The function of ultra-large von Willebrand factor multimers in high shear flow controlled by ADAMTS13

 

 Buy Article Permissions and Reprints

Summary

The paradigm that platelet aggregation, which contributes to bleeding arrest and also to thrombovascular disorders, initiates after signaling-induced platelet activation has been refuted in past recent years. Platelets can form aggregates independently of activation when soluble von Willebrand factor (VWF) is present and the shear rate exceeds a certain threshold where active A1 domains become exposed in soluble VWF multimers and can bind to platelet glycoprotein Ib. Subsequently – fostering each other – VWF can self-assemble into large nets combining with platelets into large conglomerates, which are entirely reversible when they enter a flow region with shear rates below the threshold. In addition the threshold changes from approximately 20 000 s^-1 in wall parallel flow to approximately 10 000 s^-1 in stagnation point flow. VWF containing ultra-large multimers – as when just released from endothelial storage sites – has been shown to have the highest binding potential to platelets and to each other, thus facilitating rapid platelet accrual to sites of vessel injury and exposed subendothelial structures, i.e. collagen. The VWF nets as well as the platelet-VWF conglomerates are controlled by the cleaving protease ADAMTS13 within minutes under high shear flow. Therewith the hemostatic potential is delivered where needed and the thrombogenic potential is highly controlled twofold: by flow and enzymatic proteolytic cleavage.

Zusammenfassung

In den vergangenen Jahren wurde das Paradigma infrage gestellt, dass die Initiierung der Plättchenaggregation – die zur Blutstillung und zu thrombovaskulären Störungen beiträgt – rein durch signalinduzierte Plättchenaktivierung erfolgt. In der Anwesenheit von löslichem von-Willebrand-Faktor können Thrombozyten unabhängig von ihrer Aktivierung Aggregate bilden. Dazu muss die Scherrate einen gewissen Schwellenwert überschreiten, sodass die A1-Domänen des VWF aktiviert, d. h. in löslichen VWF Multimeren exponiert werden und den Plättchenrezeptor Glykoprotein Ib binden. In der Folge sich gegenseitig verstär-kend kann VWF zu großen Netzen selbst-assemblieren und sich mit Plättchen zu gro-ßen Konglomeraten verbinden, die komplett reversibel sind, sobald sie in Flussregionen mit Scherraten unterhalb der kritischen Schwelle eintreten. Diese kritische Schwelle verringert sich von etwa 20 000 s^-1 auf etwa 10 000 s^-1 wenn statt wandparalleler Strömung eine Staupunktströmung vorliegt. Enthält VWF ultragroße Multimere – so wie nach seiner Freisetzung aus den endothelia-len Speichern – haben diese das höchste Bindungspotenzial für Plättchen und unter -einander und fördern dadurch die schnelle Ansammlung von Thrombozyten an verletzten Gefäßen und exponierten subendothelialen Strukturen wie Kollagen. Unter Flussbedingungen mit sehr hohen Scherraten kontrolliert die Protease ADAMTS13 die VWF-Netze sowie die Plättchen-VWF-Konglomera-te innerhalb von Minuten durch enzymatische VWF-Spaltung. Somit wird das hämostatische Potenzial am Bedarfsort realisiert, und das thrombogene Potenzial wird zweifach reguliert: durch die lokale Flussbedingung und die proteolytische VWF-Spaltung.

