INTRODUCTION — Von Willebrand factor (VWF) is a large multimeric glycoprotein that performs two critical functions in primary hemostasis: it acts as a bridging molecule at sites of vascular injury for normal platelet adhesion, and under high shear conditions, it promotes platelet aggregation. VWF has a third function that is important in fibrin formation, acting as a carrier for factor VIII in the circulation that maintains the normal level of factor VIII by decreasing the clearance of factor VIII fivefold [1,2].
A bleeding disorder called von Willebrand disease (VWD) occurs when VWF is deficient or qualitatively abnormal. VWD is the most common of the inherited bleeding disorders, with an estimated prevalence in the general population of 1 percent by laboratory testing [3]. Symptomatic VWD is less common, approximately 0.01 percent, as estimated in hemostasis clinics [4]. Although it is primarily a congenital disorder, there are also acquired forms of the disease.
Evaluation of patients with these disorders has improved our understanding of the functions of VWF and the pathophysiology of VWD. This has taken on greater importance as the role of VWF in inflammation, angiogenesis, and in thrombotic diseases, such as thrombotic thrombocytopenic purpura and other forms of VWF-mediated thrombosis, is increasingly recognized [5-13], and the use of new therapies for inhibiting VWF interactions is being explored [14-16].
The biology and normal functions of VWF will be reviewed here.
Diagnosis and management of disorders associated with deficient or abnormal VWF (eg, inherited VWD, acquired von Willebrand syndrome) are discussed separately:
●Pathophysiology of inherited VWD – (see "Classification and pathophysiology of von Willebrand disease")
●Diagnosis of inherited VWD – (see "Clinical presentation and diagnosis of von Willebrand disease")
●Treatment of inherited VWD – (see "von Willebrand disease (VWD): Treatment of major bleeding and major surgery")
●Diagnosis and treatment of acquired VWS – (see "Acquired von Willebrand syndrome")
BIOLOGY OF VWF — The gene for VWF is located on the short arm of chromosome 12 and is composed of 178 kilobases (kb) and 52 exons [17-20]; the VWF mRNA contains approximately 9 kb. A pseudogene is present on chromosome 22 that includes exons 23-34 of the VWF gene; these exons correspond to regions of the authentic gene that encode domains A1, A2, and A3 (see 'Domain structure' below) [21,22].
Synthesis — Von Willebrand factor is synthesized in endothelial cells [23] and megakaryocytes as a primary translation product of 2813 amino acids; it subsequently undergoes considerable processing, including dimerization and multimerization to very large forms [24]. The primary translation product contains a signal peptide of 22 amino acids followed by a propeptide of 741 residues, also known as VWF propeptide (von Willebrand antigen II) [25,26], and a mature subunit of 2050 amino acids [27]. A number of the processes described below occur simultaneously, including multimerization, tubule and Weibel-Palade body formation, and cleavage of the propeptide.
Dimerization occurs early during processing of the protein by formation of interchain disulfide bonds between the C-termini of the pro-VWF within the endoplasmic reticulum [28]. The addition of N-linked carbohydrate residues also occurs in the endoplasmic reticulum, a process that is critical to the formation of dimers and subsequent exit from this compartment [24].
The pro-VWF dimers are transported to the Golgi, where further glycosylation and sulfation occurs [29] and multimers are formed by disulfide bond formation between D3 regions of the N-termini of the pro-dimers. Cleavage of the prosequence by furin occurs at approximately the same time, but the prosequence remains to interact with the VWF protein to support multimer formation [30].Multimers of a spectrum of sizes are formed, some of which are exceedingly large, more than 20 million daltons. The presence of the propeptide is necessary for multimer formation [31], as is a low pH environment and calcium ions [32,33].
Tubule formation, which allows compaction of VWF, occurs during pro-VWF multimerization, and tubule formation drives formation of Weibel-Palade bodies where VWF is stored as large tubular multimers [34,35]. During activated release of VWF from Weibel-Palade bodies, the pH rises from the more acidic tubule environment to neutral, and this may allow the tubules to unfold in an orderly manner without tangles [30,36]. The pH change may also allow the cleavage of the prosequence by furin which occurs at approximately the same time [37].
Synthesis of VWF is regulated in part by hormones. As an example, VWF production in endothelial cells is increased by both estrogen and thyroid hormone [38,39], and increased estrogen levels during pregnancy lead to higher levels of VWF during the second and third trimesters [40].
Storage of VWF — Weibel-Palade bodies and the alpha granules of platelets serve as storage sites for VWF [41]. These granules contain ultralarge and large multimers that serve as the most hemostatic forms of VWF, and they are rapidly released by stimulation into the circulation where local hemostasis is needed. They also contain a number of proteins besides VWF including P-selectin, tissue plasminogen activator (TPA), CD63, osteoprotegerin, angiopoietin-2, interleukin 8, and others [30,42-45].
