The various states of von Willebrand factor and their function in physiology and pathophysiology

Summary

The specific interactions of von Willebrand factor (VWF) with the vessel wall, platelets or other interfaces strongly depend on (a shearinduced) 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 statefunction 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.

Keywords

VWF - shear stress - ADAMTS13 - TTP - VWD

• References

• 1 Cheng H, Yan R, Li S. et al. Shear-induced interaction of platelets with von Willebrand factor results in glycoprotein Ibalpha shedding.. Am J Physiol Heart Circ Physiol 2009; 297: H2128-2135.
• 2 Hanson E, Jood K, Karlsson S. et al. Plasma levels of von Willebrand factor in the etiologic subtypes of ischemic stroke.. J Thromb Haemost 2011; 9: 275-281.
• 3 Mannucci PM. von Willebrand factor: a marker of endothelial damage?. Arte-rioscler Thromb Vasc Biol 1998; 18: 1359-1362.
• 4 Mendolicchio GL, Ruggeri ZM. New perspectives on von Willebrand factor functions in hemostasis and thrombosis.. Semin Hematol 2005; 42: 5-14.
• 5 Moroose R, Hoyer LW. von Willebrand factor and platelet function.. Annu Rev Med 1986; 37: 157-163.
• 6 Ruggeri ZM. Structure of von Willebrand factor and its function in platelet adhesion and thrombus formation.. Best Pract Res Clin Haematol 2001; 14: 257-279.
• 7 Ruggeri ZM. The role of von Willebrand factor in thrombus formation.. Thromb Res 2007; 120 (Suppl. 01) S5-9.
• 8 Ruggeri ZM, Orje JN, Habermann R. et al. Activation-independent platelet adhesion and aggregation under elevated shear stress.. Blood 2006; 108: 1903-1910.
• 9 Sadler JE. Biochemistry and genetics of von Willebrand factor.. Annu Rev Bio-chem 1998; 67: 395-424.
• 10 Huck V, Niemeyer A, Goerge T. et al. Delay of acute intracellular pH recovery after acidosis decreases endothelial cell activation.. J Cell Physiol 2007; 211: 399-409.
• 11 Wagner DD, Frenette PS. The vessel wall and its interactions.. Blood 2008; 111: 5271-5281.
• 12 Desch A, Strozyk EA, Bauer AT. et al. Highly Invasive Melanoma Cells Activate the Vascular Endothelium via an MMP-2/Integrin avβ5-Induced Secretion of VEGF-A.. Am J Pathol 2012; 181: 693-705.
• 13 Fallah MA, Myles VM, Kruger T. et al. Acoustic driven flow and lattice Boltz-mann simulations to study cell adhesion in biofunctionalized mu-fluidic channels with complex geometry.. Biomicrofluidics 2010; 4: 0241061-10.
• 14 Goerge T, Kleineruschkamp F, Barg A. et al. Microfluidic reveals generation of platelet-strings on tumor-activated endothelium.. Thromb Haemost 2007; 98: 283-286.
• 15 Kerk N, Strozyk EA, Poppelmann B. et al. The mechanism of melanoma-associated thrombin activity and von Willebrand factor release from endothelial cells.. J Invest Dermatol 2010; 130: 2259-2268.
• 16 Schneider SW, Larmer J, Henderson RM. et al. Molecular weights of individual proteins correlate with molecular volumes measured by atomic force microscopy.. Pflugers Arch Eur J Physiol 1998; 435: 362-367.
• 17 Furlan M. Von Willebrand factor: molecular size and functional activity.. Ann Hematol 1996; 72: 341-348.
• 18 Schneppenheim R, Lenk H, Obser T. et al. Recombinant expression of mutations causing von Willebrand disease type Normandy: characterization of a combined defect of factor VIII binding and multimerization.. Thromb Haemost 2004; 92: 36-41.
• 19 Dong JF, Moake JL, Nolasco L. et al. ADAMTS-13 rapidly cleaves newly secreted ultralarge von Willebrand factor multimers on the endothelial surface under flowing conditions.. Blood 2002; 100: 4033-4039.
• 20 Metcalf DJ, Nightingale TD, Zenner HL. et al. Formation and function of Wei-bel-Palade bodies.. J Cell Sci 2008; 121: 19-27.
• 21 Barg A, Ossig R, Goerge T. et al. Soluble plasma-derived von Willebrand factor assembles to a haemostatically active filamentous network.. Thromb Haemost 2007; 97: 514-526.