• References

• 1 Reininger AJ. Function of von Willebrand factor in haemostasis and thrombosis. Haemophilia 2008; 14 (Suppl. 05) 11-26.
  PubMedGoogle Scholar
• 2 Fowler WE, Fretto LJ. Electron microscopy of von Willebrand factor. In: Zimmerman TS, Ruggeri ZM. (eds). Coagulation and Bleeding Disorders. The Role of Factor VIII and von Willebrand Factor. New York: Dekker; 1989: 181-193.
  Google Scholar
• 3 Chen H, Fallah MA, Huck V. et al. Blood-clotting-inspired reversible polymer-colloid composite assembly in flow. Nat Commun 2013; 04: 1333.
  CrossrefPubMedGoogle Scholar
• 4 Hantgan RR, Hindriks G, Taylor RG. et al. Glycoprotein Ib, von Willebrand factor, and glycoprotein IIb:IIIa are all involved in platelet adhesion to fibrin in flowing whole blood. Blood 1990; 76: 345-353.
  PubMedGoogle Scholar
• 5 Davies MJ, Thomas AC, Knapman PA, Hangartner JR. Intramyocardial platelet aggregation in patients with unstable angina suffering sudden ischemic cardiac death. Circulation 1986; 73: 418-427.
  CrossrefPubMedGoogle Scholar
• 6 Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002; 08: 1227-1234.
  CrossrefPubMedGoogle Scholar
• 7 Ruggeri ZM, Orje JN, Habermann R. et al. Activation-independent platelet adhesion and aggregation under elevated shear stress. Blood 2006; 108: 1903-1910.
  CrossrefPubMedGoogle Scholar
• 8 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.
  CrossrefPubMedGoogle Scholar
• 9 Ruggeri ZM, Dent JA, Saldivar E. Contribution of distinct adhesive interactions to platelet aggregation in flowing blood. Blood 1999; 94: 172-178.
  PubMedGoogle Scholar
• 10 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.
  CrossrefPubMedGoogle Scholar
• 11 Wellings PJ, Ku D. Mechanisms of Platelet Capture Under Very High Shear. Cardiovascular Engineering and Technology 2012; 03: 161-170.
  CrossrefPubMedGoogle Scholar
• 12 Van der Kwast TH, Stel HV, Cristen E, Bertina RM, Veerman EC. Localization of factor VIII-procoagulant antigen: an immunohistological survey of the human body using monoclonal antibodies. Blood 1986; 67: 222-227.
  PubMedGoogle Scholar
• 13 Takeuchi M, Nagura H, Kaneda T. DDAVP and epinephrine-induced changes in the localization of von Willebrand factor antigen in endothelial cells of human oral mucosa. Blood 1988; 72: 850-854.
  PubMedGoogle Scholar
• 14 Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol 1990; 06: 217-246.
  CrossrefPubMedGoogle Scholar
• 15 Harrison RL, McKee PA. Estrogen stimulates von Willebrand factor production by cultured endothelial cells. Blood 1984; 63: 657-664.
  PubMedGoogle Scholar
• 16 Wagner DD. Cell biology of von Willebrand factor. Annu Rev Cell Biol 1990; 06: 217-246.
  CrossrefPubMedGoogle Scholar
• 17 Mayadas TN, Wagner DD. von Willebrand factor biosynthesis and processing. Ann N Y Acad Sci 1991; 614: 153-166.
  CrossrefPubMedGoogle Scholar
• 18 Wagner DD, Marder VJ. Biosynthesis of von Willebrand protein by human endothelial cells: processing steps and their intracellular localization. J Cell Biol 1984; 99: 2123-2130.
  CrossrefPubMedGoogle Scholar
• 19 Tsai HM, Nagel RL, Hatcher VB, Sussman II. Multimeric composition of endothelial cell-derived von Willebrand factor. Blood 1989; 73: 2074-2076.
  PubMedGoogle Scholar
• 20 Moake JL, Rudy CK, Troll JH. et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307: 1432-1435.
  CrossrefPubMedGoogle Scholar
• 21 Wencel-Drake JD, Painter RG, Zimmerman TS, Ginsberg MH. Ultrastructural localization of human platelet thrombospondin, fibrinogen, fibronectin, and von Willebrand factor in frozen thin section. Blood 1985; 65: 929-938.
  PubMedGoogle Scholar
• 22 Ruggeri ZM, Mannucci PM, Lombardi R. et al. Multimeric composition of factor VIII/von Willebrand factor following administration of DDAVP: implications for pathophysiology and therapy of von Willebrand_s disease subtypes. Blood 1982; 59: 1272-1278.
  PubMedGoogle Scholar
