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von Willebrand Factor: Form for Function Colin A. Kretz, PhD1

1 Life Sciences Institute, University of Michigan, Ann Arbor, Michigan

Semin Thromb Hemost 2014;40:17–27.

Abstract

Keywords

► VWF structurefunction ► FVIII ► VWF biomechanics ► platelets ► ADAMTS-13

Address for correspondence Andrew Yee, PhD, Life Sciences Institute, University of Michigan, 210 Washtenaw Avenue, Ann Arbor, MI 48109 (e-mail: [email protected]).

The mechanisms by which von Willebrand factor (VWF) achieves hemostasis lie in its structure. Whereas low-molecular-weight forms have diminished hemostatic potential, ultralarge VWF (ULVWF) in excess is potentially thrombogenic. VWF comprises many subunits, which themselves comprise many repeated domains/assemblies possessing characteristic function(s). Organization of these domains/assemblies into a multimeric structure effectively links and replicates these functions. Each domain/assembly influences the synthesis, assembly, secretion, or hemostatic potential of plasma VWF. The C-terminal CT/CK domain mediates dimerization of VWF subunits in the endoplasmic reticulum, while the N-terminal D1D2 assemblies catalyzes disulfide binding between juxtaposed D3 assemblies in the trans-Golgi, creating multimers. The pHsensitive domains (A2–CT/CK) allow ULVWF multimers to orderly pack into tubules that unravel upon secretion into the circulation. Hemodynamic forces regulate the conformation of the A2 domain and thus, its accessibility to proteolytic enzyme(s) that regulate VWF’s hemostatic potential. Binding to the VWF D’D3 assemblies stabilizes coagulation factor VIII. The VWF A1 and A3 domains facilitate platelet capture onto exposed collagen(s) at sites of vascular injury. Our deeper understanding of VWF provided through the recent growth in VWF structure-function studies may potentially guide novel therapeutics for clotting or bleeding disorders.

The balance between coagulation and bleeding is strongly influenced by von Willebrand factor (VWF), whose chemical composition and structure regulates many of its hemostatic properties. In circulation, mature VWF stabilizes blood coagulation factor VIII (FVIII) and recruits platelets to sites of vascular injury where extracellular matrix proteins may be exposed. While high plasma levels of VWF positively correlates with thrombotic risks associated with cardiovascular and cerebrovascular disease, qualitative or quantitative deficiencies in VWF lead to increased bleeding risks associated with von Willebrand disease (VWD).1,2 Further highlighting VWF’s role in hemostasis, VWD patients exhibit a reduced incidence of arterial thrombosis but an increased risk for hemorrhagic stroke compared with non-VWD patients with cardiovascular disease.3,4 The mechanical properties of VWF and the affinity for its binding partners are particularly critical to thrombogenesis in stenosed arteries where pathological hemodynamic forces may otherwise prevent platelet

capture, an initial step for arterial thrombosis.5–9 The structure of each VWF domain largely dictates how VWF responds to its environment, thus regulating VWF function. Association of VWD mutations with their consequent phenotype has guided VWF structure-function studies. VWD mutations generally cluster in VWF domains that give rise to the subcategories of type 2 VWD (qualitative defects).2 For example, in VWD type 2N (reduced FVIII but often accompanied by normal VWF levels), most mutations lie in the FVIIIbinding region of VWF, disrupting the formation of the FVIII– VWF complex.2,10 Similarly, most mutations that give rise to VWD type 2B (increased affinity for platelets) or to VWD type 2M (decreased affinity for platelets) are located in the plateletbinding region of VWF.2,10 However, some mutations may also result in multiple phenotypes. Particularly, a few VWD type 2B and 2M mutations are also associated with decreased collagen binding,11,12 suggesting that VWF contains multifunctional domains or that interdomain interaction(s) exist. Dissection of

published online December 13, 2013

Copyright © 2014 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

Issue Theme Hot Topics V; Guest Editor, Emmanuel J. Favaloro, PhD, FFSc (RCPA).

DOI http://dx.doi.org/ 10.1055/s-0033-1363155. ISSN 0094-6176.

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Andrew Yee, PhD1

von Willebrand Factor

Yee, Kretz

VWF at the molecular level and the development of a VWFdeficient mouse13 have led to advancement in the understanding of the mechanisms by which the architecture of VWF regulates its function.