• 22 Alexander-Katz A, Schneider MF, Schneider SW. et al. Shear-flow-induced unfolding of polymeric globules.. Physical Rev Lett 2006; 97: 138101.
• 23 Schneider SW, Nuschele S, Wixforth A. et al. Shear-induced unfolding triggers adhesion of von Willebrand factor fibers.. Proc Natl Acad Sci 2007; 104: 7899-7903.
• 24 Goerge T, Barg A, Schnaeker EM. et al. Tumor-derived matrix metalloprotei-nase-1 targets endothelial proteinase-activated receptor 1 promoting endothe-lial cell activation.. Cancer Res 2006; 66: 7766-7774.
• 25 Goerge T, Niemeyer A, Rogge P. et al. Secretion pores in human endothelial cells during acute hypoxia.. J Membr Biol 2002; 187: 203-211.
• 26 Terraube V, Marx I, Denis CV. Role of von Willebrand factor in tumor metastasis.. Thromb Res 2007; 120 (Suppl. 02) S64-70.
• 27 Haberichter SL, Fahs SA, Montgomery RR. von Willebrand factor storage and multimerization: 2 independent intracellular processes.. Blood 2000; 96: 1808-1815.
• 28 Wagner DD. Cell biology of von Willebrand factor.. Annu Rev Cell Biol 1990; 6: 217-246.
• 29 Singh I, Themistou E, Porcar L. et al. Fluid shear induces conformation change in human blood protein von Willebrand factor in solution.. Biophys J 2009; 96: 2313-2320.
• 30 Wijeratne SS, Botello E, Yeh HC. et al. Mechanical activation of a multimeric adhesive protein through domain conformational change.. Phys Rev Lett 2013; 110: 108102.
• 31 Doggett TA, Girdhar G, Lawshe A. et al. Selectin-like kinetics and biomechanics promote rapid platelet adhesion in flow: the GPIb(alpha)-vWF tether bond.. Biophys J 2002; 83: 194-205.
• 32 Savage B, Saldivar E, Ruggeri ZM. Initiation of platelet adhesion by arrest onto fibrinogen or translocation on von Willebrand factor.. Cell 1996; 84: 289-297.
• 33 Ruggeri ZM. Von Willebrand factor: looking back and looking forward.. Thromb Haemost 2007; 98: 55-62.
• 34 Konstantinides S, Ware J, Marchese P. et al. Distinct antithrombotic consequences of platelet glycoprotein Ibalpha and VI deficiency in a mouse model of arterial thrombosis.. J Thromb Haemost 2006; 4: 2014-2021.
• 35 Savage B, Almus-Jacobs F, Ruggeri ZM. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow.. Cell 1998; 94: 657-666.
• 36 Nesbitt WS, Westein E, Tovar-Lopez FJ. et al. A shear gradient-dependent platelet aggregation mechanism drives thrombus formation.. Nat Med 2009; 15: 665-673.
• 37 Yago T, Lou J, Wu T. et al. Platelet glycoprotein Ibalpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF.. J Clin Invest 2008; 118: 3195-3207.
• 38 Colace TV, Diamond SL. Direct observation of von Willebrand factor elongation and fiber formation on collagen during acute whole blood exposure to pathological flow.. Arterioscler Thromb Vasc Biol 2013; 33: 105-113.
• 39 Sing CE, Selvidge JG, Alexander-Katz A. Von Willlebrand adhesion to surfaces at high shear rates is controlled by long-lived bonds.. Biophys J 2013; 105: 1475-1481.
• 40 Levy GG, Nichols WC, Lian EC. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.. Nature 2001; 413: 488-494.
• 41 Schneppenheim R, Budde U. von Willebrand factor: the complex molecular genetics of a multidomain and multifunctional protein.. J Thromb Haemost 2011; 9: 209-215.
• 42 Kasatkar P, Ghosh K, Shetty S. An atypical manifestation of acquired von Willebrand syndrome (AVWS) associated with systemic lupus erythematosus (SLE).. Ann Hematol 2013; 93: 173-175.
• 43 Vincentelli A, Susen S, Le Tourneau T. et al. Acquired von Willebrand syndrome in aortic stenosis.. N Engl J Med 2003; 349: 343-349.
• 44 Tiede A, Priesack J, Werwitzke S. et al. Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study.. J Thromb Haemost 2008; 6: 569-576.
• 45 Moake JL. von Willebrand factor, ADAMTS-13, and thrombotic thrombocyto-penic purpura.. Semin Hematol 2004; 41: 4-14.
• 46 Moake JL, Rudy CK, Troll JH. et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocyto-penic purpura.. N Engl J Med 1982; 307: 1432-1435.