Release of VWF — VWF is released from endothelial cells in three ways [46,47]: –
●Stimulated secretion of ultralarge and large VWF multimers from Weibel-Palade bodies releases VWF apically (into the vessel lumen).
●Nonstimulated constitutive secretion releases dimers and smaller multimers basolaterally (directed to the subendothelial extracellular matrix).
●Nonstimulated basal secretion (regulated but independent of stimulation) releases ultralarge and large multimers apically that presumably had been targeted to and are released from Weibel-Palade bodies. Multimers from basal release may comprise 50 percent of circulating VWF [47].
Stimulated release of the ultralarge and large multimers from Weibel-Palade bodies occurs in response to a number of physiologic agonists, including alpha-adrenergic agonists (such as epinephrine), thrombin, fibrin, and histamine, and after the administration of the vasopressin analogue DDAVP; G proteins play a role in the secretion [48-50]. DDAVP is used therapeutically to raise VWF levels in disorders such as VWD and uremic platelet dysfunction [49,51]; the mechanism by which it releases VWF is not fully understood, but activation of the endothelial vasopressin V2R receptor and c-AMP mediated signaling are involved [52].
Coalescence of the Weibel-Palade bodies to form pods occurs before VWF secretion [53]. During stimulated release, ultralarge multimers assemble into long strands under shear stress that remain anchored to the endothelial cells by P-selectin [54]. This allows binding of additional VWF molecules, platelets, and ADAMTS13, the primary enzyme that breaks down VWF in the circulation [54-56]. Shear stress-induced self-association producing the long strands depends on a number of sites in VWF, including unfolded A2 regions (figure 1) [57]. Ristocetin can mimic the changes induced by shear stress-induced self-association [58].
Shear stress-induced self-association of VWF is influenced by several molecules:
●High-density lipoprotein (HDL) opposes self-association, decreasing VWF strand size and influencing subsequent platelet adhesion [59].
●Low-density lipoprotein (LDL) enhances self-association and opposes HDL, regulating the length and thickness of VWF fibers produced under shear [60].
●Thrombospondin-1 influences self-association by disulfide exchange with VWF [61].
These processes and molecules may yield further targets for treatment modalities for thrombotic disorders [62].
ADAMTS13 and VWF multimers — The spectrum of VWF multimers released by agents such as DDAVP, thrombin, and collagen includes larger multimers than those usually present in the circulation [63]. Processing of the ultralarge VWF multimers takes place in the plasma within about four hours and is mediated by the metalloproteinase ADAMTS13, which is synthesized in, and released from, hepatic stellate cells, megakaryocytes, platelets, and endothelial cells [64-67]. This enzyme converts the ultralarge multimers into the slightly smaller forms normally present in the circulation by cleaving VWF in its A2 domain; it cleaves smaller (normal) VWF multimers as well, leading to the series of multimer sizes seen in the circulation [56,68-73]. Cleavage occurs preferentially on strings of VWF tethered to the endothelial surface and complexed with platelets; the fluid shear stress acting on VWF so tethered reveals the scissile bond Tyr1605-Met1606 for cleavage [74,75]. In vitro studies performed under static conditions have shown that ADAMTS13 is constitutively released from the Golgi of endothelial cells; it attaches along the entire length of the VWF where it cleaves the newly formed VWF [76]. Factor VIII plays a role in accelerating the proteolysis of these ULVWF multimers by ADAMTS13, and factor H, also released by endothelial cells, plays an inhibiting role in this cleavage [77-79].
The coding sequence of ADAMTS13 reveals that the protein is a member of the ADAMTS family of metalloproteinases (A Disintegrin And Metalloproteinase with ThromboSpondin motifs) [80-82].
The physiologic importance of the ADAMTS13 protease (the VWF cleaving enzyme) is illustrated by the presence in plasma of individuals with thrombotic thrombocytopenic purpura (TTP) of ultralarge, prothrombotic VWF multimers. This can be due to antibodies to ADAMTS13 or a congenital deficiency of the enzyme [5,6]. Individuals with TTP develop widespread platelet microthrombi in small arterioles and capillaries. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis'.)
In addition, animal studies have revealed that spontaneous thrombi are formed in microvenules in ADAMTS13-/- mice [83]. In animal models of ADAMTS13 inhibition, co-inhibition of the VWF-platelet GPIb interaction was shown to abrogate thrombus formation [84,85]. In vitro evidence indicates that some inflammatory cytokines (eg, interleukin-8) may stimulate the release of ULVWF and others may inhibit ULVWF cleavage (eg, interleukin-6), indicating a linkage between inflammation and thrombosis [86]. (See "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'Deficient ADAMTS13 activity'.)
Another mechanism may play a role in the processing of the unusually large multimers. Thrombospondin-1, by acting as a protein disulfide reductase, has been shown to reversibly generate new thiol groups in VWF and reduce the size of the multimers [87]. The relative importance of thrombospondin-1 in the determination of the size of plasma VWF multimers in humans is not fully understood; however, thrombospondin-1 competes with ADAMTS13 for interaction with the A3 domain of VWF, slowing the proteolysis of VWF by ADAMTS13 [88].
