfated [45]. Pro-VWF subunits dimerize through disulfide bonds in the neighborhood of the carboxy terminal following translocation into the endoplasmic reticulum. This tail-to-tail dimerization requires sequences of the last 150 residues. Both glycosylation and dimerization occur following the exit of the subunits from the endoplasmic reticulum [46].

The multimers of VWF in normal plasma range from 500 to 20 000 kDa that usually differ by the number of constituent VWF units. The VWF propeptide plays an important role in the assembly of multimers [47]. The D1 and D2 domains of the VWF propeptide contain CXXC sequence (Cys159-Gly-Leu-Cys162 and Cys521-Gly-Leu-Cys524), which resembles the functional site of thiol disulfide [48]. Insertion of an extra glycine into any of the sequences was compatible with the dimer formation in the endoplasmic reticulum, but the dimers were transported to the Golgi and secreted without forming multimers [49]. There are 23 cysteine residues present in between Lys273 and Lys448, out of which only six form intra-subunit disulfide bonds [50]. Multimer formation of VWF is mediated by a noncovalent interaction between two pro-polypeptides. In order to determine the involvement of different domains of VWF in the assembly to multimers, Voorberg et al.[51] have constructed and expressed a set of deletion mutants of full-length cDNA. They observed that both the D′ and the D3 domain are required for multimer assembly of VWF, including the pro-polypeptide chain. It has been demonstrated that deletion of these propeptide region of VWF resulted in the expression of only the dimeric form of VWF and prevented the synthesis of VWF multimers. Furthermore, the Tyr87Ser mutation in the pro-VWF region directly affects the multimerization and VWF biosynthesis [47]. Moreover, several naturally occurring mutations in the propeptide region of VWF (Tyr87Ser, Arg273Trp, Asn528Ser, Gly550Arg, Cys623Trp, and insertion of Gly625) showed an altered multimerization [47,52].

The multimeric size of VWF is regulated by the plasma metalloproteinase, ADAMTS13, which cleaves at a single site (Tyr1605-Met1606) in the A2 domain of VWF [53]. Recently, it was observed that residues from 1874 to 2813 of VWF (includes the VWF D4 domain) show excellent binding affinity [dissociation constant (Kd 86 nmol/l)] to ADAMTS13 [54]. It may be suggested that this novel D4-domain binding may be an initial step of a multistep interaction require for the proteolysis of VWF by ADAMTS13.

Back to Top | Article Outline
Three-dimensional structure

The crystal structure of each subdomain of A domain has been determined, showing close structural homology. Here we are discussing the structural features of each domain separately in detail.

Back to Top | Article Outline
Domain A1

The crystal structure of A1 domain has been determined in the native form [55] as well as a complex with NMC-4 fab [56,57], GPIb [58], GPIbα[59], and snake venom bitiscetin [60]. The overall fold of A1 domain is quite similar to that of A3 domain of VWF and the integrin I-domain (Fig. 1a). The structure represents a central hydrophobic parallel β-sheet flanked on two sides by amphipathic helices. A well ordered disulfide bridge is formed between Cys509 and Cys695, which connects the N-proximal and C-proximal sequences. The overall shape is cuboid, with six fairly flat faces [55]. On comparison with integrin I domains, this upper face contains the metal ion-dependent adhesion site (MIDAS) motif consisting of three closely spaced loops that together coordinate a magnesium ion [61].

Figure. No caption a...
Image Tools

The VWF-A1 contains a large number of charged amino acids, which form a salt-bridge network that wraps around the lower rim of the domain [62]. These stabilizing salt bridges are explained by the sensitivity of this region upon alanine mutagenesis [63]. There are four buried acidic residues: Glu557, which forms stabilizing salt bridges with two histidine side chains (His559 and His563); Glu626, which is buried but sits at the N-terminal end of helix α4 where it may be stabilized by the helix dipole; Asp514, which is buried and is stabilized by salt bridges formed by two arginine side chains (Arg552 and Arg611) forming a part of the salt-bridge network; and Asp520, which is buried below the upper face of the domain without a stabilizing salt-bridge partner [55,64,65].

Back to Top | Article Outline
Domain A2

The crystal structure of A2 domain has been determined very recently [13]. It is unique among VWF-A domains. The structure of A2 is devoid of α4 helix; instead, it contains a loop and cis-proline (at 1645th position of mature polypeptide). This Cis-Pro of A2 domain plays a significant role in A2 domain refolding in the extracellular environment. Interestingly, this proline is also present in trans configuration at the corresponding position of A1 and A3 subdomains. Moreover, cistrans isomerization occurs in the folded and unfolded states, corresponding to formation and breakage of hydrogen bond with Arg1618, respectively [13]. The structural analysis of A2 domain reveals that it has two independent molecules [66]. It clearly represents hydrophobic β sheet core containing antiparallel β strands in the order β3, β2, β1, β4, β5, and β6 (Fig. 1b). Asp1806 of the A3 domain has a capping function similar to Asp1614 of A2 [13]. The dipoles of the α3- and α5-helices interact with charged, capping residues, Asp1614 and Arg1618, respectively, which are invariant in A2 domain [13]. The α6-helix ends in 2 Cys residues that are linked by an unusual vicinal disulfide bond that is buried in a hydrophobic pocket [62]. These features may narrow the force range over which unfolding occurs and may also show refolding. The A2 domain provides surprising insights into the structural specializations of a domain that has evolved to be a force sensor. The A2 domain is the only domain within VWF that is not protected from unfolding by medium-range or long-range disulfide bonds.

Back to Top | Article Outline
Domain A3

Three-dimensional structure of A3 domain has been reported by many groups independently [61,67–69]. The VWF A3 domain adopts a dinucleotide-binding fold [67], consisting of a central β sheet with six strands that is surrounded by seven α helices. All β strands are parallel, except for strand β3, which is located at an edge of the sheet (Fig. 1c). The disulfide bridge between residues Cys923 and Cys1109 connects the N-terminal and C-terminal regions, and denotes the domain boundaries. The interesting feature of A3 domain is the collagen-binding site showing a markedly high concentration of negatively charged residues. This region encompasses a potential metal-binding site containing the motif DXSXS, which is required for ligand interaction in the homologous I-type domains of integrins CR3 and LFA-1. The structure of the A3 domain suggests that adhesion to collagen is primarily achieved through interactions between negatively charged residues on A3 and positively charged residues on collagen [69]. The absence of a pronounced binding groove precludes a large van der Waals surface interaction between A3 and collagen and is consistent with the low affinity for collagen of a single A3 domain and the requirement for multimeric VWF for tight association with collagen [70].

The main chain atoms of the central β-sheet overlap with the integrin αMI domain with an rms deviation of 0.5 Å. There are several surprising features of the structure: the α2-helix is replaced by a loop and helix α3 is extended by five residues; at the top of the domain, the βE-α6 loop adopts a different conformation; and α7-helix is only two turns long and is followed by an abrupt 90° turn before forming a new 8th helix ending with the C-terminal Cys-1109. The solvent accessible surface of the A3 domain is predominantly hydrophilic with the exception of a region located at the bottom and back face of the molecule [67]. Residues contributing to this hydrophobic region are Val984, Val985, Pro986, Leu994, and Val997. The proximity of this hydrophobic region to the N-terminal and C-terminal residues is consistent with a potential hydrophobic interdomain interaction site.