VWF Domain Organization Plasma VWF circulates as a large, cysteine-rich glycoprotein with multiple subunits concatemerized together by disulfide bonds. Cysteines are the most abundant amino acid in VWF (234/2,813) and are heterogeneously distributed within each subunit, resulting in many disulfide bonds that support unique domain structures and impart characteristic functions. Cloning and sequencing of VWF allowed domain assignment to segments of amino acids based on sequence homology to other proteins and on homologous repeats within VWF, providing a structural map to which functional domains relate.14–19 Recent advances in single particle imaging and analysis of proteins along with protein sequence alignments to updated databases have led to the refinement of the VWF structure map.20 In addition to redefining domain boundaries (►Fig. 1 and ►Table 1), each domain (aside from the already well characterized A domains) has been further characterized with subdomain modules (►Fig. 1 and ►Table 2).20 The N-terminal D domains of VWF (D1–D3) have been reclassified as D assemblies comprising VWDn (VWF domain, where n ¼ 1, 2, or 3), cysteine-8 (C8), trypsin-inhibitor–like, and E modules, each of which are characterized by intramolecular disulfide bridges and are described as domains within other proteins.20,21 Per module, these intramolecular disulfide bridges appear conserved across all D assemblies. The C-terminal section of VWF (distal of the A domains) is reorganized into the D4 assembly, six C domains, and a C-terminal cysteine-rich (CT) domain (also known as cysteine knot domain, CK), a configuration corroborated by the discrete structures observed from electron microscopy of VWF truncations and by proper folding and

secretion from mammalian expression systems.20,22 Distinct from the D1, D2, D’, and D3 assemblies, the D4 assembly lacks a C-terminal E module and contains a unique N-terminal module (D4N) to which the VWD4 module links via a predicted disulfide bond.20 The four modules within the D4 assembly can be seen as four tightly packed lobes by electron microscopy.20 The six tandem C domains lie distal of the D4 assembly and have similar sizes (64–85 amino acids) and shape (elongated globules, as seen by electron microscopy).20 Like the D assemblies, the VWF C domains are rich in cysteines which are predicted to form mostly intradomain disulfide linkages.20 Although regarded as a separate entity in the updated VWF domain annotation, the C2–C3 loop may be important for supporting the proper conformation of the C-terminus of the C2 domain.20 The CT/CK domain composes the C-terminus of each VWF subunit and has structural homology with the CT/CK domain of other proteins, particularly mucins, tissue growth factor β (TGF-β), and Norrie disease protein.18,23,24 Although a crystal structure has yet to be reported, a molecular model of the VWF CT/CK domain has been constructed based on TGF-β.24 Despite the low-sequence homology among the CT/CK domain of different proteins, this domain is structurally conserved, characterized by two disulfide bridges that form a ring through which a third disulfide bridge threads and by four structurally conserved β sheets.25 The CT/CK domain has a flat topology with a hydrophobic core.25 The identification of the CT/CK domain in a number of proteins that form heterodimers or homodimers and that have diverse functions supports the postulate that the CT/CK domain stabilizes its conserved hydrophobic core through dimerization.25,26

Biosynthesis and Storage VWF is synthesized in endothelial cells and megakaryocytes but is primarily secreted from endothelial cells through a regulated pathway. The structure of VWF influences its posttranslational modifications and subsequent cellular

Fig. 1 von Willebrand factor (VWF) Domain Organization. The domain organization for pre–pro VWF is shown using the classical notation (A) and the updated notation (B). The signal sequence (SS) is cleaved in the endoplasmic reticulum shortly after translation of the VWF mRNA to generate pro-VWF. The D1–D2 assemblies compose the VWF propeptide, which catalyze multimerization/concatemerization of pro-VWF dimers into a disulfide-linked linear polymer. Furin cleaves the propeptide to generate mature VWF. The location(s) of VWF-binding partners (FVIII, platelet receptors, and collagen) and the site of ADAMTS-13 proteolysis are shown. The map is not drawn to scale and is adapted from Zhou et al.20 The coordinates of each domain/assembly are given in ►Tables 1 and 2. Seminars in Thrombosis & Hemostasis

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Table 1 Domain boundaries

a

Updated notationa

Domain

Amino acid span

Domain/assembly

Amino acid span

SS

M1–C22

SS

M1–C22

D1

A23–G386

D1

A23–P385

D2

E387–G745

D2

G386–R763

D’

S764–A865

D’

S764–D864

D3

T866–G1241

D3

A865–Q1238

A1

E1260–G1479

A1

Y1271–D1459

A2

P1480–G1672

A2

R1492–S1671

A3

E1673–G1874

A3

P1684–C1872

D4

P1947–T2298

D4

S1873–T2255

B1

C2296–V2330

C1

Q2256–P2338

B2

C2340–E2365

C2

H2339–T2402

B3

C2375–V2399

C2–C3 Loop

V2403–K2429

C1

N2400–K2515

C3

V2430–P2496

C2

Q2544–K2662

C4

S2497–A2581

CT/CK

C2724–L2813

C5

R2578–P2646

C6

T2647–P2722

CT/CK

E2723–K2813

References for amino acid positions are provided in the text.

