Simulation of platelet adhesion and aggregation regulated by fibrinogen and von Willebrand factor

Summary

We propose a method to analyze platelet adhesion and aggregation computationally, taking into account the distinct properties of two plasma proteins, vonWillebrand factor (vWF) and fibrinogen (Fbg). In this method, the hydrodynamic interactions between platelet particles under simple shear flow were simulated using Stokesian dynamics based on the additivity of velocities. The binding force between particles mediated by vWF and Fbg was modeled using the Voigt model. Two Voigt models with different properties were introduced to consider the distinct behaviors of vWF and Fbg. Our results qualitatively agreed with the general observation of a previous in-vitro experiment, thus demonstrating that the significant development of thrombus formation in height requires not only vWF, but also Fbg. This agreement of simulation and experimental results qualitatively validates our model and suggests that consideration of the distinct roles of vWF and Fbg is essential to investigate the physiological and pathophysiological mechanisms of thrombus formation using a computational approach.

Keywords

Computational simulation - glycoprotein receptors - thrombus - shear flow

• References

• 1 Ruggeri ZM. Platelets in atherothrombosis. Nature Med 2002; 8: 1227-1234.
• 2 Rao AK, Holmsen H. Congenital disorders of platelet function. Semin Hematol 1986; 23: 102-118.
• 3 Goto S, Salomon DR, Ikeda Y. et al. Characterization of the unique mechanism mediating the shear-dependent binding of soluble von Willebrand factor to platelets. J Biol Chem 1995; 270: 23352-23361.
• 4 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.
• 5 Goto S, Ikeda Y, Saldivar E. et al. Distinct mechanisms of platelet aggregation as a consequence of different shearing flow conditions. J Clin Invest 1998; 101: 479-486.
• 6 Lefkovits J, Plow EF, Topol EJ. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. New Engl J Med 1995; 332: 1553-1559.
• 7 Ruggeri ZM. Von Willebrand factor and the mechanisms of platelet functions.. Springer-Verlag; : 1998
• 8 Ruggeri ZM. Platelet interactions with vessel wall components during thrombogenesis. Blood Cells Mol Dis 2006; 36: 145-147.
• 9 Hennan JK, Swillo RE, Morgan GA. et al. Pharmacologic inhibition of platelet vWF-GPIb alpha interaction prevents coronary artery thrombosis. Thromb Haemost 2006; 95: 469-475.
• 10 Penz SM, Reininger AJ, Toth O. et al. Glycoprotein Ibalpha inhibition and ADP receptor antagonists, but not aspirin, reduce platelet thrombus formation in flowing blood exposed to atherosclerotic plaques. Thromb Haemost 2007; 97: 435-443.
• 11 Ruggeri ZM. Von Willebrand factor: looking back and looking forward. Thromb Haemost 2007; 98: 55-62.
• 12 Wadanoli M, Sako D, Shaw GD. et al. The von Willebrand factor antagonist (GPG-290) prevents coronary thrombosis without prolongation of bleeding time. Thromb Haemost 2007; 98: 397-405.
• 13 Fogelson AL. Continuum models of platelet-aggregation – Formulation and mechanical-properties. Siam J Appl Math 1992; 52: 1089-1110.
• 14 Wang NT, Fogelson AL. Computational methods for continuum models of platelet aggregation. J Comp Phys 1999; 151: 649-675.
• 15 Tamagawa M, Matsuo S. Predictions of thrombus formation using lattice Boltzmann method – (Modeling of adhesion force for particles to wall). Japan Soc Mechan Eng Int J C-Mechanical Systems Machine Elements and Manufacturing 2004; 47: 1027-1034.
• 16 Kamada H, Tsubota K, Wada S. et al. Computer simulation of formation and collapse of primary thrombus due to platelet aggregation using particle method. Transact Japan Soc Mechan Eng B 2006; 72: 1109-1115.
• 17 Pivkin IV, Richardson PD, Karniadakis G. Blood flow velocity effects and role of activation delay time on growth and form of platelet thrombi. Proc Natl Acad Sci USA 2006; 103: 17164-17169.
• 18 Miyazaki H, Yamaguchi T. Formation and destruction of primary thrombi under the influence of blood flow and von Willebrand factor analyzed by a discrete element method. Biorheology 2003; 40: 265-272.
• 19 Yano K, Mori D, Tsubota K. et al. Analysis of Destruction Process of the Primary Thrombus Under the Influence of the Blood Flow. J Biomech Sci Eng 2007; 2: 34-44.
• 20 Weiss HJ, Rogers J. Fibrinogen and platelets in the primary arrest of bleeding. Studies in two patients with congenital afibrinogenemia. New Engl J Med 1971; 285: 369-374.
• 21 Tschopp TB, Weiss HJ, Baumgartner HR. Decreased adhesion of platelets to subendothelium in von Willebrand's disease. J Lab Clin Med 1974; 83: 296-300.
• 22 Ruggeri ZM. von Willebrand factor and fibrinogen. Curr Opin Cell Biol 1993; 5: 898-906.
• 23 Satoh A, Chantrell RW, Coverdale GN. et al. Stokesian Dynamics Simulations of Ferromagnetic Colloidal Dispersions in a Simple Shear Flow. J Colloid Interface Sci 1998; 203: 233-248.
• 24 Satoh A. Comparison of approximations between additivity of velocities and additivity of forces for Stokesian dynamics methods. J Colloid Interface Sci 2001; 243: 342-350.
• 25 Durlofsky L, Brady JF, Bossis G. Dynamic Simulation of Hydrodynamically Interacting Particles. J Fluid Mech 1987; 180: 21-49.
• 26 Frojmovic MM, Milton JG. Human platelet size, shape, and related functions in health and disease. Physiol Rev 1982; 62: 185-261.
• 27 Kim S, Karrila SJ. Microhydrodynamics. Principles and Selected Applications.. Butterworth-Heinemann, Stoneham; : 1991
• 28 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.