Journal of Vascular Surgery
Volume 40, Issue 3 , Pages 536-542, September 2004

Deep vein thrombosis resolution is not accelerated with increased neovascularization☆

Presented at the Sixteenth Annual Meeting of the American Venous Forum, Kissimmee, Fla, Feb 26-29, 2004.

  • Manu R. Varma, BS

      Affiliations

    • Jobst Vascular Research Laboratories, Section of Vascular Surgery, Departments of Surgery, University of Michigan Medical School, Ann Arbor, Mich USA
    • ,
  • Daria M. Moaveni, BS

      Affiliations

    • Jobst Vascular Research Laboratories, Section of Vascular Surgery, Departments of Surgery, University of Michigan Medical School, Ann Arbor, Mich USA
    • ,
  • Nicholas A. Dewyer

      Affiliations

    • Jobst Vascular Research Laboratories, Section of Vascular Surgery, Departments of Surgery, University of Michigan Medical School, Ann Arbor, Mich USA
    • ,
  • Andrea J. Varga, BS

      Affiliations

    • Jobst Vascular Research Laboratories, Section of Vascular Surgery, Departments of Surgery, University of Michigan Medical School, Ann Arbor, Mich USA
    • ,
  • K.Barry Deatrick, BA

      Affiliations

    • Jobst Vascular Research Laboratories, Section of Vascular Surgery, Departments of Surgery, University of Michigan Medical School, Ann Arbor, Mich USA
    • ,
  • Steven L. Kunkel, PhD

      Affiliations

    • Pathology, University of Michigan Medical School, Ann Arbor, Mich USA
    • ,
  • Gilbert R. Upchurch Jr, MD

      Affiliations

    • Jobst Vascular Research Laboratories, Section of Vascular Surgery, Departments of Surgery, University of Michigan Medical School, Ann Arbor, Mich USA
    • ,
  • Thomas W. Wakefield, MD

      Affiliations

    • Jobst Vascular Research Laboratories, Section of Vascular Surgery, Departments of Surgery, University of Michigan Medical School, Ann Arbor, Mich USA
    • ,
  • Peter K. Henke, MD

      Affiliations

    • Jobst Vascular Research Laboratories, Section of Vascular Surgery, Departments of Surgery, University of Michigan Medical School, Ann Arbor, Mich USA
    • Corresponding Author InformationReprint requests: Peter K. Henke, MD, 1500 E Medical Center Dr, 2210D Taubman Center, Ann Arbor, MI 48109, USA

Received 3 March 2004; accepted 24 May 2004. published online 19 August 2004.

Abstract 

Introduction

Deep venous thrombosis (DVT) resolution involves fibrinolysis, neovascularization, and fibrosis. We hypothesized that promoting neovascularization would accelerate DVT resolution.

Methods

A rat model of stasis DVT was produced with proximal ligation of the inferior vena cava (IVC) and all visible tributaries. One μg of interferon inducible protein (IP-10; angiostatic chemokine), basic fibroblast growth factor (bFGF; pro-angiogenic cytokine), epithelial neutrophil activating protein (ENA-78; pro-angiogenic chemokine), or saline solution control was injected into the IVC after ligation, and then via tail vein injection daily until sacrifice at either 4 or 8 days. Peripheral blood counts were measured, and thrombus weight was recorded at sacrifice. Laser Doppler in vivo imaging was used to estimate post-thrombotic IVC blood flow. Immunohistologic assessment of the thrombosed IVC for polymorphonuclear neutrophils (PMNs), monocytes (ED-1), and laminin (neovascular channels) was performed or the thrombus was separated from the IVC and assayed for keratinocyte cytokine (KC), monocyte chemotactic protein-1 (MCP-1), bFGF with enzyme-linked immunosorbent assay (ELISA), and total collagen with a direct colorimetric assay.

Results

Peripheral blood and intrathrombus PMNs and monocytes were not significantly different in the treated or control rats. There were no differences in any measure at 4 days. At 8 days, thrombus neovascularity, but not weight or collagen content, was increased in rats treated with bFGF or ENA-78 compared with control rats (17.6 ± 0.93, 16.2 ± 0.97 vs 13.2 ± 0.79; channels/5 high-power fields (hpf; n = 6-10; P < .05). Post DVT IVC blood flow was significantly increased in bFGF-treated rats but not in rats treated with IP-10 or ENA-78, as compared with control rats. Rats treated with ENA-78 had increased intrathrombus bFGF compared with control rats (85 ± 27 pg/mg protein vs 20 ± 6 pg/mg protein; n = 6; P < .05), but other mediators were not significantly different in treated rats compared with control rats.

Conclusion

Pro-angiogenic compounds increase thrombus neovascularization, but this does not correlate with smaller or less fibrotic DVT. Mechanisms other than neovascularization may be more important to hasten DVT dissolution.

Abstract 

Clinical relevance

Improved therapy for deep venous thrombosis (DVT) will ideally increase the rate of thrombus dissolution and eliminate the bleeding risks of anticoagulation. This study evaluated promoting DVT neovascularization with angiogenic chemokines, and, while successful by experimental measures, this did not translate into smaller DVT. Solely promoting thrombus neovascularization will not likely speed resolution.

 

☆ Supported by the Lifeline Foundation, and von Liebig Mentored Clinical Scientist Development Award K-08 HL#69780 (P.K.H.).Competition of interest: none.

PII: S0741-5214(04)00726-8

doi:10.1016/j.jvs.2004.05.023

Journal of Vascular Surgery
Volume 40, Issue 3 , Pages 536-542, September 2004

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