Contraction of blood clots and thrombi: pathogenic and clinical significance

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Abstract

This review is the frst systematic description of spontaneous blood clot shrinkage, aka clot retraction or contraction. The driver of this process is the contraction of the actin-myosin complex inside activated platelets. The platelet contractile force is transmitted via focal contacts to extracellular fbrin fbers, causing compaction of the three-dimensional fbrin network along with the embedded erythrocytes. The main structural consequences of clot contraction include redistribution of the fbrin-platelet meshwork toward the periphery of the clot and compression of erythrocytes in the core of the clot followed by their deformation into polyhedral cells called “polyhedrocytes”. These structural signatures of clot contraction in ex vivo thrombi and thrombotic emboli derived from various locations indicate that thrombi undergo intravital contraction within blood vessels in vivo. Pathogenic consequences of clot contraction may vary. Thus, contraction of a thrombus changes the vessel lumen, thereby modulating local blood flow in the thrombotic occlusion area. Thrombus shrinkage changes its porosity and permeability for fbrinolytic enzymes. The extent of thrombus compression and densifcation can determine the likelihood of its mechanical rupture, i. e. thrombotic embolization. Several clinical studies have revealed that clot contraction is suppressed in the blood of patients with (pro)thrombotic conditions, such as ischemic stroke, venous thrombosis, and systemic lupus erythematosus. This reduction of clot contraction is due to platelet dysfunction caused by their chronic hyperactivation and energetic exhaustion. Clot contraction depends significantly on cellular and protein composition of the blood; in particular, a high hematocrit and hyperfbrinogenemia both reduce clot contraction, while activated monocytes enhance clot contraction by expressing tissue factor and promoting thrombin generation. The degree of clot contraction abnormalities in thrombotic states generally correlates with disease severity, which confrms the pathogenic importance of clot contraction. In patients with pulmonary embolism clot contraction is decreased signifcantly compared to that in isolated venous thrombosis, indirectly suggesting that a less compacted thrombus is more prone to embolization. This observation points to a potential diagnostic and prognostic value of the clot contraction assay as a novel test for ongoing or threatening thromboembolism. Collectively, contraction of blood clots and thrombi is an underappreciated and understudied process that has a major pathogenic and clinical signifcance in (pro)thrombotic conditions of various etiologies.

About the authors

R. I. Litvinov

University of Pennsylvania School of Medicine;
Kazan (Volga region) Federal University

Email: fake@neicon.ru

Rustem I. Litvinov – MD, PhD, Professor, Senior Research Investigator, Department of Cell and Developmental Biology, University of Pennsylvania School of Medicine; Adjunct Professor, Department of Biochemistry and Biotechnology, Institute of Fundamental Medicine and Biology; Chief Researcher, Head of the Laboratory “Protein-Cell Interactions”, Kazan (Volga region) Federal University

421 Curie Blvd., Philadelphia, Pennsylvania, 19104, 

18 Kremlevskaya ul., Kazan, 420008

United States

A. D. Peshkova

Kazan (Volga region) Federal University

Author for correspondence.
Email: alinapeshkova@list.ru

Alina D. Peshkova – Postgraduate Student, Department of Biochemistry and Biotechnology, Institute of Fundamental Medicine and Biology; Junior Research Fellow, Laboratory “Protein-Cell Interactions”