The structural comparison among A1, A2, and A3 domains reveals that they all contain similar fold (Fig. 1d). The rms deviation of backbone carbon atoms of A1 domain with that of A2 and A3 is 1.91 and 2.746 Å2, respectively, while the rms deviation of A2 domain with A3 is only 1.597 Å2, which reveals that A2 and A3 are more similar structurally as compared to A1 domain.

Back to Top | Article Outline
Biological functions

VWF performs a large number of functions in the human body [14–16,71]; binding to factor VIII and platelet surface glycoprotein is prominent among them [6,72,73]. The binding of VWF to platelets is regulated by its initial interaction with connective tissue and also by shear stress in flowing blood. We have predicted the functional protein–protein interaction network using an online server STRING [74]. VWF shows interaction with various proteins in order to perform many important functions (Fig. 2 and Table 2). The biological functions of VWF are described here in detail.

Figure. No caption a...
Image Tools
Table 2
Table 2
Image Tools
Back to Top | Article Outline
Platelet adhesion

VWF does not interact with circulating platelets in the absence of injury [75]. However, in the course of damage the endothelium allows VWF to bind with constituents of subendothelial connective tissue. Another report suggests that platelet and collagen adhesion increases the platelet aggregation induced by binding of VWF [76]. Site-directed mutagenesis studies on A2-domain showed that Arg834Gln and Arg834Trp mutant showed a remarkable decrease in platelet adhesion to collagen type III under flow conditions [77]. The Arg-Gly-Asp sequence (1744–1746 of mature polypeptide) of VWF is considered as a recognition site for integrin receptor, which promotes endothelial cell adhesion [78].

Back to Top | Article Outline
Binding to collagens

VWF binds specifically to several collagens in vitro including types I, II, III, IV, V, and VI, but it does not bind to the denatured gelatin [69]. Platelet adhesion is also supported by fibrillar collagen of type I or type III under high shear condition [79]. Binding sites for fibrillar collagen have been found in the A1 and A3 domains of VWF [67,80]. But the major collagen-binding site of multimeric VWF is found in the domain A3.

Back to Top | Article Outline
Binding to platelet GPIb

The VWF has strong affinity for platelet GPIb [81]. Such kind of interaction requires the glycoprotein (GPlb IX-V complex), with significant affinity for VWF. GPIb serves as one of the essential receptors for VWF and plays a crucial role in platelet thrombus formation [82]. Undeniably, the binding of multimeric VWF to GPIb results in platelet activation and may lead to adhesion and aggregation. GPlb-IX-V consists of at least four polypeptide chains encoded by separate genes: GPIbα, GPIbβ, GPIx, GPv. GPIbα, and GPIbβ are disulfide-linked and associate noncovalently with GPIbα chain [83,84]. Optimal binding requires sulfation of tyrosine residues at positions 276, 278, and 279 [85]. VWF-dependent platelet adhesion occurs optimally under conditions of high fluid shear stress [82]. The small bacterial glycopeptide antibiotic ristocetin dimerizes and binds to both VWF and platelets and causes platelet aggregation by inducing VWF to bind GPIbα[86]. The GPIb-binding site on VWF is localized in A1 domain [84]. VWF in solution does not bind tightly to platelets because the intrinsic affinity of each binding site is low. Multivalent binding is difficult in solution because of the conformational flexibility of VWF [87]. Immobilization of VWF in connective tissue could restrict the motion of multiple binding sites, distributing them favorably to bind several GPIb receptors and retain platelets at the vessel wall [88].

Back to Top | Article Outline
Binding of von Willebrand factor to platelet integrin αIIββ3

The αIIββ3 is a member of the integrin family of cell-surface receptors that does not bind to VWF. When platelets are activated by thrombin, αIIββ3 is able to bind fibrinogen, fibronectin, or VWF with high affinity [89]. This interaction is not sufficient for platelet adhesion, but specific inhibition of αIIββ3 function impairs the adhesion of platelets to surfaces coated with either VWF or collagen. Therefore, αIIββ3 may contribute to platelet adhesion that is initiated through GPIb binding to VWF [90,91].

Back to Top | Article Outline
Fluid shear stress

The VWF-mediated platelet adhesion depends on fluid shear stress [11]. As blood flows through the vessel, velocity is maximum at the center and falls to zero at the vessel walls [86]. In the formation of a thrombus, platelets must bind to the vessel wall despite these opposing forces. It has been observed that at low shear rates of veins and normal arteries, platelet adhesion is not stimulated by VWF. However, at shear rates greater than 1000 s−1, platelet adhesion is strongly dependent on VWF [92]. The rapid interaction between GPIbα and VWF promotes the reversible tethering of platelets that approach the wall [93]. The slowly moving tethered platelets adhere irreversibly through the slow binding of cell surface αIIβ3 to ligands in connective tissue [94]. Keuren et al.[95] showed that the C-domain of VWF is a critical determinant of platelet adhesion to fibrin under conditions of high shear stress. Moreover, the transition from GPIb-dependent to integrin-dependent binding is accelerated by platelet activation, which can be mediated by constituents of connective tissue such as collagen or by soluble platelet agonists including ADP or epinephrine [96].

Back to Top | Article Outline
Stabilization of blood coagulation factor VIII

Patients with hemophilia have low levels of factor VIII and normal levels of VWF, whereas patients with severe von Willebrand disease (VWD) have undetectable levels of VWF and factor VIII. This behavior reflects the dependence of normal factor VIII survival on the formation of noncovalent interaction between factor VIII and VWF [11]. It has been observed that all sizes of VWF multimers bind to factor VIII with similar affinity [85]. In fact, almost all VWF subunits can bind with factor VIII, but adsorption of VWF to surfaces markedly decreases the stoichiometry of binding. The factor VIII-binding site on VWF is located within the amino terminal 272 amino acid residues of the mature subunit [97]. The corresponding VWF-binding site on factor VIII is near the amino terminus of the 80 kDa light chain. The factor VIII light chain consists of residues 1649–2332 of the factor VIII precursor. The VWF-binding site involves amino acids in the segment between residues 1669–1689, and optimal binding requires sulfation of Tyr1680 [85]. When factor VIII is activated during blood coagulation, thrombin cleaves it at Arg1689. This cleavage destroys the VWF-binding site and releases factor VIIIA [98]. In type IIN VWD a mutation in D′ domain of VWF (Gln290His and Cys297Arg in mature VWF sequence) causes a dramatic decrease in the binding of VWF to factor VIII [99].

Back to Top | Article Outline
Binding to sulfatides

Sulfatides are sulfated glycosphingolipids present on cell surfaces that bind to adhesive proteins including VWF. VWF binds specifically with high affinity to sulfated glycolipids. Such binding probably provides VWF the ability to agglutinate erythrocytes as evident from two other sulfatide-binding proteins, such as laminin and thrombospondin [100]. Interestingly, characteristics of VWF binding to sulfatides resemble those of VWF binding to platelets. Studies have showed that the sulfatide-binding site of VWF is located in amino acid residues Gln626–Val646 in the A1domain. Interestingly, the A1 domain also contains the binding site for GPIb, a site that has been reported to be distinct from the sulfatide-binding site. Moreover, the interaction of sulfatides with VWF affects GPIb-mediated platelet adhesion under flow conditions [101]. Another finding by Christophe et al.[102] suggests that the sequence 569–584 of VWF is a part of the interactive site for sulfatides or may influence its activity that is distinct from the domain involved in heparin binding. Nakayama et al.[103] performed alanine mutation, and they observed that 10 mutants showed decreased sulfatide-binding including four novel mutations at Arg1392, Arg1395, Arg1399, and Lys1423.

