Affinage

VWF

von Willebrand factor · UniProt P04275

Length
2813 aa
Mass
309.3 kDa
Annotated
2026-06-11
100 papers in source corpus 43 papers cited in narrative 43 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

VWF is a large, endothelial- and megakaryocyte-derived multimeric glycoprotein that links primary hemostasis to platelet adhesion, thrombus formation, and vascular inflammation (PMID:3874428, PMID:15985541). It is synthesized as a 2813-aa pre-pro-protein with a repetitive domain architecture (D1-D2-D'-D3-A1-A2-A3-D4-B1-B2-C1-C2), whose D1-D2 propeptide is obligatory for assembly of dimers into higher-order multimers, while dimerization itself is propeptide-independent (PMID:3019665, PMID:3500851). VWF expression is both necessary and sufficient to drive biogenesis of Weibel-Palade bodies (WPBs), the endothelial storage granules into which it recruits cargo such as P-selectin and t-PA; multimerization is dispensable for WPB formation but propeptide-directed trafficking of mature VWF is required, and a propeptide D2-domain mutation (N528S) that introduces an ectopic glycan abolishes multimerization and storage (PMID:15331450, PMID:20335223, PMID:10634936). WPB exocytosis is tightly gated: Gα12/α-SNAP mediate both basal and evoked secretion while Gαq/RhoA contribute to evoked release, Rab27a/MyRIP anchor mature WPBs to peripheral actin to restrain premature secretion, BLOC-2/exocyst control endosomal input and clamp release, and endothelial PTP1B suppresses exocytosis by dephosphorylating SNAP23 (PMID:19270261, PMID:24081657, PMID:32614949, PMID:38563147). Once secreted, VWF strings are tethered to the endothelial surface through an A2-domain interaction with extracellular vimentin and are size-regulated by ADAMTS13, which cleaves the A2 domain at Y1605-M1606 in a shear-dependent manner requiring A2 unfolding (modulated by N1574 glycosylation), preferentially processing platelet-bound multimers (PMID:17901248, PMID:17975018, PMID:19822897, PMID:26840720, PMID:30355099). The VWF A1 domain engages platelet GPIbα to initiate a Lyn→Src→Syk→SLP-76→PI3K→Btk→ERK/PLCγ2→PKC cascade culminating in thromboxane A2 generation and αIIbβ3 activation (PMID:15985541, PMID:16020504, PMID:16788103). The circulating VWF propeptide remains non-covalently bound to the D'D3 domain of mature VWF and attenuates GPIbα-dependent platelet adhesion (PMID:22452980). Plasma clearance of VWF and its associated FVIII is governed by sinusoidal stabilin-2 and CLEC4M and by macrophage LRP1 binding to a K1405-K1408 cluster in the A1 domain (PMID:30124466, PMID:30740857, PMID:38996211). Beyond hemostasis, VWF promotes vascular smooth muscle cell proliferation via A2-domain binding to LRP4/αvβ3 signaling and drives thromboinflammation in ischemic stroke, sickle cell vaso-occlusion, traumatic brain injury, and venous thrombosis (PMID:35969769, PMID:33507292, PMID:33576766, PMID:22712744).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1986 High

    Establishing the complete VWF coding sequence and domain architecture defined the modular protein from which all subsequent structure-function dissection proceeded.

    Evidence full-length cDNA assembly and in vitro expression of the precursor in mammalian cells

    PMID:3019665

    Open questions at the time
    • Did not establish how individual domains map to specific binding partners
    • Glycosylation and multimer assembly not addressed
  2. 1987 High

    Resolved whether the propeptide is needed for assembly, showing it is obligatory for multimerization beyond dimers but not for dimerization itself.

    Evidence heterologous expression of propeptide-deleted VWF in COS-1 cells with multimer analysis

    PMID:3500851

    Open questions at the time
    • Molecular mechanism by which the propeptide catalyzes inter-dimer disulfide bonding not defined
    • Did not address storage granule formation
  3. 2004 High

    Determined that VWF itself drives the biogenesis of its storage organelle, resolving whether WPBs require a dedicated scaffold or VWF alone.

    Evidence loss-of-function in VWF-null canine endothelial cells plus rescue with VWF constructs and orthogonal P-selectin/VWFpp readouts

    PMID:10634936 PMID:15331450

    Open questions at the time
    • Trafficking machinery directing VWF to WPBs not identified here
    • Why propeptide alone is insufficient unresolved
  4. 2006 High

    Mapped the platelet GPIb-IX signaling cascade triggered by VWF engagement, establishing the kinase hierarchy ending in TXA2-dependent integrin activation.

    Evidence genetic knockout platelet lines (Lyn, Src, Syk, SLP-76, PLCγ2, Btk) plus pharmacological epistasis and an in vivo thrombosis model

    PMID:11916084 PMID:15613029 PMID:15985541 PMID:16020504 PMID:16788103

    Open questions at the time
    • How A1-GPIbα binding mechanically couples to Lyn activation not resolved
    • Quantitative thresholds linking shear to signaling not defined
  5. 2007 High

    Showed that ADAMTS13 cleavage is conformationally and substrate-state regulated, preferentially processing shear-unfolded, platelet-bound VWF.

    Evidence cone-plate shear assay with anti-GPIbα blockade, deglycosylation, N1574 mutagenesis, SPR, and A2-domain cleavage assays

    PMID:17901248 PMID:17975018

    Open questions at the time
    • In vivo contribution of N1574 glycosylation to multimer size unquantified
    • Structural basis of glycan-modulated unfolding not solved
  6. 2009 High

    Defined how secreted ADAMTS13 reaches and progressively cleaves cell-anchored VWF strings, and showed Rab27a/MyRIP anchoring controls multimer size of released VWF.

    Evidence HUVEC string cleavage with ADAMTS13 domain-antibody blockade and siRNA depletion of Rab27a/MyRIP with flow-based string assays

    PMID:19270261 PMID:19822897

    Open questions at the time
    • Spatial regulation of constitutive ADAMTS13 release not fully defined
    • Link between actin anchoring and multimer maturation incompletely mapped
  7. 2010 High

    Established that the cleaved propeptide remains a functional regulator, binding D'D3 to attenuate platelet adhesion, and identified disease-relevant trafficking defects.