• 23 Fernandez MF, Ginsberg MH, Ruggeri ZM. et al. Multimeric structure of platelet factor VIII/von Willebrand factor: the presence of larger multimers and their reassociation with thrombinstimulated platelets. Blood 1982; 60: 1132-1138.
  PubMedGoogle Scholar
• 24 Koutts J, Walsh PN, Plow EF. et al. Active release of human platelet factor VIII-related antigen by adenosine diphosphate, collagen, and thrombin. J Clin Invest 1978; 62: 1255-1263.
  CrossrefPubMedGoogle Scholar
• 25 Lowe EJ, Werner EJ. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome in children and adolescents. Semin Thromb Hemost 2005; 31: 717-730.
  Article in Thieme ConnectPubMedGoogle Scholar
• 26 Nesheim M, Pittman DD, Giles AR. et al. The effect of plasma von Willebrand factor on the binding of human factor VIII to thrombin-activated human platelets. J Biol Chem 1991; 266: 17815-17820.
  PubMedGoogle Scholar
• 27 Michaux G, Pullen TJ, Haberichter SL, Cutler DF. P-selectin binds to the D_-D3 domains of von Willebrand factor in Weibel-Palade bodies. Blood 2006; 107: 3922-3924.
  CrossrefPubMedGoogle Scholar
• 28 Padilla A, Moake JL, Bernardo A. et al. P-selectin anchors newly released ultralarge von Willebrand factor multimers to the endothelial cell surface. Blood 2004; 103: 2150-2156.
  CrossrefPubMedGoogle Scholar
• 29 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.
  CrossrefPubMedGoogle Scholar
• 30 Ruggeri ZM, Ware J, Ginsburg D. et al. (eds). Thrombosis and Hemorrhage. Philadelphia, PA: Lippincott Williams & Wilkins; 2003: 246-265.
  Google Scholar
• 31 Mannucci PM. Treatment of von Willebrand’s disease. N Engl J Med 2004; 351: 683-694.
  CrossrefPubMedGoogle Scholar
• 32 Goodeve AC, Rosén S, Verbruggen B. Haemophilia A and von Willebrand’s disease. Haemophilia 2010; 16 (Suppl. 05) 79-84.
  CrossrefPubMedGoogle Scholar
• 33 Gill JC. Treatment of urgent bleeding in von Willebrand disease. Thromb Res 2007; 120 (Suppl. 01) S21-S25.
  CrossrefPubMedGoogle Scholar
• 34 Lethagen S, Kyrle PA, Castaman G. et al. von Willebrand factor/factor VIII concentrate (Haemate P) dosing based on pharmacokinetics: a prospective multicenter trial in elective surgery. J Thromb Haemost 2007; 05: 1420-1430.
  CrossrefPubMedGoogle Scholar
• 35 Berntorp E. Haemate P/Humate-P: a systematic review. Thromb Res 2009; 124 (Suppl. 01) S11-S14.
  CrossrefPubMedGoogle Scholar
• 36 Favaloro EJ, Lloyd J, Rowell J. et al. Comparison of the pharmacokinetics of two von Willebrand factor concentrates [Biostate and AHF (High Purity)] in people with von Willebrand disorder. A randomised cross-over, multi-centre study. Thromb Haemost 2007; 97: 922-930.
  Article in Thieme ConnectPubMedGoogle Scholar
• 37 Borel-Derlon A, Federici AB, Roussel-Robert V. et al. Treatment of severe von Willebrand disease with a high-purity von Willebrand factor concentrate (Wilfactin®): a prospective study of 50 patients. J Thromb Haemost 2007; 05: 1115-1124.
  CrossrefPubMedGoogle Scholar
• 38 Goudemand J, Scharrer I, Berntorp E. et al. Pharmacokinetic studies on Wilfactin, a von Willebrand factor concentrate with a low factor VIII content treated with three virus-inactivations/removal methods. J Thromb Haemost 2005; 03: 2219-2227.
  CrossrefPubMedGoogle Scholar
• 39 Mannucci PM, Kempton CL, Laffan MA. et al. Recombinant human von Willebrand factor-plasma free manufactured: first-in-human study evaluating pharmacokinetics, demonstrating safety and tolerability in severe VWD. J Thromb Haemost. 2011 09. 02
  PubMedGoogle Scholar
• 40 Fischer BE. Recombinant von Willebrand factor: Potential therapeutic use. J Thromb Thrombolysis 1999; 08: 197-205.
  CrossrefPubMedGoogle Scholar
• 41 Turecek PL, Schrenk G, Rottensteiner H. et al. Structure and function of a recombinant von Willebrand factor drug candidate. Semin Thromb Hemost 2010; 36: 510-521.
  Article in Thieme ConnectPubMedGoogle Scholar
• 42 Kragh T, Napoleone M, Fallah MA. et al. High shear dependent von Willebrand factor self-assembly fostered by platelet interaction and controlled by ADAMTS13. Thromb Res 2014; 133: 1079-1087.
