Plasmin Inhibition Increases MMP-9 Activity and Decreases Vein Wall Stiffness During Venous Thrombosis Resolution

Dewyer, Nicholas A.; Sood, Vikram; Lynch, Erin M.; Luke, Catherine E.; Upchurch, Gilbert R.; Wakefield, Thomas W.; Kunkel, Steven L.; Henke, Peter K.

doi:10.1016/j.jss.2007.03.064

Cited by 34 publications

(37 citation statements)

References 49 publications

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“…Conversely, those with chronic DVT may have a thinner vein wall due to incomplete thrombus resolution, whereby the thrombus doesn’t fully attach to the vein wall, and thus full resolution does not occur. The vein wall itself is a source of plasmin and other proteases/proteinases that promote thrombus resolution 9, 29. Although by different pathology, venous varicosities show increases in histologically measured vein wall thickness 15, 30.…”

Section: Discussionmentioning

confidence: 99%

Postthrombotic vein wall remodeling: Preliminary observations

Deatrick

Elfline

Baker

et al. 2011

Journal of Vascular Surgery

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Background Post-thrombotic syndrome (PTS) is characterized by a fibrotic vein injury following deep vein thrombosis (DVT). We sought to quantify the change in vein wall thickness in patients who fail to resolve DVT by 6 months and whether there were differences in blood or plasma levels of inflammatory proteins associated with venous remodeling. Methods Patients presenting with confirmed lower extremity DVT were prospectively recruited for this study. Duplex imaging of the lower extremity venous system was performed, and blood was collected at entrance and repeat evaluation with blood draw and ultrasound imaging at 1 and 6 months. DVT resolution and thickness of the vein wall was quantified by ultrasound imaging in each segment affected by thrombus, and a contralateral, unaffected vein wall served as a control. Gene and protein expression of inflammatory markers were examined from leukocytes and serum, respectively. ANOVA or Student’s t-tests were used, and a P <.05 was significant. N = 10 – 12 for all analyses. Results 32 patients (12 patients with DVT resolution at 6 months, 10 patients with persistent thrombus at 6 months, and 10 healthy controls) were compared. Both resolving and non-resolving DVT were associated with 1.5 – 1.8 fold increased vein wall thickness at 6 months (P = .008) as compared with non affected vein wall segments. However, the thickness of the affected segments was 1.4 fold greater in patients who had total resolution of the DVT by 6 months than in patients who had persistent chronic thrombus 6 months after presentation (P = .01). There was a 4 – 5 fold increased level of matrix metalloproteinase-9 (MMP9) in thrombosed patients compared with non-thrombosed patient controls (P <.05), while Toll like receptor-9 (TLR-9) expression was 3 fold less than controls (P <.05) at enrollment. D-dimer and P-selectin were higher in thrombosed as compared to controls at diagnosis, but not at 6 months. Both TLR4 (marker of inflammation) and P-selectin gene expression were higher in leukocytes from patients with chronic DVT compared to those who resolved at one month after diagnosis (P <.05). Conclusions This preliminary study suggests ongoing vein wall remodeling after DVT, measurable by ultrasound and associated with certain biomarkers. At 6 months, the vein wall is markedly thickened, and directly correlates with resolution. This suggests that the vein wall response is initiated early following thrombus formation, and persists even in the presence of total resolution.

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Section: Discussionmentioning

confidence: 99%

Postthrombotic vein wall remodeling: Preliminary observations

Deatrick

Elfline

Baker

et al. 2011

Journal of Vascular Surgery

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“…37 At 1 and 2 weeks after DVT, DM showed an evident up-regulation of MMP-2 and MMP-9, probably derived from macrophages within the wall and the thrombus, as a response to increased inflammatory cytokines 38 or to decreased uPA activity. 39 In addition, a decrease at 2 weeks was associated at the same time point with increased collagen deposition, suggesting decreased collagenolysis that may contribute to vein wall injury.…”

Section: ™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™mentioning

confidence: 95%

Deep vein thrombosis resolution is impaired in diet-induced type 2 diabetic mice

Bouzeghrane

Zhang

Gevry

2008

Journal of Vascular Surgery

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“…MMPs play an important role in the degradation of extracellular matrix and basement membrane components to allow the migration of vascular smooth muscle cells, and contribute to acute and chronic fibrotic diseases [22][23][24][25][26][27]. Furthermore, MMP activity is indispensable for the process of thrombus resolution [28][29][30][31][32]. This prompted us to hypothesize that MMPs are candidates for considering the age of venous thrombi.…”

Section: Introductionmentioning

confidence: 99%

Immunohistochemical detection of MMP-2 and MMP-9 in a stasis-induced deep vein thrombosis model and its application to thrombus age estimation

et al. 2010

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We immunohistochemically examined the expression of matrix metalloproteinase (MMP)-2 and MMP-9 using venous thrombi developed by ligation of the inferior vena cava (IVC) in mice. Both MMP-2- and MMP-9- positive cells could be detected in the whole course of thrombus formation after IVC ligation. Morphometrically, their number was greatest 14 days after IVC ligation and thereafter, gradually decreased at 21 days. The number of MMP-9-positive cells was significantly higher than that of MMP-2-positive cells at 1 to 7 days. The average ratio of MMP-9 to MMP-2 (MMP-9/MMP-2 ratio) was >2.0 in all thrombus samples at 1-5 days. After 7 days, the MMP-9/MMP-2 ratio was less than 2.0. These observations implied that an MMP-9/MMP-2 ratio markedly exceeding 2.0 strongly indicates an age of 5 days or less. Furthermore, an MMP-9/MMP-2 ratio of <2.0 probably indicates an age of more than 7 days. The present study demonstrated that the immunohistochemical detection of intrathrombotic MMP-2 and MMP-9 was suitable to estimate the age of venous thrombi.

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Plasmin Inhibition Increases MMP-9 Activity and Decreases Vein Wall Stiffness During Venous Thrombosis Resolution

Abstract: Introduction-Deep venous thrombosis (DVT) resolution involves the plasmin and the matrix metalloproteinase (MMP) system. This study tested the hypothesis that pharmacological inhibition of the plasmin system would impair DVT resolution and worsen vein wall damage.

Cited by 34 publications

References 49 publications

Postthrombotic vein wall remodeling: Preliminary observations

Postthrombotic vein wall remodeling: Preliminary observations

Deep vein thrombosis resolution is impaired in diet-induced type 2 diabetic mice

Immunohistochemical detection of MMP-2 and MMP-9 in a stasis-induced deep vein thrombosis model and its application to thrombus age estimation

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