Back to Top | Article Outline
Binding to heparin

It has been demonstrated that there is significant impairment of VWF function in the plasma of acutely heparinized patients. VWF is also known to bind heparin through the domain that lies in close proximity to GPIb binding domain in the region amino acids 449–728 [104]. Heparin can inhibit VWF platelet hemostatic interactions. It has been suggested that heparin may interfere with platelet function, and therapeutic doses of heparin can prolong the bleeding time. Furthermore, heparin could inhibit ristocetin-mediated platelet agglutination. All these activities are associated with heparin due to its strong affinity for VWF [105]. Using synthetic peptide binding studies it was suggested that the 23-residue sequence (Tyr565-Ala587) of VWF retains the consensus motif that binds heparin with appreciable affinity [105]. Sobel et al.[104] investigated the mechanism of heparin-induced inhibition of VWF function and suggested that the effect of heparin is independent of ristocetin, and heparin most likely acts not at the platelet surface but in solution by binding VWF and impairs the capacity of VWF to bind the platelet.

Back to Top | Article Outline
Von Willebrand disease

Von Willebrand disease (VWD) is an inherited genetic bleeding disorder that can be inherited from either parent and affects males and females equally [106,107]. VWD is a congenital extrinsic platelet defect resulting in platelet dysfunction [108] and is commonly reported in dogs, swine, horses, cattle, and cats. This autosomally inherited disorder is caused by either qualitative (type II) or quantitative (types I and III) deficiency of VWF. VWD results primarily in abnormal primary hemostasis (platelet plug formation) and prolongation of bleeding time in vivo caused by a lack of functional VWF [109].

The release of VWF is enhanced by involvement of some modulators such as histamine, fibrin, and estrogen [110]. Furthermore, the release of α granules of platelets is stimulated by collagen, platelet-activating factor, thrombin, and adenosine diphosphate [110]. Although there are small, medium, and large multimers of VWF, the multimers with high molecular mass are most active during hemostasis because they have large numbers of binding sites per molecule and their physical characteristics can be altered under certain conditions of blood flow [111]. Broadly, there are four hereditary types of VWD: type I, type II, type III, and platelet-type [112].

Back to Top | Article Outline
Type I

Type I is the most common and mildest form of VWD [113]. The main symptom of type I VWD is a significant mucocutaneous bleeding history. In type I, the level of VWF in the blood and the levels of factor VIII may also be reduced [114]. The condition becomes worse by taking aspirin and other nonsteroidal anti-inflammatory drugs. People with type I VWD usually do not bleed spontaneously but can have significant bleeding with trauma, surgery, or tooth extraction [115]. Recently, Othman et al.[116] have studied the effect of a 13-bp deletion in the promoter of the VWF gene in a patient with type I VWD. They showed that the 13-bp deletion mutation alters the binding of Ets (and possibly GATA) proteins to the VWF promoter and significantly reduces VWF expression, thus playing a central pathogenic role in the type I VWD.

Back to Top | Article Outline
Type II

Type II is accounts for 15–20% of VWD cases [117]. It is a variant of the disease with primarily qualitative defects of VWF (abnormal function) [118]. This disease can be either autosomal dominant or autosomal recessive. The type II VWD can further be classified into four subtypes: IIA, IIB, IIM, and IIN. The type IIA VWD is by far the most common [119]. Bernardi et al.[120] detected two transversions in two unrelated type IIA VWD: a C to A at nucleotide 8821 and a T to A at nucleotide 8830, resulting in the missense mutations Pro864His and Val867Glu, respectively.

Type IIB VWD is a rare autosomally inherited bleeding disorder, usually characterized by enhanced ristocetin-induced platelet aggregation in platelet-rich plasma [121]. Type IIB VWD has typically characteristic features: increased ristocetin-induced platelet agglutination at low ristocetin concentration, selective loss of plasma high-molecular-weight multimers, and mutations involving exon 28 of the VWF gene that codes for the A1 domain of VWF, the known contact site for platelet GPIb [118,122]. This is a disease with an autosomal dominant inheritance, characterized by an abnormal VWF structure resulting in enhanced affinity to platelet glycoprotein GPIbα that may result in moderate-to-severe thrombocytopenia [123].

Type IIM is also a type II VWD, characterized by a decreased platelet-directed function that is not due to a decrease in high-molecular-weight multimers [121]. It also occurs due to the decreased VWF activity [124]. The mutations Glu561Ser, Phe606Ile, and Ile662Phe, observed in VWD type IIM, have decreased VWF:RCo and retain normal botrocetin-induced binding to platelet GPIb. In addition, charged-to-alanine mutations at Glu626, Asp520, Lys534, Lys48, Lys534, Lys569, Lys642, Lys64, and Lys549 of VWF resulted in reduced ristocetin-induced binding, but not botrocetin-induced binding of VWF to platelets [125].

The type IIN VWF is also rare and is characterized by a decreased affinity for factor VIII. In type IIN VWD, the presence of abnormal VWF with an altered factor VIII-binding site results in diminished or no factor VIII–VWF interaction, which leads to a defective coagulation with generally normal primary hemostasis. It is recessively inherited disease and clinically similar to mild hemophilia. Till now there are seven of the eight reported missense mutations associated with type IIN VWD located in the D′ domain. A mutation Asp879Asn in prepro-VWF (position 116 in mature VWF) resulted in decreased factor VIII due to an induced conformational change in the D′ domain [126]. Another missense mutation (Thr791Met) is shown to induce a factor VIII binding defect. A large number of mutations have been reported in type IIN VWD by Mazurier et al.[127].

Back to Top | Article Outline
Type III

Type III is an autosomal recessive inherited bleeding disorder and the most severe form of VWD due to being homozygous for the defective gene. Type III VWD is much less common with frequency estimated at approximately one per million. This disease results in a remarkable decrease or absence of VWF and is associated with moderate-to-severe bleeding symptoms (epistaxis, menorrhagia, arthropathy, and postoperative bleeding) [128]. Major clinical features involve excessive mucocutaneous bleeding and prolonged oozing after surgical procedures. Patients with type III VWD may have severe bleeding not only in the mucocutaneous areas but also in the joints because factor VIII is also very reduced. Furthermore, hematomas and hemarthrosis are also observed because factor VIII levels are as low as in moderate–mild hemophiliacs [129]. There are a large number of mutations reported in type III VWD. Interestingly, most mutations identified are ‘null’ mutations, resulting in a lack of expression of VWF due to nonsense, frame shift, splice site, and large deletion mutations.

