Abstract
The study on the polymerization of fibrinogen molecules into fibrin monomers and eventually a stable, mechanically robust fibrin clot is a persistent and enduring topic in the field of thrombosis and hemostasis. Despite many research advances in fibrin polymerization, the change in the structure of fibrin clots and its influence on the formation of a fibrous protein network are still poorly understood. In this paper, we develop a new computational method to simulate fibrin clot polymerization using dissipative particle dynamics simulations. With an effective combination of reactive molecular dynamics formularies and many body dissipative particle dynamics principles, we constructed the reactive dissipative particle dynamics (RDPD) model to predict the complex network formation of fibrin clots and branching of the fibrin network. The 340 kDa fibrinogen molecule is converted into a spring-bead coarse-grain system with 11 beads using a topology representing network algorithm, and using RDPD, we simulated polymerization and formation of the fibrin clot. The final polymerized structure of the fibrin clot qualitatively agrees with experimental results from the literature, and to the best of our knowledge this is the first molecular-based study that simulates polymerization and structure of fibrin clots.
Graphical abstract
Similar content being viewed by others
References
Agnelli G (2004) Prevention of venous thromboembolism in surgical patients. Circulation 110:IV4–12 https://doi.org/10.1161/01.CIR.0000150639.98514.6c
Anderson FA Jr, Spencer FA (2003) Risk factors for venous thromboembolism. Circulation 107:I9–16. https://doi.org/10.1161/01.CIR.0000078469.07362.E6
Arkhipov A, Freddolino PL, Schulten K (2006) Stability and dynamics of virus capsids described by coarse-grained modeling. Structure 14:1767–1777. https://doi.org/10.1016/j.str.2006.10.003
Aronow WS (2004) The prevention of venous thromboembolism in older adults: guidelines. J Gerontol Seri A Biol Sci Med Sci 59:42–47
Averett RD, Menn B, Lee EH, Helms CC, Barker T, Guthold M (2012) A modular fibrinogen model that captures the stress–strain behavior of fibrin fibers. Biophys J 103:1537–1544. https://doi.org/10.1016/j.bpj.2012.08.038
Bajpai AK (2008) Fibrinogen adsorption onto macroporous polymeric surfaces: correlation with biocompatibility aspects. J Mater Sci Mater Med 19:343–357. https://doi.org/10.1007/s10856-006-0024-y
Baradet TC, Haselgrove JC, Weisel JW (1995) Three-dimensional reconstruction of fibrin clot networks from stereoscopic intermediate voltage electron microscope images and analysis of branching. Biophys J 68:1551–1560
Baranowska HM, Olszewski KJ (1996) The hydration of proteins in solutions by self-diffusion coefficients NMR study. Bba-Gen Subj 1289:312–314. https://doi.org/10.1016/0304-4165(95)00141-7
Beutler TC, Mark AE, van Schaik RC, Gerber PR, van Gunsteren WF (1994) Avoiding singularities and numerical instabilities in free energy calculations based on molecular simulations. Chem Phys Lett 222:529–539
Bode W, Mayr I, Baumann U, Huber R, Stone SR, Hofsteenge J (1989) The refined 1.9 A crystal structure of human alpha-thrombin: interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment. EMBO J 8:3467–3475
Boryczko K, Dzwinel W, Yuen DA (2004) Modeling fibrin aggregation in blood flow with discrete-particles. Comput Method Programs Biomed 75:181–194. https://doi.org/10.1016/j.cmpb.2004.02.001