18 Kremlevskaya ul., Kazan, 420008

Russian Federation

References

  1. Kasahara K, Kaneda M, Miki T, Iida K, Sekino-Suzuki N, Kawashima I, Suzuki H, Shimonaka M, Arai M, Ohno-Iwashita Y, Kojima S, Abe M, Kobayashi T, Okazaki T, Souri M, Ichinose A, Yamamoto N. Clot retraction is mediated by factor XIII-dependent fbrin-αIIbβ3-myosin axis in platelet sphingomyelin-rich membrane rafts. Blood. 2013;122(19):3340–8. doi: 10.1182/blood-2013-04-491290.
  2. Lam WA, Chaudhuri O, Crow A, Webster KD, Li TD, Kita A, Huang J, Fletcher DA. Mechanics and contraction dynamics of single platelets and implications for clot stiffening. Nat Mater. 2011;10(1):61–6. doi: 10.1038/nmat2903.
  3. Carr ME Jr. Development of platelet contractile force as a research and clinical measure of platelet function. Cell Biochem Biophys. 2003;38(1):55–78. doi: 10.1385/CBB:38:1:55.
  4. Léon C, Eckly A, Hechler B, Aleil B, Freund M, Ravanat C, Jourdain M, Nonne C, Weber J, Tiedt R, Gratacap MP, Severin S, Cazenave JP, Lanza F, Skoda R, Gachet C. Megakaryocyte-restricted MYH9 inactivation dramatically affects hemostasis while preserving platelet aggregation and secretion. Blood. 2007;110(9):3183–91. doi: 10.1182/blood-2007-03-080184.
  5. Mattheij NJ, Gilio K, van Kruchten R, Jobe SM, Wieschhaus AJ, Chishti AH, Collins P, Heemskerk JW, Cosemans JM. Dual mechanism of integrin αIIbβ3 closure in procoagulant platelets. J Biol Chem. 2013;288(19):13325–36. doi: 10.1074/jbc.M112.428359.
  6. Carr ME Jr. Measurement of platelet force: the Hemodyne hemostasis analyzer. Clin Lab Manage Rev. 1995;9(4):312–4, 316–8, 320.
  7. Тарковская ЛР. Изучение ретрактильной активности тромбоцитов у здоровых людей и у больных с нарушениями гемостаза. Автореферат диссертации на соискание ученой степени кандидата биологических наук. Санкт-Петербург; 2001.
  8. Reid TJ, Snider R, Hartman K, Greilich PE, Carr ME, Alving BM. A method for the quantitative assessment of platelet-induced clot retraction and clot strength in fresh and stored platelets. Vox Sang. 1998;75(4):270–7. doi: 10.1046/j.1423-0410.1998.7540270.x.
  9. Tutwiler V, Litvinov RI, Lozhkin AP, Peshkova AD, Lebedeva T, Ataullakhanov FI, Spiller KL, Cines DB, Weisel JW. Kinetics and mechanics of clot contraction are governed by the molecular and cellular composition of the blood. Blood. 2016;127(1):149–59. doi: 10.1182/blood-2015-05-647560.
  10. Sinauridze EI, Vuimo TA, Tarandovskiy ID, Ovsepyan RA, Surov SS, Korotina NG, Serebriyskiy II, Lutsenko MM, Sokolov AL, Ataullakhanov FI. Thrombodynamics, a new global coagulation test: Measurement of heparin efciency. Talanta. 2018;180:282–91. doi: 10.1016/j.talanta.2017.12.055.
  11. Egot M, Kauskot A, Lasne D, Gaussem P, Bachelot-Loza C. Biphasic myosin II light chain activation during clot retraction. Thromb Haemost. 2013;110(6):1215–22. doi: 10.1160/TH13-04-0335.
  12. von Brühl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, Khandoga A, Tirniceriu A, Coletti R, Köllnberger M, Byrne RA, Laitinen I, Walch A, Brill A, Pfeiler S, Manukyan D, Braun S, Lange P, Riegger J, Ware J, Eckart A, Haidari S, Rudelius M, Schulz C, Echtler K, Brinkmann V, Schwaiger M, Preissner KT, Wagner DD, Mackman N, Engelmann B, Massberg S. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med. 2012;209(4): 819–35. doi: 10.1084/jem.20112322.
  13. Swystun LL, Liaw PC. The role of leukocytes in thrombosis. Blood. 2016;128(6):753–62. doi: 10.1182/blood-2016-05-718114.
  14. Byrnes JR, Duval C, Wang Y, Hansen CE, Ahn B, Mooberry MJ, Clark MA, Johnsen JM, Lord ST, Lam WA, Meijers JC, Ni H, Ariëns RA, Wolberg AS. Factor XIIIa-dependent retention of red blood cells in clots is mediated by fbrin α-chain crosslinking. Blood. 2015;126(16): 1940–8. doi: 10.1182/blood-2015-06-652263.