  CrossrefPubMedGoogle Scholar
• 43 Siedlecki CA, Lestini BJ, Kottke-Marchant KK. et al. Shear-dependent changes in the three-dimensional structure of human von Willebrand factor. Blood 1996; 88: 2939-2950.
  CrossrefPubMedGoogle Scholar
• 44 Schneider SW, Nuschele S, Wixforth A. et al. Shear-induced unfolding triggers adhesion of von Willebrand factor fibers. Proc Natl Acad Sci USA 2007; 104: 7899-7903.
  CrossrefPubMedGoogle Scholar
• 45 Perkkio J, Wurzinger LJ, Schmid-Schönbein H. Plasma and platelet skimming at T-junctions. Thromb Res 1987; 45: 517-526.
  CrossrefPubMedGoogle Scholar
• 46 Gaehtgens P. Distribution of flow and red cell flux in the microcirculation. Scand J Clin Lab Invest Suppl 1981; 156: 83-87.
  PubMedGoogle Scholar
• 47 Chen H, Angerer JI, Napoleone M. et al. Hematocrit and flow rate regulate the adhesion of platelets to von Willebrand factor. Biomicrofluidics 2013; 07: 064113.
  CrossrefPubMedGoogle Scholar
• 48 Kumar A, Graham MD. Margination and segregation in confined flows of blood and other multicomponent suspensions. Soft Matter 2012; 08: 10536-10548.
  CrossrefPubMedGoogle Scholar
• 49 Carr RT, Xiao J. Plasma skimming in vascular trees: numerical estimates of symmetry recovery lengths. Microcirculation 1995; 02: 345-353.
  CrossrefPubMedGoogle Scholar
• 50 Kumar A, Graham MD. Mechanism of margination in confined flows of blood and other multicomponent suspensions. Phys Rev Lett 2012; 109: 108102.
  CrossrefPubMedGoogle Scholar
• 51 Kumar A, Graham MD. Segregation by membrane rigidity in flowing binary suspensions of elastic capsules. Phys Rev E Stat Nonlin Soft Matter Phys 2011; 84: 066316.
  CrossrefPubMedGoogle Scholar
• 52 Reasor Jr DA, Mehrabadi M, Ku DN, Aidun CK. Determination of critical parameters in platelet margination. Ann Biomed Eng 2013; 41: 238-249.
  CrossrefPubMedGoogle Scholar
• 53 Zhao H, Shaqfeh E, Narsimhan V. Shear-induced particle migration and margination in a cellular suspension. Physics of Fluids. 2012 24.
  PubMedGoogle Scholar
• 54 Zhao H, Shaqfeh ESG. Shear-induced platelet margination in a microchannel. Phys Rev E Stat Nonlin Soft Matter Phys 2011; 83: 061924.
  CrossrefPubMedGoogle Scholar
• 55 Livio M, Gotti E, Marchesi D. et al. Uraemic bleeding: role of anaemia and beneficial effect of red cell transfusions. Lancet 1982; 02: 1013-1015.
  PubMedGoogle Scholar
• 56 Yago T, Lou J, Wu T. et al. Platelet glycoprotein lb alpha forms catch bonds with human WT vWF but not with type 2B von Willebrand disease vWF. J Clin Invest 2008; 118: 3195-3207.
  PubMedGoogle Scholar
• 57 Ganderton T, Wong JWH, Schroeder C, Hogg PJ. Lateral self-association of VWF involves the Cys2431-Cys2453 disulfide/dithiol in the C2 domain. Blood 2011; 118: 5312-5318.
  CrossrefPubMedGoogle Scholar
• 58 Moake JL, Rudy CK, Troll JH. et al. Unusually large plasma factor VIII:von Willebrand factor multimers in chronic relapsing thrombotic thrombocytopenic purpura. N Engl J Med 1982; 307: 1432-1435.
  CrossrefPubMedGoogle Scholar
• 59 Padilla A, Moake JL, Bernardo A. et al. P-selectin anchors newly released ultralarge von Willebrand factor multimers to the endothelial cell surface. Blood 2004; 103: 2150-2156.
  CrossrefPubMedGoogle Scholar
• 60 Mannucci PM, Canciani MT, Forza I. et al. Changes in health and disease of the metalloprotease that cleaves von Willebrand factor. Blood 2001; 98: 2730-2735.
  CrossrefPubMedGoogle Scholar
• 61 Mannucci PM, Kempton C, Millar C. et al. Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial. Blood 2013; 122: 648-657.
  CrossrefPubMedGoogle Scholar
• 62 Camilleri RS, Scully M, Thomas M. et al. A phenotype-genotype correlation of ADAMTS13 mutations in congenital TTP patients treated in the United Kingdom. J Thromb Haemost 2012; 10: 1792-1801.
  CrossrefPubMedGoogle Scholar
• 63 Perutelli P, Amato S, Molinari AC. ADAMTS-13 activity in von Willebrand disease. Thromb Res 2006; 117: 685-688.
  CrossrefPubMedGoogle Scholar