Back to Top | Article Outline
Platelet-type von Willebrand disease

Platelet-type VWD (PT-VWD), also known as pseudo-VWD, is an autosomal dominant type of VWD caused by mutations of the VWF receptor on platelets, specifically the GPIbα[130]. PT-VWD is usually misdiagnosed and considered as type IIB VWD, which shows similar bleeding and phenotypic profiles [131]. This disease results from an abnormally high affinity interaction between the platelet membrane glycoprotein Ib/IX/V complex and VWF. Othman et al.[132] reported three missense mutations for PT-VWD, Gly233Val, Met239Val, and Gly233Ser, which are located within the C-terminal disulfide loop of the 45-kDa domain of GP1bα, and a 27-bp deletion in the macroglycopeptide-coding region of GP1bα. Such mutations cause structural changes in GP1bα, and are responsible for the PT-VWD phenotype [133].

Back to Top | Article Outline
Clinical measurements of von Willebrand factor

The assay of VWF is necessary for diagnosis of the quantitative VWD. Numerous methods are available for the clinical quantification of VWF in blood plasma [134]. VWF activity may be assayed by measuring VWF antigen, or the ratio of VWF:ristocetin cofactor (RCo) or the ratio of VWF:collagen binding activities. The most used method for VWF:RCo assay depends on ristocetin-induced platelet aggregation or agglutination. Recently, a simple method is developed for VWF measurement that is based on flow cytometry having superior accuracy, specificity, and sensitivity [135]. The VWF and collagen binding (VWF:CB assay) can significantly reduce the diagnostic error rate as compared to the VWF:RCo assay [136–138]. Later, VWF-FVIII binding assay has been used for the investigation of patients with suspected VWDIIN [139]. Interestingly, such an assay provides an accurate measurement of VWF:FVIII binding activity and helps in the identification of homozygous patients with VWDIIN and heterozygous carriers. Day by day various new methods are emerging for the accurate diagnosis of VWD [140,141].

Back to Top | Article Outline

Conclusion

It is evident from the analysis of VWF that it is a clinically important protein. Therefore, we extensively studied VWF in terms of its structure and functions. VWF is synthesized exclusively in endothelial cells and megakaryocytes. It shows a strong binding with collagen, integrin GPIb, factor VIII, platelet integrin αɪɪββ3, and several other compounds. VWD is an inheritable bleeding disorder that affects the clotting ability of blood. This disease may further be classified into type I, type II, and type III diseases. The structure analysis of VWF is critically important for the development of structure and function relationship and its association with diseases.

Back to Top | Article Outline

Acknowledgements

M.I.H. is grateful to the Department of Science and Technology, Government of India for the award of young scientist fellowship. F.A. is especially grateful to the Council of Scientific and Industrial Research, and University Grants Commission, Government of India, for financial assistance.

Back to Top | Article Outline
Conflict of interests

The authors state they have no conflicts of interest.

Back to Top | Article Outline

References

1. Hough C, Cuthbert CD, Notley C, Brown C, Hegadorn C, Berber E, et al. Cell type-specific regulation of von Willebrand factor expression by the E4BP4 transcriptional repressor. Blood 2005; 105:1531–1539.

2. Jin SY, Skipwith CG, Zheng XL. Amino acid residues Arg(659), Arg(660), and Tyr(661) in the spacer domain of ADAMTS13 are critical for cleavage of von Willebrand factor. Blood 2010; 115:2300–2310.

3. Fujimura Y, Fukui H, Usami Y, Titani K. Domain structure of human von Willebrand factor, and its modulators involved in the platelet adhesion process in vitro. Rinsho Ketsueki 1991; 32:475–480.

4. Sadler JE. von Willebrand factor assembly and secretion. J Thromb Haemost 2009; 7 (Suppl 1):24–27.

5. Meyer D, Girma JP. von Willebrand factor: structure and function. Thromb Haemost 1993; 70:99–104.

6. Pimanda J, Hogg P. Control of von Willebrand factor multimer size and implications for disease. Blood Rev 2002; 16:185–192.

7. Reininger AJ. Function of von Willebrand factor in haemostasis and thrombosis. Haemophilia 2008; 14 (Suppl 5):11–26.

8. Reidy MA, Chopek M, Chao S, McDonald T, Schwartz SM. Injury induces increase of von Willebrand factor in rat endothelial cells. Am J Pathol 1989; 134:857–864.

9. Li S, Wang Z, Liao Y, Zhang W, Shi Q, Yan R, et al. The glycoprotein Ibalpha-von Willebrand factor interaction induces platelet apoptosis. J Thromb Haemost 2010; 8:341–350.

10. Vischer UM, Wagner DD. von Willebrand factor proteolytic processing and multimerization precede the formation of Weibel-Palade bodies. Blood 1994; 83:3536–3544.

11. Skipwith CG, Cao W, Zheng XL. Factor VIII and platelets synergistically accelerate cleavage of von Willebrand factor by ADAMTS13 under fluid shear stress. J Biol Chem 2010; 285:28596–28603.

12. Fuchs B, Budde U, Schulz A, Kessler CM, Fisseau C, Kannicht C. Flow-based measurements of von Willebrand factor (VWF) function: Binding to collagen and platelet adhesion under physiological shear rate. Thromb Res. 2010; 125:239–245.

13. Zhang Q, Zhou YF, Zhang CZ, Zhang X, Lu C, Springer TA. Structural specializations of A2, a force-sensing domain in the ultralarge vascular protein von Willebrand factor. Proc Natl Acad Sci U S A 2009; 106:9226–9231.

14. Moroose R, Hoyer LW. von Willebrand factor and platelet function. Annu Rev Med 1986; 37:157–163.

15. Sadler JE. Biochemistry and genetics of von Willebrand factor. Annu Rev Biochem 1998; 67:395–424.

16. Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol 1990; 6:217–246.

17. Millar CM, Brown SA. Oligosaccharide structures of von Willebrand factor and their potential role in von Willebrand disease. Blood Rev 2006; 20:83–92.

18. Mayadas TN, Wagner DD. von Willebrand factor biosynthesis and processing. Ann N Y Acad Sci 1991; 614:153–166.

19. Bonthron DT, Handin RI, Kaufman RJ, Wasley LC, Orr EC, Mitsock LM, et al. Structure of prepro-von Willebrand factor and its expression in heterologous cells. Nature 1986; 324:270–273.

20. Purvis AR, Sadler JE. A covalent oxidoreductase intermediate in propeptide-dependent von Willebrand factor multimerization. J Biol Chem 2004; 279:49982–49988.

21. Verweij CL. Biosynthesis of human von Willebrand factor. Haemostasis 1988; 18:224–245.

22. Yamamoto K, de Waard V, Fearns C, Loskutoff DJ. Tissue distribution and regulation of murine von Willebrand factor gene expression in vivo. Blood 1998; 92:2791–2801.

23. Aird WC, Jahroudi N, Weiler-Guettler H, Rayburn HB, Rosenberg RD. Human von Willebrand factor gene sequences target expression to a subpopulation of endothelial cells in transgenic mice. Proc Natl Acad Sci U S A 1995; 92:4567–4571.

24. Denis CV, Marx I, Badirou I, Pendu R, Christophe O. Mouse models to study von Willebrand factor structure-function relationships in vivo. Hamostaseologie 2009; 29:17–18.