    Evidence SPR binding kinetics, domain-specific antibodies, flow chamber adhesion assays, and expression of the N528S propeptide mutant

    PMID:20335223 PMID:20705333 PMID:22452980

    Open questions at the time
    • Physiological extent of propeptide-mediated suppression in vivo unquantified
    • TSP1 competition with ADAMTS13 limited to in vitro biochemistry
  8. 2013 High

    Identified the G-protein machinery distinguishing basal from evoked WPB exocytosis, with Gα12/α-SNAP obligatory for both and Gαq/RhoA selective for evoked release.

    Evidence EC-specific Gα12/13 KO mice, HUVEC siRNA, in vitro binding assays, and inhibitory minigene peptide in perfused lungs

    PMID:24081657

    Open questions at the time
    • Upstream receptors coupling to Gα12 for basal secretion not defined
    • Membrane fusion machinery downstream not connected here
  9. 2016 High

    Provided quantitative single-molecule confirmation that shear-induced A2 unfolding gates ADAMTS13 cleavage above a defined shear threshold.

    Evidence fluorescence correlation spectroscopy in a microfluidic shear cell with Brownian hydrodynamics simulations

    PMID:26840720

    Open questions at the time
    • In vivo shear-rate distributions relative to the measured threshold not mapped
    • Influence of platelet binding on the unfolding threshold not tested
  10. 2018 High

    Identified the receptor systems clearing the VWF-FVIII complex and the A2-vimentin tether retaining strings at the endothelial surface.

    Evidence stabilin-2 and CLEC4M binding/internalization assays with KO and PK studies, plus vimentin-KO arteries and A2-protein blocking with stroke models

    PMID:30124466 PMID:30355099 PMID:30740857

    Open questions at the time
    • Relative quantitative contribution of each clearance receptor in humans not resolved
    • Mechanism coupling A2-vimentin tethering to string stability incomplete
  11. 2020 High

    Separated WPB maturation from exocytic control, identifying BLOC-2 as required for endosomal input/maturation and exocyst as a paradoxical clamp on release.

    Evidence siRNA depletion, BLOC-2 reciprocal Co-IP, exocyst inhibitor Endosidin2, and WPB ultrastructure/multimer analysis

    PMID:32614949

    Open questions at the time
    • How exocyst simultaneously promotes maturation and clamps release mechanistically unresolved
    • Endosomal cargo delivered to WPBs not enumerated
  12. 2021 High

    Demonstrated that endothelial VWF drives thromboinflammation across distinct disease settings (sickle cell vaso-occlusion, TBI, venous thrombosis) and identified the A1 LRP1-clearance cluster and the GPIbα cytoplasmic tail signaling requirement.

    Evidence endothelial-specific VWF KO in SCD mice with ADAMTS13 rescue, A2-protein blocking in TBI, PTP1B-KO/SNAP23 phosphorylation studies, K1405-K1408 mutagenesis with in vivo clearance, and CRISPR GPIbα tail-deletion platelets

    PMID:22712744 PMID:26209660 PMID:33507292 PMID:34134470 PMID:35969769 PMID:38563147 PMID:38996211

    Open questions at the time
    • Therapeutic windows of A2-domain blockade in humans untested
    • Cross-talk between clearance and thromboinflammatory roles not integrated
  13. 2022 High

    Extended VWF function beyond hemostasis to vascular remodeling, showing A2-domain binding to LRP4/αvβ3 drives smooth muscle cell proliferation and neointimal hyperplasia.

    Evidence siRNA against αv and LRP4, RAP inhibition, proximity ligation/Co-IP, and VWF-KO mouse injury models

    PMID:33576766

    Open questions at the time
    • Signaling downstream of αvβ3 in VSMCs not delineated
    • Whether circulating versus locally secreted VWF mediates this not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How VWF transcriptional induction (by GATA factors, HMGB1-TLR2-SP1, hyperglycemia) and pathogen/leukocyte interactions (S. aureus ClfA, SLC44A2 neutrophils) integrate with the secretion-cleavage-clearance axis to set VWF function in disease remains open.
  • Transcriptional regulators identified largely in single-lab, context-specific models
  • Integration of bacterial and leukocyte adhesion roles with hemostatic functions not established

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4 GO:0098631 cell adhesion mediator activity 4 GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005576 extracellular region 4 GO:0031410 cytoplasmic vesicle 4 GO:0005794 Golgi apparatus 2 GO:0005886 plasma membrane 2
Pathway
R-HSA-109582 Hemostasis 4 R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-168256 Immune System 3
Partners
ADAMTS13CLEC4MGP1BALRP1LRP4STAB2THBS1VIM
Complex memberships
VWF-FVIII complexWeibel-Palade body

