Ukr.Biochem.J. 2013; Volume 85, Issue 6, Nov-Dec, pp. 94-105


A novel mechanism controlling the growth of hemostatic thrombi

V. K. Lishko, I. S. Yermolenko, N. P. Podolnikova, T. P. Ugarova

School of Life Sciences, Arizona State University, Tempe, AZ USA

Current knowledge of the mechanisms of blood coagulation does not provide an answer to one pivotal question: why is, in contrast to a pathological thrombus, the growth of normal hemostatic clot after blood vessel injury suddenly terminated? In the present paper, we summarize the results of our investigations that give an answer to this question. We show that the surface of fibrin clot in the circulation is coated with a thin metastable layer of fibrinogen which is not able to support adhesion of blood cells. Consequently, platelets and leukocytes, the cells expressing adhesive integrins, are incapable of consolidating­ their grip on the surface and washed away by blood flow, thereby preventing the thrombus propagation. The cells that escaped this fibrinogen shield and reached a solid fibrin matrix use an additional mechanism – the ability to activate plasminogen bound either to the surface of cells or to fibrin. Plasmin formed at the interface between the cells and the clot locally degrades fibrin resulting in the fragmentation of the surface rendering it unstable, non-adhesive and therefore non-thrombogenic. Thus, the growth of hemostatic thrombus is halted by two mechanisms, fibrinogen- and plasminogen-dependent, both of which are based on the same principle – the generation of the mechanically unstable, non-adhesive surface.

Keywords: , , , , ,


  1. Falati S, Gross P, Merrill-Skoloff G, Furie BC, Furie B. Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Nat Med. 2002 Oct;8(10):1175-81. PubMed, CrossRef
  2. Kamocka MM, Mu J, Liu X, Chen N, Zollman A, Sturonas-Brown B, Dunn K, Xu Z, Chen DZ, Alber MS, Rosen ED. Two-photon intravital imaging of thrombus development. J Biomed Opt. 2010 Jan-Feb;15(1):016020. PubMed, PubMedCentral, CrossRef
  3. Cooley BC. In vivo fluorescence imaging of large-vessel thrombosis in mice. Arterioscler Thromb Vasc Biol. 2011 Jun;31(6):1351-6. PubMed, PubMedCentral, CrossRef
  4. van Aken PJ, Emeis JJ. Organization of experimentally induced arterial thrombosis in rats: the first six days. Artery. 1982;11(2):156-73. PubMed
  5. van Ryn J, Lorenz M, Merk H, Buchanan MR, Eisert WG. Accumulation of radiolabelled platelets and fibrin on the carotid artery of rabbits after angioplasty: effects of heparin and dipyridamole. Thromb Haemost. 2003 Dec;90(6):1179-86. PubMed
  6. Groves HM, Kinlough-Rathbone RL, Richardson M, Jørgensen L, Moore S, Mustard JF. Thrombin generation and fibrin formation following injury to rabbit neointima. Studies of vessel wall reactivity and platelet survival. Lab Invest. 1982 Jun;46(6):605-12. PubMed
  7. McGuinness CL, Humphries J, Waltham M, Burnand KG, Collins M, Smith A. Recruitment of labelled monocytes by experimental venous thrombi. Thromb Haemost. 2001 Jun;85(6):1018-24. PubMed
  8. Lishko VK, Burke T, Ugarova T. Antiadhesive effect of fibrinogen: a safeguard for thrombus stability. Blood. 2007 Feb 15;109(4):1541-9. PubMed, PubMedCentral, CrossRef
  9. Schielen WJ, Voskuilen M, Tesser GI, Nieuwenhuizen W. The sequence A alpha-(148-160) in fibrin, but not in fibrinogen, is accessible to monoclonal antibodies. Proc Natl Acad Sci USA. 1989 Nov;86(22):8951-4. PubMed, PubMedCentral, CrossRef
  10. Zamarron C, Ginsberg MH, Plow EF. Monoclonal antibodies specific for a conformationally altered state of fibrinogen. Thromb Haemost. 1990 Aug 13;64(1):41-6. PubMed
  11. Ugarova TP, Budzynski AZ, Shattil SJ, Ruggeri ZM, Ginsberg MH, Plow EF. Conformational changes in fibrinogen elicited by its interaction with platelet membrane glycoprotein GPIIb-IIIa. J Biol Chem. 1993 Oct 5;268(28):21080-7. PubMed
  12. Lishko VK, Kudryk B, Yakubenko VP, Yee VC, Ugarova TP. Regulated unmasking of the cryptic binding site for integrin alpha M beta 2 in the gamma C-domain of fibrinogen. Biochemistry. 2002 Oct 29;41(43):12942-51. PubMed, CrossRef
  13. Podolnikova NP, Yermolenko IS, Fuhrmann A, Lishko VK, Magonov S, Bowen B, Enderlein J, Podolnikov AV, Ros R, Ugarova TP. Control of integrin alphaIIb beta3 outside-in signaling and platelet adhesion by sensing the physical properties of fibrin(ogen) substrates. Biochemistry. 2010 Jan 12;49(1):68-77. PubMed, PubMedCentral, CrossRef
  14. Lishko VK, Yermolenko IS, Owaynat H, Ugarova TP. Fibrinogen counteracts the antiadhesive effect of fibrin-bound plasminogen by preventing its activation by adherent U937 monocytic cells. J Thromb Haemost. 2012 Jun;10(6):1081-90.  PubMed, PubMedCentral, CrossRef
  15. Yermolenko IS, Fuhrmann A, Magonov SN, Lishko VK, Oshkadyerov SP, Ros R, Ugarova TP. Origin of the nonadhesive properties of fibrinogen matrices probed by force spectroscopy. Langmuir. 2010 Nov 16;26(22):17269-77. PubMed, PubMedCentral, CrossRef
  16. Yermolenko IS, Lishko VK, Ugarova TP, Magonov SN. High-resolution visualization of fibrinogen molecules and fibrin fibers with atomic force microscopy.  Biomacromolecules. 2011 Feb 14;12(2):370-9.  PubMedCrossRef
  17. Yermolenko IS, Gorkun OV, Fuhrmann A, Podolnikova NP, Lishko VK, Oshkadyerov SP, Lord ST, Ros R, Ugarova TP. The assembly of nonadhesive fibrinogen matrices depends on the αC regions of the fibrinogen molecule. J Biol Chem. 2012 Dec 7;287(50):41979-90. PubMed, PubMedCentral, CrossRef
  18. Sakharov DV, Rijken DC. Superficial accumulation of plasminogen during plasma clot lysis. Circulation. 1995 Oct 1;92(7):1883-90. PubMed
  19. Lishko VK, Yermolenko IS, Ugarova TP. Plasminogen on the surfaces of fibrin clots prevents adhesion of leukocytes and platelets. J Thromb Haemost. 2010 Apr;8(4):799-807. PubMed, PubMedCentral, CrossRef

Creative CommonsThis work is licensed under a Creative Commons Attribution 4.0 International License.