  15. Booth NA, Bennett B. Fibrinolysis and thrombosis. Baillieres Clin Haematol. 1994;7(3):559– 72.
  16. Kunitada S, FitzGerald GA, Fitzgerald DJ. Inhibition of clot lysis and decreased binding of tissue-type plasminogen activator as a consequence of clot retraction. Blood. 1992;79(6): 1420–7.
  17. Collet JP, Montalescot G, Lesty C, Weisel JW. A structural and dynamic investigation of the facilitating effect of glycoprotein IIb/IIIa inhibitors in dissolving platelet-rich clots. Circ Res. 2002;90(4):428–34.
  18. Taylor FB Jr, Müller-Eberhard HJ. Qualitative description of factors involved in the retraction and lysis of dilute whole blood clots and in the aggregation and retraction of platelets. J Clin Invest. 1970;49(11):2068–85. doi: 10.1172/JCI106425.
  19. Carroll RC, Gerrard JM, Gilliam JM. Clot retraction facilitates clot lysis. Blood. 1981;57(1): 44–8.
  20. Bucay I, O'Brien ET 3rd, Wulfe SD, Superfne R, Wolberg AS, Falvo MR, Hudson NE. Physical determinants of fbrinolysis in single fbrin fbers. PLoS One. 2015;10(2):e0116350. doi: 10.1371/journal.pone.0116350.
  21. Cines DB, Lebedeva T, Nagaswami C, Hayes V, Massefski W, Litvinov RI, Rauova L, Lowery TJ, Weisel JW. Clot contraction: compression of erythrocytes into tightly packed polyhedra and redistribution of platelets and fbrin. Blood. 2014;123(10):1596–603. doi: 10.1182/blood-2013-08-523860.
  22. Gottlob R, Stockinger L, Pötting U, Schattenmann G. Studies on thrombolysis with streptokinase. 3. Morphological examinations of thrombi-thrombus retraction and secondary swelling and the termination of lysibility because of organization. Thromb Diath Haemorrh. 1971;25(2):354–78.
  23. Ząbczyk M, Sadowski M, Zalewski J, Undas A. Polyhedrocytes in intracoronary thrombi from patients with ST-elevation myocardial infarction. Int J Cardiol. 2015;179:186–7. doi: 10.1016/j.ijcard.2014.10.004.
  24. Zalewski J, Bogaert J, Sadowski M, Woznicka O, Doulaptsis K, Ntoumpanaki M, Ząbczyk M, Nessler J, Undas A. Plasma fbrin clot phenotype independently affects intracoronary thrombus ultrastructure in patients with acute myocardial infarction. Thromb Haemost. 2015;113(6):1258–69. doi: 10.1160/TH14-090801.
  25. Peshkova AD, Malyasyov DV, Bredikhin RA, Le Minh G, Andrianova IA, Tutwiler V, Nagaswami C, Weisel JW, Litvinov RI. Reduced contraction of blood clots in patients with venous thromboembolism is a possible thrombogenic and embologenic mechanism. TH Open. 2018;2:e104–15. doi: 10.1055/s-0038-1635572.
  26. Tutwiler V, Peshkova AD, Andrianova IA, Khasanova DR, Weisel JW, Litvinov RI. Contraction of blood clots is impaired in acute ischemic stroke. Arterioscler Thromb Vasc Biol. 2017;37(2):271–9. doi: 10.1161/ATVBAHA.116.308622.
  27. Liebeskind DS, Sanossian N, Yong WH, Starkman S, Tsang MP, Moya AL, Zheng DD, Abolian AM, Kim D, Ali LK, Shah SH, Towfghi A, Ovbiagele B, Kidwell CS, Tateshima S, Jahan R, Duckwiler GR, Viñuela F, Salamon N, Villablanca JP, Vinters HV, Marder VJ, Saver JL. CT and MRI early vessel signs reflect clot composition in acute stroke. Stroke. 2011;42(5):1237–43. doi: 10.1161/STROKEAHA.110.605576.
  28. Le Minh G, Peshkova AD, Andrianova IA, Sibgatullin TB, Maksudova AN, Weisel JW, Litvinov RI. Impaired contraction of blood clots as a novel prothrombotic mechanism in systemic lupus erythematosus. Clin Sci (Lond). 2018;132(2): 243–54. doi: 10.1042/CS20171510.

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Copyright (c) 2018 Litvinov R.I., Peshkova A.D.

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