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1985 VWF cDNA was isolated, mapping the gene to chromosome 12p12–12pter; VWF mRNA accounts for ~0.3% of endothelial cell mRNA and was undetectable in several other tissues, establishing endothelial-cell-specific expression. cDNA cloning, chromosomal mapping, Northern blot/expression analysis Science High 3874428
1986 Full-length VWF cDNA encodes a 2813-aa pre-pro-protein with a highly repetitive domain structure (D1-D2-D'-D3-A1-A2-A3-D4-B1-B2-C1-C2), including a 741-aa propeptide (equivalent to von Willebrand Antigen II) and a 2050-aa mature subunit; in-vitro expression confirmed synthesis of the unglycosylated precursor. Full-length cDNA assembly, in vitro expression in mammalian cells The EMBO journal High 3019665
1987 The VWF propeptide (domains D1-D2) is required for multimerization beyond the dimer stage but not for dimerization itself; COS-1 cells expressing propeptide-deleted VWF assembled only dimers, not higher multimers. Heterologous expression of wild-type and propeptide-deleted VWF cDNA in COS-1 cells, multimer analysis The EMBO journal High 3500851
2004 VWF is both necessary and sufficient for Weibel-Palade body (WPB) formation in endothelial cells: VWD (VWF-null) canine aortic endothelial cells lacked WPBs, and re-expression of wild-type VWF restored WPBs that recruited endogenous P-selectin. VWF multimerization is not required for WPB creation, but the VWF propeptide alone cannot independently form WPBs. Expression of wild-type and mutant VWF in VWF-null canine endothelial cells; confocal immunostaining for P-selectin, VWFpp, and VWF Blood High 15331450
2005 VWF binding to platelet GPIb-IX initiates a signaling cascade (Lyn → Src → Syk → SLP-76 → PI3K → PLCγ2 → PKC) leading to thromboxane A2 (TXA2) production, which is required for αIIbβ3 activation and platelet aggregation. LAT and FcRγ-chain are not required for TXA2 production but are required for granule secretion and aggregation. Mouse platelets genetically deficient in Lyn, Src, Syk, SLP-76, PLCγ2, LAT, or FcRγ-chain; wortmannin inhibition; botrocetin/VWF stimulation assays Blood High 15985541
2005 VWF/GPIb-induced platelet aggregation requires Src family kinase- and ERK-mediated TXA2 generation; Erk2 phosphorylation and TXA2 release were abolished by the Src inhibitor PP2 and the PLC inhibitor U73122, and MEK inhibition (U0126) abolished VWF-induced aggregation in non-aspirin-treated platelets. Pharmacological inhibition (PP2, U73122, U0126, aspirin) in washed human platelets stimulated with VWF/ristocetin; Erk2 phosphorylation assays Blood High 16020504
2006 Bruton tyrosine kinase (Btk) is essential for VWF/GPIb-induced TXA2 production and GPIb-dependent arterial thrombus formation in vivo; Btk acts downstream of Lyn, Syk, SLP-76, and PI3K and upstream of ERK1/2, PLCγ2, and PKC in the signaling cascade. Btk-deficient mouse platelets; botrocetin/VWF stimulation; ferric chloride carotid artery thrombosis model; pharmacological epistasis Blood High 16788103
2007 ADAMTS13 preferentially cleaves platelet-VWF complexes under fluid shear stress rather than soluble VWF alone; platelet-dependent cleavage was blocked by anti-GPIbα antibody or soluble GPIbα fragment, and consumed large VWF multimers selectively. Cone-plate viscometer shear assay; anti-GPIbα blocking; multimeric gel analysis Blood High 17901248
2007 N-linked glycans on VWF modulate its susceptibility to ADAMTS13 cleavage; removal of N-linked glycans (PNGaseF) increased ADAMTS13 affinity ~4-fold and allowed cleavage without denaturant. Specific mutation of N1574 (not N1515) increased ADAMTS13 proteolysis and allowed cleavage in the absence of urea, at least partly through a conformational mechanism. PNGaseF deglycosylation; site-directed mutagenesis of N1515 and N1574; surface plasmon resonance; ADAMTS13 cleavage assays with recombinant VWF and isolated VWF-A2 domain Blood High 17975018
2009 Rab27a and its effector MyRIP localize to mature Weibel-Palade bodies and anchor them to peripheral actin; siRNA depletion of either protein caused loss of peripheral WPB localization, increased basal and stimulated VWF secretion, and release of less-multimerized VWF, resulting in shorter VWF strings under flow. siRNA depletion in primary human endothelial cells; live imaging; VWF multimer analysis; flow-based string assay Blood High 19270261
2009 Endothelial ADAMTS13 is released constitutively from the Golgi to the cell exterior without storage organelle, and cleaves secreted and cell-anchored VWF strings at Y1605-M1606 progressively; blocking different ADAMTS13 domains with antibodies revealed ADAMTS13 attachment along the length of VWF strings. HUVEC culture under static conditions; ADAMTS13 mRNA quantification; anti-ADAMTS13 domain antibody blockade; VWF string cleavage assay Blood High 19822897
2010 The VWF propeptide (VWFpp) binds to the D'D3 domain of mature VWF with high affinity (KD = 0.2 nM at pH 6.2/10 mM Ca2+) and weaker but significant affinity under physiologic conditions (KD = 25 nM); this interaction in the circulation attenuates platelet adhesion and GpIbα-binding activity of VWF. Surface plasmon resonance; development of anti-VWF D'D3 monoclonal antibodies; flow chamber platelet adhesion assays; shear-induced platelet aggregation Blood High 22452980
