The role of urokinase plasminogen activator and plasmin activator inhibitor-1 on vein wall remodeling in experimental deep vein thrombosis

Baldwin, Joe F.; Sood, Vikram; Elfline, Megan; Luke, Catherine E.; Dewyer, Nicholas A.; Díaz, José; Myers, Dan D.; Wakefield, Thomas W.; Henke, Peter K.

doi:10.1016/j.jvs.2012.02.054

Cited by 45 publications

(53 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Serpine 1, also known as plasminogen activation inhibitory factor 1, is a member of the serine protease inhibitor gene family. The Serpine 1 gene has been shown to be located at chromosome 7q21.2-q22 and to encode a protein with a relative molecular mass of 48,000-50,000 kDa (Baldwin et al, 2012). Serpine 1 is primarily synthetized by liver cells, fibroblasts, myocardial cells, macrophages, fat cells, and vascular endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

TGF-β1 and Serpine 1 expression changes in traumatic deep vein thrombosis

Mo¹,

Zhang²,

Ji³

et al. 2015

Genet. Mol. Res.

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 99%

TGF-β1 and Serpine 1 expression changes in traumatic deep vein thrombosis

Mo¹,

Zhang²,

Ji³

et al. 2015

Genet. Mol. Res.

View full text Add to dashboard Cite

“…Five representative high-power fields were examined circumferentially around the diameter of the vein and scored according to a previously validated scoring system (Supplementary Table II, online only). 9,10,13 …”

Section: Methodsmentioning

confidence: 99%

“…13 Results of previous animal studies suggest that treatment with LMWH may augment fibrinolysis. 8,14 Alternatively, LMWH may affect vein wall remodeling in a nonthrombus-dependent mechanism through its interactions with PAI-1.…”

mentioning

confidence: 99%

See 1 more Smart Citation

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

Obi

Diaz

Ballard-Lipka

et al. 2014

Journal of Vascular Surgery: Venous and Lymphatic Disorders

Self Cite

View full text Add to dashboard Cite

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 ρg/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-lβ (68.6 ± 31.0 vs 223.4 ± 28.9 ρg/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 4.3 ± 3.8 ρg/mg total protein; n = 5) and vein wall interleukin-13 (187.2 ± 57.6 vs 9.9 ± 1.1 ρg/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. Clinical Relevance The pathophysiologic mechanism of post-thrombotic syndrome is not well understood clinically or experimentally. In this study, we evaluated the effect of the prominent fibrinolytic mechanism, plasminogen activator inhibitor 1 (PAI-1), and low-molecular-weight heparin (LMWH) on vein wall injury after thrombosis. We show here that LMWH is protective from vein wall fibrosis, but this is abrogated in PAI-1-deleted mice. This is also correlated with monocyte vein wall influx. These data support the clinical observation that LMWH may be protective from post-thrombotic vein wall injury in a PAI-1-dependent manner.

show abstract

“…Amputation and death from pulmonary embolism caused by DVT are the most severe complications in traumatic orthopedics (Baldwin et al, 2012). However, the research on early diagnosis and prevention of DVT is still deficient.…”

Section: Discussionmentioning

confidence: 99%

Detection of targets and their mechanisms for early diagnosis of traumatic deep vein thrombosis

Jw¹,

Df²,

Gl³

et al. 2015

Genet. Mol. Res.

View full text Add to dashboard Cite

ABSTRACT. The purpose of this investigation was to identify targets for the early diagnosis and predictors of deep venous thrombosis (DVT) and the role of these targets in the formation of venous thrombosis. A model of DVT was constructed in rats. Thromboses and venous walls were sampled for reverse transcription polymerase chain reaction study, and blood was sampled for enzyme-linked immunosorbent assay studies. Vein endothelial cells were cultured to observe the effects of interleukin (IL)-17 on the expression of tissue plasminogen activator (t-PA)/plasminogen activator inhibitor type 1 (PAI-1). IL-17 monoclonal antibody was used to study its effect on preventing the formation of DVT. One-hundred and twenty hours after the animal model was constructed, significant DVT started to form. Polymerase chain reaction tests showed that immediately after the model was created, the expression of IL-17 increased greatly, whereas the balance between t-PA and PAI-1 was disrupted just before DVT formed. The increase of serum IL-17 was positively related with the formation of DVT. Thus, the application of IL-17 monoclonal antibody could reduce the formation of DVT in J.W. Mo et al. 2414©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (1): 2413-2421 (2015) rats. IL-17 might be a target for the early diagnosis of DVT and should be further studied to assess its clinical value.

show abstract

The role of urokinase plasminogen activator and plasmin activator inhibitor-1 on vein wall remodeling in experimental deep vein thrombosis

Cited by 45 publications

References 42 publications

TGF-β1 and Serpine 1 expression changes in traumatic deep vein thrombosis

TGF-β1 and Serpine 1 expression changes in traumatic deep vein thrombosis

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

Detection of targets and their mechanisms for early diagnosis of traumatic deep vein thrombosis

Contact Info

Product

Resources

About