Coagulation potential of immobilised factor VIII in flow-dependent fibrin generation on platelet surfaces

 

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Summary

Coagulation factor VIII (FVIII) plays an essential role in haemostasis. To date, physiologic activity of FVIII circulating in the bloodstream (S-FVIII) is evaluated by classic coagulation assays. However, the functional relevance of FVIII (-von Willebrand factor complex) immobilised on thrombogenic surfaces (I-FVIII) remains unclear. We used an in vitro perfusion chamber system to evaluate the function of I-FVIII in the process of mural thrombus formation under whole blood flow conditions. In perfusion of either control or synthetic haemophilic blood, the intra-thrombus fibrin generation on platelet surfaces significantly increased as a function of I-FVIII, independent of S-FVIII, under high shear rate conditions. This I-FVIII effect was unvarying regardless of anti-FVIII inhibitor levels in synthetic haemophilic blood. Thus, our results illustrate coagulation potentials of immobilised clotting factors, distinct from those in the bloodstream, under physiologic flow conditions and may give a clue for novel therapeutic approaches for haemophilic patients with anti-FVIII inhibitors.

• References

• 1 Sixma JJ, Waster J. The hemostatic plug. Semin Hematol 1977; 14: 265-299.
  PubMedGoogle Scholar
• 2 Weiss HJ. Platelet physiology and abnormalities of platelet function. N Engl J Med 1975; 293: 531-541.
  CrossrefPubMedGoogle Scholar
• 3 Furie B, Furie BC. Thrombus formation in vivo. J Clin Invest 2005; 115: 3355-3362.
  CrossrefPubMedGoogle Scholar
• 4 Davie EW, Ratnoff OD. Waterfall sequence for intrinsic blood clotting. Science 1964; 145: 1310-1312.
  CrossrefPubMedGoogle Scholar
• 5 Hoyer L. The factor VIII complex: Structure and function. Blood 1981; 58: 1-13.
  PubMedGoogle Scholar
• 6 Fay PJ. Factor VIII structure and function. Int J Hematol 2006; 83: 103-108.
  CrossrefPubMedGoogle Scholar
• 7 Mizuno T, Sugimoto M, Matsui H. et al. Visual evaluation of blood coagulation during mural thrombogenesis under high shear flow. Thromb Res 2008; 121: 855-864.
  CrossrefPubMedGoogle Scholar
• 8 Hamada M, Sugimoto M, Matsui H. et al. Antithrombotic properties of pravastatin reducing intra-thrombus fibrin deposition under high shear blood flow conditions. Thromb Haemost 2011; 105: 313-320.
  Article in Thieme ConnectPubMedGoogle Scholar
• 9 Sugimoto M, Mohri H, McClintock RA. et al. Identification of discontinuous von Willebrand factor sequences involved in complex formation with botrocetin. A model for the regulation of von Willebrand factor binding to platelet glycoprotein Ib. J Biol Chem 1991; 266: 18172-18178.
  PubMedGoogle Scholar
• 10 Weiss HJ, Sussman II, Hoyer LW. Stabilisation of factor VIII in plasma by the von Willebrand factor: Studies on posttransfusion and dissociated factor VIII and in patients with von Willebrand’s disease. J Clin Invest 1977; 60: 390-404.
  CrossrefPubMedGoogle Scholar
• 11 Kamisue S, Shima M, Nishimura T. et al. Abnormal factor VIII Hiroshima: defect in crucial proteolytic cleavage by thrombin at Arg1689 detected by a novel ELISA. Br J Haematol 1994; 86: 106-111.
  CrossrefPubMedGoogle Scholar
• 12 Kuwahara M, Sugimoto M, Tsuji S. et al. Cytosolic calcium changes in a process of platelet adhesion and cohesion on a von Willebrand factor-coated surface under flow conditions. Blood 1999; 94: 1149-1155.
  PubMedGoogle Scholar
• 13 Matsui H, Sugimoto M, Mizuno T. et al. Distinct and concerted functions of von Willebrand factor and fibrinogen in mural thrombus growth under high shear flow. Blood 2002; 100: 3604-3610.
  CrossrefPubMedGoogle Scholar
• 14 Sugimoto M, Matsui H, Mizuno T. et al. Mural thrombus generation in type 2A and 2B von Willebrand disease under flow conditions. Blood 2003; 101: 915-920.
  CrossrefPubMedGoogle Scholar
• 15 Shida Y, Nishio K, Sugimoto M. et al. Functional imaging of shear-dependent activity of ADAMTS13 in regulating mural thrombus growth under whole blood flow conditions. Blood 2008; 111: 1295-1298.
  PubMedGoogle Scholar
• 16 Tsuji S, Sugimoto M, Miyata S. et al. Real-time analysis of mural thrombus formation in various platelet aggregation disorders: distinct shear-dependent roles of platelet receptors and adhesive proteins under flow. Blood 1999; 94: 968-975.
  PubMedGoogle Scholar
• 17 Atkinson BT, Jasuja R, Chen VM. et al. Laser-induced endothelial cell activation supports fibrin formation. Blood 2010; 116: 4675-4683.
  CrossrefPubMedGoogle Scholar
• 18 Sadler JE. Biochemistry and genetics of von Willebrand factor. [pic][pic]Ann Rev Biochem 1998; 67: 395-424.
  CrossrefPubMedGoogle Scholar
• 19 Lenting PJ, van Mourick JA, Mertens K. The life cycle of coagulation factor VIII in view of its structure and function. Blood 1998; 92: 3983-3996.
  PubMedGoogle Scholar
• 20 Kuharsky A L, Fogelson A L. Surface-mediated control of blood coagulation: the role of binding site densities and platelet deposition. Biophys J 2001; 80: 1050-1074.
  CrossrefPubMedGoogle Scholar
• 21 Berny MA, Munnix IC, Auger JM. et al. Spatial distribution of factor Xa, thrombin, and fibrin(ogen) on thrombi at venous shear. PLoS One 2010; 05: e10415.
  CrossrefPubMedGoogle Scholar
• 22 Leiderman K, Fogelson AL. Grow with the flow: a spatial-temporal model of platelet deposition and blood coagulation under flow. Math Med Biol 2011; 28: 47-84.
  CrossrefPubMedGoogle Scholar