After processing, plasma VWF consists of a series of multimers varying in size from tetramers to multimers of over 40 subunits (greater than 20 million daltons); the basic repeating unit is either a dimer or a tetramer [89,90]. VWF circulates as flexible 2 nm thick strands in a tangled coil configuration [91]. Its structure becomes more linear under conditions of high shear stress such as those observed in small vessels or vessels narrowed by atherosclerotic plaque [92]. The linear conformation appears to be the functional form for binding to the platelet receptor, glycoprotein Ib (GPIb), which mediates platelet adhesion and aggregation under conditions of high shear (see below) [93]. The normal half-life of circulating VWF is approximately 8 to 12 hours.
Clearance of VWF from the circulation — Several different receptors participate in the clearance of VWF from the circulation.
●One mechanism involves the loss of terminal sialic acid with aging of the protein (or due to gene mutations), exposing a penultimate galactose residue [94]. Receptors for this mechanism include:
•The Ashwell-Morrell receptor (which clears hyposialated N-linked galactose residues) [95,96].
•The macrophage galactose-type lectin receptor (which clears O-linked and N-linked galactose residues) [96,97].
●The LRP1 receptor on macrophages clears VWF via exposure of shear stress-induced interactive sites in VWF [97]; N-linked sites within the VWF A2 domain that are exposed by the unfolding of VWF are able to bind to the LRP1 receptor, which mediates clearance [95].
●CLEC4M receptors, members of the C-type lectin domain family 4, bind to and internalize VWF, decreasing VWF levels [98].
●Other receptors are also associated with decreased levels of VWF [97]. (See 'Plasma VWF levels' below.)
Plasma VWF levels — Plasma VWF concentrations vary widely among healthy individuals. The normal concentration of VWF in plasma is 500 to 1000 mcg/dL. Platelets contain approximately 15 percent of the quantity of VWF present in an equal quantity of platelet-poor plasma [99]. Although variable clearance may play a role, other factors are also responsible for the variability in VWF levels, including polymorphisms in the VWF gene [100-104]. Polymorphisms in genes that can modify glycosylation, affect secretion of VWF, or modify VWF clearance from plasma include [103]:
●Genes modifying VWF glycosylation include fucosyltransferases, ABO blood group glycosyltransferases, and beta-galactoside alpha 2,3 sialyltransferase 4.
●Genes modifying VWF secretion include SNARE proteins that are important in the fusion of secretory vesicles with the plasma membrane and gene variations encoding the arginine vasopressin 2 receptor.
●Genes modifying clearance of VWF include single nucleotide variations in genes such as LRP1 (encodes a protein that binds VWF under high shear), CLEC4M (encodes a lectin receptor that interacts with N-linked glycans), and STAB2 (encodes a lectin-like scavenger receptor that is associated with the clearance of VWF and factor VIII).
A portion of the carbohydrate structure in VWF is related to ABO blood type, and it has a major influence on the level of circulating VWF: the plasma concentration of VWF in adults with type O blood is approximately 25 to 30 percent lower than those with types A, B, or AB. This is due to a portion of the carbohydrate present on VWF that is similar to the blood groups and influences the clearance of VWF [105-113]. These physiologic differences may not be present during the first year of life, perhaps related to the slow postnatal development of the blood group system [114].
Domain structure — The VWF protein is composed of a series of homologous domains, with most regions repeated three to six times. These include (in order) three D domains, three A domains, a fourth D domain, and six C domains [115]. The carboxy terminus of the protein contains a carboxy-terminal cysteine knot (CTCK) [116].
Each domain has different functional properties (figure 1):
●D' and the contiguous part of D3 contains the binding site for factor VIII [117-119]
●A1 contains binding sites for platelet GPIb, heparin, collagen, and ristocetin [120-122]
●A2 contains the cleavage site for ADAMTS13 [68,121]
●A3 contains the primary binding site for collagen [121]
●C4 contains a binding site for the platelet integrin alphaIIb-beta3 (GPIIb/IIIa) [116]
●CTCK contains the dimerization interface [116]
Each D domain (referred to as a "D assembly") is subdivided into several modules based on their electron microscopic appearance; they are named VWD, C8 (cysteine 8), TIL (trypsin-inhibitor-like), E, and D4N modules. The C domains have also been divided into six C regions based on structural studies and by homology with the known structure of other proteins. Platelet binding via the integrin alphaIIb-beta3 is assigned to C4. The CTCK crystal structure has revealed a highly reinforced dimerization interface; this extremely strong binding surface explains how large VWF multimers can assemble and resist the exceptionally high shear forces from blood flow at sites of clot formation [116,123].
