title: The various states of von Willebrand factor and their function in physiology and pathophysiology.
abstract: The specific interactions of von Willebrand factor (VWF) with the vessel wall, platelets or other interfaces strongly depend on (a shear-induced) VWF activation. Shear flow has been shown to induce a conformational transition of VWF, but is modulated by its thermodynamic state (state-function relationship). The state in turn is determined by physical (e.g. vessel geometry), physico-chemical (e.g. pH) and molecular-biological (e.g. mutants, binding) factors. Combining established results with recent insights, we reconstruct VWF biology and its state-function relationship from endothelial cell release to final degradation in the human vasculature. After VWF secretion, endothelial-anchored and shear activated VWF multimers can rapidly interact with surrounding colloids, typically with platelets. Simultaneously, this VWF activation enables ADAMTS13 to cleave VWF multimers thereby limiting VWF binding capacity. The subsequent cell-surface dissociation leads to a VWF recoiling to a globular conformation, shielding from further degradation by ADAMTS13. High local concentrations of these soluble VWF multimers, transported to the downstream vasculature, are capable for an immediate reactivation and re-polymerisation initiating colloid-binding or VWF-colloid aggregation at the site of inflamed endothelium, vessel injuries or pathological high-shear areas. Focusing on these functional steps in the lifecycle of VWF, its qualitative and quantitative deficiencies in the different VWD types will facilitate more precise diagnostics and reliable risk stratification for prophylactic therapies. The underlying biophysical principles are of general character, which broadens prospective studies on the physiological and pathophysiological impact of VWF and VWF-associated diseases and beares hope for a more universal understanding of an entire class of phenomena.
authors.forename: Volker
authors.initials: V
authors.lastname: Huck
authors.affiliation: Prof. Dr. Matthias F. Schneider, Biological Physics Group, Boston University, Department of Mechanical Engineering, 110 Cummington Street, Boston, MA 02215, USA, Tel.: +1 617 353 3951, Fax: +1 617 353 3951, E-mail: mfs@bu.edu.
authors.forename: Matthias F
authors.initials: MF
authors.lastname: Schneider
authors.forename: Christian
authors.initials: C
authors.lastname: Gorzelanny
authors.affiliation: Prof. Dr. Stefan W. Schneider, Department of Dermatology, Experimental Dermatology, Heidelberg University, Medical Faculty Mannheim, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany, Tel: +49 621 383 6901, Fax:+49 621 383 6903, E-mail: stefan.schneider@medma.uni-heidelberg.de.
authors.forename: Stefan W
authors.initials: SW
authors.lastname: Schneider
mesh_terms: D051722:ADAM Proteins / Q000378:metabolism; D000071120:ADAMTS13 Protein; D000494:Allosteric Regulation; D000818:Animals; D001778:Blood Coagulation Disorders / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D009154:Mutation / Q000235:genetics; D015539:Platelet Activation; D011485:Protein Binding; D011487:Protein Conformation; D055503:Protein Multimerization; D059748:Proteolysis; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014841:von Willebrand Factor / Q000737:chemistry / Q000502:physiology*
chemical_list: D014841:von Willebrand Factor; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
keywords: ADAMTS13; TTP; VWD; VWF; shear stress