25. Baud’huin M, Duplomb L, Teletchea S, Charrier C, Maillasson M, Fouassier M, et al. Factor VIII-von Willebrand factor complex inhibits osteoclastogenesis and controls cell survival. J Biol Chem 2009; 284:31704–31713.

26. Quan L, Ishikawa T, Zhao D, Michiue T, Yoshida C, Chen JH, et al. Immunohistochemistry of von Willebrand factor in the lungs with regard to the cause of death in forensic autopsy. Leg Med (Tokyo) 2009; 11 (Suppl 1):S294–S296.

27. Zhang X, Halvorsen K, Zhang CZ, Wong WP, Springer TA. Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor. Science 2009; 324:1330–1334.

28. van den Biggelaar M, Bierings R, Storm G, Voorberg J, Mertens K. Requirements for cellular co-trafficking of factor VIII and von Willebrand factor to Weibel-Palade bodies. J Thromb Haemost 2007; 5:2235–2242.

29. Scheja A, Akesson A, Geborek P, Wildt M, Wollheim CB, Wollheim FA, et al. Von Willebrand factor propeptide as a marker of disease activity in systemic sclerosis (scleroderma). Arthritis Res 2001; 3:178–182.

30. Hattori R, Hamilton KK, Fugate RD, McEver RP, Sims PJ. Stimulated secretion of endothelial von Willebrand factor is accompanied by rapid redistribution to the cell surface of the intracellular granule membrane protein GMP-140. J Biol Chem 1989; 264:7768–7771.

31. Collins P, Wilkie M, Razak K, Abbot S, Harley S, Bax C, et al. Cyclosporine and cremaphor modulate von Willebrand factor release from cultured human endothelial cells. Transplantation 1993; 56:1218–1223.

32. Cleator JH, Zhu WQ, Vaughan DE, Hamm HE. Differential regulation of endothelial exocytosis of P-selectin and von Willebrand factor by protease-activated receptors and cAMP. Blood 2006; 107:2736–2744.

33. Vischer UM, Wollheim CB. Epinephrine induces von Willebrand factor release from cultured endothelial cells: involvement of cyclic AMP-dependent signalling in exocytosis. Thromb Haemost 1997; 77:1182–1188.

34. Mannucci PM. Platelet von Willebrand factor in inherited and acquired bleeding disorders. Proc Natl Acad Sci U S A 1995; 92:2428–2432.

35. Favaloro EJ, Thom J, Patterson D, Just S, Dixon T, Koutts J, et al. Desmopressin therapy to assist the functional identification and characterisation of von Willebrand disease: differential utility from combining two (VWF:CB and VWF:RCo) von Willebrand factor activity assays? Thromb Res 2009; 123:862–868.

36. Johnsen J, Lopez JA. VWF secretion: what's in a name? Blood 2008; 112:926–927.

37. Giblin JP, Hewlett LJ, Hannah MJ. Basal secretion of von Willebrand factor from human endothelial cells. Blood 2008; 112:957–964.

38. Ginsburg D, Handin RI, Bonthron DT, Donlon TA, Bruns GA, Latt SA, et al. Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science 1985; 228:1401–1406.

39. Mancuso DJ, Tuley EA, Westfield LA, Worrall NK, Shelton-Inloes BB, Sorace JM, et al. Structure of the gene for human von Willebrand factor. J Biol Chem 1989; 264:19514–19527.

40. Collins CJ, Underdahl JP, Levene RB, Ravera CP, Morin MJ, Dombalagian MJ, et al. Molecular cloning of the human gene for von Willebrand factor and identification of the transcription initiation site. Proc Natl Acad Sci U S A 1987; 84:4393–4397.

41. Ruggeri ZM, Ware J. von Willebrand factor. FASEB J 1993; 7:308–316.

42. Sporn LA, Marder VJ, Wagner DD. Inducible secretion of large, biologically potent von Willebrand factor multimers. Cell 1986; 46:185–190.

43. Chen Q, Zhang Y, Johnson DM, Goetinck PF. Assembly of a novel cartilage matrix protein filamentous network: molecular basis of differential requirement of von Willebrand factor A domains. Mol Biol Cell 1999; 10:2149–2162.

44. Carew JA, Quinn SM, Stoddart JH, Lynch DC. O-Linked carbohydrate of recombinant von Willebrand factor influences ristocetin-induced binding to platelet glycoprotein 1b. J Clin Invest 1992; 90:2258–2267.

45. Carew JA, Browning PJ, Lynch DC. Sulfation of von Willebrand factor. Blood 1990; 76:2530–2539.

46. van Schooten CJ, Denis CV, Lisman T, Eikenboom JC, Leebeek FW, Goudemand J, et al. Variations in glycosylation of von Willebrand factor with O-linked sialylated T antigen are associated with its plasma levels. Blood 2007; 109:2430–2437.

47. Rosenberg JB, Haberichter SL, Jozwiak MA, Vokac EA, Kroner PA, Fahs SA, et al. The role of the D1 domain of the von Willebrand factor propeptide in multimerization of VWF. Blood 2002; 100:1699–1706.

48. Tjernberg P, Vos HL, Castaman G, Bertina RM, Eikenboom JC. Dimerization and multimerization defects of von Willebrand factor due to mutated cysteine residues. J Thromb Haemost 2004; 2:257–265.

49. Hommais A, Stepanian A, Fressinaud E, Mazurier C, Pouymayou K, Meyer D, et al. Impaired dimerization of von Willebrand factor subunit due to mutation A2801D in the CK domain results in a recessive type 2A subtype IID von Willebrand disease. Thromb Haemost 2006; 95:776–781.

50. Dong Z, Thoma RS, Crimmins DL, McCourt DW, Tuley EA, Sadler JE. Disulfide bonds required to assemble functional von Willebrand factor multimers. J Biol Chem 1994; 269:6753–6758.

51. Voorberg J, Fontijn R, van Mourik JA, Pannekoek H. Domains involved in multimer assembly of von Willebrand factor (vWF): multimerization is independent of dimerization. EMBO J 1990; 9:797–803.

52. Gaucher C, Dieval J, Mazurier C. Characterization of von Willebrand factor gene defects in two unrelated patients with type IIC von Willebrand disease. Blood 1994; 84:1024–1030.

53. Zanardelli S, Crawley JT, Chion CK, Lam JK, Preston RJ, Lane DA. ADAMTS13 substrate recognition of von Willebrand factor A2 domain. J Biol Chem 2006; 281:1555–1563.

54. Zanardelli S, Chion AC, Groot E, Lenting PJ, McKinnon TA, Laffan MA, et al. A novel binding site for ADAMTS13 constitutively exposed on the surface of globular VWF. Blood 2009; 114:2819–2828.

55. Emsley J, Cruz M, Handin R, Liddington R. Crystal structure of the von Willebrand factor A1 domain and implications for the binding of platelet glycoprotein Ib. J Biol Chem 1998; 273:10396–10401.

56. Celikel R, Madhusudan, Varughese KI, Shima M, Yoshioka A, Ware J, et al. Crystal structure of NMC-4 fab antivon Willebrand factor A1 domain. Blood Cells Mol Dis. 1997; 23:123–134.