Brambilla S, Ruosi C, La Maida GA, Caserta S (2004) Prevention of venous thromboembolism in spinal surgery. Eur Spine J Off Publ Eur Spine Soc Eur Spinal Deform Soc Eur Sect Cerv Spine Res Soc 13:1–8. https://doi.org/10.1007/s00586-003-0538-7
Brown AC, Barker TH (2014) Fibrin-based biomaterials: modulation of macroscopic properties through rational design at the molecular level. Acta Biomater 10:1502–1514. https://doi.org/10.1016/j.actbio.2013.09.008
Castner DG, Ratner BD (2002) Biomedical surface science: foundations to frontiers. Surf Sci 500:28–60. https://doi.org/10.1016/S0039-6028(01)01587-4
Chueh JY, Kuhn AL, Puri AS, Wilson SD, Wakhloo AK, Gounis MJ (2013) Reduction in distal emboli with proximal flow control during mechanical thrombectomy: a quantitative in vitro study. Stroke 44:1396–1401. https://doi.org/10.1161/STROKEAHA.111.670463
Chueh JY, Wakhloo AK, Hendricks GH, Silva CF, Weaver JP, Gounis MJ (2011) Mechanical characterization of thromboemboli in acute ischemic stroke and laboratory embolus analogs. AJNR Am J Neuroradiol 32:1237–1244. https://doi.org/10.3174/ajnr.A2485
Cimminiello C, Planes A, Samama MM (2004) Prevention of venous thromboembolism after orthopedic surgery: the EXPRESS study. J Thromb Haemost JTH 2:2036–2040. https://doi.org/10.1111/j.1538-7836.2004.01006.x
Collins R, Scrimgeour A, Yusuf S, Peto R (1988) Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. New Engl J Med 318:1162–1173. https://doi.org/10.1056/NEJM198805053181805
Cupelli C, Henrich B, Glatzel T, Zengerle R, Moseler M, Santer M (2008) Dynamic capillary wetting studied with dissipative particle dynamics. New J Phys 10 https://doi.org/10.1088/1367-2630/10/4/043009
Davison SP, Venturi ML, Attinger CE, Baker SB, Spear SL (2004) Prevention of venous thromboembolism in the plastic surgery patient. Plast Reconstr Surg 114:43E–51E
Doolittle RF (1984) Fibrinogen and Fibrin. Annu Rev Biochem 53:195–229
Dowling NF, Austin H, Dilley A, Whitsett C, Evatt BL, Hooper WC (2003) The epidemiology of venous thromboembolism in Caucasians and African–Americans: the GATE study. J Thromb Haemost JTH 1:80–87
Eriksson BI, Dahl OE (2004) Prevention of venous thromboembolism following orthopaedic surgery: clinical potential of direct thrombin inhibitors. Drugs 64:577–595
Fox BA, Yee VC, Pedersen LC, Le Trong I, Bishop PD, Stenkamp RE, Teller DC (1999) Identification of the calcium binding site and a novel ytterbium site in blood coagulation factor XIII by x-ray crystallography. J Biol Chem 274:4917–4923
Freddolino PL, Arkhipov A, Shih AY, Yin Y, Chen Z, Schulten K (2008) Application of residue-based and shape-based coarse graining to biomolecular simulations. Coarse Grain Condens Phase Biomol Syst 28: 299–315
Fukue H, Anderson K, McPhedran P, Clyne L, McDonagh J (1992) A unique factor XIII inhibitor to a fibrin-binding site on factor XIIIA. Blood 79:65–74
Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG (2004) Prevention of venous thromboembolism: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 126:338S–400S. https://doi.org/10.1378/chest.126.3_suppl.338S
Ghoufi A, Emile J, Malfreyt P (2013) Recent advances in many body dissipative particles dynamics simulations of liquid–vapor interfaces. Eur Phys J E 36:1–12. https://doi.org/10.1140/Epje/I2013-13010-7
Gounis MJ, Nogueira RG, Mehra M, Chueh J, Wakhloo AK (2013) A thromboembolic model for the efficacy and safety evaluation of combined mechanical and pharmacologic revascularization strategies. J Neurointerv Surg 5(Suppl 1):i85–89. https://doi.org/10.1136/neurintsurg-2012-010435
Greenberg CS, Dobson JV, Miraglia CC (1985) Regulation of plasma factor XIII binding to fibrin in vitro. Blood 66:1028–1034
