Download PDF
Thromb Haemost 2007; 98(05): 1045-1055
DOI: 10.1160/TH07-03-0190
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Fibrotic injury after experimental deep vein thrombosis is determined by the mechanism of thrombogenesis

Peter K. Henke
1   Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Manu R. V. Varma
1   Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Daria K. Moaveni
1   Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Nicholas A. Dewyer
1   Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Andrea J. Moore
1   Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Erin M. Lynch
1   Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Christopher Longo
1   Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Barry C. Deatrick
1   Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Steven L. Kunkel
1   Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Gilbert R. Upchurch Jr.
1   Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
,
Thomas W. Wakefield
1   Jobst Vascular Surgery Laboratory, Section of Vascular Surgery, University of Michigan Medical School, Ann Arbor, Michigan, USA
› Author Affiliations
Further Information

Publication History

Received 13 March 2007

Accepted after resubmission 03 August 2007

Publication Date:
30 November 2017 (online)

    Permissions and Reprints

Summary

Vessel wall matrix changes occur after injury, although this has not been well studied in the venous system. This study tested the hypothesis that the thrombus dictates the vein wall response and vein wall damage is directly related to the duration of thrombus contact. To determine the injury response over time, rats underwent inferior vena cava (IVC) ligation to produce a stasis thrombus, with harvest at various time points to 28 days (d). Significant vein wall matrix changes occurred with biomechanical injury (stiffness) peaking at 7–14 d, with concurrent early reduction in total collagen, an increase in early matrix metalloproteinase (MMP)-9 and late MMP-2, and concomitant increase in tumor necrosis factor (TNF)α, monocyte chemoattractant( MCP)-1 and tumor growth factor (TGF)β (all P <0.05). To isolate the effect of the thrombus and its mechanism of genesis, rats underwent 7 d or limited stasis (24 hours), non-stasis thrombosis, or non-thrombotic IVC occlusion (Silicone plug). Vein wall stiffness was increased seven-fold, with a five-fold reduction in collagen, and 5.5- to seven-fold increase in TNFα, MCP-1, and TGFβ with 7 d stasis as compared with controls (all P <0.05). By Picosirus red staining analysis, collagenolysis was significantly greater with 7 d stasis injury (P = 0.01) but neither MMP-9 nor MMP-2 activity correlated with injury mechanism. In addition, vein wall cellular proliferation and uPA gene expression paralled the stasis thrombotic injury. Limited stasis, non-stasis thrombosis and non-thrombotic IVC occlusion showed a lesser inflammatory response. These data suggest both a static component and the thrombus directs vein wall injury via multiple mechanisms.

