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Fibronectin maintains the balance between hemostasis and thrombosis

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Abstract

Fibronectin is a dimeric protein widely distributed in solid tissues and blood. This major extracellular matrix protein is indispensable for embryogenesis and plays crucial roles in many physiological and pathological processes. Fibronectin pre-mRNA undergoes alternative splicing to generate over 20 splicing variants, which are categorized as either plasma fibronectin (pFn) or cellular fibronectin (cFn). All fibronectin variants contain integrin binding motifs, as well as N-terminus collagen and fibrin binding motifs. With motifs that can be recognized by platelet integrins and coagulation factors, fibronectin, especially pFn, has long been suspected to be involved in hemostasis and thrombosis, but the exact function of fibronectin in these processes is controversial. The advances made using intravital microscopy models and fibronectin deficient and mutant mice have greatly facilitated the direct investigation of fibronectin function in vivo. Recent studies revealed that pFn is a vital hemostatic factor that is especially crucial for hemostasis in both genetic and anticoagulant-induced deficiencies of fibrin formation. pFn may also be an important self-limiting regulator to prevent hemorrhage as well as excessive thrombus formation and vessel occlusion. In addition to pFn, cFn is found to be prothrombotic and may contribute to thrombotic complications in various diseases. Further investigations of the role of pFn and cFn in thrombotic and hemorrhagic diseases may provide insights into development of novel therapeutic strategies (e.g., pFn transfusion) for the maintenance of the fine balance between hemostasis and thrombosis.

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References

  1. George EL, Georges-Labouesse EN, Patel-King RS, Rayburn H, Hynes RO (1993) Defects in mesoderm, neural tube and vascular development in mouse embryos lacking fibronectin. Development 119(4):1079–1091

    CAS  PubMed  Google Scholar 

  2. Mosher DF (1989) Fibronectin. Academic Press, San Diego

    Google Scholar 

  3. Hynes RO (1990) Fibronectins. Springer, New York

    Book  Google Scholar 

  4. Ni H, Yuen PS, Papalia JM, Trevithick JE, Sakai T, Fassler R, Hynes RO, Wagner DD (2003) Plasma fibronectin promotes thrombus growth and stability in injured arterioles. Proc Natl Acad Sci USA 100(5):2415–2419. doi:10.1073/pnas.2628067100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ni H (2006) Unveiling the new face of fibronectin in thrombosis and hemostasis. J Thromb Haemost 4(5):940–942. doi:10.1111/j.1538-7836.2006.01899.x

    Article  CAS  PubMed  Google Scholar 

  6. Wang Y, Carrim N, Ni H (2015) Fibronectin orchestrates thrombosis and hemostasis. Oncotarget 6(23):19350–19351

    Article  PubMed  PubMed Central  Google Scholar 

  7. Morrison PR, Edsall JT, Miller SG (1948) Preparation and properties of serum and plasma proteins; the separation of purified fibrinogen from fraction I of human plasma. J Am Chem Soc 70(9):3103–3108

    Article  CAS  PubMed  Google Scholar 

  8. Stathakis NE, Mosesson MW (1977) Interactions among heparin, cold-insoluble globulin, and fibrinogen in formation of the heparin-precipitable fraction of plasma. J Clin Invest 60(4):855–865. doi:10.1172/JCI108840

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Stathakis NE, Mosesson MW, Chen AB, Galanakis DK (1978) Cryoprecipitation of fibrin–fibrinogen complexes induced by the cold-insoluble globulin of plasma. Blood 51(6):1211–1222

    CAS  PubMed  Google Scholar 

  10. Gahmberg CG, Hakomori SI (1973) Altered growth behavior of malignant cells associated with changes in externally labeled glycoprotein and glycolipid. Proc Natl Acad Sci USA 70(12):3329–3333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hynes RO (1973) Alteration of cell-surface proteins by viral transformation and by proteolysis. Proc Natl Acad Sci USA 70(11):3170–3174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ruoslahti E, Vaheri A, Kuusela P, Linder E (1973) Fibroblast surface antigen: a new serum protein. Biochim Biophys Acta 322(2):352–358

    Article  CAS  PubMed  Google Scholar 

  13. Ruoslahti E, Vaheri A (1974) Novel human serum protein from fibroblast plasma membrane. Nature 248(5451):789–791

    Article  CAS  PubMed  Google Scholar 

  14. Yamada KM, Weston JA (1974) Isolation of a major cell surface glycoprotein from fibroblasts. Proc Natl Acad Sci USA 71(9):3492–3496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hynes RO, Wyke JA (1975) Alterations in surface proteins in chicken cells transformed by temperature-sensitive mutants of Rous sarcoma virus. Virology 64(2):492–504

    Article  CAS  PubMed  Google Scholar 

  16. Stone KR, Smith RE, Joklik WK (1974) Changes in membrane polypeptides that occur when chick embryo fibroblasts and NRK cells are transformed with avian sarcoma viruses. Virology 58(1):86–100

    Article  CAS  PubMed  Google Scholar 

  17. Hogg NM (1974) A comparison of membrane proteins of normal and transformed cells by lactoperoxidase labeling. Proc Natl Acad Sci USA 71(2):489–492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ruoslahti E (1988) Fibronectin and its receptors. Annu Rev Biochem 57:375–413. doi:10.1146/annurev.bi.57.070188.002111

    Article  CAS  PubMed  Google Scholar 

  19. Keski-Oja J, Mosher DF, Vaheri A (1976) Cross-linking of a major fibroblast surface-associated glycoprotein (fibronectin) catalyzed by blood coagulation factor XIII. Cell 9(1):29–35