Greer IA (2004) Prevention of venous thromboembolism in pregnancy. European J Med Res 9:135–145
Groot RD, Warren PB (1997) Dissipative particle dynamics: bridging the gap between atomistic and mesoscopic simulation. J Chem Phys 107:4423–4435
Hall CE, Slayter HS (1959) The fibrinogen molecule: its size, shape, and mode of polymerization. J Biophys Biochem Cytol 5:11–16
Hoover WG (1985) Canonical dynamics: equilibrium phase-space distributions. Phys Rev A 31:1695–1697
Humphrey W, Dalke A, Schulten K (1996) VMD: visual molecular dynamics. J Mol Graph 14:33–38
Iorio A (2004) Prevention of venous thromboembolism after major orthopedic surgery: summing up evidence about old and new antithrombotic agents. J Thromb Haemost JTH 2:1055–1057. https://doi.org/10.1111/j.1538-7836.2004.00753.x
Jiang Y, Li J, Liu Y, Li YC, Zhang WG (2015) Risk factors for deep vein thrombosis after orthopedic surgery and the diagnostic value of D-dimer. Ann Vasc Surg 29:675–681. https://doi.org/10.1016/j.avsg.2014.12.022
Kakkar VV, De Lorenzo F (1998) Prevention of venous thromboembolism in general surgery. Bailliere’s Clin Haematol 11:605–619
Kearon C (2003) Epidemiology of postoperative venous thromboembolism: lessons from an administrative data base. Thromb Haemost 90:367–368
Kollman JM, Pandi L, Sawaya MR, Riley M, Doolittle RF (2009) Crystal structure of human fibrinogen. Biochemistry 48:3877–3886. https://doi.org/10.1021/bi802205g
Kroegel C, Reissig A (2003) Principle mechanisms underlying venous thromboembolism: epidemiology, risk factors, pathophysiology and pathogenesis. Respir Int Rev Thorac Dis 70:7–30. https://doi.org/10.1159/000068427
Kyrle PA, Eichinger S (2005) Deep vein thrombosis. Lancet 365:1163–1174. https://doi.org/10.1016/S0140-6736(05)71880-8
Lam WA et al (2011) Mechanics and contraction dynamics of single platelets and implications for clot stiffening. Nat Mat 10:61–66. https://doi.org/10.1038/nmat2903
Lee AY (2003) Epidemiology and management of venous thromboembolism in patients with cancer. Thromb Res 110:167–172
Li F, Wang X, Huang W, Ren W, Cheng J, Zhang M, Zhao Y (2014) Risk factors associated with the occurrence of silent pulmonary embolism in patients with deep venous thrombosis of the lower limb. Phlebology 29:442–446. https://doi.org/10.1177/0268355513487331
Li Z, Hu GH, Wang ZL, Ma YB, Zhou ZW (2013) Three dimensional flow structures in a moving droplet on substrate: A dissipative particle dynamics study. Phys Fluids 25:072103. https://doi.org/10.1063/1.4812366
Liu CY (1981) Mechanism of thrombin binding by fibrin. Ann N Y Acad Sci 370:545–550
Liu CY, Nossel HL, Kaplan KL (1979) The binding of thrombin by fibrin. J Biol Chem 254:10421–10425
Liu LP et al (2014) Risk assessment of deep-vein thrombosis after acute stroke: a prospective study using clinical factors. CNS Neurosci Ther 20:403–410. https://doi.org/10.1111/cns.12227
Luo ZH et al (2012) Creation of fibrinogen-enhanced experimental blood clots to evaluate mechanical thrombectomy devices for treatment of acute stroke: an in vitro study. J Vasc Interv Radiol JVIR 23:1077–1083. https://doi.org/10.1016/j.jvir.2012.04.031
Ma L, Wen Z (2017) Risk factors and prognosis of pulmonary embolism in patients with lung cancer. Medicine 96:e6638. https://doi.org/10.1097/MD.0000000000006638
Martinetz T, Schulten K (1994) Topology representing networks. Neural Netw 7:507–522. https://doi.org/10.1016/0893-6080(94)90109-0