2010 Thrombospondin-1 (TSP1) binds to VWF A2 and A3 domains and competitively inhibits ADAMTS13 binding and cleavage activity by up to 70%, providing a mechanism by which TSP1 protects VWF from ADAMTS13 proteolysis. ELISA-based binding assays with recombinant VWF domains (A1, A2, A3) and full-length VWF; Western blot and residual collagen-binding assay for ADAMTS13 activity inhibition Thrombosis research Medium 20705333
2010 A homozygous N528S mutation in the VWF propeptide D2 domain introduces an ectopic N-glycosylation site near a disulfide isomerase consensus sequence, causing defective multimerization and failure of VWF trafficking to storage granules; wild-type propeptide alone trafficked normally, demonstrating that the defect is in mature VWF transport by its mutant propeptide. Patient phenotyping; heterologous mammalian cell expression of N528S-VWF; immunostaining; multimer analysis; propeptide trafficking assays Blood High 20335223
2013 Gα12 and α-SNAP are obligatory mediators of both basal and thrombin-evoked VWF secretion from endothelial cells; Gα12 N-terminal residues 10-15 bind α-SNAP, and an α-SNAP binding-domain minigene peptide blocked both basal and evoked VWF secretion. Gαq/RhoA/p115-RhoGEF contribute to evoked but not basal VWF secretion. EC-specific Gα12/Gα13 knockout mice; siRNA knockdown in HUVECs; in vitro binding assays; overexpression of activated Gα12; isolated buffer-perfused mouse lungs Blood High 24081657
2016 Shear-induced unfolding of the VWF A2 domain permits ADAMTS13 cleavage of full-length VWF multimers; enzymatic rate shows a sigmoidal increase with shear rate (threshold γ̇1/2 = 5522/s) as measured in real time by fluorescence correlation spectroscopy, consistent with Brownian hydrodynamics simulations. Fluorescence correlation spectroscopy; microfluidic shear cell; multimer gel analysis; Michaelis-Menten kinetics under denaturing conditions; Brownian hydrodynamics simulations Biophysical journal High 26840720
2018 Stabilin-2 on sinusoidal endothelial cells binds and internalizes VWF and FVIII in a VWF-dependent manner; stabilin-2-deficient mice showed prolonged VWF-FVIII half-life and decreased immune response to human VWF-FVIII complex, establishing stabilin-2 as a clearance and immunoregulatory receptor for the VWF-FVIII complex. Cell-based binding/internalization assays; stabilin-2 KO mice; pharmacokinetic infusion studies; immunogenic response quantification; heterologous expression of stabilin-2 variant p.E2377K The Journal of clinical investigation High 30124466
2018 Extracellular vimentin on the endothelial surface tethers VWF strings via interaction with the VWF A2 domain; VWF string formation was reduced in vimentin-KO arteries and by treatment with recombinant A2 domain protein or anti-vimentin antibody; A2 protein improved cortical reperfusion after experimental stroke. Pressurized cerebral artery preparations; Vim-KO mice; recombinant A2 protein and antibody blocking; laser speckle contrast imaging; middle cerebral artery occlusion mouse model Stroke High 30355099
2019 Extracellular PAD4 citrullinates ADAMTS13 on specific arginine residues, dramatically inhibiting its enzymatic activity; this leads to accumulation of VWF-platelet strings in vivo, accelerates thrombus formation after vessel injury, and can be reversed by injection of non-citrullinated recombinant ADAMTS13. Mass spectrometry identification of citrullination sites; in vitro ADAMTS13 activity assays; r-huPAD4 injection in mice; intravital microscopy of VWF-platelet strings; ferric chloride thrombosis model; patient plasma citrullination measurements Circulation research High 31248335
2019 CLEC4M on liver sinusoidal endothelial cells binds and internalizes FVIII through VWF-dependent and VWF-independent mechanisms; VWF-independent binding is mediated by mannose-exposed N-linked glycans on FVIII and involves clathrin-coated pit endocytosis for lysosomal catabolism. Cell-based binding/internalization assays in CLEC4M-expressing HEK293 cells; solid-phase binding assays; in vivo hydrodynamic liver transfer; immunohistochemistry Journal of thrombosis and haemostasis High 30740857
2020 BLOC-2 and the exocyst complex cooperate in WPB biogenesis by mediating endosomal input required for VWF maturation into high-molecular-weight multimers; BLOC-2 depletion impairs WPB exocytosis, whereas exocyst depletion paradoxically augments exocytosis, identifying exocyst as a clamp on VWF release separable from its role in VWF maturation. siRNA depletion; immunoprecipitation of BLOC-2; small-molecule exocyst inhibitor (Endosidin2); WPB ultrastructure analysis; VWF multimer analysis of releasates Blood High 32614949
2021 Endothelial VWF is critical for vaso-occlusion in sickle cell disease; endothelial-specific VWF deletion reduced hemolysis, vascular occlusion, and organ damage in TNF-induced VOE in humanized SCD mice, and ADAMTS13 administration reduced plasma VWF and attenuated inflammation and vaso-occlusion. Endothelial-specific VWF knockout mice crossed to humanized SCD mice; ADAMTS13 infusion; measurement of hemolysis, vascular occlusion, organ damage Proceedings of the National Academy of Sciences High 35969769