    Article  CAS  PubMed  Google Scholar 

  20. Kuusela P, Ruoslahti E, Engvall E, Vaheri A (1976) Immunological interspecies cross-reactions of fibroblast surface antigen (fibronectin). Immunochemistry 13(8):639–642

    Article  CAS  PubMed  Google Scholar 

  21. Vaheri A, Ruoslahti E, Mosher DF (1978) Fibroblast surface protein: [papers from a conference held by the New York Academy of Sciences, New York, Nov. 30– Dec. 2, 1977]. Ann N Y Acad Sci 312:1–456

    Article  Google Scholar 

  22. Schwarzbauer JE, Tamkun JW, Lemischka IR, Hynes RO (1983) Three different fibronectin mRNAs arise by alternative splicing within the coding region. Cell 35(2 Pt 1):421–431

    Article  CAS  PubMed  Google Scholar 

  23. Kornblihtt AR, Pesce CG, Alonso CR, Cramer P, Srebrow A, Werbajh S, Muro AF (1996) The fibronectin gene as a model for splicing and transcription studies. FASEB J 10(2):248–257

    CAS  PubMed  Google Scholar 

  24. Sakai T, Johnson KJ, Murozono M, Sakai K, Magnuson MA, Wieloch T, Cronberg T, Isshiki A, Erickson HP, Fassler R (2001) Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis. Nat Med 7(3):324–330. doi:10.1038/85471

    Article  CAS  PubMed  Google Scholar 

  25. Takahashi S, Leiss M, Moser M, Ohashi T, Kitao T, Heckmann D, Pfeifer A, Kessler H, Takagi J, Erickson HP, Fassler R (2007) The RGD motif in fibronectin is essential for development but dispensable for fibril assembly. J Cell Biol 178(1):167–178. doi:10.1083/jcb.200703021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Reheman A, Yang H, Zhu G, Jin W, He F, Spring CM, Bai X, Gross PL, Freedman J, Ni H (2009) Plasma fibronectin depletion enhances platelet aggregation and thrombus formation in mice lacking fibrinogen and von Willebrand factor. Blood 113(8):1809–1817. doi:10.1182/blood-2008-04-148361

    Article  CAS  PubMed  Google Scholar 

  27. Muro AF, Chauhan AK, Gajovic S, Iaconcig A, Porro F, Stanta G, Baralle FE (2003) Regulated splicing of the fibronectin EDA exon is essential for proper skin wound healing and normal lifespan. J Cell Biol 162(1):149–160. doi:10.1083/jcb.200212079

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fukuda T, Yoshida N, Kataoka Y, Manabe R, Mizuno-Horikawa Y, Sato M, Kuriyama K, Yasui N, Sekiguchi K (2002) Mice lacking the EDB segment of fibronectin develop normally but exhibit reduced cell growth and fibronectin matrix assembly in vitro. Cancer Res 62(19):5603–5610

    CAS  PubMed  Google Scholar 

  29. Astrof S, Crowley D, Hynes RO (2007) Multiple cardiovascular defects caused by the absence of alternatively spliced segments of fibronectin. Dev Biol 311(1):11–24. doi:10.1016/j.ydbio.2007.07.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Schwarzbauer JE (1991) Fibronectin: from gene to protein. Curr Opin Cell Biol 3(5):786–791

    Article  CAS  PubMed  Google Scholar 

  31. Pankov R, Yamada KM (2002) Fibronectin at a glance. J Cell Sci 115(Pt 20):3861–3863

    Article  CAS  PubMed  Google Scholar 

  32. White ES, Muro AF (2011) Fibronectin splice variants: understanding their multiple roles in health and disease using engineered mouse models. IUBMB Life 63(7):538–546. doi:10.1002/iub.493

    Article  CAS  PubMed  Google Scholar 

  33. Leiss M, Beckmann K, Giros A, Costell M, Fassler R (2008) The role of integrin binding sites in fibronectin matrix assembly in vivo. Curr Opin Cell Biol 20(5):502–507. doi:10.1016/j.ceb.2008.06.001

    Article  CAS  PubMed  Google Scholar 

  34. Pytela R, Pierschbacher MD, Ginsberg MH, Plow EF, Ruoslahti E (1986) Platelet membrane glycoprotein IIb/IIIa: member of a family of Arg-Gly-Asp-specific adhesion receptors. Science 231(4745):1559–1562

    Article  CAS  PubMed  Google Scholar 

  35. Ruoslahti E, Pierschbacher MD (1986) Arg-Gly-Asp: a versatile cell recognition signal. Cell 44(4):517–518

    Article  CAS  PubMed  Google Scholar 

  36. Pierschbacher MD, Ruoslahti E (1984) Variants of the cell recognition site of fibronectin that retain attachment-promoting activity. Proc Natl Acad Sci USA 81(19):5985–5988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110(6):673–687

    Article  CAS  PubMed  Google Scholar 

  38. Yang JT, Rayburn H, Hynes RO (1993) Embryonic mesodermal defects in alpha 5 integrin-deficient mice. Development 119(4):1093–1105

    CAS  PubMed  Google Scholar 

  39. Yang JT, Bader BL, Kreidberg JA, Ullman-Cullere M, Trevithick JE, Hynes RO (1999) Overlapping and independent functions of fibronectin receptor integrins in early mesodermal development. Dev Biol 215(2):264–277. doi:10.1006/dbio.1999.9451

    Article  CAS  PubMed  Google Scholar 

  40. Geiger B, Bershadsky A, Pankov R, Yamada KM (2001) Transmembrane crosstalk between the extracellular matrix–cytoskeleton crosstalk. Nat Rev Mol Cell Biol 2(11):793–805. doi:10.1038/35099066