Martinez MCL, Rodes V, Delatorre JG (1984) Estimation of the shape and size of fibrinogen in solution from its hydrodynamic properties using theories for bead models and cylinders. Int J Biol Macromol 6:261–265. https://doi.org/10.1016/0141-8130(84)90005-9
MathWorks I (2012) MATLAB and statistics toolbox release. The MathWorks, Natick
Michetti CP, Franco E, Coleman J, Bradford A, Trickey AW (2015) Deep vein thrombosis screening and risk factors in a high-risk trauma population. J Surg Res 199:545–551. https://doi.org/10.1016/j.jss.2015.04.069
Mills R (1973) Self-diffusion in normal and heavy water in the range 1–45. deg. J Phys Chem 77:685–688
Minnema MC et al (2004) Prevention of venous thromboembolism with low molecular-weight heparin in patients with multiple myeloma treated with thalidomide and chemotherapy. Leukemia 18:2044–2046. https://doi.org/10.1038/sj.leu.2403533
Mismetti P, Laporte S, Zufferey P, Epinat M, Decousus H, Cucherat M (2004) Prevention of venous thromboembolism in orthopedic surgery with vitamin K antagonists: a meta-analysis. J Thromb Haemost JTH 2:1058–1070. https://doi.org/10.1111/j.1538-7836.2004.00757.x
Moftakhar P et al (2013) Density of thrombus on admission CT predicts revascularization efficacy in large vessel occlusion acute ischemic stroke. Stroke 44:243–245. https://doi.org/10.1161/STROKEAHA.112.674127
Moiseyev G, Bar-Yoseph PZ (2013) Computational modeling of thrombosis as a tool in the design and optimization of vascular implants. J Biomech 46:248–252. https://doi.org/10.1016/j.jbiomech.2012.11.002
Muller M, Burchard W (1981) Quasi-elastic light-scattering from fibrinogen and fibrin intermediate structures. Int J Biol Macromol 3:71–76. https://doi.org/10.1016/0141-8130(81)90070-2
Murday J, Cotts R (1970) Self-diffusion in liquids: H2O, D2O, and Na. J Chem Phys 53:4724–4725
Nosé S (1984) A molecular dynamics method for simulations in the canonical ensemble. Mol Phys 52:255–268
Palmer G, Fritz O, Hallett F (1979) Quasielastic light-scattering studies on human fibrinogen and fibrin I. Fibrinogen Biopolym 18:1647–1658
Pechik I, Madrazo J, Mosesson MW, Hernandez I, Gilliland GL, Medved L (2004) Crystal structure of the complex between thrombin and the central E region of fibrin. Proc Natl Acad Sci USA 101:2718–2723. https://doi.org/10.1073/pnas.0303440101
Phillips JC et al (2005) Scalable molecular dynamics with NAMD. J Comput Chem 26:1781–1802. https://doi.org/10.1002/jcc.20289
Plimpton S, Crozier P, Thompson A (2007) LAMMPS-large-scale atomic/molecular massively parallel simulator, vol 18. Sandia National Laboratories, Albuquerque
Qiu Y, Ciciliano J, Myers DR, Tran R, Lam WA (2015) Platelets and physics: How platelets "feel" and respond to their mechanical microenvironment. Blood Rev 29:377–386. https://doi.org/10.1016/j.blre.2015.05.002
Rose T, Di Cera E (2002) Three-dimensional modeling of thrombin–fibrinogen interaction. J Biol Chem 277:18875–18880. https://doi.org/10.1074/jbc.M110977200
Ryan EA, Mockros LF, Weisel JW, Lorand L (1999) Structural origins of fibrin clot rheology. Biophys J 77:2813–2826. https://doi.org/10.1016/s0006-3495(99)77113-4
Stukowski A (2010) Visualization and analysis of atomistic simulation data with OVITO-the open visualization tool. Model Simul Mater Sci 18:015012. https://doi.org/10.1088/0965-0393/18/1/015012
Sutton JT, Ivancevich NM, Perrin SR Jr, Vela DC, Holland CK (2013) Clot retraction affects the extent of ultrasound-enhanced thrombolysis in an ex vivo porcine. Thromb Model Ultrasound Med Biol 39:813–824. https://doi.org/10.1016/j.ultrasmedbio.2012.12.008
