Vein wall re-endothelialization after deep vein thrombosis is improved with low-molecular-weight heparin

Moaveni, Daria K.; Lynch, Erin M.; Luke, Catherine E.; Sood, Vikram; Upchurch, Gilbert R.; Wakefield, Thomas W.; Henke, Peter K.

doi:10.1016/j.jvs.2007.11.040

Cited by 35 publications

(42 citation statements)

References 43 publications

(42 reference statements)

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“…These data are congruent with other studies reporting that a smaller thrombus does not correlate with a favorable vein wall response. 13,17,32,33 Our results suggest that the beneficial effect of LMWH on the vein wall fibrotic response is independent of thrombus size but dependent on the presence of PAI-1.…”

Section: Discussionmentioning

confidence: 61%

“…Previous experiments have confirmed that LMWH treatment results in less collagenolysis, 20 decreased fibrotic response, 39 and improved endothelial recovery, 33 and thus increased collagen gene expression may represent normal or advantageous vein wall healing response. Intrathrombus IL-1β was decreased in animals treated with LMWH in our study, perhaps secondary to a diminished inflammatory response in the setting of a smaller thrombus size.…”

Section: Discussionmentioning

confidence: 88%

“…Interestingly, vein wall IL-1β was not similarly decreased, and thus vein wall inflammatory cytokine response occurred independently of magnitude of thrombosis. Ex vivo, IL-1β– stimulated LMWH-treated vein wall demonstrates an increased collagen gene expression compared with controls, 33 suggesting that LMWH may modulate endothelial response to local cytokines. LMWH did not decrease profibrotic IL-13 in our study as demonstrated by others, 39 but we did demonstrate markedly elevated IL-13 in PAI-1 −/− mice.…”

Section: Discussionmentioning

confidence: 99%

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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

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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.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

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

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“…The cDNA obtained was amplified using TaqPolymerase (Promega, Madison, WI) in the Rotor-Gene quantitative real-time polymerase chain reaction system (Quiagen, Hilden, Germany). SYBR green intercalating dye was used to monitor levels of DNA amplification for each gene 18. Commercially available primers were purchased for the following genes of interest: B-Actin RefSeq# NM_001101.3, CRP RefSeq# NM_000567.2, IL-6 RefSeq# NM 000600.3, MMP9 RefSeq# NM_004994.2, MMP2 RefSeq# NM_004530.2, SELP, RefSeq# NM_003005.3, SELPLG RefSeq# NM_003006.3, TLR4 RefSeq# NM_138554.3, and TLR9 RefSeq# NM_017442.2.…”

Section: Methodsmentioning

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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“…24 This observation has been shown chronically as well, with impaired endothelial responses through day 14 after DVT in a rodent model. 25 The endothelium is critical for normal vessel homeostasis, primarily maintaining an anticoagulant state by nitric oxide release, thrombomodulin expression, and antithrombin binding sites. 26 …”

Section: Pathophysiology Of Pts: Clinical Observations and Experimentmentioning

confidence: 99%

An update on etiology, prevention, and therapy of postthrombotic syndrome

Henke

Comerota

2011

Journal of Vascular Surgery

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Postthrombotic syndrome is a common sequelae resulting from deep venous thrombosis. The primary interventions are prevention and treatment, both of which many vascular specialists may not always recognize. We review the definition, epidemiology, the basic pathophysiology, and preventative management for postthrombotic syndrome. The current primary medical and interventional treatment modalities to decrease the occurrence of postthrombotic syndrome are also highlighted. Many of these treatments are currently available and simply need to be adhered to, whereas others are a shift in the paradigm, focusing on active thrombus removal.

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Vein wall re-endothelialization after deep vein thrombosis is improved with low-molecular-weight heparin

Cited by 35 publications

References 43 publications

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

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

Postthrombotic vein wall remodeling: Preliminary observations

An update on etiology, prevention, and therapy of postthrombotic syndrome

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