Each mature VWF monomer contains binding sites for collagen, platelet integrins, factor VIII, and other VWF monomers. Since the larger VWF multimers contain repeated binding sites, they are well suited to act as bridging molecules between platelets and the vascular subendothelium: The repeated binding sites allow multiple interactions with both platelet receptors and subendothelial structures at sites of vessel injury. (See 'Multimerization and hemostasis' below.)
Many mutations associated with von Willebrand disease (VWD) disrupt the dimerization interface, which likely accounts for bleeding phenotypes associated with these mutations. (See "Classification and pathophysiology of von Willebrand disease".)
FUNCTIONS OF VWF
Multimerization and hemostasis — VWF functions in primary hemostasis by forming an adhesive bridge between platelets and vascular subendothelial structures as well as between adjacent platelets at sites of endothelial injury [124]. It also plays a role in fibrin clot formation by acting as a protective carrier protein for factor VIII which has a greatly shortened half-life unless it is bound to VWF [1,125,126].
As noted above, the high molecular weight VWF multimers are the most active forms of VWF. The large multimers provide multiple binding sites that can interact with both platelet receptors and subendothelial structures at sites of injury. The ultralarge VWF multimers released from platelets and endothelial cells are even more hemostatically active than the largest forms of VWF in normal plasma, and they are considered prothrombotic, binding spontaneously to platelets in the circulation [127]. (See 'Plasma VWF levels' above.)
The large VWF multimers are stored in secretory granules in endothelial cells (Weibel-Palade bodies) and platelets (alpha granules) [41,128,129]. (See 'Storage of VWF' above.)
They are actively secreted by agonists such as thrombin and fibrin, resulting in both luminal and abluminal secretion of large multimers of VWF:
●Abluminal secretion contributes to the binding of platelets to the subendothelium of injured blood vessels.
●Luminal secretion of ultralarge and large multimers enhances VWF binding to platelets (via GPIb) and may also increase the local concentration of factor VIII to enhance clot formation at the site of injury [24].
Although both plasma and platelet VWF play a role in normal hemostasis, studies in chimeric pigs in which plasma and platelet VWF are dissociated, suggest that plasma but not platelet VWF is essential for the development of arterial thrombosis [130]. Thrombosis occurred as expected in pigs with normal plasma VWF and no platelet VWF, while no thrombosis occurred in pigs with absent plasma VWF but normal platelet VWF. In further studies, ear bleeding times were partially corrected by addition of plasma VWF, but showed less correction in animals expressing only platelet VWF, suggesting that plasma VWF definitely contributes to the maintenance of a normal bleeding time and hemostasis.
Binding to platelets — The binding of VWF to platelets and subendothelial components is critical for normal platelet adhesion and for the platelet aggregation that occurs at high shear rates. Binding to platelets requires initial activation or alteration in the structure of VWF so that the binding sites in the A1 domain (figure 1) [120-122,131] can engage the platelet receptor GPIb-IX-V complex on the platelet surface [93,132,133] This binding occurs even on nonactivated platelets [134].
An autoinhibitory module (AIM) composed of discontinuous sequences located at each end of the A1 domain in VWF masks A1 and prevents the binding of VWF to platelet GPIb in the circulation. Under high shear conditions, this inhibition by the AIM module is released, and the A1 domain becomes exposed and can bind platelet GPIb [135]. Ristocetin appears to act in a similar manner to activate VWF [135].
The shear stress that occurs in small arterioles and atherosclerotic arteries (shear rates >1000/second) causes a conformational change in VWF from a globular to a linear form in which the A1 domains are exposed [92] and unhindered (the AIM module releases its inhibition) [57].
Vimentin, a structural protein found in plasma and on the surface of platelets, has been shown to enhance the binding of VWF to the platelet surface under high shear stress [136].
On the other hand, circulating beta 2 glycoprotein I binds to VWF and acts to inhibit the binding of activated VWF to GPIb; this decreases platelet adhesion. In some autoimmune settings, antibodies to beta 2 glycoprotein I remove this inhibition of VWF binding, which may contribute to thrombosis [137,138]. (See "Clinical manifestations of antiphospholipid syndrome".)
A second platelet receptor for VWF, integrin alphaIIb-beta3 (GPIIb/IIIa), does not bind VWF unless the platelets are activated [132,134]. With platelet activation, alphaIIb-beta3 undergoes a conformational change and becomes accessible on the platelet surface. The platelet activation can be brought about by a variety of agents, including activation induced by GPIb binding to immobilized VWF strands, which transmits a signal within the platelet [139].
The platelet alphaIIb-beta3-VWF interaction appears to contribute to the final, irreversible binding of platelets to the subendothelium after VWF has bound to GPIb [133]. The alphaIIb-beta3 interaction with VWF may also contribute to platelet aggregation, especially under high shear conditions; under low shear conditions platelet aggregation is mediated primarily by fibrinogen binding to alphaIIb-beta3 [134,140-142].