57. Celikel R, Varughese KI, Madhusudan, Yoshioka A, Ware J, Ruggeri ZM. Crystal structure of the von Willebrand factor A1 domain in complex with the function blocking NMC-4 Fab. Nat Struct Biol. 1998; 5:189-194.

58. Cruz MA, Diacovo TG, Emsley J, Liddington R, Handin RI. Mapping the glycoprotein Ib-binding site in the von Willebrand factor A1 domain. J Biol Chem 2000; 275:19098–19105.

59. Huizinga EG, Tsuji S, Romijn RA, Schiphorst ME, de Groot PG, Sixma JJ, et al. Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science 2002; 297:1176–1179.

60. Maita N, Nishio K, Nishimoto E, Matsui T, Shikamoto Y, Morita T, et al. Crystal structure of von Willebrand factor A1 domain complexed with snake venom, bitiscetin: insight into glycoprotein Ibalpha binding mechanism induced by snake venom proteins. J Biol Chem 2003; 278:37777–37781.

61. Bienkowska J, Cruz M, Atiemo A, Handin R, Liddington R. The von Willebrand factor A3 domain does not contain a metal ion-dependent adhesion site motif. J Biol Chem 1997; 272:25162–25167.

62. Mayadas TN, Wagner DD. Vicinal cysteines in the prosequence play a role in von Willebrand factor multimer assembly. Proc Natl Acad Sci U S A 1992; 89:3531–3535.

63. Matsushita T, Sadler JE. Identification of amino acid residues essential for von Willebrand factor binding to platelet glycoprotein Ib. Charged-to-alanine scanning mutagenesis of the A1 domain of human von Willebrand factor. J Biol Chem 1995; 270:13406–13414.

64. Lacy DB, Wigelsworth DJ, Scobie HM, Young JA, Collier RJ. Crystal structure of the von Willebrand factor A domain of human capillary morphogenesis protein 2: an anthrax toxin receptor. Proc Natl Acad Sci U S A 2004; 101:6367–6372.

65. Hirotsu S, Mizuno H, Fukuda K, Qi MC, Matsui T, Hamako J, et al. Crystal structure of bitiscetin, a von Willebrand factor-dependent platelet aggregation inducer. Biochemistry 2001; 40:13592–13597.

66. Gao W, Anderson PJ, Majerus EM, Tuley EA, Sadler JE. Exosite interactions contribute to tension-induced cleavage of von Willebrand factor by the antithrombotic ADAMTS13 metalloprotease. Proc Natl Acad Sci U S A 2006; 103:19099–19104.

67. Huizinga EG, Martijn van der Plas R, Kroon J, Sixma JJ, Gros P. Crystal structure of the A3 domain of human von Willebrand factor: implications for collagen binding. Structure 1997; 5:1147–1156.

68. Nishida N, Miyazawa M, Sumikawa H, Sakakura M, Shimba N, Takahashi H, et al. Backbone 1H, 13C, and 15N resonance assignments of the von Willebrand factor A3 domain. J Biomol NMR 2002; 24:357–358.

69. Riddell AF, Gomez K, Millar CM, Mellars G, Gill S, Brown SA, et al. Characterization of W1745C and S1783A: 2 novel mutations causing defective collagen binding in the A3 domain of von Willebrand factor. Blood 2009; 114:3489–3496.

70. Romijn RA, Westein E, Bouma B, Schiphorst ME, Sixma JJ, Lenting PJ, et al. Mapping the collagen-binding site in the von Willebrand factor-A3 domain. J Biol Chem 2003; 278:15035–15039.

71. Fischer BE, Schlokat U, Reiter M, Mundt W, Dorner F. Biochemical and functional characterization of recombinant von Willebrand factor produced on a large scale. Cell Mol Life Sci 1997; 53:943–950.

72. Park SW, Choi SY. Long-term expression of von Willebrand Factor by a VSV-G pseudotyped lentivirus enhances the functional activity of secreted B-Domain-deleted Coagulation Factor VIII. Mol Cells 2007; 24:125–131.

73. Franchini M, Lippi G. The role of von Willebrand factor in hemorrhagic and thrombotic disorders. Crit Rev Clin Lab Sci 2007; 44:115–149.

74. Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P, et al. The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 2011; 39:D561–568.

75. Sadler JE. Biomedicine. Contact – how platelets touch von Willebrand factor. Science 2002; 297:1128–1129.

76. Laduca FM, Bell WR, Bettigole RE. Platelet-collagen adhesion enhances platelet aggregation induced by binding of VWF to platelets. Am J Physiol 1987; 253:H1208–1214.

77. Lankhof H, Damas C, Schiphorst ME, Ijsseldijk MJ, Bracke M, Furlan M, et al. Recombinant vWF type 2A mutants R834Q and R834W show a defect in mediating platelet adhesion to collagen, independent of enhanced sensitivity to a plasma protease. Thromb Haemost 1999; 81:976–983.

78. Dejana E, Lampugnani MG, Giorgi M, Gaboli M, Federici AB, Ruggeri ZM, et al. Von Willebrand factor promotes endothelial cell adhesion via an Arg-Gly-Asp-dependent mechanism. J Cell Biol 1989; 109:367–375.

79. Ruggeri ZM. Structure and function of von Willebrand factor: relationship to von Willebrand's disease. Mayo Clin Proc 1991; 66:847–861.

80. Morales LD, Martin C, Cruz MA. The interaction of von Willebrand factor-A1 domain with collagen: mutation G1324S (type 2 M von Willebrand disease) impairs the conformational change in A1 domain induced by collagen. J Thromb Haemost 2006; 4:417–425.

81. Kang I, Raghavachari M, Hofmann CM, Marchant RE. Surface-dependent expression in the platelet GPIb binding domain within human von Willebrand factor studied by atomic force microscopy. Thromb Res 2007; 119:731–740.

82. Dayananda KM, Singh I, Mondal N, Neelamegham S. Von Willebrand Factor self-association on platelet GpIb{alpha} under hydrodynamic shear: effect on shear-induced platelet activation. Blood 2010; 116:3990–3998.

83. Bonnefoy A, Vermylen J, Hoylaerts MF. Inhibition of von Willebrand factor-GPIb/IX/V interactions as a strategy to prevent arterial thrombosis. Expert Rev Cardiovasc Ther 2003; 1:257–269.

84. Shimizu A, Matsushita T, Kondo T, Inden Y, Kojima T, Saito H, et al. Identification of the amino acid residues of the platelet glycoprotein Ib (GPIb) essential for the von Willebrand factor binding by clustered charged-to-alanine scanning mutagenesis. J Biol Chem 2004; 279:16285–16294.

85. Leyte A, van Schijndel HB, Niehrs C, Huttner WB, Verbeet MP, Mertens K, et al. Sulfation of Tyr1680 of human blood coagulation factor VIII is essential for the interaction of factor VIII with von Willebrand factor. J Biol Chem 1991; 266:740–746.

86. Scott JP, Montgomery RR, Retzinger GS. Dimeric ristocetin flocculates proteins, binds to platelets, and mediates von Willebrand factor-dependent agglutination of platelets. J Biol Chem 1991; 266:8149–8155.

87. Gardiner EE, Arthur JF, Shen Y, Karunakaran D, Moore LA, Am Esch JS 2nd, et al. GPIbalpha-selective activation of platelets induces platelet signaling events comparable to GPVI activation events. Platelets 2010; 21:244–252.