    Article  CAS  PubMed  Google Scholar 

  41. Pankov R, Cukierman E, Katz BZ, Matsumoto K, Lin DC, Lin S, Hahn C, Yamada KM (2000) Integrin dynamics and matrix assembly: tensin-dependent translocation of alpha(5)beta(1) integrins promotes early fibronectin fibrillogenesis. J Cell Biol 148(5):1075–1090

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Singh P, Carraher C, Schwarzbauer JE (2010) Assembly of fibronectin extracellular matrix. Annu Rev Cell Dev Biol 26:397–419. doi:10.1146/annurev-cellbio-100109-104020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Aota S, Nomizu M, Yamada KM (1994) The short amino acid sequence Pro-His-Ser-Arg-Asn in human fibronectin enhances cell-adhesive function. J Biol Chem 269(40):24756–24761

    CAS  PubMed  Google Scholar 

  44. Bowditch RD, Hariharan M, Tominna EF, Smith JW, Yamada KM, Getzoff ED, Ginsberg MH (1994) Identification of a novel integrin binding site in fibronectin. Differential utilization by beta 3 integrins. J Biol Chem 269(14):10856–10863

    CAS  PubMed  Google Scholar 

  45. Cho J, Mosher DF (2006) Role of fibronectin assembly in platelet thrombus formation. J Thromb Haemost 4(7):1461–1469. doi:10.1111/j.1538-7836.2006.01943.x

    Article  CAS  PubMed  Google Scholar 

  46. Ginsberg MH, Forsyth J, Lightsey A, Chediak J, Plow EF (1983) Reduced surface expression and binding of fibronectin by thrombin-stimulated thrombasthenic platelets. J Clin Invest 71(3):619–624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Zhai Z, Wu J, Xu X, Ding K, Ni R, Hu W, Sun Z, Ni H (2007) Fibrinogen controls human platelet fibronectin internalization and cell-surface retention. J Thromb Haemost 5(8):1740–1746. doi:10.1111/j.1538-7836.2007.02625.x

    Article  CAS  PubMed  Google Scholar 

  48. Ginsberg MH, Painter RG, Forsyth J, Birdwell C, Plow EF (1980) Thrombin increases expression of fibronectin antigen on the platelet surface. Proc Natl Acad Sci USA 77(2):1049–1053

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ni H, Papalia JM, Degen JL, Wagner DD (2003) Control of thrombus embolization and fibronectin internalization by integrin alpha IIb beta 3 engagement of the fibrinogen gamma chain. Blood 102(10):3609–3614. doi:10.1182/blood-2003-03-0850

    Article  CAS  PubMed  Google Scholar 

  50. Schwarzbauer JE (1991) Identification of the fibronectin sequences required for assembly of a fibrillar matrix. J Cell Biol 113(6):1463–1473

    Article  CAS  PubMed  Google Scholar 

  51. McKeown-Longo PJ, Mosher DF (1985) Interaction of the 70,000-mol-wt amino-terminal fragment of fibronectin with the matrix-assembly receptor of fibroblasts. J Cell Biol 100(2):364–374

    Article  CAS  PubMed  Google Scholar 

  52. Mosher DF (1975) Cross-linking of cold-insoluble globulin by fibrin-stabilizing factor. J Biol Chem 250(16):6614–6621

    CAS  PubMed  Google Scholar 

  53. Wang Y, Reheman A, Spring CM, Kalantari J, Marshall AH, Wolberg AS, Gross PL, Weitz JI, Rand ML, Mosher DF, Freedman J, Ni H (2014) Plasma fibronectin supports hemostasis and regulates thrombosis. J Clin Invest 124(10):4281–4293. doi:10.1172/JCI74630

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Cho J, Mosher DF (2006) Enhancement of thrombogenesis by plasma fibronectin cross-linked to fibrin and assembled in platelet thrombi. Blood 107(9):3555–3563. doi:10.1182/blood-2005-10-4168

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Tomasini-Johansson BR, Kaufman NR, Ensenberger MG, Ozeri V, Hanski E, Mosher DF (2001) A 49-residue peptide from adhesin F1 of Streptococcus pyogenes inhibits fibronectin matrix assembly. J Biol Chem 276(26):23430–23439. doi:10.1074/jbc.M103467200

    Article  CAS  PubMed  Google Scholar 

  56. Rostagno AA, Schwarzbauer JE, Gold LI (1999) Comparison of the fibrin-binding activities in the N- and C-termini of fibronectin. Biochem J 338(Pt 2):375–386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Corbett SA, Lee L, Wilson CL, Schwarzbauer JE (1997) Covalent cross-linking of fibronectin to fibrin is required for maximal cell adhesion to a fibronectin-fibrin matrix. J Biol Chem 272(40):24999–25005

    Article  CAS  PubMed  Google Scholar 

  58. Mosher DF, Schad PE (1979) Cross-linking of fibronectin to collagen by blood coagulation factor XIIIa. J Clin Invest 64(3):781–787. doi:10.1172/JCI109524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Moretti FA, Chauhan AK, Iaconcig A, Porro F, Baralle FE, Muro AF (2007) A major fraction of fibronectin present in the extracellular matrix of tissues is plasma-derived. J Biol Chem 282(38):28057–28062. doi:10.1074/jbc.M611315200

    Article  CAS  PubMed  Google Scholar 

  60. Buratti E, Muro AF, Giombi M, Gherbassi D, Iaconcig A, Baralle FE (2004) RNA folding affects the recruitment of SR proteins by mouse and human polypurinic enhancer elements in the fibronectin EDA exon. Mol Cell Biol 24(3):1387–1400