packaging and trafficking. Following translation, two proVWF subunits (consisting of D1-CT/CK domains) dimerize at their CT/CK domain in the endoplasmic reticulum (ER) via one or three intermolecular disulfide bonds.24 Despite its structural homology with the CT/CK domain of other proteins, VWF does not dimerize with other proteins that contain a CT/CK domain. Deletion of the C-terminal 151 amino acids, which encompass the CT/CK domain, from VWF results in intracellular degradation of pro-VWF monomers.27 Characterization of cellular fractions of recombinantly expressed Nterminal VWF fragments (D1–D3 assemblies) indicated that the neutral environment of the ER also promotes a transient, intrasubunit disulfide bond between the propeptide (D1D2 assemblies) and the D’D3 assemblies in a small fraction of VWF fragments, which may influence VWF ER-to-Golgi transport.28 The mechanism(s) by which intermolecular and intramolecular VWF interactions form in the ER requires further investigation. Posttranslational modifications continue for pro-VWF homodimers following transport to the Golgi. Following further glycosylation and acclimation to the acidic environment, pro-VWF dimers begin to assemble into multimers in the trans-Golgi via a process deduced from biochemical and electron microscopy studies with VWF fragments spanning the A1–CT/CK domains or the D1–D3 assemblies. Exposure of VWF fragments (A1–CT/CK) to acidic pH induces selfassociation between parallel domains (A2–C6) of the two subunits within a dimer, accompanied by a twist(s) along the

Table 2 Modules within VWF D assembliesa Assembly

Modules

Amino acid span

D1

VWD1

A23–S204

C8–1

P205–C291

TIL1

S292–P349

E1

C350–P385

VWD2

G386–K564

C8–2

Q565–C648

D2

D’ D3

D4

TIL2

E649–P708

E2

C709–R763

TIL’

S764–P828

E’

C829–D864

VWD3

A865–V1037

C8–3

P1038–C1126

TIL3

P1127–P1197

E3

V1198–Q1238

D4N

S1873–C1948

VWD4

V1949–Q2124

C8–4

P2125–C2199

TIL4

A2200–T2255

Abbreviaion: VWF, von Willebrand factor. a Coordinates of modules within D assemblies adapted from Zhou et al.20 Seminars in Thrombosis & Hemostasis

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Classical notationa

von Willebrand Factor

Yee, Kretz

longitudinal axis of the dimer at the VWF C domains.20,22 The acidic pH and calcium content in the trans-Golgi also alters the N–terminal conformation of the propeptide such that the D1D2 assemblies of VWF fragments spanning D1–D3 dissociate from the D’D3 assembly and dimerizes with the other D1D2 assemblies of the same pro-VWF dimer.29 With this rearrangement, D1–D3 fragments aggregate into helical coils that are sufficiently large to represent ultralarge VWF (ULVWF) and that are structurally similar to the VWF coils observed in Weibel–Palade bodies (WPB), the VWF storage vesicles in endothelial cells.29,30 More importantly, the dimerized D1D2 assemblies can then catalyze disulfide bonds (C1099–C1099 and C1142–C1142) between proVWF dimers juxtaposed to each other (i.e., interdimer disulfide bridging).29,31 This oxidoreductase activity of the propeptide requires protonation of H395 (achieved by the acidic pH) and a positive charge at amino acid position 460 (normally occupied by a histidine residue whose functional group is positively charged).32 The D1D2-dimer is cleaved by furin (between R763 and S764) in the trans-Golgi but remains noncovalently associated with mature, multimeric VWF.33,34 Although proteolytic processing of the propeptide is not necessary for multimer formation,35–37 several mutations (scattered across the gene) alter VWF multimerization.38 Deletion of the propeptide results in a secreted VWF dimer (ΔPro) whose subunits are linked only at the CT/CK domain, demonstrating that the D’D3 assemblies alone do not possess the ability to form intermolecular disulfide bonds.39 Vesicles containing multimeric VWF exit the trans-Golgi and mature into WPB through a multimerization-independent and cytoplasmic protein–dependent pathway(s).40–42 Whether mature, multimeric VWF can or cannot self-assemble into a compact, coiled structure independently of cellular components remains to be seen.