88. Mekrache M, Bachelot-Loza C, Ajzenberg N, Saci A, Legendre P, Baruch D. Activation of pp125FAK by type 2B recombinant von Willebrand factor binding to platelet GPIb at a high shear rate occurs independently of alpha IIb beta 3 engagement. Blood 2003; 101:4363–4371.

89. Brill A, Fuchs TA, Chauhan AK, Yang JJ, De Meyer SF, Kollnberger M, et al. von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models. Blood 2011; 117:1400–1407.

90. D'Souza SE, Ginsberg MH, Plow EF. Arginyl-glycyl-aspartic acid (RGD): a cell adhesion motif. Trends Biochem Sci 1991; 16:246–250.

91. Aoki T, Tomiyama Y, Honda S, Mihara K, Yamanaka T, Okubo M, et al. Association of the antagonism of von Willebrand factor but not fibrinogen by platelet alphaIIbbeta3 antagonists with prolongation of bleeding time. J Thromb Haemost 2005; 3:2307–2314.

92. Wu YP, de Groot PG, Sixma JJ. Shear-stress-induced detachment of blood platelets from various surfaces. Arterioscler Thromb Vasc Biol 1997; 17:3202–3207.

93. Auton M, Sedlak E, Marek J, Wu T, Zhu C, Cruz MA. Changes in thermodynamic stability of von Willebrand factor differentially affect the force-dependent binding to platelet GPIbalpha. Biophys J 2009; 97:618–627.

94. Vettore S, Scandellari R, Moro S, Lombardi AM, Scapin M, Randi ML, et al. Novel point mutation in a leucine-rich repeat of the GPIbalpha chain of the platelet von Willebrand factor receptor, GPIb/IX/V, resulting in an inherited dominant form of Bernard-Soulier syndrome affecting two unrelated families: the N41H variant. Haematologica 2008; 93:1743–1747.

95. Keuren JF, Baruch D, Legendre P, Denis CV, Lenting PJ, Girma JP, et al. von Willebrand factor C1C2 domain is involved in platelet adhesion to polymerized fibrin at high shear rate. Blood 2004; 103:1741–1746.

96. Bergmeier W, Piffath CL, Goerge T, Cifuni SM, Ruggeri ZM, Ware J, et al. The role of platelet adhesion receptor GPIbalpha far exceeds that of its main ligand, von Willebrand factor, in arterial thrombosis. Proc Natl Acad Sci U S A 2006; 103:16900–16905.

97. Foster PA, Fulcher CA, Marti T, Titani K, Zimmerman TS. A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor. J Biol Chem 1987; 262:8443–8446.

98. Leyte A, Verbeet MP, Brodniewicz-Proba T, Van Mourik JA, Mertens K. The interaction between human blood-coagulation factor VIII and von Willebrand factor. Characterization of a high-affinity binding site on factor VIII. Biochem J 1989; 257:679–683.

99. Hilbert L, Jorieux S, Proulle V, Favier R, Goudemand J, Parquet A, et al. Two novel mutations, Q1053H and C1060R, located in the D3 domain of von Willebrand factor, are responsible for decreased FVIII-binding capacity. Br J Haematol 2003; 120:627–632.

100. Roberts DD, Williams SB, Gralnick HR, Ginsburg V. von Willebrand factor binds specifically to sulfated glycolipids. J Biol Chem 1986; 261:3306–3309.

101. Borthakur G, Cruz MA, Dong JF, McIntire L, Li F, Lopez JA, et al. Sulfatides inhibit platelet adhesion to von Willebrand factor in flowing blood. J Thromb Haemost 2003; 1:1288–1295.

102. Christophe O, Obert B, Meyer D, Girma JP. The binding domain of von Willebrand factor to sulfatides is distinct from those interacting with glycoprotein Ib, heparin, and collagen and resides between amino acid residues Leu 512 and Lys 673. Blood 1991; 78:2310–2317.

103. Nakayama T, Matsushita T, Yamamoto K, Mutsuga N, Kojima T, Katsumi A, et al. Identification of amino acid residues responsible for von Willebrand factor binding to sulfatide by charged-to-alanine-scanning mutagenesis. Int J Hematol 2008; 87:363–370.

104. Sobel M, McNeill PM, Carlson PL, Kermode JC, Adelman B, Conroy R, et al. Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo. J Clin Invest 1991; 87:1787–1793.

105. Sobel M, Soler DF, Kermode JC, Harris RB. Localization and characterization of a heparin binding domain peptide of human von Willebrand factor. J Biol Chem 1992; 267:8857–8862.

106. Rodeghiero F, Castaman G, Dini E. Epidemiological investigation of the prevalence of von Willebrand's disease. Blood 1987; 69:454–459.

107. Ginsburg D, Bowie EJ. Molecular genetics of von Willebrand disease. Blood 1992; 79:2507–2519.

108. Victor M, Rugeri L, Nougier C, Meunier S, Fretigny M, Negrier C, et al. Contribution of genetical analysis for diagnosis of von Willebrand's disease type 2B. Haemophilia 2009; 15:610–612.

109. Kreuz W. von Willebrand's disease: from discovery to therapy – milestones in the last 25 years. Haemophilia 2008; 14 (Suppl 5):1–2.

110. Rugeri L, Beguin S, Hemker C, Bordet JC, Fleury R, Chatard B, et al. Thrombin-generating capacity in patients with von Willebrand's disease. Haematologica 2007; 92:1639–1646.

111. Pergolizzi RG, Jin G, Chan D, Pierre L, Bussel J, Ferris B, et al. Correction of a murine model of von Willebrand disease by gene transfer. Blood 2006; 108:862–869.

112. Michiels JJ, Berneman Z, Gadisseur A, van der Planken M, Schroyens W, van de Velde A, et al. Classification and characterization of hereditary types 2A, 2B, 2C, 2D, 2E, 2M, 2N, and 2U (unclassifiable) von Willebrand disease. Clin Appl Thromb Hemost 2006; 12:397–420.

113. Goodeve AC. The genetic basis of von Willebrand disease. Blood Rev 2010; 24:123–134.

114. Sadler JE. Low von Willebrand factor: sometimes a risk factor and sometimes a disease. Hematol Am Soc Hematol Educ Program 2009:106–112.

115. Haberichter SL, Castaman G, Budde U, Peake I, Goodeve A, Rodeghiero F, et al. Identification of type 1 von Willebrand disease patients with reduced von Willebrand factor survival by assay of the VWF propeptide in the European study: molecular and clinical markers for the diagnosis and management of type 1 VWD (MCMDM-1VWD). Blood 2008; 111:4979–4985.

116. Othman M, Chirinian Y, Brown C, Notley C, Hickson N, Hampshire D, et al. Functional characterization of a 13 bp deletion (c.-1522_-1510del13) in the promoter of the von Willebrand factor gene in type 1 von Willebrand disease. Blood 2010; 116:3645–3652.

117. Kujovich JL. von Willebrand's disease and menorrhagia: prevalence, diagnosis, and management. Am J Hematol 2005; 79:220–228.