2021 Conformation-dependent hyperadhesive VWF with an exposed A1 domain is released acutely after traumatic brain injury and can be selectively blocked by a recombinant VWF A2-domain protein (A2), which reduced TBI-induced death by >50%, protected the endothelium from extracellular vesicle-induced injury, and prevented consumptive coagulopathy by blocking the exposed A1 domain. Recombinant VWF A2-domain protein infusion in mice with lateral fluid percussion TBI; measurement of platelet activation, microvesiculation, coagulation parameters, neurological function; endothelial protection assays Blood High 33507292
2021 The VWF A1 domain contains a conserved cluster of four lysine residues (K1405-K1408) that mediates binding to macrophage LRP1 clusters II and IV; alanine mutagenesis of this cluster attenuated VWF binding to LRP1 and significantly reduced in vivo VWF clearance, establishing LRP1-mediated macrophage clearance as a physiologically relevant VWF degradation pathway. Alanine mutagenesis of K1405-K1408; binding assays with LRP1 clusters II and IV and HEK-LRP1 cells; in vivo clearance of VWF-4A mutant; BT200 (rondaptivon pegol) competition assays; macrophage galactose lectin and SR-AI binding assays Blood High 38996211
2022 VWF mediates vascular smooth muscle cell (VSMC) proliferation and migration through binding of the VWF A2 domain to LRP4, which signals through αvβ3 integrin; siRNA against αv integrin or LRP4, and LRP inhibitor RAP, abolished proliferation; proximity ligation and immunoprecipitation confirmed LRP4-αvβ3 co-association. VWF-deficient mice showed reduced neointimal hyperplasia in carotid ligation and femoral denudation models. siRNA knockdown of αv integrin and LRP4; LRP inhibitor (RAP); confocal fluorescence microscopy; proximity ligation assay; immunoprecipitation; VWF-deficient mouse carotid and femoral injury models Cardiovascular research High 33576766
2024 Endothelial PTP1B deletion promotes VWF exocytosis by reducing PTP1B-mediated tyrosine dephosphorylation of SNAP23; increased SNAP23 phosphorylation enhances Weibel-Palade body membrane fusion and VWF release, which in turn drives neutrophil adhesion and venous thromboinflammation. Inducible endothelial PTP1B KO mice; inferior vena cava ligation thrombosis model; primary endothelial cell mechanistic studies; SNAP23 phosphorylation assays; VWF-blocking antibodies; intravital microscopy Circulation research High 38563147
2002 VWF interaction with GPIb-IX-V activates two distinct tyrosine kinase pathways in platelets: Pyk2 phosphorylation is independent of calcium mobilization and PKC but downstream of Syk, whereas FAK phosphorylation requires TXA2, αIIbβ3, calcium, and PKC; both kinases require actin polymerization and translocate to the cytoskeleton. Human platelet stimulation with vWF; inhibitors of TxA2, calcium chelation, PKC, Syk (piceatannol), cytochalasin D; RGDS peptide; FAK and Pyk2 phosphorylation immunoblotting Thrombosis and haemostasis Medium 11916084
2004 In botrocetin/VWF-stimulated washed platelets, GPIbα-mediated agglutination produces TXA2 via calcium-independent PKC and PLA2 activities; TXA2 causes dense granule secretion and, together with ADP, is required for αIIbβ3 activation and aggregation; α-granule secretion requires ADP signaling through P2Y1 then P2Y12. Mouse platelets deficient in TXA2 receptors, Gαq, or αIIbβ3; pharmacological inhibitors; botrocetin/VWF stimulation; granule secretion and aggregation assays Journal of thrombosis and haemostasis Medium 15613029
2015 Platelet-derived VWF is not required for normal hemostasis or arterial thrombosis, but aggravates ischemic stroke injury via a GPIb-dependent mechanism; platelet VWF blockade with anti-GPIb antibody reduced cerebral infarct size in chimeric mice carrying only platelet VWF. Bone marrow transplantation between C57BL/6J and Vwf−/− mice to generate platelet-VWF-specific chimeras; tail bleeding, carotid thrombosis, and middle cerebral artery occlusion models; GPIb-blocking antibody Blood High 26209660
2016 Vps33b facilitates VWF-positive vesicular trafficking in megakaryocytes to α-granule vacuoles; HSC-specific Vps33b deletion abolished α-granules in platelets and megakaryocytes, and disrupted co-localization of Sec22b with Vwf-positive vesicles; Vps33b associates with VIPAS39, α-tubulin, and SEC22B. Tamoxifen-inducible HSC-specific Vps33b KO mice; co-immunoprecipitation; mass spectrometry; immunoblotting; pull-down assays; confocal microscopy of proplatelet Vwf-positive vesicles The Journal of pathology Medium 27319744
2018 SARS-CoV-2 spike protein S1 RBD induces endothelial VWF secretion through ACE2 in an ARF6 activation-dependent manner; pharmacological inhibitor studies defined a downstream signaling cascade from ACE2 to VWF exocytosis. In vitro endothelial cell stimulation with S1 RBD; pharmacological inhibitors of ACE2 signaling pathway components; ARF6 activation assay; VWF secretion measurement International journal of molecular sciences Medium 36982738
2012 The GPIbα intracellular tail (last 24 residues containing 14-3-3 and PI3K binding sites) is required for VWF-dependent platelet signaling and GPVI-mediated signaling; GPIbαΔsig/Δsig platelets bound VWF normally but formed fewer filopodia, had decreased Syk phosphorylation and αIIbβ3 activation upon CRP stimulation, and formed smaller aggregates on collagen under shear. CRISPR-Cas9 GPIbα intracellular tail deletion mouse; flow-based platelet adhesion and aggregation assays; intracellular signaling (pSyk) assays; collagen microchannel aggregation at multiple shear rates Haematologica High 34134470