• 47 Moake JL. The role of von Willebrand factor (vWF) in thrombotic thrombocy-topenic purpura (TTP) and the hemolytic-uremic syndrome (HUS).. Prog Clin Biol Res 1990; 337: 135-140.
• 48 Bernardo A, Ball C, Nolasco L. et al. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von Willebrand factor multimers under flow.. Blood 2004; 104: 100-106.
• 49 Chen J, Fu X, Wang Y. et al. Oxidative modification of von Willebrand factor by neutrophil oxidants inhibits its cleavage by ADAMTS13.. Blood 2009; 115: 706-712.
• 50 Crawley JT, Lane DA, Woodward M. et al. Evidence that high von Willebrand factor and low ADAMTS-13 levels independently increase the risk of a non-fatal heart attack.. J Thromb Haemost 2008; 6: 583-588.
• 51 Babich V, Knipe L, Hewlett L. et al. Differential effect of extracellular acidosis on the release and dispersal of soluble and membrane proteins secreted from the Weibel-Palade body.. J Biol Chem 2009; 284: 12459-12468.
• 52 Erent M, Meli A, Moisoi N. et al. Rate, extent and concentration dependence of histamine-evoked Weibel-Palade body exocytosis determined from individual fusion events in human endothelial cells.. J Physiol 2007; 583: 195-212.
• 53 Springer TA. Biology and physics of von Willebrand factor concatamers.. J Thromb Haemost 2011; 9 (Suppl. 01) 130-143.
• 54 Babich V, Meli A, Knipe L. et al. Selective release of molecules from Weibel-Pa-lade bodies during a lingering kiss.. Blood 2008; 111: 5282-5290.
• 55 Berriman JA, Li S, Hewlett LJ. et al. Structural organization of Weibel-Palade bodies revealed by cryo-EM of vitrified endothelial cells.. Proc Natl Acad Sci USA 2009; 106: 17407-17412.
• 56 Huang J, Roth R, Heuser JE. et al. Integrin alpha(v)beta(3) on human endothe-lial cells binds von Willebrand factor strings under fluid shear stress.. Blood 2009; 113: 1589-1597.
• 57 Padilla A, Moake JL, Bernardo A. et al. P-selectin anchors newly released ultra-large von Willebrand factor multimers to the endothelial cell surface.. Blood 2004; 103: 2150-2156.
• 58 Roberts DD, Williams SB, Gralnick HR. et al. von Willebrand factor binds specifically to sulfated glycolipids.. J Biol Chem 1986; 261: 3306-3309.
• 59 Chauhan AK, Goerge T, Schneider SW. et al. Formation of platelet strings and microthrombi in the presence of ADAMTS-13 inhibitor does not require P-selectin or beta3 integrin.. J Thromb Haemost 2007; 5: 583-589.
• 60 Pappelbaum KI, Gorzelanny C, Grassle S. et al. Ultralarge von Willebrand Factor Fibers Mediate Luminal Staphylococcus aureus Adhesion to an Intact En-dothelial Cell Layer Under Shear Stress.. Circulation 2013; 128: 50-59.
• 61 Chauhan AK, Kisucka J, Brill A. et al. ADAMTS13: a new link between thrombosis and inflammation.. J Exp Med 2008; 205: 2065-2074.
• 62 Brill A, Fuchs TA, Chauhan AK. et al. von Willebrand factor-mediated platelet adhesion is critical for deep vein thrombosis in mouse models.. Blood 2011; 117: 1400-1407.
• 63 Tangelder GJ, Slaaf DW, Arts T. et al. Wall shear rate in arterioles in vivo: least estimates from platelet velocity profiles.. Am J Physiol 1988; 254: H1059-1064.
• 64 Truskey GA, Yuan F, Katz DF. Transport Phenomena in Biological Systems.. 2nd ed.. Prentice Hall; Upper Saddle River, New Jersey: 07458 2009
• 65 Back LD, Radbill JR, Crawford DW. Analysis of pulsatile, viscous blood flow through diseased coronary arteries of man.. J Biomech 1977; 10: 339-353.
• 66 Westein E, van der Meer AD, Kuijpers MJ. et al. Atherosclerotic geometries exacerbate pathological thrombus formation poststenosis in a von Willebrand factor-dependent manner.. Proc Natl Acad Sci USA 2013; 110: 1357-1362.
• 67 Singh I, Shankaran H, Beauharnois ME. et al. Solution structure of human von Willebrand factor studied using small angle neutron scattering.. J Biol Chem 2006; 281: 38266-38275.