Keywords

Veins - thrombosis - inflammation - collagen - vascular biology
 

  • References

  • 1 Heit JA, Silverstein MD, Mohr DN. et al. The epidemiology of venous thromboembolism in the community. Thromb Haemost 2001; 86: 452-463.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Prandoni P, Lensing AW, Cogo A. et al. The longterm clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
    CrossrefPubMedGoogle Scholar
  • 3 Delis KT, Bountouroglou D, Mansfield AO. Venous claudication in iliofemoral thrombosis: Long-term effects on venous hemodynamics, clinical status, and quality of life. Ann Surg 2004; 239: 118-126.
    CrossrefPubMedGoogle Scholar
  • 4 Henke PK, Pearce CG, Moaveni DM. et al. Targeted deletion of CCR2 impairs deep vein thombosis resolution in a mouse model. J Immunol 2006; 177: 3388-3397.
    CrossrefPubMedGoogle Scholar
  • 5 Henke PK, Varga A, De S. et al. Deep vein thrombosis resolution is modulated by monocyte CXCR2-mediated activity in a mouse model. Arterioscler Thromb Vasc Biol 2004; 24: 1130-1137.
    CrossrefPubMedGoogle Scholar
  • 6 Wakefield TW, Strieter RM, Wilke CA. et al. Venous thrombosis-associated inflammation and attenuation with neutralizing antibodies to cytokines and adhesion molecules. Arterioscler Thromb Vasc Biol 1995; 15: 258-268.
    CrossrefPubMedGoogle Scholar
  • 7 Myers Jr. DD, Henke PK, Bedard PW. et al. Treatment with an oral small molecule inhibitor of P selectin (PSI-697) decreases vein wall injury in a rat stenosis model of venous thrombosis. J Vasc Surg 2006; 44: 625-632.
    CrossrefPubMedGoogle Scholar
  • 8 Deatrick KB, Eliason JL, Lynch EM. et al. Vein wall remodeling after deep vein thrombosis involves matrix metalloproteinases and late fibrosis in a mouse model. J Vasc Surg 2005; 42: 140-148.
    CrossrefPubMedGoogle Scholar
  • 9 Henke PK, Varma MR, Deatrick KB. et al. Neutrophils modulate post-thrombotic vein wall remodeling but not thrombus neovascularization. Thromb Haemost 2006; 95: 272-281.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Meissner MH, Manzo RA, Bergelin RO. et al. Deep venous insufficiency: the relationship between lysis and subsequent reflux. J Vasc Surg 1993; 18: 596-605 discussion 606–608.
    CrossrefPubMedGoogle Scholar
  • 11 Mewissen MW. Catheter-directed thrombolysis for lower extremity deep vein thrombosis. Tech Vasc Interv Radiol 2001; 4: 111-114.
    CrossrefPubMedGoogle Scholar
  • 12 See-Tho K, Harris Jr. EJ. Thrombosis with outflow obstruction delays thrombolysis and results in chronic wall thickening of rat veins. J Vasc Surg 1998; 28: 115-122 discussion 123.
    CrossrefPubMedGoogle Scholar
  • 13 Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res 2003; 92: 827-839.
    CrossrefPubMedGoogle Scholar
  • 14 Coats Jr. WD, Whittaker P, Cheung DT. et al. Collagen content is significantly lower in restenotic versus nonrestenotic vessels after balloon angioplasty in the atherosclerotic rabbit model. Circulation 1997; 95: 1293-1300.
    CrossrefPubMedGoogle Scholar
  • 15 Zhu YK, Liu X, Wang H. et al. Interactions between monocytes and smooth-muscle cells can lead to extracellular matrix degradation. J Allergy Clin Immunol 2001; 108: 989-996.
    CrossrefPubMedGoogle Scholar
  • 16 Gillitzer R, Goebeler M. Chemokines in cutaneous wound healing. J Leukoc Biol 2001; 69: 513-521.
    PubMedGoogle Scholar
  • 17 Brasselet C, Durand E, Addad F. et al. Collagen and elastin cross-linking: a mechanism of constrictive remodeling after arterial injury. Am J Physiol Heart Circ Physiol 2005; 289: H2228-2233.
    CrossrefPubMedGoogle Scholar
  • 18 Shanley CJ, Gharaee-Kermani M, Sarkar R. et al. Transforming growth factor-beta 1 increases lysyl oxidase enzyme activity and mRNA in rat aortic smooth muscle cells. J Vasc Surg 1997; 25: 446-452.
    CrossrefPubMedGoogle Scholar
  • 19 Rectenwald JE, Deatrick KB, Sukheepod P. et al. Experimental pulmonary embolism: effects of the thrombus and attenuation of pulmonary artery injury by low-molecular-weight heparin. J Vasc Surg 2006; 43: 800-808.
    CrossrefPubMedGoogle Scholar
  • 20 Zhu Y, Farrehi PM, Fay WP. Plasminogen activator inhibitor type 1 enhances neointima formation after oxidative vascular injury in atherosclerosis-prone mice. Circulation 2001; 103: 3105-3110.
    CrossrefPubMedGoogle Scholar
  • 21 Borges LF, Gutierrez PS, Marana HR. et al. Picrosirius- polarization staining method as an efficient histopathological tool for collagenolysis detection in vesical prolapse lesions. Micron 2007; 38: 580-583.
    CrossrefPubMedGoogle Scholar
  • 22 Cuttle L, Nataatmadja M, Fraser JF. et al. Collagen in the scarless fetal skin wound: detection with picrosirius- polarization. Wound Repair Regen 2005; 13: 198-204.
    CrossrefPubMedGoogle Scholar
  • 23 Ginzinger DG. Gene quantification using real-time quantitative PCR: an emerging technology hits the mainstream. Exp Hematol 2002; 30: 503-512.
    CrossrefPubMedGoogle Scholar
  • 24 Newby AC. Dual role of matrix metalloproteinases (matrixins) in intimal thickening and atherosclerotic plaque rupture. Physiol Rev 2005; 85: 1-31.
    CrossrefPubMedGoogle Scholar
  • 25 Garcia-Touchard A, Henry TD, Sangiorgi G. et al. Extracellular proteases in atherosclerosis and restenosis. Arterioscler Thromb Vasc Biol 2005; 25: 1119-1127.
    CrossrefPubMedGoogle Scholar
  • 26 Lijnen HR, Van Hoef B, Lupu F. et al. Function of the plasminogen/plasmin and matrix metalloproteinase systems after vascular injury in mice with targeted inactivation of fibrinolytic system genes. Arterioscler Thromb Vasc Biol 1998; 18: 1035-1045.
    CrossrefPubMedGoogle Scholar
  • 27 Davis GE, Senger DR. Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ Res 2005; 97: 1093-1107.
    CrossrefPubMedGoogle Scholar
  • 28 Taipale J, Keski-Oja J. Growth factors in the extracellular matrix. Faseb J 1997; 11: 51-59.
    CrossrefPubMedGoogle Scholar
  • 29 Singh I, Burnand KG, Collins M. et al. Failure of thrombus to resolve in urokinase-type plasminogen activator gene-knockout mice: rescue by normal bone marrow-derived cells. Circulation 2003; 107: 869-875.
    CrossrefPubMedGoogle Scholar
  • 30 Strauss BH, Chisholm RJ, Keeley FW. et al. Extracellular matrix remodeling after balloon angioplasty injury in a rabbit model of restenosis. Circ Res 1994; 75: 650-658.
    CrossrefPubMedGoogle Scholar
  • 31 Kovacs EJ. Fibrogenic cytokines: the role of immune mediators in the development of scar tissue. Immunol Today 1991; 12: 17-23.
    CrossrefPubMedGoogle Scholar
  • 32 Chou DH-I, Lee W, McCulloch CA. TNFα inactivation of collagen receptors. J Immunol 1996; 156: 4354-4362.
    PubMedGoogle Scholar
  • 33 Houghton AM, Quintero PA, Perkins DL. et al. Elastin fragments drive disease progression in a murine model of emphysema. J Clin Invest 2006; 116: 753-759.
    CrossrefPubMedGoogle Scholar