Factor VIII Stabilization VWF derives part of its hemostatic potential by stabilizing plasma FVIII. Nilsson et al first demonstrated the dependency of plasma FVIII stability on circulating VWF by transfusing plasma fraction I-O from a hemophilia A patient (deficient in FVIII but not VWF) into a VWD patient (deficient in VWF but not FVIII), which resulted in a transient elevation of FVIII levels from approximately 5% to a peak of approximately 20%.43 This stabilization effect is achieved through the noncovalent interaction between circulating VWF and plasma FVIII, which results in a tightly bound complex (KD ¼ 0.2–0.9 nM).44–47 High-molecular-weight and low-molecular-weight multimeric VWF have similar binding affinities for FVIII.48 VWD patients characterized with loss of high-molecularweight VWF multimers (i.e., VWD types 2A and 2B) have a FVIII-to-VWF antigen (VWF:Ag) ratio (a measure of FVIII levels normalized to VWF levels in plasma) comparable with that of healthy controls.12,49 However, Turecek et al suggest that lower-molecular-weight forms of VWF may have a decreased FVIII-binding capacity.50 In the absence of VWF, FVIII is rapidly cleared from the circulation, explaining the moderate hemophilia-like phenotype in the setting Seminars in Thrombosis & Hemostasis

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of severe VWF deficiency.2,13 VWF mutations that prohibit FVIII binding (VWD type 2N) also results in a rapid clearance of FVIII, leading to a mild-to-moderate hemophilia-like phenotype.2 The N-terminal structure of circulating, mature VWF strongly influences plasma FVIII stabilization. Mutations in VWF that inhibit furin-mediated cleavage of the propeptide prevent FVIII binding to multimeric VWF, likely because of steric hindrance.35–37 Similar to mature VWF, ΔPro begins the N-termini with S764 but exhibits a sixfold reduced affinity for FVIII, suggesting that propeptide processing of the D’D3 assemblies optimizes VWF for FVIII association.47 Interestingly, although each molecule of mature VWF contains multiple copies of FVIII-binding sites that may be saturated in vitro, the stoichiometry is about 1 FVIII molecule to 50–100 subunits of VWF in vivo.44,48 Although a detailed structure of VWF in complex with FVIII has yet to be solved, several lines of evidence point to the importance of the D’D3 assemblies in binding FVIII. Proteolysis with granzyme M removes S764–L1039 from mature VWF and abolishes the FVIII-binding capacity of multimeric VWF.51 A minimal, proteolytic VWF fragment spanning S764–R1035, which compose the N-terminus of the D’D3 assembly and excludes the cysteines (C1099 and C1142) that coordinate multimerization, has been reported to bind FVIII.52 Peptide mapping the VWF D’ assembly has implicated residues L809–E818, R826–A837, and R852–C863 in forming a docking site for FVIII.53 Disruption of the D’ structure by nonsynonymous mutations, C788Y and C858F, leads to a loss of VWF-FVIII interaction.54 Chemical footprinting of FVIIIbound VWF identified K773 within the D’ assembly as an important residue in forming the FVIII-binding site of VWF.55 However, the S764–R1035 proteolytic fragment of VWF has a weaker affinity for FVIII (KD ¼ 48.5 nM) than for a longer, proteolytic VWF fragment (S764–E2128, KD ¼ 0.82 nM), implicating a role for VWF segments distal of R1035 in stabilizing FVIII.46 Although a majority of registered VWD type 2N mutations lie within the S7640–R1035 segment, a few are located C-terminal of R1035.10

Hemostatic and Thrombotic Mechanisms Platelet recruitment to sites of vascular injury additionally defines VWF’s hemostatic potential. VWF responds to acute changes in the blood flow patterns through conformational changes that activate its adhesive properties. In pressuredriven flow, such as in blood vessels, a velocity gradient is formed between the center of the vessel (where the fluid axial velocity reaches a maximum) and the vessel wall (where the fluid axial velocity is zero because of friction). This flow profile can be described as a simple shear flow. The velocity gradient in shear flow defines the shear rate (expressed with a unit of reciprocal time) and is maximal nearest to the wall. Objects within the flow field (e.g., blood constituents and the vessel wall) are subject to mechanical deformation (i.e., physical distortion), which can be described as a combination of shear stresses (the tangential forces per unit area) and normal stresses (the perpendicular forces per unit area).