2012 Increased inflammation in ADAMTS13-deficient mice after ischemic stroke is VWF-dependent: double-deficient (ADAMTS13−/−;VWF−/−) mice had the same reduced inflammation as VWF−/− mice alone, demonstrating that ADAMTS13 limits brain injury by reducing VWF-mediated neutrophil infiltration and cytokine production. ADAMTS13−/−, VWF−/−, and double-KO mice; transient middle cerebral artery occlusion; MPO activity; immunohistochemistry for neutrophils; cytokine quantification; neutrophil depletion Journal of thrombosis and haemostasis High 22712744
2003 In porcine aortic endothelial cells lacking Weibel-Palade bodies, VWF propeptide traffics to the Golgi (cycling between stacked Golgi and earlier compartments) but mature VWF does not form WPBs and is not acutely released, demonstrating that VWF propeptide and mature VWF have divergent intracellular trafficking when WPBs are absent. RT-PCR; Western blot; immunostaining with Golgi marker; stimulated secretion assays in porcine and human aortic endothelial cells Atherosclerosis Medium 12618268
2000 Expression of pro-VWF cDNA in VWF-negative ECV304 endothelial cells restored Weibel-Palade body formation and directed tissue-type plasminogen activator (t-PA) into these granules, demonstrating that VWF expression is sufficient to form functional secretory WPBs and that t-PA is co-stored with VWF in WPBs. Stable transfection of pro-VWF cDNA into ECV304 cells; immunostaining; stimulated secretion with calcium ionophore A23187; t-PA storage assay Biochimica et biophysica acta Medium 10634936
2021 Slc44a2/HNA-3a expression on neutrophils mediates their adhesion to VWF under venous shear rates (100 s−1) independently of β2 integrin; HNA-3b-expressing neutrophils have impaired VWF adhesion; Slc44a2-KO mice show massively reduced neutrophil recruitment in inflamed mesenteric venules after endothelial degranulation. Flow chamber adhesion assays with transfected HEK293T cells or donor neutrophils; β2 integrin blocking; LPS preactivation; intravital microscopy in SLC44A2-KO mice after histamine stimulation Blood High 33556175
2006 A single amino acid substitution R2657Q in the VWF protein (encoded by SNP +7970G>A in the CASA/RkJ Vwf allele) confers significantly increased VWF biosynthesis in vitro and elevated plasma VWF in vivo, representing a gain-of-function natural variant. In vitro recombinant VWF expression comparing A/J and CASA/RkJ alleles; SNP identification; quantitative biosynthesis assays; in vivo plasma VWF measurement in congenic mice Blood High 16873672
2018 Two common VWF SNVs, rs1063856 (c.2365A>G) and rs1063857 (c.2385T>C), independently increase plasma VWF levels by prolonging VWF mRNA half-life (increased biosynthesis) and by reducing in vivo VWF clearance (lower VWFpp/VWF:Ag ratio; longer VWF half-life in Vwf-KO mice infused with recombinant VWF). Genotypic/phenotypic analysis in European controls; recombinant VWF expression in vitro; mRNA stability assays; in vivo pharmacokinetics in Vwf-KO mice Blood advances High 29980574
2022 Hyperglycemia-induced oxidative stress in endothelial cells upregulates VWF expression through the transcription factor GATA1, which drives vWF-mediated adhesion of tumor cells to the endothelium and promotes transendothelial migration and lung metastasis. STZ-induced hyperglycemia mouse model; primary lung EC gene expression; siRNA knockdown of vWF; chromatin immunoprecipitation for GATA1 on the vWF promoter; tumor adhesion and transendothelial migration assays Oncogene Medium 35094008
2017 GATA3 mediates upregulation of VWF transcription in lung adenocarcinoma tumor vasculature; conditioned media from A549 cancer cells increased vWF expression in HUVECs, and ChIP assays confirmed direct GATA3 binding to the +220 GATA binding motif on the human VWF promoter. Co-culture conditioned media system; ChIP assay; siRNA knockdown of GATA3 and ERG; immunohistochemistry of tumor microarrays Oncotarget Medium 29299165
2016 Hypoxia-induced HMGB1 upregulates vWF expression through a TLR2-MYD88-SP1 signaling pathway; TLR2 silencing abolished MYD88 expression, vWF expression, and SP1 phosphorylation, and blocked Sp1 binding to the Vwf promoter. Murine acute hypoxia model; TLR2 agonist/neutralizing antibody; HMGB1 inhibitor; Tlr2 siRNA silencing; SP1 inhibitor; promoter binding assay European journal of immunology Medium 27480067
2021 Staphylococcus aureus ClfA interacts with VWF via vWF-binding protein (vWbp) to form an ultra-strong ternary complex (~2000 pN); force spectroscopy showed that vWbp activates a direct, dock-lock-and-latch-type ClfA–VWF interaction, representing a mechanism of bacterial exploitation of VWF for adhesion. Atomic force microscopy–based single-molecule force spectroscopy on living bacteria; recombinant protein binding experiments Communications biology Medium 33846500
2017 Hagfish (Myxine glutinosa) possess a functional Vwf gene encoding a simpler protein than gnathostome VWF that notably lacks an A3 domain (collagen-binding domain present only in jawed vertebrates); hagfish Vwf forms high-molecular-weight multimers in plasma and CHO cells, and botrocetin promotes VWF-dependent thrombocyte aggregation, establishing VWF as originating in the ancestral vertebrate after divergence from urochordates. Genomic identification; stable CHO cell expression; multimer analysis; botrocetin-induced aggregation assays; immunohistochemistry; electron microscopy for Weibel-Palade bodies Blood Medium 28899852