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Caputi M, Casari G, Guenzi S, Tagliabue R, Sidoli A, Melo CA, Baralle FE (1994) A novel bipartite splicing enhancer modulates the differential processing of the human fibronectin EDA exon. Nucleic Acids Res 22(6):1018–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Chauhan AK, Iaconcig A, Baralle FE, Muro AF (2004) Alternative splicing of fibronectin: a mouse model demonstrates the identity of in vitro and in vivo systems and the processing autonomy of regulated exons in adult mice. Gene 324:55–63

    Article  CAS  PubMed  Google Scholar 

  63. Cramer P, Caceres JF, Cazalla D, Kadener S, Muro AF, Baralle FE, Kornblihtt AR (1999) Coupling of transcription with alternative splicing: RNA pol II promoters modulate SF2/ASF and 9G8 effects on an exonic splicing enhancer. Mol Cell 4(2):251–258

    Article  CAS  PubMed  Google Scholar 

  64. Huh GS, Hynes RO (1993) Elements regulating an alternatively spliced exon of the rat fibronectin gene. Mol Cell Biol 13(9):5301–5314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Huh GS, Hynes RO (1994) Regulation of alternative pre-mRNA splicing by a novel repeated hexanucleotide element. Genes Dev 8(13):1561–1574

    Article  CAS  PubMed  Google Scholar 

  66. Kornblihtt AR, Umezawa K, Vibe-Pedersen K, Baralle FE (1985) Primary structure of human fibronectin: differential splicing may generate at least 10 polypeptides from a single gene. EMBO J 4(7):1755–1759

    CAS  PubMed  PubMed Central  Google Scholar 

  67. White ES, Baralle FE, Muro AF (2008) New insights into form and function of fibronectin splice variants. J Pathol 216(1):1–14. doi:10.1002/path.2388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Schwarzbauer JE, Spencer CS, Wilson CL (1989) Selective secretion of alternatively spliced fibronectin variants. J Cell Biol 109(6 Pt 2):3445–3453

    Article  CAS  PubMed  Google Scholar 

  69. Liao YF, Gotwals PJ, Koteliansky VE, Sheppard D, Van De Water L (2002) The EIIIA segment of fibronectin is a ligand for integrins alpha 9beta 1 and alpha 4beta 1 providing a novel mechanism for regulating cell adhesion by alternative splicing. J Biol Chem 277(17):14467–14474. doi:10.1074/jbc.M201100200

    Article  CAS  PubMed  Google Scholar 

  70. Tan MH, Sun Z, Opitz SL, Schmidt TE, Peters JH, George EL (2004) Deletion of the alternatively spliced fibronectin EIIIA domain in mice reduces atherosclerosis. Blood 104(1):11–18. doi:10.1182/blood-2003-09-3363

    Article  CAS  PubMed  Google Scholar 

  71. Chauhan AK, Moretti FA, Iaconcig A, Baralle FE, Muro AF (2005) Impaired motor coordination in mice lacking the EDA exon of the fibronectin gene. Behav Brain Res 161(1):31–38. doi:10.1016/j.bbr.2005.02.020

    Article  CAS  PubMed  Google Scholar 

  72. Chauhan AK, Kisucka J, Cozzi MR, Walsh MT, Moretti FA, Battiston M, Mazzucato M, De Marco L, Baralle FE, Wagner DD, Muro AF (2008) Prothrombotic effects of fibronectin isoforms containing the EDA domain. Arterioscler Thromb Vasc Biol 28(2):296–301. doi:10.1161/ATVBAHA.107.149146

    Article  CAS  PubMed  Google Scholar 

  73. Guan JL, Hynes RO (1990) Lymphoid cells recognize an alternatively spliced segment of fibronectin via the integrin receptor alpha 4 beta 1. Cell 60(1):53–61

    Article  CAS  PubMed  Google Scholar 

  74. Wayner EA, Garcia-Pardo A, Humphries MJ, McDonald JA, Carter WG (1989) Identification and characterization of the T lymphocyte adhesion receptor for an alternative cell attachment domain (CS-1) in plasma fibronectin. J Cell Biol 109(3):1321–1330

    Article  CAS  PubMed  Google Scholar 

  75. Zerlauth G, Wolf G (1984) Plasma fibronectin as a marker for cancer and other diseases. Am J Med 77(4):685–689

    Article  CAS  PubMed  Google Scholar 

  76. Tomasini-Johansson B, Mosher DF (2009) Plasma fibronectin concentration in inbred mouse strains. Thromb Haemost 102(6):1278–1280. doi:10.1160/TH09-03-0141

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Wang Y, Gallant RC, Ni H (2016) Extracellular matrix proteins in the regulation of thrombus formation. Curr Opin Hematol 23(3):280–287

    Article  CAS  PubMed  Google Scholar 

  78. Mackman N (2008) Triggers, targets and treatments for thrombosis. Nature 451(7181):914–918. doi:10.1038/nature06797

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Reheman A, Xu X, Reddy EC, Ni H (2014) Targeting activated platelets and fibrinolysis: hitting two birds with one stone. Circ Res 114(7):1070–1073. doi:10.1161/CIRCRESAHA.114.303600

    Article  CAS  PubMed  Google Scholar 

  80. Ruggeri ZM (1997) Mechanisms initiating platelet thrombus formation. Thromb Haemost 78(1):611–616

    CAS  PubMed  Google Scholar 

  81. Wang Y, Andrews M, Yang Y, Lang S, Jin JW, Cameron-Vendrig A, Zhu G, Reheman A, Ni H (2012) Platelets in thrombosis and hemostasis: old topic with new mechanisms. Cardiovasc Hematol Disord Drug Targets 12(2):126–132