Binding to subendothelium — All of the precise components in the subendothelial connective tissue to which VWF binds are not defined. VWF binds to multiple types of collagen (types I, II, III, IV, V, and VI) [143,144], but type VI collagen, which binds within the A1 domain, appears to be especially important [145,146]. Type IV collagen also binds at the A1 domain of VWF and is crucial for platelet binding under high shear [147]. Binding of collagen types I and III may also be important [148]. Free thiols in the C domain of VWF are a requirement for VWF binding to collagen [149]. Collagen binding appears to induce a conformational change within the factor VIII-binding motif of VWF that lowers the affinity of VWF for factor VIII, perhaps releasing factor VIII locally to aid in the formation of the fibrin clot [150].
Stabilization of factor VIII — Factor VIII is an important protein cofactor in the pathway of thrombin generation. (See "Overview of hemostasis".)
The plasma concentration of factor VIII is reduced in patients with hemophilia A and VWD. The low factor VIII concentration in VWD is due to the decreased levels of VWF, since VWF normally protects factor VIII from proteolytic inactivation by activated protein C and its cofactor protein S [118,125,126]. VWF domains D’D3 have been shown to be sufficient to stabilize endogenous factor VIII, and they are being developed as an innovative treatment for hemophilia A [151]. The same product should also be sufficient for treatment of VWD type 2N, but this is not yet been tested. With VWF present, the inactivation of factor VIII by activated protein C is slowed 10- to 20-fold [125,126]; without this protection, the half-life of factor VIII is only about two hours [1]. The effect of a low factor VIII concentration is that patients with VWD have a defect in fibrin clot formation as well as a reduction in primary platelet plug formation.
VWF can bind factor VIII only when factor VIII has not been cleaved by thrombin [152]. After thrombin cleavage, activated factor VIII (fVIIIa) is released from VWF and becomes a fully functional, active cofactor in ongoing thrombin generation, and it can be inactivated by activated protein C [125].
Other functions of VWF — Additional functions of VWF include roles in inflammation, such as leukocyte extravasation and recruitment to the endothelial cell surface and regulation of complement activation; VWF also plays roles in angiogenesis, angiodysplasia, cell proliferation, and apoptosis [12,153,154].
SUMMARY
●Production – Von Willebrand factor (VWF) is synthesized in endothelial cells and megakaryocytes, regulated in part by estrogen and thyroid hormones. VWF is a large multimeric glycoprotein with a spectrum of multimer sizes, some of which are >20 million daltons. (See 'Synthesis' above.)
•Smaller VWF multimers are constitutively secreted from endothelial cells and megakaryocytes. Larger, more functional multimers are targeted to cytoplasmic storage granules (Weibel-Palade bodies and platelet alpha granules). (See 'Storage of VWF' above.)
•Active secretion of the larger, most functional VWF multimers (including ultralarge multimers) occurs in response to a number of physiologic agonists, including alpha-adrenergic agonists (eg, epinephrine), thrombin, fibrin, and histamine, and after the administration of the vasopressin analogue DDAVP. Basal (unstimulated) secretion of VWF also occurs and may be responsible for up to 50 percent of the circulating VWF. (See 'Release of VWF' above.)
●Multimer processing – Processing of "prothrombotic" ultralarge multimers occurs at the endothelial cell and platelet surface in the plasma by the metalloproteinase ADAMTS13 (figure 1). Severe ADAMTS13 deficiency increases the risk for thrombotic thrombocytopenic purpura (TTP), in which an excess of ultralarge VWF multimers can cause widespread platelet microthrombi in small arterioles and capillaries. (See 'ADAMTS13 and VWF multimers' above and "Pathophysiology of TTP and other primary thrombotic microangiopathies (TMAs)", section on 'TTP pathogenesis'.)
●Clearance – The plasma concentration of VWF is affected by several components, in particular the ABO blood group of the individual, which determines its clearance. Adults with type O blood have approximately 30 percent lower VWF levels than those with types A, B, or AB. VWF levels are elevated during the second and third trimesters of pregnancy regardless of blood group due to increased estrogen promoting production of VWF. (See 'Clearance of VWF from the circulation' above.)
●Functions – The major functions of VWF are promoting normal platelet adhesion and aggregation, the latter at high shear rates, and stabilizing unactivated factor VIII in the plasma. (See 'Functions of VWF' above.)
•VWF bridges platelets to the subendothelium at sites of vascular injury (platelet adhesion). Under high shear conditions, it promotes platelet aggregation. (See 'Binding to platelets' above and 'Binding to subendothelium' above.)
•VWF acts as a carrier for factor VIII in the circulation, increasing the factor VIII half-life fivefold and maintaining normal factor VIII levels. (See 'Stabilization of factor VIII' above.)
●VWD – Von Willebrand disease (VWD) is a mucocutaneous bleeding disorder that occurs when VWF is deficient or qualitatively abnormal. Bleeding may be due to loss of one or more of these functions. Diagnosis and treatment of inherited VWD and acquired von Willebrand syndrome are discussed separately. (See "Classification and pathophysiology of von Willebrand disease" and "Clinical presentation and diagnosis of von Willebrand disease" and "von Willebrand disease (VWD): Treatment of major bleeding and major surgery" and "Acquired von Willebrand syndrome".)