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1985 Human von Willebrand factor (vWF): isolation of complementary DNA (cDNA) clones and chromosomal localization. Science (New York, N.Y.) 417 3874428
1986 Full-length von Willebrand factor (vWF) cDNA encodes a highly repetitive protein considerably larger than the mature vWF subunit. The EMBO journal 241 3019665
2002 Expression of the endothelial markers PECAM-1, vWf, and CD34 in vivo and in vitro. Experimental and molecular pathology 189 12009786
2007 Platelet-VWF complexes are preferred substrates of ADAMTS13 under fluid shear stress. Blood 132 17901248
2006 Bruton tyrosine kinase is essential for botrocetin/VWF-induced signaling and GPIb-dependent thrombus formation in vivo. Blood 122 16788103
1987 Expression of variant von Willebrand factor (vWF) cDNA in heterologous cells: requirement of the pro-polypeptide in vWF multimer formation. The EMBO journal 115 3500851
2009 Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage. Blood 104 19822897
2017 ADAMTS13 controls vascular remodeling by modifying VWF reactivity during stroke recovery. Blood 94 28428179
2005 Src family kinase-mediated and Erk-mediated thromboxane A2 generation are essential for VWF/GPIb-induced fibrinogen receptor activation in human platelets. Blood 92 16020504
2009 Rab27a and MyRIP regulate the amount and multimeric state of VWF released from endothelial cells. Blood 88 19270261
2011 VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population. Blood 86 22197721
2005 Platelet-derived VWF-cleaving metalloprotease ADAMTS-13. Journal of thrombosis and haemostasis : JTH 86 16176307
2019 Plasma Peptidylarginine Deiminase IV Promotes VWF-Platelet String Formation and Accelerates Thrombosis After Vessel Injury. Circulation research 85 31248335
2021 Increased VWF and Decreased ADAMTS-13 in COVID-19: Creating a Milieu for (Micro)Thrombosis. Seminars in thrombosis and hemostasis 81 33893632
2007 N-linked glycosylation of VWF modulates its interaction with ADAMTS13. Blood 81 17975018
2012 ADAMTS13 reduces VWF-mediated acute inflammation following focal cerebral ischemia in mice. Journal of thrombosis and haemostasis : JTH 79 22712744
2015 Role of fluid shear stress in regulating VWF structure, function and related blood disorders. Biorheology 78 26600266
2018 The endothelial cell receptor stabilin-2 regulates VWF-FVIII complex half-life and immunogenicity. The Journal of clinical investigation 69 30124466
2005 Botrocetin/VWF-induced signaling through GPIb-IX-V produces TxA2 in an alphaIIbbeta3- and aggregation-independent manner. Blood 65 15985541
2016 Levels of Serum 25(OH)VD3, HIF-1α, VEGF, vWf, and IGF-1 and Their Correlation in Type 2 Diabetes Patients with Different Urine Albumin Creatinine Ratio. Journal of diabetes research 61 27069929
2021 ADAMTS13 regulation of VWF multimer distribution in severe COVID-19. Journal of thrombosis and haemostasis : JTH 60 34053187
2016 Shear-Induced Unfolding and Enzymatic Cleavage of Full-Length VWF Multimers. Biophysical journal 57 26840720
2015 Platelet-derived VWF is not essential for normal thrombosis and hemostasis but fosters ischemic stroke injury in mice. Blood 57 26209660
2022 Sustained VWF-ADAMTS-13 axis imbalance and endotheliopathy in long COVID syndrome is related to immune dysfunction. Journal of thrombosis and haemostasis : JTH 55 35875995
2004 Re-establishment of VWF-dependent Weibel-Palade bodies in VWD endothelial cells. Blood 51 15331450
2013 Increased VWF antigen levels and decreased ADAMTS13 activity in preeclampsia. Hematology (Amsterdam, Netherlands) 48 23433535
2016 Regulation of VWF expression, and secretion in health and disease. Current opinion in hematology 43 26771163
2004 The roles of ADP and TXA in botrocetin/VWF-induced aggregation of washed platelets. Journal of thrombosis and haemostasis : JTH 42 15613029
2019 The endothelial lectin clearance receptor CLEC4M binds and internalizes factor VIII in a VWF-dependent and independent manner. Journal of thrombosis and haemostasis : JTH 40 30740857
2010 Thrombospondin-1 and ADAMTS13 competitively bind to VWF A2 and A3 domains in vitro. Thrombosis research 39 20705333
2006 Regulated release of VWF and FVIII and the biologic implications. Pediatric blood & cancer 39 16470522
2022 The role of VWF/FVIII in thrombosis and cancer progression in multiple myeloma and other hematological malignancies. Journal of thrombosis and haemostasis : JTH 38 35644028
2019 The ADAMTS13-VWF axis is dysregulated in chronic thromboembolic pulmonary hypertension. The European respiratory journal 38 30655285
2018 Extracellular Vimentin/VWF (von Willebrand Factor) Interaction Contributes to VWF String Formation and Stroke Pathology. Stroke 36 30355099
2021 Conformation-dependent blockage of activated VWF improves outcomes of traumatic brain injury in mice. Blood 35 33507292
2013 Correlation between endogenous VWF:Ag and PK parameters and bleeding frequency in severe haemophilia A subjects during three-times-weekly prophylaxis with rFVIII-FS. Haemophilia : the official journal of the World Federation of Hemophilia 35 24252058
2007 A common 253-kb deletion involving VWF and TMEM16B in German and Italian patients with severe von Willebrand disease type 3. Journal of thrombosis and haemostasis : JTH 32 17371490
2010 The mutation N528S in the von Willebrand factor (VWF) propeptide causes defective multimerization and storage of VWF. Blood 31 20335223
2021 Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rates. Blood 30 33556175
2022 Microlyse: a thrombolytic agent that targets VWF for clearance of microvascular thrombosis. Blood 29 34752601
2022 COVID-19 microthrombosis: unusually large VWF multimers are a platform for activation of the alternative complement pathway under cytokine storm. International journal of hematology 29 35316498
2012 von Willebrand factor (VWF) propeptide binding to VWF D'D3 domain attenuates platelet activation and adhesion. Blood 29 22452980
2023 Small Extracellular Vesicle-Derived vWF Induces a Positive Feedback Loop between Tumor and Endothelial Cells to Promote Angiogenesis and Metastasis in Hepatocellular Carcinoma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 28 37387563
2016 Vps33b regulates Vwf-positive vesicular trafficking in megakaryocytes. The Journal of pathology 28 27319744
2022 The VWF/LRP4/αVβ3-axis represents a novel pathway regulating proliferation of human vascular smooth muscle cells. Cardiovascular research 26 33576766
2021 Plasma and rhADAMTS13 reduce trauma-induced organ failure by restoring the ADAMTS13-VWF axis. Blood advances 26 34505883
2017 Resveratrol attenuates hydrogen peroxide‑induced apoptosis, reactive oxygen species generation, and PSGL‑1 and VWF activation in human umbilical vein endothelial cells, potentially via MAPK signalling pathways. Molecular medicine reports 26 29207192
2001 Crotalin, a vWF and GP Ib cleaving metalloproteinase from venom of Crotalus atrox. Thrombosis and haemostasis 26 11776320
2020 Low VWF levels in children and lack of association with bleeding in children undergoing tonsillectomy. Blood advances 25 31905240
2020 VWF maturation and release are controlled by 2 regulators of Weibel-Palade body biogenesis: exocyst and BLOC-2. Blood 23 32614949
2020 Emerging mechanisms to modulate VWF release from endothelial cells. The international journal of biochemistry & cell biology 23 33301925