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The former is mathematically defined as the product of the shear rate and the fluid viscosity whereas the latter is defined as the fluid pressure. Because the vessel wall is stationary relative to the axial velocity of flowing blood, the deformation at the vessel wall surface is usually described by the shear stress. Conversely, blood components may be located anywhere within the flow field and experience varied levels of stress (though greatest near the wall); thus, the amount of force exerted in the fluid phase is usually enumerated by the shear rate. Furthermore, shear flow can be mathematically represented as a combination of rotational and elongational components (i.e., vorticity and elongational rate, respectively).56 The extended state of polymers such as DNA and VWF under shear flow (i.e., polymers under tension) is destabilized by end-over-end tumbling caused by the rotational component (i.e., compaction of extended polymers).56 Under pure elongational flow (i.e., no rotational component), polymers extend longer and show a greater sensitivity to the rate of deformation (i.e., elongational rate dominates shear rate as vorticity goes to zero).56,57 In stenotic vessels and at sites of vessel wall rupture, the change in vessel wall geometry causes an increase in the elongational component of shear flow, which is thought to promote the stabilization of tensile forces applied to VWF.57,58 Severe vascular stenosis has been estimated to increase the shear rate by 1 to 2 orders of magnitude (from 103 to 104–105/s).6,7 The peak tension experienced by extended VWF increases with the square of the length of a VWF multimer, indicating that the higher-molecular-weight forms of VWF are subject to greater deformation.58 Less conformational changes can be detected in VWF composed of two subunits than in multimeric VWF exposed to the same shear rate.59 Furthermore, the critical shear rate at which VWF extends depends on its initial conformation; molecular modeling of VWF predicts that a greater shear rate (approximately 100-fold) is required to unravel and extend VWF from a collapsed, globular state than from a loosely coiled state.60 The maximal shear rate near the wall likely causes highly dynamic conformational changes in VWF that facilitates rapid platelet capture to sites of vascular damage. Binding to several types of collagen as well as other extracellular matrix proteins in an injured vessel exposed to flowing blood is thought to immobilize and tether VWF.19,61 The VWF A1 and A3 domains both bind to fibrillar and pepsin-treated (i.e., exposed telopeptides) collagen types I and III.62–64 VWF also binds to fibrillar and pepsin-treated collagen type VI but primarily through the A1 domain, which is more pronounced with pepsin-treated collagen type VI.65,66 Low-molecular-weight forms of VWF appear to have a lower avidity for collagen types I, III, and VI than high-molecular-weight VWF multimers.12 VWF interacts with collagens under stasis and flow, puzzling the role of fluid force–induced conformational changes in VWF immobilization. Schneider et al suggest that (1) below a critical shear rate, VWF remains coiled in a flowing fluid which may disrupt weak VWF-collagen interaction(s) and that (2) above the critical shear rate, coiled VWF transitions into an extended conformation that exposes multiple collagen-binding sites, promoting firm adherence because of an increased avidity.60 Using a microfluidic chamber to

Yee, Kretz

model severe stenosis, Colace and Diamond demonstrate that VWF deposits onto collagen type I upon acute exposure to pathological shear rates (104–105/s) in a constricted channel but not in the acceleration zone (proximal to the constriction) where elongational flow dominates.9,57 However, because of its viscoelastic properties, VWF accelerated into a constriction may remain briefly extended. Mechanically extended VWF recoils into its loosely coiled state in approximately 100 to 300 ms (which may be longer for VWF fibers selfassociated into fibrils under shear flow) upon removal of shear forces,59,60 sufficiently longer than required for passage through experimental constrictions where VWF-mediated platelet aggregation initiates.6,9 Importantly, adherent VWF is primarily subjected to elongational flow, which should lower the rate of deformation threshold for extension. Anchored VWF can be seen forming long strings under shear flow.67 The time required to fully extend various sizes of multimeric VWF under different hemodynamic forces has yet to be comprehensively measured. Crystal structure analysis has indicated that upon collagen type III binding, the diverse conformations that the unbound VWF A3 domain adopts are forced into a select conformation in which the VWF collagenbinding interface comprises two hydrophobic patches and one salt bridge.68 Whether binding of collagen type I similarly orders the A3 domain remains to be seen. The requirement of the intramolecular disulfide bridge within the A3 domain (C1686–C1872) for VWF–collagen interaction is not clear. It is noteworthy that mutations (L1696R and P1824H) buried within the A3 domain reduce the affinity of VWF for collagen types I and III, pointing to the importance of the A3 domain structure in mediating hemostasis.69 Although it is tempting to postulate that shear forces facilitate the exposure of the hydrophobic patches in the VWF collagen-binding interface, the mechanism by which the VWF A3 and A1 domains interact with all different types of collagen under mechanical load requires further investigation. The same fluid mechanical forces that elongate multimeric VWF are also responsible for activating the VWF-dependent platelet recruitment mechanism. The initial, transient VWF– platelet interaction decelerates platelets from the high flow environment to facilitate platelet activation necessary for platelet plug formation.70,71 Both the VWF platelet-binding domain (A1) and its platelet receptor (GPIbα) require conformational changes induced by mutations, tension, or a biochemical cofactor to form a heteroduplex. Whether under pure tension or shear flow, A1 in complex with GPIbα exists in two states.8,70 Single molecule experiments have revealed a flex-bond in which A1 weakly binds GPIbα initially before transitioning into a high affinity state with an increasing rate of tension.8 This high affinity state has a bond strength of approximately 10–11.5 pN, which can be achieved in multimeric VWF composed of approximately 200 subunits but not approximately 100 subunits or less subjected to pathological shear stress (100 dyne/cm2).8,58,72,73 The high affinity state between A1 and GPIbα is achieved by stabilizing the C-terminal GPIbα β-switch and the N-terminal GPIbα β-finger onto A1, forming a discontiguous interface that also includes a contact between A1 and several leucine-rich repeats in Seminars in Thrombosis & Hemostasis