• 68 Sing CE, Alexander-Katz A. Elongational flow induces the unfolding of von Willebrand factor at physiological flow rates.. Biophys J 2010; 98: L35-37.
• 69 Zhang X, Halvorsen K, Zhang CZ. et al. Mechanoenzymatic cleavage of the ultralarge vascular protein von Willebrand factor.. Science 2009; 324: 1330-1334.
• 70 Tsai HM. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion.. Blood 1996; 87: 4235-4244.
• 71 Fallah MA, Huck V, Niemeyer V. et al. Circulating but not immobilized N-deg-lycosylated von Willebrand factor increases platelet adhesion under flow conditions.. Biomicrofluidics 2013; 7: 044124.
• 72 Chen H, Fallah MA, Huck V. et al. Blood-clotting-inspired reversible polymer-colloid composite assembly in flow.. Nat Commun 2013; 4: 1333.
• 73 Reininger AJ. Platelet function under high shear conditions.. Hamostaseologie 2009; 29: 21-22 24.
• 74 Reininger AJ. Function of von Willebrand factor in haemostasis and thrombosis.. Haemophilia 2008; 14 (Suppl. 05) 11-26.
• 75 Zhou YF, Eng ET, Zhu J. et al. Sequence and structure relationships within von Willebrand factor.. Blood 2012; 120: 449-458.
• 76 Friedrichs J, Legate KR, Schubert R. et al. A practical guide to quantify cell adhesion using single-cell force spectroscopy.. Methods 2013; 60: 169-178.
• 77 Leitner M, Fantner GE, Fantner EJ. et al. Increased imaging speed and force sensitivity for bio-applications with small cantilevers using a conventional AFM setup.. Micron 2012; 43: 1399-1407.
• 78 Ju L, Dong JF, Cruz MA. et al. The N-terminal flanking region of the A1 domain regulates the force-dependent binding of von Willebrand factor to platelet gly-coprotein Ibalpha.. J Biol Chem 2013; 288: 32289-32301.
• 79 Kim J, Zhang CZ, Zhang X. et al. A mechanically stabilized receptor-ligand flex-bond important in the vasculature.. Nature 2010; 466: 992-995.
• 80 Reininger AJ. VWF attributes--impact on thrombus formation.. Thromb Res 2008; 122 (Suppl. 04) S9-13.
• 81 Chauhan AK, Kisucka J, Lamb CB. et al. von Willebrand factor and factor VIII are independently required to form stable occlusive thrombi in injured veins.. Blood 2007; 109: 2424-2429.
• 82 Denis C, Methia N, Frenette PS. et al. A mouse model of severe von Willebrand disease: defects in hemostasis and thrombosis.. Proc Natl Acad Sci USA 1998; 95: 9524-9529.
• 83 Ni H, Denis CV, Subbarao S. et al. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen.. J Clin Invest 2000; 106: 385-392.
• 84 McKinnon TA, Chion AC, Millington AJ. et al. N-linked glycosylation of VWF modulates its interaction with ADAMTS13.. Blood 2008; 111: 3042-3049.
• 85 Weyrich AS, Lindemann S, Zimmerman GA. The evolving role of platelets in inflammation.. J Thromb Haemost 2003; 1: 1897-1905.
• 86 Pendu R, Terraube V, Christophe OD. et al. P-selectin glycoprotein ligand 1 and beta2-integrins cooperate in the adhesion of leukocytes to von Willebrand factor.. Blood 2006; 108: 3746-3752.
• 87 Petri B, Broermann A, Li H. et al. von Willebrand factor promotes leukocyte extravasation.. Blood 2010; 116: 4712-4719.
• 88 Hillgruber C, Steingraber AK, Poppelmann B. et al. Blocking Von Willebrand Factor for Treatment of Cutaneous Inflammation.. J Invest Dermatol 2013; 134: 77-86.
• 89 Rauch A, Wohner N, Christophe OD. et al. On the versatility of von Willebrand factor.. Mediterr J Hematol Infect Dis 2013; 5: e2013046.
• 90 Yuan H, Deng N, Zhang S. et al. The unfolded von Willebrand factor response in bloodstream: the self-association perspective.. J Hematol Oncol 2012; 5: 65.
• 91 Casari C, Lenting PJ, Wohner N. et al. Clearance of von Willebrand factor.. J Thromb Haemost 2013; 11 (Suppl. 01) 202-211.
• 92 Oggianu L, Lancellotti S, Pitocco D. et al. The oxidative modification of von Willebrand factor is associated with thrombotic angiopathies in diabetes melli-tus.. PLoS One 2013; 8: e55396.