    Article  CAS  PubMed  Google Scholar 

  82. Ruggeri ZM (2002) Platelets in atherothrombosis. Nat Med 8(11):1227–1234. doi:10.1038/nm1102-1227

    Article  CAS  PubMed  Google Scholar 

  83. Jackson SP (2007) The growing complexity of platelet aggregation. Blood 109(12):5087–5095. doi:10.1182/blood-2006-12-027698

    Article  CAS  PubMed  Google Scholar 

  84. Lei X, Reheman A, Hou Y, Zhou H, Wang Y, Marshall AH, Liang C, Dai X, Li BX, Vanhoorelbeke K, Ni H (2014) Anfibatide, a novel GPIb complex antagonist, inhibits platelet adhesion and thrombus formation in vitro and in vivo in murine models of thrombosis. Thromb Haemost 111(2):279–289. doi:10.1160/TH13-06-0490

    Article  CAS  PubMed  Google Scholar 

  85. Nieswandt B, Brakebusch C, Bergmeier W, Schulte V, Bouvard D, Mokhtari-Nejad R, Lindhout T, Heemskerk JW, Zirngibl H, Fassler R (2001) Glycoprotein VI but not alpha2beta1 integrin is essential for platelet interaction with collagen. EMBO J 20(9):2120–2130. doi:10.1093/emboj/20.9.2120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Mazzucato M, Cozzi MR, Battiston M, Jandrot-Perrus M, Mongiat M, Marchese P, Kunicki TJ, Ruggeri ZM, De Marco L (2009) Distinct spatio-temporal Ca2+ signaling elicited by integrin alpha2beta1 and glycoprotein VI under flow. Blood 114(13):2793–2801. doi:10.1182/blood-2008-12-193490

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ni H, Denis CV, Subbarao S, Degen JL, Sato TN, Hynes RO, Wagner DD (2000) Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest 106(3):385–392. doi:10.1172/JCI9896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Yang H, Reheman A, Chen P, Zhu G, Hynes RO, Freedman J, Wagner DD, Ni H (2006) Fibrinogen and von Willebrand factor-independent platelet aggregation in vitro and in vivo. J Thromb Haemost 4(10):2230–2237. doi:10.1111/j.1538-7836.2006.02116.x

    Article  CAS  PubMed  Google Scholar 

  89. Dunne E, Spring CM, Reheman A, Jin W, Berndt MC, Newman DK, Newman PJ, Ni H, Kenny D (2012) Cadherin 6 has a functional role in platelet aggregation and thrombus formation. Arterioscler Thromb Vasc Biol 32(7):1724–1731. doi:10.1161/ATVBAHA.112.250464

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Reheman A, Tasneem S, Ni H, Hayward CP (2010) Mice with deleted multimerin 1 and alpha-synuclein genes have impaired platelet adhesion and impaired thrombus formation that is corrected by multimerin 1. Thromb Res 125(5):e177–e183. doi:10.1016/j.thromres.2010.01.009

    Article  CAS  PubMed  Google Scholar 

  91. Gui T, Reheman A, Funkhouser WK, Bellinger DA, Hagaman JR, Stafford DW, Monahan PE, Ni H (2007) In vivo response to vascular injury in the absence of factor IX: examination in factor IX knockout mice. Thromb Res 121(2):225–234. doi:10.1016/j.thromres.2007.03.026

    Article  CAS  PubMed  Google Scholar 

  92. Wang Y, Vachon E, Zhang J, Cherepanov V, Kruger J, Li J, Saito K, Shannon P, Bottini N, Huynh H, Ni H, Yang H, McKerlie C, Quaggin S, Zhao ZJ, Marsden PA, Mustelin T, Siminovitch KA, Downey GP (2005) Tyrosine phosphatase MEG2 modulates murine development and platelet and lymphocyte activation through secretory vesicle function. J Exp Med 202(11):1587–1597. doi:10.1084/jem.20051108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Polanowska-Grabowska R, Simon CG Jr, Gear AR (1999) Platelet adhesion to collagen type I, collagen type IV, von Willebrand factor, fibronectin, laminin and fibrinogen: rapid kinetics under shear. Thromb Haemost 81(1):118–123

    CAS  PubMed  Google Scholar 

  94. Wu YP, de Groot PG, Sixma JJ (1997) Shear-stress-induced detachment of blood platelets from various surfaces. Arterioscler Thromb Vasc Biol 17(11):3202–3207

    Article  CAS  PubMed  Google Scholar 

  95. Houdijk WP, de Groot PG, Nievelstein PF, Sakariassen KS, Sixma JJ (1986) Subendothelial proteins and platelet adhesion. von Willebrand factor and fibronectin, not thrombospondin, are involved in platelet adhesion to extracellular matrix of human vascular endothelial cells. Arteriosclerosis 6(1):24–33

    Article  CAS  PubMed  Google Scholar 

  96. Houdijk WP, Sixma JJ (1985) Fibronectin in artery subendothelium is important for platelet adhesion. Blood 65(3):598–604

    CAS  PubMed  Google Scholar 

  97. Houdijk WP, Sakariassen KS, Nievelstein PF, Sixma JJ (1985) Role of factor VIII-von Willebrand factor and fibronectin in the interaction of platelets in flowing blood with monomeric and fibrillar human collagen types I and III. J Clin Invest 75(2):531–540. doi:10.1172/JCI111729

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Bastida E, Escolar G, Ordinas A, Sixma JJ (1987) Fibronectin is required for platelet adhesion and for thrombus formation on subendothelium and collagen surfaces. Blood 70(5):1437–1442