1 : Purified human factor VIII procoagulant protein: comparative hemostatic response after infusions into hemophilic and von Willebrand disease dogs.
2 : von Willebrand factor to the rescue.
3 : Epidemiological investigation of the prevalence of von Willebrand's disease.
4 : Impact, diagnosis and treatment of von Willebrand disease.
5 : von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome.
6 : Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura.
7 : Thrombotic microangiopathies.
8 : Inhibition of von Willebrand factor-mediated platelet activation and thrombosis by the anti-von Willebrand factor A1-domain aptamer ARC1779.
9 : Genetic variation associated with plasma von Willebrand factor levels and the risk of incident venous thrombosis.
10 : Protective anti-inflammatory effect of ADAMTS13 on myocardial ischemia/reperfusion injury in mice.
11 : ADAMTS13 deficiency exacerbates VWF-dependent acute myocardial ischemia/reperfusion injury in mice.
12 : von Willebrand factor and inflammation.
13 : von Willebrand factor regulation of blood vessel formation.
14 : von Willebrand factor: an emerging target in stroke therapy.
15 : Preclinical Development of a vWF Aptamer to Limit Thrombosis and Engender Arterial Recanalization of Occluded Vessels.
16 : Extracellular Vimentin/VWF (von Willebrand Factor) Interaction Contributes to VWF String Formation and Stroke Pathology.
17 : Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization.
18 : Molecular cloning of cDNA for human von Willebrand factor: authentication by a new method.
19 : Cloning and characterization of two cDNAs coding for human von Willebrand factor.
20 : Construction of cDNA coding for human von Willebrand factor using antibody probes for colony-screening and mapping of the chromosomal gene.
21 : Sublocalization of von Willebrand factor pseudogene to 22q11.22-q11.23 by in situ hybridization in a 46,X,t(X;22)(pter;q11.21) translocation.
22 : von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends.
23 : Tissue distribution of factor VIII gene expression in vivo--a closer look.
24 : Cell biology of von Willebrand factor.
25 : von Willebrand's disease antigen II. A new plasma and platelet antigen deficient in severe von Willebrand's disease.
26 : Propolypeptide of von Willebrand factor circulates in blood and is identical to von Willebrand antigen II.
27 : Amino acid sequence of human von Willebrand factor.
28 : Topology and order of formation of interchain disulfide bonds in von Willebrand factor.
29 : Sulfation of von Willebrand factor.
30 : Formation and function of Weibel-Palade bodies.
31 : Expression of variant von Willebrand factor (vWF) cDNA in heterologous cells: requirement of the pro-polypeptide in vWF multimer formation.
32 : Initial glycosylation and acidic pH in the Golgi apparatus are required for multimerization of von Willebrand factor.
33 : In vitro multimerization of von Willebrand factor is triggered by low pH. Importance of the propolypeptide and free sulfhydryls.
34 : Assembly of Weibel-Palade body-like tubules from N-terminal domains of von Willebrand factor.
35 : Weibel-Palade bodies: a window to von Willebrand disease.
36 : The physiological function of von Willebrand's factor depends on its tubular storage in endothelial Weibel-Palade bodies.
37 : Preferred sequence requirements for cleavage of pro-von Willebrand factor by propeptide-processing enzymes.
38 : Estrogen stimulates von Willebrand factor production by cultured endothelial cells.
39 : Increase by tri-iodothyronine of endothelin-1, fibronectin and von Willebrand factor in cultured endothelial cells.
40 : Haemostatic changes and acquired activated protein C resistance in normal pregnancy.
41 : Eccentric localization of von Willebrand factor in an internal structure of platelet alpha-granule resembling that of Weibel-Palade bodies.
42 : GMP-140, a platelet alpha-granule membrane protein, is also synthesized by vascular endothelial cells and is localized in Weibel-Palade bodies.
43 : PADGEM (GMP140) is a component of Weibel-Palade bodies of human endothelial cells.
44 : CD63 is a component of Weibel-Palade bodies of human endothelial cells.
45 : The Tie-2 ligand angiopoietin-2 is stored in and rapidly released upon stimulation from endothelial cell Weibel-Palade bodies.
46 : Basal secretion of von Willebrand factor from human endothelial cells.
47 : von Willebrand factor multimerization and the polarity of secretory pathways in endothelial cells.
48 : The effects of epinephrine infusion in patients with von Willebrand's disease.
49 : 1-Deamino-8-d-arginine vasopressin: a new pharmacological approach to the management of haemophilia and von Willebrands' diseases.
50 : G protein-dependent basal and evoked endothelial cell vWF secretion.
51 : Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia.
52 : Cellular mechanisms of the hemostatic effects of desmopressin (DDAVP).