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GPIbα.74 Coupling of A1 to GPIbα is also stabilized by longrange electrostatic interactions that reside outside the interface.74 The secondary structures within the A1 domain are held together by a network of salt bridges whose organization might be optimized for GPIbα binding by an intramolecular disulfide bridge.75,76 Flanking residues that extend from the characteristic intramolecular disulfide bridge (particularly the N-terminal arm) are thought to mask the A1 interface for GPIbα but unfold under mechanical, biochemical, or genetic influences to expose the GPIbα-binding residues.74,75,77–80 Transiently tethered platelets are subsequently secured through the interactions between the VWF RGD amino acid sequence in the C4 domain and its platelet receptor GPIIb/IIIa, the target of abciximab and eptifibatide, and between other ligands and their platelet receptors.20,81,82 Biochemical activation of A1 with either ristocetin, an antibiotic, or botrocetin, a snake venom, results in VWFdependent platelet aggregation. However, these cofactors bind to different sites of VWF, resulting in different mechanisms of A1 activation that may confound ristocetin-based VWD diagnosis.75,83,84 The mechanism by which ristocetin induces A1-GPIbα binding simulates mechanically induced A1 activation more closely than botrocetin.8,85 In addition, whereas botrocetin is insensitive to the size of VWF, ristocetin induces VWF–GPIbα interaction preferentially with highermolecular-weight forms of VWF.86 Consequently, patients with VWD types 2A or 2B (i.e., absence of high-molecularweight forms of VWF) exhibit a diminished VWF ristocetin cofactor activity (VWF:RCo)-to-VWF:Ag ratio (a measure of platelet-binding activity normalized to plasma VWF levels) relative to healthy controls.12,49,87–89 Noteworthy, VWD type 2B mutations that increase the affinity of A1 for GPIbα lead to enhanced VWF proteolysis (discussed later) and thus lead to the ironically low VWF:RCo-to-VWF:Ag ratio. The biomechanics of multimeric VWF are in agreement with the observations that high–molecular-weight forms of VWF have a greater hemostatic and thrombotic potential than low-molecular-weight forms. Mutations that give rise to VWD types 2A and 2B result in a loss of high-molecularweight VWF, leading to an increased bleeding risk.2 Compared with healthy controls, whole blood from VWD type 2A or 2B patients perfused over collagen type I at high shear rates ( > 1,000/s) exhibit markedly diminished thrombogenesis.90 In agreement, mouse models of VWD types 2A and 2B have a strikingly reduced capacity to occlude arterioles challenged with ferric chloride.91,92 Conversely, plasma from mice with circulating ULVWF perfused over collagen type I at a shear rate of 750/s exhibit accelerated thrombogenesis.93 Interestingly, disulfide reduction of ULVWF to smaller-molecularweight multimers with N-acetylcysteine results in a reduced thrombotic risk, possibly because of diminished platelet or collagen-binding activity.94–96

Multimer Size Regulation Controlling the size of multimeric VWF in the circulation is crucial to maintaining the balance between bleeding and thrombotic risks. Electron microscopy of plasma VWF has Seminars in Thrombosis & Hemostasis