    CAS  PubMed  Google Scholar 

  99. Nievelstein PF, D’Alessio PA, Sixma JJ (1988) Fibronectin in platelet adhesion to human collagen types I and III. Use of nonfibrillar and fibrillar collagen in flowing blood studies. Arteriosclerosis 8(2):200–206

    Article  CAS  PubMed  Google Scholar 

  100. Wang Y, Ni H (2015) Fibronectin: extra domain brings extra risk? Blood 125(20):3043–3044. doi:10.1182/blood-2015-03-630855

    Article  CAS  PubMed  Google Scholar 

  101. Moon DG, Kaplan JE, Mazurkewicz JE (1986) The inhibitory effect of plasma fibronectin on collagen-induced platelet aggregation. Blood 67(2):450–457

    CAS  PubMed  Google Scholar 

  102. Santoro SA (1983) Inhibition of platelet aggregation by fibronectin. Biochem Biophys Res Commun 116(1):135–140

    Article  CAS  PubMed  Google Scholar 

  103. Dixit VM, Haverstick DM, O’Rourke K, Hennessy SW, Broekelmann TJ, McDonald JA, Grant GA, Santoro SA, Frazier WA (1985) Inhibition of platelet aggregation by a monoclonal antibody against human fibronectin. Proc Natl Acad Sci USA 82(11):3844–3848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Thurlow PJ, Kenneally DA, Connellan JM (1990) The role of fibronectin in platelet aggregation. Br J Haematol 75(4):549–556

    Article  CAS  PubMed  Google Scholar 

  105. Arneson MA, Hammerschmidt DE, Furcht LT, King RA (1980) A new form of Ehlers–Danlos syndrome. Fibronectin corrects defective platelet function. JAMA 244(2):144–147

    CAS  PubMed  Google Scholar 

  106. Kamykowski GW, Mosher DF, Lorand L, Ferry JD (1981) Modification of shear modulus and creep compliance of fibrin clots by fibronectin. Biophys Chem 13(1):25–28

    Article  CAS  PubMed  Google Scholar 

  107. Okada M, Blomback B, Chang MD, Horowitz B (1985) Fibronectin and fibrin gel structure. J Biol Chem 260(3):1811–1820

    CAS  PubMed  Google Scholar 

  108. Niewiarowska J, Cierniewski CS (1982) Inhibitory effect of fibronectin on the fibrin formation. Thromb Res 27(5):611–618

    Article  CAS  PubMed  Google Scholar 

  109. Procyk R, King RG (1990) The elastic modulus of fibrin clots and fibrinogen gels: the effect of fibronectin and dithiothreitol. Biopolymers 29(3):559–565. doi:10.1002/bip.360290311

    Article  CAS  PubMed  Google Scholar 

  110. Collet JP, Moen JL, Veklich YI, Gorkun OV, Lord ST, Montalescot G, Weisel JW (2005) The alphaC domains of fibrinogen affect the structure of the fibrin clot, its physical properties, and its susceptibility to fibrinolysis. Blood 106(12):3824–3830. doi:10.1182/blood-2005-05-2150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yang H, Lang S, Zhai Z, Li L, Kahr WH, Chen P, Brkic J, Spring CM, Flick MJ, Degen JL, Freedman J, Ni H (2009) Fibrinogen is required for maintenance of platelet intracellular and cell-surface P-selectin expression. Blood 114(2):425–436. doi:10.1182/blood-2008-03-145821

    Article  CAS  PubMed  Google Scholar 

  112. Andrews M (2011) Signal-dependent translation of the platelet transcriptome: the effects of alphaIIb beta3 integrin-ligand interaction on platelet protein synthesis. University of Toronto, Toronto

    Google Scholar 

  113. Matuskova J, Chauhan AK, Cambien B, Astrof S, Dole VS, Piffath CL, Hynes RO, Wagner DD (2006) Decreased plasma fibronectin leads to delayed thrombus growth in injured arterioles. Arterioscler Thromb Vasc Biol 26(6):1391–1396. doi:10.1161/01.ATV.0000216282.58291.c6

    Article  CAS  PubMed  Google Scholar 

  114. Xu X, Wu J, Zhai Z, Zhou R, Wang X, Wang H, Ding K, Sun Z, Ni H (2006) A novel fibrinogen Bbeta chain frameshift mutation in a patient with severe congenital hypofibrinogenaemia. Thromb Haemost 95(6):931–935. doi:10.1160/TH06-01-0020

    CAS  PubMed  Google Scholar 

  115. Falati S, Gross P, Merrill-Skoloff G, Furie BC, Furie B (2002) Real-time in vivo imaging of platelets, tissue factor and fibrin during arterial thrombus formation in the mouse. Nat Med 8(10):1175–1181. doi:10.1038/nm782

    Article  CAS  PubMed  Google Scholar 

  116. Stalker TJ, Traxler EA, Wu J, Wannemacher KM, Cermignano SL, Voronov R, Diamond SL, Brass LF (2013) Hierarchical organization in the hemostatic response and its relationship to the platelet-signaling network. Blood 121(10):1875–1885. doi:10.1182/blood-2012-09-457739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Hou Y, Carrim N, Wang Y, Gallant RC, Marshall A, Ni H (2015) Platelets in hemostasis and thrombosis: novel mechanisms of fibrinogen-independent platelet aggregation and fibronectin-mediated protein wave of hemostasis. J Biomed Res 29(6):437–444. doi:10.7555/JBR.29.20150121