53 : von Willebrand factor remodeling during exocytosis from vascular endothelial cells.
54 : P-selectin anchors newly released ultralarge von Willebrand factor multimers to the endothelial cell surface.
55 : Local elongation of endothelial cell-anchored von Willebrand factor strings precedes ADAMTS13 protein-mediated proteolysis.
56 : ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions.
57 : von Willebrand factor self-association is regulated by the shear-dependent unfolding of the A2 domain.
58 : Ristocetin-induced self-aggregation of von Willebrand factor.
59 : High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion.
60 : High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion.
61 : The unfolded von Willebrand factor response in bloodstream: the self-association perspective.
62 : Functional architecture of Weibel-Palade bodies.
63 : Multimeric structure of platelet factor VIII/von Willebrand factor: the presence of larger multimers and their reassociation with thrombin-stimulated platelets.
64 : ADAMTS13 is expressed in hepatic stellate cells.
65 : Platelet-derived VWF-cleaving metalloprotease ADAMTS-13.
66 : Human endothelial cells synthesize and release ADAMTS-13.
67 : Apical sorting of ADAMTS13 in vascular endothelial cells and Madin-Darby canine kidney cells depends on the CUB domains and their association with lipid rafts.
68 : Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis.
69 : Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion.
70 : Changes in von Willebrand factor-cleaving protease (ADAMTS13) activity after infusion of desmopressin.
71 : Insights into von Willebrand factor proteolysis: clinical implications.
72 : Characterization of a core binding site for ADAMTS-13 in the A2 domain of von Willebrand factor.
73 : ADAMTS13 cleavage efficiency is altered by mutagenic and, to a lesser extent, polymorphic sequence changes in the A1 and A2 domains of von Willebrand factor.
74 : Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress.
75 : Unraveling the scissile bond: how ADAMTS13 recognizes and cleaves von Willebrand factor.
76 : Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage.
77 : Factor VIII accelerates proteolytic cleavage of von Willebrand factor by ADAMTS13.
78 : Light chain of factor VIII is sufficient for accelerating cleavage of von Willebrand factor by ADAMTS13 metalloprotease.
79 : The interaction between factor H and VWF increases factor H cofactor activity and regulates VWF prothrombotic status.
80 : Purification of human von Willebrand factor-cleaving protease and its identification as a new member of the metalloproteinase family.
81 : Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13).
82 : Structure of von Willebrand factor-cleaving protease (ADAMTS13), a metalloprotease involved in thrombotic thrombocytopenic purpura.
83 : Systemic antithrombotic effects of ADAMTS13.
84 : Inhibition of von Willebrand factor-platelet glycoprotein Ib interaction prevents and reverses symptoms of acute acquired thrombotic thrombocytopenic purpura in baboons.
85 : Evaluation of efficacy and safety of the anti-VWF Nanobody ALX-0681 in a preclinical baboon model of acquired thrombotic thrombocytopenic purpura.
86 : Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow.
87 : Control of von Willebrand factor multimer size by thrombospondin-1.
88 : Role of thrombospondin-1 in control of von Willebrand factor multimer size in mice.
89 : Factor VIII-related protein circulates in normal human plasma as high molecular weight multimers.
90 : Studies on factor VIII-related protein. II. Estimation of molecular size differences between factor VIII oligomers.
91 : Substructure of human von Willebrand factor.
92 : Shear-dependent changes in the three-dimensional structure of human von Willebrand factor.
93 : Identification of a site in the alpha chain of platelet glycoprotein Ib that participates in von Willebrand factor binding.
94 : An intrinsic mechanism of secreted protein aging and turnover.
95 : N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance.
96 : A novel role for the macrophage galactose-type lectin receptor in mediating von Willebrand factor clearance.
97 : Clearance of von Willebrand factor.
98 : The C-type lectin receptor CLEC4M binds, internalizes, and clears von Willebrand factor and contributes to the variation in plasma von Willebrand factor levels.
99 : Subcellular platelet factor VIII antigen and von Willebrand factor.
100 : Variation at the von Willebrand factor (vWF) gene locus is associated with plasma vWF:Ag levels: identification of three novel single nucleotide polymorphisms in the vWF gene promoter.
101 : Getting at the variable expressivity of von Willebrand disease.
102 : Genetic determinants of plasma von Willebrand factor antigen levels: a target gene SNP and haplotype analysis of ARIC cohort.
103 : Genetic regulation of plasma von Willebrand factor levels in health and disease.
104 : Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels.
105 : The effect of ABO blood group on the diagnosis of von Willebrand disease.
106 : Heterogeneous detection of A-antigen on von Willebrand factor derived from platelets, endothelial cells and plasma.
107 : Amount of H antigen expressed on circulating von Willebrand factor is modified by ABO blood group genotype and is a major determinant of plasma von Willebrand factor antigen levels.
108 : An influence of ABO blood group on the rate of proteolysis of von Willebrand factor by ADAMTS13.