2017 GATA3-induced vWF upregulation in the lung adenocarcinoma vasculature. Oncotarget 23 29299165
2022 The GPIbα intracellular tail - role in transducing VWF- and collagen/GPVI-mediated signaling. Haematologica 22 34134470
2022 Hyperglycemia-induced oxidative stress promotes tumor metastasis by upregulating vWF expression in endothelial cells through the transcription factor GATA1. Oncogene 21 35094008
2018 A factor VIII-nanobody fusion protein forming an ultrastable complex with VWF: effect on clearance and antibody formation. Blood 21 30064978
2017 Laboratory Testing for von Willebrand Factor Collagen Binding (VWF:CB). Methods in molecular biology (Clifton, N.J.) 20 28804845
2016 HMGB1 facilitates hypoxia-induced vWF upregulation through TLR2-MYD88-SP1 pathway. European journal of immunology 20 27480067
2015 Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans. American journal of hematology 20 25779970
2002 Proline-rich tyrosine kinase 2 and focal adhesion kinase are involved in different phases of platelet activation by vWF. Thrombosis and haemostasis 20 11916084
2022 Endothelial VWF is critical for the pathogenesis of vaso-occlusive episode in a mouse model of sickle cell disease. Proceedings of the National Academy of Sciences of the United States of America 19 35969769
2013 G protein-dependent basal and evoked endothelial cell vWF secretion. Blood 19 24081657
2024 The aptamer BT200 blocks interaction of K1405-K1408 in the VWF-A1 domain with macrophage LRP1. Blood 18 38996211
2021 von Willebrand factor antigen levels are associated with burden of rare nonsynonymous variants in the VWF gene. Blood 18 33556167
2021 Identification of VWF as a Novel Biomarker in Lung Adenocarcinoma by Comprehensive Analysis. Frontiers in oncology 18 33968738
2020 ADAMTS13 activity, high VWF and FVIII levels in the pathogenesis of deep vein thrombosis. Thrombosis research 18 33212380
2019 In Vitro Measurement and Modeling of Platelet Adhesion on VWF-Coated Surfaces in Channel Flow. Biophysical journal 18 30824114
2019 Hemophilia A and B mice, but not VWF-/-mice, display bone defects in congenital development and remodeling after injury. Scientific reports 18 31594977
2018 Molecular Imaging of VWF (von Willebrand Factor) and Platelet Adhesion in Postischemic Impaired Microvascular Reflow. Circulation. Cardiovascular imaging 18 30571316
2017 Laboratory Testing for von Willebrand Factor Antigen (VWF:Ag). Methods in molecular biology (Clifton, N.J.) 18 28804844
2010 Polymorphisms and mutations in vWF and ADAMTS13 genes and their correlation with plasma levels of FVIII and vWF in patients with deep venous thrombosis. Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis 18 20682599
2023 New perspectives on the induction and acceleration of immune-associated thrombosis by PF4 and VWF. Frontiers in immunology 17 36926331
2012 PR3 and elastase alter PAR1 signaling and trigger vWF release via a calcium-independent mechanism from glomerular endothelial cells. PloS one 17 22952809
2006 Enhanced VWF biosynthesis and elevated plasma VWF due to a natural variant in the murine Vwf gene. Blood 17 16873672
2021 Staphylococcus aureus vWF-binding protein triggers a strong interaction between clumping factor A and host vWF. Communications biology 16 33846500
2020 Association between ADAMTS13 activity-VWF antigen imbalance and the therapeutic effect of HAIC in patients with hepatocellular carcinoma. World journal of gastroenterology 16 33362379
2010 Immunoexpression of MMP-9, VEGF, and vWF in central and peripheral giant cell lesions of the jaws. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 16 21198871
2023 The contribution of the sinusoidal endothelial cell receptors CLEC4M, stabilin-2, and SCARA5 to VWF-FVIII clearance in thrombosis and hemostasis. Journal of thrombosis and haemostasis : JTH 15 37085036
2022 rhADAMTS13 reduces oxidative stress by cleaving VWF in ischaemia/reperfusion-induced acute kidney injury. Acta physiologica (Oxford, England) 15 34989474
2022 Single-cell transcriptional analysis of human endothelial colony-forming cells from patients with low VWF levels. Blood 15 35143643
2018 The common VWF single nucleotide variants c.2365A>G and c.2385T>C modify VWF biosynthesis and clearance. Blood advances 15 29980574
2008 The role of VWF in the immunogenicity of FVIII. Thrombosis research 15 18549909
2023 Molecular Analysis of SARS-CoV-2 Spike Protein-Induced Endothelial Cell Permeability and vWF Secretion. International journal of molecular sciences 14 36982738
2018 Coupling of a specific photoreactive triple-helical peptide to crosslinked collagen films restores binding and activation of DDR2 and VWF. Biomaterials 14 30099278
2007 Circulating endothelial cell count, plasma vWF and soluble ICAM-1 levels following primary or elective percutaneous coronary intervention. Atherosclerosis 14 17959181
2003 Differential intracellular trafficking of von Willebrand factor (vWF) and vWF propeptide in porcine endothelial cells lacking Weibel-Palade bodies and in human endothelial cells. Atherosclerosis 14 12618268
2024 Endothelial PTP1B Deletion Promotes VWF Exocytosis and Venous Thromboinflammation. Circulation research 13 38563147
2022 Heterogeneity and reciprocity of FVIII and VWF expression, and the response to shear stress in cultured human endothelial cells. Journal of thrombosis and haemostasis : JTH 13 35950488
2005 VWF-cleaving protease (ADAMTS13) in premature infants. Acta paediatrica (Oslo, Norway : 1992) 13 15981755
2000 Regulated von Willebrand factor (vWf) secretion is restored by pro-vWf expression in a transfectable endothelial cell line. Biochimica et biophysica acta 13 10634936
2023 Identification of ORM1, vWF, SPARC, and PPBP as immune-related proteins involved in immune thrombocytopenia by quantitative LC-MS/MS. Clinical proteomics 12 37355563
2020 von Willebrand factor promotes platelet-induced metastasis of osteosarcoma through activation of the VWF-GPIb axis. Journal of bone oncology 12 33101888
2017 Identification of extant vertebrate Myxine glutinosa VWF: evolutionary conservation of primary hemostasis. Blood 12 28899852
2022 Multifaceted pathomolecular mechanism of a VWF large deletion involved in the pathogenesis of severe VWD. Blood advances 11 34861678
2020 Association of von Willebrand factor (vWF) expression with lymph node metastasis and hemodynamics in papillary thyroid carcinoma. European review for medical and pharmacological sciences 11 32196607
2001 Increased glomerular Vwf after kidney irradiation is not due to increased biosynthesis or endothelial cell proliferation. Radiation research 11 11418069
2023 Elevated LDL Cholesterol Increases Microvascular Endothelial VWF and Thromboinflammation After Myocardial Infarction. Arteriosclerosis, thrombosis, and vascular biology 10 37128919
2022 Contribution of ADAMTS13-independent VWF regulation in sickle cell disease. Journal of thrombosis and haemostasis : JTH 10 35753044
2022 Lower levels of vWF are associated with lower risk of cardiovascular disease. Research and practice in thrombosis and haemostasis 10 36381288
2021 ADAMTS-13-VWF axis in sickle cell disease patients. Annals of hematology 10 33404693
2021 Role of ADAMTS13, VWF and F8 genes in deep vein thrombosis. PloS one 10 34662354

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