Tanaka K (1975) Measurements of self-diffusion coefficients of water in pure water and in aqueous-electrolyte solutions. J Chem Soc Farad T 1(71):1127–1131. https://doi.org/10.1039/F19757101127
Tofts P et al (2000) Test liquids for quantitative MRI measurements of self-diffusion coefficient in vivo. Magn Reson Med 43:368–374
Tomaru T, Uchida Y, Masuo M, kato A, Sugimoto T (1987) Experimental canine arterial thrombus formation and thrombolysis: a fiberoptic study. Am Heart J 114:63–69. https://doi.org/10.1016/0002-8703(87)90308-5
Verlet L (1967) Computer experiments on classical fluids.I. Thermodynamical Properties of Lennard–Jones. Mol Phys Rev 159:98. https://doi.org/10.1103/Physrev.159.98
Wang CY et al (2016) Risk factors and clinical features of acute pulmonary embolism in children from the community. Thromb Res 138:86–90. https://doi.org/10.1016/j.thromres.2015.12.005
Wang J (1951) Self-diffusion and structure of liquid water. I. Measurement of self-diffusion of liquid water with deuterium as tracer. J Am Chem Soc 73:510–513
Wang JH (1965) Self-diffusion coefficients of water. J Phys Chem 69:4412. https://doi.org/10.1021/J100782a510
Wang WW, King MR (2012) Multiscale modeling of platelet adhesion and thrombus growth. Ann Biomed Eng 40:2345–2354. https://doi.org/10.1007/s10439-012-0558-8
Weisel JW (1986) Fibrin assembly. Lateral aggregation and the role of the two pairs of fibrinopeptides. Biophys J 50:1079–1093. https://doi.org/10.1016/S0006-3495(86)83552-4
Weisel JW (2004) The mechanical properties of fibrin for basic scientists and clinicians. Biophys Chem 112:267–276. https://doi.org/10.1016/j.bpc.2004.07.029
White RH (2003) The epidemiology of venous thromboembolism. Circulation 107:I4–8. https://doi.org/10.1161/01.CIR.0000078468.11849.66
Wiltzius P, Dietler G, Kanzig W, Haberli A, Straub PW (1982) Fibrin polymerization studied by static and dynamic light-scattering as a function of fibrinopeptide: a release. Biopolymers 21:2205–2223. https://doi.org/10.1002/bip.360211109
Yamaguchi T, Ishikawa T, Imai Y, Matsuki N, Xenos M, Deng Y, Bluestein D (2010) Particle-based methods for multiscale modeling of blood flow in the circulation and in devices: challenges and future directions. Sixth International Bio-Fluid Mechanics Symposium and Workshop March 28–30, 2008 Pasadena, California. Ann Biomed Eng 38:1225–1235
Zhang H et al (2017) Incidence and risk factors of deep vein thrombosis (DVT) after total hip or knee arthroplasty: a retrospective study with routinely applied venography. Blood Coagul Fibrinol Int J Haemost Thromb 28:126–133. https://doi.org/10.1097/MBC.0000000000000556
Acknowledgements
Research reported in this publication was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under Award Number K01HL115486. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was also supported in part by resources and technical expertise from the Georgia Advanced Computing Resource Center (GACRC), a partnership between the University of Georgia’s Office of the Vice President for Research and Office of the Vice President for Information Technology.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Supplementary material 1 (mp4 22818 KB)
Supplementary material 2 (mp4 22808 KB)
Supplementary material 3 (mov 61376 KB)
Rights and permissions
About this article
Cite this article
Yesudasan, S., Wang, X. & Averett, R.D. Fibrin polymerization simulation using a reactive dissipative particle dynamics method. Biomech Model Mechanobiol 17, 1389–1403 (2018). https://doi.org/10.1007/s10237-018-1033-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10237-018-1033-8