109 : Bombay phenotype is associated with reduced plasma-VWF levels and an increased susceptibility to ADAMTS13 proteolysis.
110 : ABO blood group determines plasma von Willebrand factor levels: a biologic function after all?
111 : Effect of von Willebrand factor Y/C1584 on in vivo protein level and function and interaction with ABO blood group.
112 : A shorter von Willebrand factor survival in O blood group subjects explains how ABO determinants influence plasma von Willebrand factor.
113 : Blood group significantly influences von Willebrand factor increase and half-life after desmopressin in von Willebrand disease Vicenza.
114 : Association of ABO(H) and I blood group system development with von Willebrand factor and Factor VIII plasma levels in children and adolescents.
115 : Association of ABO(H) and I blood group system development with von Willebrand factor and Factor VIII plasma levels in children and adolescents.
116 : Sequence and structure relationships within von Willebrand factor.
117 : Interaction of the von Willebrand factor (vWF) with collagen. Localization of the primary collagen-binding site by analysis of recombinant vWF a domain polypeptides.
118 : Requirements of von Willebrand factor to protect factor VIII from inactivation by activated protein C.
119 : A major factor VIII binding domain resides within the amino-terminal 272 amino acid residues of von Willebrand factor.
120 : Identification of discontinuous von Willebrand factor sequences involved in complex formation with botrocetin. A model for the regulation of von Willebrand factor binding to platelet glycoprotein Ib.
121 : Molecular modeling of ligand and mutation sites of the type A domains of human von Willebrand factor and their relevance to von Willebrand's disease.
122 : Interaction of von Willebrand factor domain A1 with platelet glycoprotein Ibalpha-(1-289). Slow intrinsic binding kinetics mediate rapid platelet adhesion.
123 : Highly reinforced structure of a C-terminal dimerization domain in von Willebrand factor.
124 : von Willebrand factor.
125 : Inactivation of human factor VIII by activated protein C. Cofactor activity of protein S and protective effect of von Willebrand factor.
126 : von Willebrand factor mediates protection of factor VIII from activated protein C-catalyzed inactivation.
127 : Increased von Willebrand factor binding to platelets in single episode and recurrent types of thrombotic thrombocytopenic purpura.
128 : Immunolocalization of von Willebrand protein in Weibel-Palade bodies of human endothelial cells.
129 : Platelet von Willebrand factor--structure, function and biological importance.
130 : Function of von Willebrand factor after crossed bone marrow transplantation between normal and von Willebrand disease pigs: effect on arterial thrombosis in chimeras.
131 : Shielding the front-strand beta 3 of the von Willebrand factor A1 domain inhibits its binding to platelet glycoprotein Ibalpha.
132 : Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor.
133 : Shear-dependent rolling on von Willebrand factor of mammalian cells expressing the platelet glycoprotein Ib-IX-V complex.
134 : Modulation of platelet function through adhesion receptors. A dual role for glycoprotein IIb-IIIa (integrin alpha IIb beta 3) mediated by fibrinogen and glycoprotein Ib-von Willebrand factor.
135 : Delimiting the autoinhibitory module of von Willebrand factor.
136 : Platelet adhesion involves a novel interaction between vimentin and von Willebrand factor under high shear stress.
137 : beta2-Glycoprotein I inhibits von Willebrand factor dependent platelet adhesion and aggregation.
138 : Association between beta2-glycoprotein I plasma levels and the risk of myocardial infarction in older men.
139 : Identification of a juxtamembrane mechanosensitive domain in the platelet mechanosensor glycoprotein Ib-IX complex.
140 : Thrombin-induced exposure and prostacyclin inhibition of the receptor for factor VIII/von Willebrand factor on human platelets.
141 : ADP-dependent common receptor mechanism for binding of von Willebrand factor and fibrinogen to human platelets.
142 : Human platelets possess an inducible and saturable receptor specific for fibrinogen.
143 : Adsorption of von Willebrand factor/factor VIII by the genetically distinct interstitial collagens.
144 : The interaction between collagens and factor VIII/von Willebrand factor: investigation of the structural requirements for interaction.
145 : Morphological relationships of von Willebrand factor, type VI collagen, and fibrillin in human vascular subendothelium.
146 : Platelet adhesion and aggregation on human type VI collagen surfaces under physiological flow conditions.
147 : Crucial role for the VWF A1 domain in binding to type IV collagen.
148 : Mutations in the A3 domain of von Willebrand factor inducing combined qualitative and quantitative defects in the protein.
149 : Blocking von Willebrand factor free thiols inhibits binding to collagen under high and pathological shear stress.
150 : Collagen-bound von Willebrand factor has reduced affinity for factor VIII.
151 : BIVV001 Fusion Protein as Factor VIII Replacement Therapy for Hemophilia A.
152 : Association of the factor VIII light chain with von Willebrand factor.
153 : von Willebrand factor: the old, the new and the unknown.
154 : von Willebrand factor is a cofactor in complement regulation.