118. Casonato A, Gallinaro L, Cattini MG, Pontara E, Padrini R, Bertomoro A, et al. Reduced survival of type 2B von Willebrand factor, irrespective of large multimer representation or thrombocytopenia. Haematologica 2010; 95:1366–1372.

119. Federici AB, Berntorp E, Lee CA. The 80th anniversary of von Willebrand's disease: history, management and research. Haemophilia 2006; 12:563–572.

120. Bernardi F, Casonato A, Marchetti G, Gemmati D, Bizzaro N, Pontara E, et al. Two novel mutations (Pro864His, Val867Glu) causing type 2A von Willebrand disease and affecting a single restriction site in exon 28. Br J Haematol 1998; 103:885–887.

121. Ruggeri ZM, Pareti FI, Mannucci PM, Ciavarella N, Zimmerman TS. Heightened interaction between platelets and factor VIII/von Willebrand factor in a new subtype of von Willebrand's disease. N Engl J Med 1980; 302:1047–1051.

122. Jackson SC, Sinclair GD, Cloutier S, Duan Z, Rand ML, Poon MC. The Montreal platelet syndrome kindred has type 2B von Willebrand disease with the VWF V1316 M mutation. Blood 2009; 113:3348–3351.

123. Federici AB, Mannucci PM, Castaman G, Baronciani L, Bucciarelli P, Canciani MT, et al. Clinical and molecular predictors of thrombocytopenia and risk of bleeding in patients with von Willebrand disease type 2B: a cohort study of 67 patients. Blood 2009; 113:526–534.

124. Hermans C, Batlle J. Autosomal dominant von Willebrand disease type 2 M. Acta Haematol 2009; 121:139–144.

125. Hillery CA, Mancuso DJ, Evan Sadler J, Ponder JW, Jozwiak MA, Christopherson PA, et al. Type 2 M von Willebrand disease: F606I and I662F mutations in the glycoprotein Ib binding domain selectively impair ristocetin – but not botrocetin-mediated binding of von Willebrand factor to platelets. Blood 1998; 91:1572–1581.

126. Allen S, Abuzenadah AM, Blagg JL, Hinks J, Nesbitt IM, Goodeve AC, et al. Two novel type 2N von Willebrand disease-causing mutations that result in defective factor VIII binding, multimerization, and secretion of von Willebrand factor. Blood 2000; 95:2000–2007.

127. Mazurier C, Goudemand J, Hilbert L, Caron C, Fressinaud E, Meyer D. Type 2N von Willebrand disease: clinical manifestations, pathophysiology, laboratory diagnosis and molecular biology. Best Pract Res Clin Haematol 2001; 14:337–347.

128. Castaman G, Rodeghiero F, Tosetto A, Cappelletti A, Baudo F, Eikenboom JC, et al. Hemorrhagic symptoms and bleeding risk in obligatory carriers of type 3 von Willebrand disease: an international, multicenter study. J Thromb Haemost 2006; 4:2164–2169.

129. Federici AB. Clinical diagnosis of von Willebrand disease. Haemophilia 2004; 10 (Suppl 4):169–176.

130. Othman M, Hamilton A. Platelet-type von Willebrand disease: results of a worldwide survey from the Canadian PT-VWD project. Acta Haematol 2010; 123:126–128.

131. Favaloro EJ, Patterson D, Denholm A, Mead S, Gilbert A, Collins A, et al. Differential identification of a rare form of platelet-type (pseudo-) von Willebrand disease (VWD) from Type 2B VWD using a simplified ristocetin-induced-platelet-agglutination mixing assay and confirmed by genetic analysis. Br J Haematol 2007; 139:623–626.

132. Othman M, Notley C, Lavender FL, White H, Byrne CD, Lillicrap D, et al. Identification and functional characterization of a novel 27-bp deletion in the macroglycopeptide-coding region of the GPIBA gene resulting in platelet-type von Willebrand disease. Blood 2005; 105:4330–4336.

133. Murata M, Russell SR, Ruggeri ZM, Ware J. Expression of the phenotypic abnormality of platelet-type von Willebrand disease in a recombinant glycoprotein Ib alpha fragment. J Clin Invest 1993; 91:2133–2137.

134. Turecek PL, Siekmann J, Schwarz HP. Comparative study on collagen-binding enzyme-linked immunosorbent assay and ristocetin cofactor activity assays for detection of functional activity of von Willebrand factor. Semin Thromb Hemost 2002; 28:149–160.

135. Chen D, Daigh CA, Hendricksen JI, Pruthi RK, Nichols WL, Heit JA, et al. A highly-sensitive plasma von Willebrand factor ristocetin cofactor (VWF:RCo) activity assay by flow cytometry. J Thromb Haemost 2008; 6:323–330.

136. Favaloro EJ. An update on the von Willebrand factor collagen binding assay: 21 years of age and beyond adolescence but not yet a mature adult. Semin Thromb Hemost 2007; 33:727–744.

137. Baronciani L, Federici AB, Cozzi G, Canciani MT, Mannucci PM. von Willebrand factor collagen binding assay in von Willebrand disease type 2A, 2B, and 2M. J Thromb Haemost 2006; 4:2088–2090.

138. Hayata K, Nakayama T, Matsushita T, Sakano K. A new binding assay of von Willebrand factor and glycoprotein Ib using solid-phase biotinylated platelets. J Pharmacol Sci 2008; 108:217–221.

139. Zhukov O, Popov J, Ramos R, Vause C, Ruden S, Sferruzza A, et al. Measurement of von Willebrand factor-FVIII binding activity in patients with suspected von Willebrand disease type 2N: application of an ELISA-based assay in a reference laboratory. Haemophilia 2009; 15:788–796.

140. Hillarp A, Stadler M, Haderer C, Weinberger J, Kessler CM, Romisch J. Improved performance characteristics of the von Willebrand factor ristocetin cofactor activity assay using a novel automated assay protocol. J Thromb Haemost 2010; 8:2216–2223.

141. Favaloro EJ, Mohammed S, McDonald J. Validation of improved performance characteristics for the automated von Willebrand factor ristocetin cofactor activity assay. J Thromb Haemost 2010; 8:2842–2844.

Cited By:

This article has been cited 3 time(s).

Current Opinion in Virology
Virus-induced humoral immunity: on how B cell responses are initiated
Zabel, F; Kundig, TM; Bachmann, MF
Current Opinion in Virology, 3(3): 357-362.
10.1016/j.coviro.2013.05.004
CrossRef
Biochimie
Membrane-bound mucin modular domains: From structure to function
Jonckheere, N; Skrypek, N; Frenois, F; Van Seuningen, I
Biochimie, 95(6): 1077-1086.
10.1016/j.biochi.2012.11.005
CrossRef
Journal of Thrombosis and Haemostasis
Characterizing polymorphisms and allelic diversity of von Willebrand factor gene in the 1000 Genomes
Wang, QY; Song, J; Gibbs, RA; Boerwinkle, E; Dong, JF; Yu, FL
Journal of Thrombosis and Haemostasis, 11(2): 261-269.
10.1111/jth.12093
CrossRef
Back to Top | Article Outline
Keywords:

biomarker; blood clotting; cell adhesion; fibrinogen-binding; hemostasis; integrin GPIb; von Willebrand diseases; von Willebrand factor

© 2012 Lippincott Williams & Wilkins, Inc.

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.