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estimated the length of each multimeric strand to be approximately 0.1–2 μm.97 Although all sizes of multimeric VWF may be secreted, exocytosis of WPB in endothelial cells releases predominantly high-molecular-weight VWF that may partially comprise ULVWF that can stretch to more than 100 μm in length under shear flow and that is rapidly processed to reduce VWF’s thrombotic potential.67,98 Moake et al first proposed a VWF depolymerase with proteolytic or disulfide-reducing properties that regulate the size of VWF.99 This depolymerase was later identified by four independent groups as ADAMTS-13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member-13), a metalloprotease produced from hepatic stellate cells and secreted into the circulation.100–105 As in the regulation of VWF’s adhesive properties, hemodynamic forces also regulate the enzymatic cleavage of multimeric VWF by ADAMTS-13 through mechanically induced conformational changes in VWF. ADAMTS-13 proteolyzes the bond between Y1605 and M1606 in the VWF A2 domain.106,107 This bond is normally inaccessible without any denaturation or deformation of VWF.67,106–108 Single molecule experiments employing optical tweezers have revealed that increasing tensile forces exponentially accelerate the rate of A2 unfolding and that the minimum unfolding force depends not only on the length of VWF but also logarithmically on the rate of applied tension.58 The intrinsic A2 unfolding rate (no tension) is very slow (ku0 ¼ 0.0007–0.003/s).58,109 Also, unfolded A2 exhibits compliance and a slow intrinsic refolding rate (kf0 ¼ 0.1–0.7/s) that results in A2 refolding on a time scale sufficiently long (seconds) for ADAMTS-13 cleavage (kcat/KM ¼  1–10/μM/s).58,109–111 These viscoelastic properties characterize the A2 domain as a VWF force-sensor in that only sufficiently long VWF multimers (especially ULVWF) may be unfolded by physiological tensile forces (i.e., arterial levels of shear rate) and allow ADAMTS-13 proteolysis.58 Comparable findings of tension-induced unfolding of larger VWF fragments that span all A domains confirm the A2 domain as a force-sensor, but that flanking VWF domains may bear some of the tensile stress.112 Although yet to be directly tested, deformation of the disulfide bridges resident in the A1 and A3 domains are not likely to contribute to VWF unfolding as simple models of disulfide bonds in peptides resist breaking at tensile forces that are at least 10-fold greater than the unfolding force estimated for VWF.58,112,113 The A1, A2, and A3 domains are similarly structured (►Fig. 2), but three key features confer unique mechanosensitive properties specifically to the A2 domain.109,114–116 First, the position where the α4 helix resides in the A1 and A3 domains is instead occupied by an unstructured α4-less loop in the A2 domain.114 Though unstructured, the α4-less loop achieves conformational stability through only two charged interactions with neighboring α helices and shields the Y1605/M1606 scissile bond located on the β4 sheet that is buried in the A2 hydrophobic core.114 This configuration may have been evolutionary selected to weaken the stability that an α-helix would otherwise provide, thereby reducing the unfolding force threshold or slowing A2 refolding.114 Second, a C-terminal vicinal disulfide bond (C1669–C1670) locks the hydrophobic core by interacting with the β4 sheet, forming a

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Fig. 2 The von Willebrand factor (VWF) A domains. The crystal structures for the VWF A1 (A, PDB 1AUQ), 75 A2 (B, PDB 3ZQK), 116 and A3 (C, PDB 1ATZ)135 domains were visualized in PyMOL and are shown to highlight the unique features of the A2 domain. The N-terminus (N) and C-terminus (C) are marked. All three A domains are similarly structured with core β-sheets and outer α-helices (light blue). However, the A2 domain contains the ADAMTS-13 cleavage site (Y1605/M1606T, red) in its β4 sheet. The unstructured α 4 -less loop in the A2 domain (dark blue, B) corresponds to the α 4-helix in the A1 and A3 domains (dark blue, A and C, respectively). A single disulfide bond (yellow) is formed by vicinal cysteines in the A2 domain (B) but by distant cysteines that link the N- and C-termini of the A1 and A3 domains (A and C). Whereas the A1 and A3 domains contain no metal-binding sites, the A2 domain contains a calcium- (gray sphere, B) binding site.