    PubMed Central  Google Scholar 

  118. Castellanos M, Leira R, Serena J, Blanco M, Pedraza S, Castillo J, Davalos A (2004) Plasma cellular-fibronectin concentration predicts hemorrhagic transformation after thrombolytic therapy in acute ischemic stroke. Stroke 35(7):1671–1676. doi:10.1161/01.STR.0000131656.47979.39

    Article  CAS  PubMed  Google Scholar 

  119. Kanters SD, Banga JD, Algra A, Frijns RC, Beutler JJ, Fijnheer R (2001) Plasma levels of cellular fibronectin in diabetes. Diabetes Care 24(2):323–327

    Article  CAS  PubMed  Google Scholar 

  120. Peters JH, Maunder RJ, Woolf AD, Cochrane CG, Ginsberg MH (1989) Elevated plasma levels of ED1+ (“cellular”) fibronectin in patients with vascular injury. J Lab Clin Med 113(5):586–597

    CAS  PubMed  Google Scholar 

  121. Vincent PA, Rebres RA, Lewis EP, Vt Hurst, Saba TM (1993) Release of ED1 fibronectin from matrix of perfused lungs after vascular injury is independent of protein synthesis. Am J Physiol 265(5 Pt 1):L485–L492

    CAS  PubMed  Google Scholar 

  122. Prakash P, Kulkarni PP, Lentz SR, Chauhan AK (2015) Cellular fibronectin containing extra domain A promotes arterial thrombosis in mice through platelet Toll-like receptor 4. Blood 125(20):3164–3172. doi:10.1182/blood-2014-10-608653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Dhanesha N, Ahmad A, Prakash P, Doddapattar P, Lentz SR, Chauhan AK (2015) Genetic ablation of extra domain A of fibronectin in hypercholesterolemic mice improves stroke outcome by reducing thrombo-inflammation. Circulation. doi:10.1161/CIRCULATIONAHA.115.016540

    PubMed  Google Scholar 

  124. Doddapattar P, Gandhi C, Prakash P, Dhanesha N, Grumbach IM, Dailey ME, Lentz SR, Chauhan AK (2015) Fibronectin splicing variants containing extra domain A promote atherosclerosis in mice through toll-like receptor 4. Arterioscler Thromb Vasc Biol 35(11):2391–2400. doi:10.1161/ATVBAHA.115.306474

    Article  CAS  PubMed  Google Scholar 

  125. Maurer E, Schaff M, Receveur N, Bourdon C, Mercier L, Nieswandt B, Dubois C, Jandrot-Perrus M, Goetz J, Lanza F, Gachet C, Mangin PH (2015) Fibrillar cellular fibronectin supports efficient platelet function and procoagulant activity. Thromb Haemost 114(6):1175–1188. doi:10.1160/TH14-11-0958

    Article  PubMed  Google Scholar 

  126. Heit JA (2008) The epidemiology of venous thromboembolism in the community. Arterioscler Thromb Vasc Biol 28(3):370–372. doi:10.1161/ATVBAHA.108.162545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Schulz C, Engelmann B, Massberg S (2013) Crossroads of coagulation and innate immunity: the case of deep vein thrombosis. J Thromb Haemost 11(Suppl 1):233–241. doi:10.1111/jth.12261

    Article  PubMed  Google Scholar 

  128. von Bruhl ML, Stark K, Steinhart A, Chandraratne S, Konrad I, Lorenz M, Khandoga A, Tirniceriu A, Coletti R, Kollnberger 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 (2012) Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 209(4):819–835. doi:10.1084/jem.20112322

    Article  CAS  Google Scholar 

  129. Brill A, Fuchs TA, Savchenko A, Thomas GM, Martinod K, De Meyer SF, Bhandari AA, Wagner DD (2012) Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost. doi:10.1111/j.1538-7836.2011.04544.x

    PubMed Central  Google Scholar 

  130. Fuchs TA, Brill A, Duerschmied D, Schatzberg D, Monestier M, Myers DD Jr, Wrobleski SK, Wakefield TW, Hartwig JH, Wagner DD (2010) Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 107(36):15880–15885. doi:10.1073/pnas.1005743107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zardi L, Siri A, Carnemolla B, Santi L, Gardner WD, Hoch SO (1979) Fibronectin: a chromatin-associated protein? Cell 18(3):649–657

    Article  CAS  PubMed  Google Scholar 

  132. McMaster GK, Zardi L (1982) DNA-binding domains of human fibronectin. Biochem Biophys Res Commun 107(2):609–617

    Article  CAS  PubMed  Google Scholar 

  133. Pecheniuk NM, Elias DJ, Deguchi H, Averell PM, Griffin JH (2008) Elevated plasma fibronectin levels associated with venous thromboembolism. Thromb Haemost 100(2):224–228

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Farrell DH (2008) New risk factor for venous thromboembolism? Thromb Haemost 100(2):173–174

    CAS  PubMed  Google Scholar 

  135. McMillan R, Durette C (2004) Long-term outcomes in adults with chronic ITP after splenectomy failure. Blood 104(4):956–960. doi:10.1182/blood-2003-11-3908

    Article  CAS  PubMed  Google Scholar 

  136. Severinsen MT, Engebjerg MC, Farkas DK, Jensen AO, Norgaard M, Zhao S, Sorensen HT (2015) Risk of venous thromboembolism in patients with primary chronic immune thrombocytopenia: a Danish population-based cohort study. Br J Haematol 152(3):360–362. doi:10.1111/j.1365-2141.2010.08418.x

    Article  Google Scholar 

  137. Li C, Piran S, Chen P, Lang S, Zarpellon A, Jin JW, Zhu G, Reheman A, van der Wal DE, Simpson EK, Ni R, Gross PL, Ware J, Ruggeri ZM, Freedman J, Ni H (2011) The maternal immune response to fetal platelet GPIbalpha causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies. J Clin Invest 121(11):4537–4547. doi:10.1172/JCI57850

