Disease relevance of VWF

• On subendothelial matrix, endogenous vWF and adsorbed plasma vWF synergistically initiate platelet recruitment, and alpha2beta1 remains key along with alpha(IIb)beta3 for normal thrombus development at all but low shear rates [1].
• The venom factor acts on formaldehyde-fixed platelets and is effective with decalcified, heparinized, and afibrinogenemic plasmas but not with severe von Willebrand disease plasmas or with normal plasmas in which the von Willebrand factor has been neutralized by specific antibodies [2].
• Glanzmann thrombasthenia: deficient binding of von Willebrand factor to thrombin-stimulated platelets [3].
• Primary binding domain of bovine von Willebrand factor fragment expressed in E. coli [4].
• CONCLUSIONS: Hyperglycemia activates BAECs and promotes secretion of vWF, a marker of endothelial cell damage [5].

High impact information on VWF

• Type I collagen fibrils exposed to flowing blood adsorb von Willebrand factor (vWF), to which platelets become initially tethered with continuous surface translocation mediated by the membrane glycoprotein Ib alpha [1].
• Heparin inhibition of von Willebrand factor-dependent platelet function in vitro and in vivo [6].
• The intravenous administration of heparin to patients before open heart surgery reduced ristocetin cofactor activity by 58% (P less than 0.01, t test), and this impairment of von Willebrand factor-dependent platelet function was closely related to plasma heparin levels (r2 = 0.9), but not to plasma von Willebrand factor (vWF) levels [6].
• Endothelial cells as well as smooth muscle cells bound 125I-labeled vWF in a ristocetin-dependent manner, with a Kd of 7.9 nM [7].
• These studies demonstrate that freshly obtained vessels with a continuous layer of native endothelium can support activation of Factor X and prothrombin: vessel-bound Factor IXa can activate Factor X in the presence of VWF/Factor VIII [8].

Biological context of VWF

• In the first exon, potentially involved in endothelial-cell-specific transcription, the binding site for factor Sp1 is present in bo vWF, whereas the GATA sequence is replaced by a GACA sequence [9].
• Recent studies from two laboratories, including ours, were published regarding the cell-specific transcription of reporter genes controlled by the human (hu) vWF promoter in transfected bovine (bo) endothelial cells and cells of non-endothelial origins [9].
• In order to verify that the regulatory domains previously characterized in the 5' region of hu vWF are also present in bo vWF, we have sequenced 1.9 kb upstream from the cap site, plus five exons [9].
• von Willebrand factor (vWF), a multimeric glycoprotein important for hemostasis, is specifically synthesized in endothelial cells and in platelet precursors (megakaryocytes) [9].
• von Willebrand factor is a large multimeric plasma protein which plays important roles in platelet aggregation, blood coagulation and probably also in the adhesion of endothelial cells [10].

Anatomical context of VWF

• It appears possible that any process which causes the surface membranes of platelets to become spatially close will allow expression of VWF activity [11].
• There were no differences in LH pulse characteristics, area of VWF staining, proliferation index, steroidogenic cell characteristics, basal or LH-stimulated progesterone production by luteal cells between cows with an early or late progesterone rise (P > 0.10) [12].
• Interaction of blood platelets with a microfibrillar extract from adult bovine aorta: requirement for von Willebrand factor [13].
• von Willebrand factor (vWf) is synthesized as a large precursor that dimerizes in the endoplasmic reticulum and forms multimers in the trans- and post-Golgi compartments of megakaryocytes and endothelial cells [14].
• The -60/+19 vWF gene core promoter is transactivated in HeLa cells by cotransfecting with Ets-1 or Erg (Ets-related gene) expression plasmids [15].

Associations of VWF with chemical compounds

• This probe codes for the major adhesion domain of vWF that includes the GPIb, collagen and heparin binding domains [16].
• Cysteine residues #471, 474, 509 and 695, which form intrachain bonds in human vWF, are also present in the bovine vWF sequence [16].
• VWF binding to formaldehyde-fixed platelets was dependent on the presence of a promoter such as ristocetin [11].
• Polycations, such as poly(L-lysine) and Polybrene, also promoted the formation of platelet aggregates and facilitated the binding of VWF to platelets [11].
• Inhibition of von Willebrand factor-dependent platelet function by increased platelet cyclic AMP and its prevention by cytoskeleton-disrupting agents [17].

Physical interactions of VWF

• However, in endothelial cells, mutation of the VWF E4BP4 binding motif not only restores but also further elevates VWF promoter activity, suggesting that E4BP4 may be part of a coordinated binding complex [18].

Other interactions of VWF

• An NF1-like protein functions as a repressor of the von Willebrand factor promoter [19].
• Western blots of cell extracts demonstrated binding of 125I-Factor IX at Mr approximately equal to 140,000 which was blocked by excess Factor IX, but not antisera to Factor VIII, von Willebrand factor, alpha 2-macroglobulin, or epidermal growth factor receptor [20].
• Plasma contains factors, conceivably the adhesive proteins fibronectin and von Willebrand factor, that promote the Mg2(+)-independent mechanism [21].
• Tissue-type plasminogen activator (t-PA) immunoreactivity colocalized with von Willebrand factor, a marker for Weibel-Palade bodies [22].
• The deduced amino acid sequence contains nine thrombospondin type 1 repeats that alternate with sequences sharing similarities with the D-domain of von Willebrand factor [23].

Analytical, diagnostic and therapeutic context of VWF

• To determine directly the location of the epitope for each mAb on the bovine pp-vWF molecule, we tested the reactivity of mAbs by immunoblotting toward peptide fragments obtained by digestion with lysylendopeptidase [24].
• We have previously reported the identification of a region of the vWf gene that regulates its cell-type-specific expression in cell culture [19].
• Physical changes associated with anti-vWF-induced uptake of vWF are not seen in platelets that are involved in hemostatic plug formation or clot retraction [25].
• Secretion of vWF by BAECs under physiological glucose and high glucose conditions with or without thiamine (200 micromol/L) supplementation was studied with enzyme-linked immunosorbent assay [5].
• Characterization of von Willebrand factor interaction with collagens in real time using surface plasmon resonance [26].

References