tension-resisting substructure that balances the relatively loose conformation of the α4-less loop and establishes a threshold at which elongational forces must overcome to unfold the A2 domain.114,117 Third, a calcium ion bound to the α3β4 loop stabilizes the native, unfolded A2 conformation and coordinates quicker refolding of stressed A2.109,115,116 Mutations that affect any of these three features result in an increased susceptibility to ADAMTS-13 proteolysis, leading to VWD type 2A group 2, and highlight that the force balance between hemodynamics and VWF viscoelasticity maintains VWF’s hemostatic potential.116–118 Conversely, ADAMTS-13 deficiency leads to an accumulation of ULVWF and raises the risk of thrombosis.93,119,120 Many other factors affect ADAMTS-13–mediated proteolysis of VWF. Cleavage at the Y1605/M1606 scissile bond depends on VWF interaction with ADAMTS-13 exosites. ADAMTS-13 is composed of an N-terminal metalloprotease domain, a disintegrin-like domain, a cysteine-rich domain, a spacer domain, eight thrombospondin type 1 (TSP) domains, and two C-terminal CUB domains. Contacts between the ADAMTS-13 fifth and eight TSP and CUB domains with discontiguous segments of the VWF D4–C6 domains and between the ADAMTS-13 spacer, disintegrin-like, and the metalloprotease domains with discontiguous segments of the VWF A2 domain position the metalloprotease active site over the VWF Y1605/M1606 scissile bond.121 Importantly, the selfassociation of VWF induced by acidic pH (i.e., in the transGolgi and WPB) unpacks at neutral pH (i.e., in plasma), which avail the VWF D4–C6 domains to ADAMTS-13.22 The modest interaction (KD ¼ 100 nM) between the C-terminal sections of ADAMTS-13 and VWF122 suggests that these two proteins may exist as a complex in circulation and that intermediately sized or uncleaved high-molecular-weight plasma VWF may be primed for proteolysis upon elongation. However, the behavior of the VWF D4-CK domains under shear and elongational flow has yet to be fully understood.

Adding mass to VWF under shear flow sensitizes the A2 domain to ADAMTS-13 proteolysis. Whether modeled as a chain of beads-and-rods or beads-and-springs, polymers stretch and align along the flow axis as elongation or shear rates increase, with larger structures exhibiting greater sensitivity.123,124 Likewise, shear-induced binding of platelets to high-molecular-weight VWF result in extended complexes that are akin to beads on a string and that are preferentially and multiply cleaved by ADAMTS-13.67,125,126 In VWD type 2B, mutations increase the affinity of A1 for GPIbα, causing spontaneous VWF–platelet interactions that are expected to promote shear-dependent proteolysis by ADAMTS-13 and subsequent loss of high-molecular-weight VWF.2,127 Conversely, VWD type 2M mutations decrease the affinity of A1 for GPIbα, which likely explains a slight increase in highmolecular-weight forms of VWF.2 In addition, FVIII (specifically its light chain) has also been reported to enhance ADAMTS-13-mediated proteolysis of multimeric VWF by an unknown mechanism that is unlikely due to the added mass (approximately 70 kDa for FVIII light chain vs. approximately 50 MDa for 200-mer VWF).128 However, severely hemophilic patients do not present with ULVWF and have VWF multimer patterns that are no different from pooled normal plasma.129 The redox state of VWF and its role in ADAMTS-13mediated proteolysis has recently been gaining attention. Shear force induced deformation and biochemical denaturation (e.g., ristocetin and urea) predisposes VWF to oxidation by reactive oxygen species, a marker of inflammation.108,130,131 Oxidation of VWF by either hypochlorous acid (HOCl) or a combination of hydrogen peroxide (H2O2) and myeloperoxidase (MPO) converts methionine to methionine sulfoxide, resulting in the inhibition of ADAMTS-13mediated cleavage and an enhancement of VWF’s adhesiveness.130,131 Interestingly, though resistant to ADAMTS-13 cleavage, oxidized VWF remains prone to proteolysis by leukocyte serine proteases (e.g., elastase and cathepsin G), Seminars in Thrombosis & Hemostasis

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pointing to alternative mechanisms that may control the size of VWF.132 Noteworthy, other proteases (e.g., plasmin, thrombin, and matrix metalloproteinase 9) have been reported to cleave VWF.133,134

11 Larsen DM, Haberichter SL, Gill JC, Shapiro AD, Flood VH. Vari-

Conclusion

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Biophysical, biochemical, genetic, and clinical perspectives have culminated into a greater understanding of the structural and molecular biology of VWF. Assembly of findings across multiple disciplines seems to parallel the structure-function of VWF. Each VWF domain possesses unique feature(s) that define their function(s) and that alone may not fully achieve hemostasis. Functional selection of VWF domains and their orchestration into a flexible multimer that is highly responsive to hemodynamic forces have resulted in a hemostatically competent molecule that balances blood between bleeding and thrombosis. The insights gained from the recent growth in studies of VWF structure-function may guide the development of novel therapeutics for bleeding or clotting disorders.

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Acknowledgement We thank Dr. David Ginsburg for helpful comments in the preparation of this review article.

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Seminars in Thrombosis & Hemostasis

Vol. 40

No. 1/2014

27

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von Willebrand Factor

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