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Li J, van der Wal DE, Zhu G, Xu M, Yougbare I, Ma L, Vadasz B, Carrim N, Grozovsky R, Ruan M, Zhu L, Zeng Q, Tao L, Zhai ZM, Peng J, Hou M, Leytin V, Freedman J, Hoffmeister KM, Ni H (2015) Desialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia. Nat Commun 6:7737. doi:10.1038/ncomms8737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Webster ML, Zhu G, Li Y, Ni H (2008) Fc-independent phagocytosis: implications for intravenous IgG therapy in immune thrombocytopenia. Cardiovasc Hematol Disord Drug Targets 8(4):278–282

    Article  CAS  PubMed  Google Scholar 

  140. Zeng Q, Zhu L, Tao L, Bao J, Yang M, Simpson EK, Li C, van der Wal DE, Chen P, Spring CM, Wang M, Zhang L, Ruan C, Hou M, Xia R, Ni H (2011) Relative efficacy of steroid therapy in immune thrombocytopenia mediated by anti-platelet GPIIbIIIa versus GPIbalpha antibodies. Am J Hematol. doi:10.1002/ajh.22211

    Google Scholar 

  141. Li C, Li J, Li Y, Lang S, Yougbare I, Zhu G, Chen P, Ni H (2012) Crosstalk between platelets and the immune system: old systems with new discoveries. Adv Hematol 2012:384685. doi:10.1155/2012/384685

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  142. Li J, van der Wal DE, Zhu L, Vadasz B, Simpson EK, Li C, Webster ML, Zhu G, Lang S, Chen P, Zeng Q, Ni H (2013) Fc-independent phagocytosis: implications for IVIG and other therapies in immune-mediated thrombocytopenia. Cardiovasc Hematol Disord Drug Targets 13(1):50–58

    Article  CAS  PubMed  Google Scholar 

  143. Yougbare I, Lang S, Yang H, Chen P, Zhao X, Tai WS, Zdravic D, Vadasz B, Li C, Piran S, Marshall A, Zhu G, Tiller H, Killie MK, Boyd S, Leong-Poi H, Wen XY, Skogen B, Adamson SL, Freedman J, Ni H (2015) Maternal anti-platelet beta3 integrins impair angiogenesis and cause intracranial hemorrhage. J Clin Invest 125(4):1545–1556. doi:10.1172/JCI77820

    Article  PubMed  PubMed Central  Google Scholar 

  144. Yougbare I, Zdravic D, Ni H (2015) Angiogenesis and bleeding disorders in FNAIT. Oncotarget 6(18):15724–15725

    Article  PubMed  PubMed Central  Google Scholar 

  145. Ni H, Chen P, Spring CM, Sayeh E, Semple JW, Lazarus AH, Hynes RO, Freedman J (2006) A novel murine model of fetal and neonatal alloimmune thrombocytopenia: response to intravenous IgG therapy. Blood 107(7):2976–2983. doi:10.1182/blood-2005-06-2562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Palumbo JS, Zogg M, Talmage KE, Degen JL, Weiler H, Isermann BH (2004) Role of fibrinogen- and platelet-mediated hemostasis in mouse embryogenesis and reproduction. J Thromb Haemost 2(8):1368–1379. doi:10.1111/j.1538-7836.2004.00788.x

    Article  CAS  PubMed  Google Scholar 

  147. Andrew M, Paes B, Milner R, Johnston M, Mitchell L, Tollefsen DM, Castle V, Powers P (1988) Development of the human coagulation system in the healthy premature infant. Blood 72(5):1651–1657

    CAS  PubMed  Google Scholar 

  148. Foster C, Shennan AH (2014) Fetal fibronectin as a biomarker of preterm labor: a review of the literature and advances in its clinical use. Biomark Med 8(4):471–484. doi:10.2217/bmm.14.28

    Article  CAS  PubMed  Google Scholar 

  149. Puetz J (2013) Fresh frozen plasma: the most commonly prescribed hemostatic agent. J Thromb Haemost 11(10):1794–1799. doi:10.1111/jth.12351

    CAS  PubMed  Google Scholar 

  150. Callum JL, Karkouti K, Lin Y (2009) Cryoprecipitate: the current state of knowledge. Transfus Med Rev 23(3):177–188. doi:10.1016/j.tmrv.2009.03.001

    Article  PubMed  Google Scholar 

  151. Allain JP (1984) Non Factor VIII related constituents in concentrates. Scand J Haematol Suppl 41:173–180

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Room 420, LKSKI-Keenan Research Centre for Biomedical Science, Department of Laboratory Medicine, St. Michael’s Hospital, 209 Victoria Street, Toronto, ON, M5B 1W8, Canada

    Yiming Wang & Heyu Ni

  2. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada

    Yiming Wang & Heyu Ni

  3. Canadian Blood Services, Toronto, ON, Canada

    Yiming Wang & Heyu Ni

  4. Toronto Platelet Immunobiology Group, Toronto, ON, Canada

    Yiming Wang & Heyu Ni

  5. Department of Physiology, University of Toronto, Toronto, ON, Canada

    Heyu Ni

  6. Department of Medicine, University of Toronto, Toronto, ON, Canada

    Heyu Ni

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Wang, Y., Ni, H. Fibronectin maintains the balance between hemostasis and thrombosis. Cell. Mol. Life Sci. 73, 3265–3277 (2016). https://doi.org/10.1007/s00018-016-2225-y

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