Low-molecular-weight heparin modulates vein wall fibrotic response in a plasminogen activator inhibitor 1-dependent manner

作者：Obi Andrea T; Diaz Jose A; Ballard Lipka Nicole L; Roelofs Karen J; Farris Diana M; Lawrence Daniel A; Henke Peter K^*; Wakefield Thomas W

来源：Journal of Vascular Surgery-Venous and Lymphatic Disorders, 2014, 2(4): 441-+.

DOI：10.1016/j.jvsv.2014.02.004

Background: Treatment with low-molecular-weight heparin (LMWH) favorably alters the vein wall response to deep venous thrombosis (DVT), although the mechanisms remain unclear. Previous studies have suggested that LMWH alters the levels of circulating plasminogen activator inhibitor 1 (PAI-1), a known mediator of fibrosis, and may improve endogenous fibrinolysis. We hypothesized that LMWH favorably alters the vein wall response by binding of PAI-1 and acceleration of fibrinolysis.
Methods: Wild-type and PAI-1(-/-) mice underwent treatment with LMWH after induction of occlusive DVT. Vein wall and plasma were harvested and analyzed by enzyme-linked immunosorbent assay, zymography, real-time polymerase chain reaction, and immunohistochemistry.
Results: Wild-type mice treated with LMWH exhibited diminished vein wall fibrosis (0.6 +/- 0.6 vs 1.4 +/- 0.2; P < .01; n = 5) and elevation of circulating PAI-1 (1776 +/- 342 vs 567 +/- 104 rho g/mL; P < .01; n = 5) compared with untreated controls after occlusive DVT. PAI-1(-/-) mice treated with LMWH were not similarly protected from fibrosis, despite improved thrombus resolution. Treatment with LMWH was associated with decreased intrathrombus interleukin-1 beta (68.6 +/- 31.0 vs 223.4 +/- 28.9 rho g/mg total protein; P < .01; n = 5) but did not alter inflammatory cell recruitment to the vein wall. PAI-1(-/-) mice exhibited significantly elevated intrathrombus (257.2 +/- 51.5 vs 14.3 +/- 3.8 pg/mg total protein; n = 5) and vein wall interleukin-13 (187.2 +/- 57.6 vs 9.9 +/- 1.1 rho g/mg total protein; P < .05; n = 5) as well as vein wall F4/80 positively staining monocytes (53 +/- 11 vs 16 +/- 2 cells/5 high-power fields; P < .05; n = 4).
Conclusions: LMWH did not accelerate venous thrombosis resolution but did protect against vein wall fibrosis in a PAI-1-dependent manner in an occlusive DVT model. Lack of PAI-1 correlated with accelerated venous thrombosis resolution but no protection from fibrosis. PAI-1 inhibition as a treatment strategy for DVT is likely to accelerate clearance of the thrombus but may come at the expense of increased vein wall fibrosis.

• 出版日期2014-10