The tissue plasminogen activator and urokinase response in vivo during natural resolution of venous thrombus

Northeast, A.; Soo, Kenneth; Bobrow, Linda G.; Gaffney, Patrick J.; Burnand, K. G.

doi:10.1016/s0741-5214(95)70041-2

Cited by 48 publications

(48 citation statements)

References 36 publications

(8 reference statements)

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“…Indeed, the ratio of thrombus uPA to PAI-1 was elevated in the CCR2 Ϫ/Ϫ mice but was normalized with the addition of IFN-␥ (possibly because of restored MMP-9 activity). We speculate that later differences in DVT resolution associated with significantly fewer uPA ϩ cells in the CCR2 Ϫ/Ϫ mice (at 8 and 12 days) were probably secondary to impaired monocyte influx, because monocytes are primary sources of uPA (26,27). It is also unlikely that the CCR2 Ϫ/Ϫ mice had any intrinsic procoagulant or fibrinolytic defects, given that as baseline clotting parameters were similar.…”

Section: Discussionmentioning

confidence: 88%

“…Monocytes release and direct smooth muscle cell proangiogenic mediator release, uPA, as well as MMP activity (5,8,26,45). In support of this contention is that Ab inhibition and genetic deletion of IFN-␥ did not impair DVT resolution, probably because these thrombi had a normal content of F4/80 and CCR2 ϩ cells.…”

Section: Discussionmentioning

confidence: 92%

“…The pathobiology of angiogenesis also involves CCR2 signaling (13,24,25). Fibrinolysis of venous thrombi is thought to be primarily mediated by urokinase plasminogen activator (uPA) from monocytic cells (26), as evidenced from impaired venous thrombus resolution in mice lacking uPA but not tissue-type plasminogen activator (27). Linked to the plasminogen activators are the matrix metalloproteinases (MMP), particularly MMP-2 and MMP-9, and which modulate collagen and matrix turnover in vessel wall remodeling and early wound healing (6,28,29).…”

Section: Eep Vein Thrombosis (Dvt)mentioning

confidence: 99%

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Targeted Deletion of CCR2 Impairs Deep Vein Thombosis Resolution in a Mouse Model

Henke

Pearce

Moaveni

et al. 2006

The Journal of Immunology

111

177

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CCR2 is required for monocyte recruitment in many inflammatory processes, as well as conferring Th1 lymphokine responses. Deep vein thrombosis (DVT) resolution represents a specific inflammatory response whereby the thrombus must be dissolved for restoration of blood flow. Using a stasis model of DVT in the mouse, we investigated the role of CCR2 on DVT resolution. Genetic deletion of CCR2 (CCR2−/−) was associated with larger thrombi at early and later time points, increased thrombus collagen, fewer thrombus monocytes (F4/80), and significantly impaired neovascularization. IL-2 and IFN-γ were significantly reduced in early CCR2−/− thrombi, whereas MCP-1 was significantly increased, and Th2 lymphokines were unaffected. Supplementation of CCR2−/− mice with IFN-γ normalized early thrombus resolution without increasing monocyte influx. Neither Ab depletion of IFN-γ nor genetic deletion of IFN-γ impaired early DVT resolution. Early fibrinolysis was not impaired in CCR2−/− mice, but a significant reduction in both matrix metalloproteinase (MMP)-2 and MMP-9 activity was observed. However, only MMP-9 activity was restored with administration of IFN-γ. We conclude that an early CCR2-dependent Th1 lymphokine response predominates in normal DVT resolution, mediates this in part by MMP-9 activation, but is not solely dependent on IFN-γ.

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Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 92%

Section: Eep Vein Thrombosis (Dvt)mentioning

confidence: 99%

See 1 more Smart Citation

Targeted Deletion of CCR2 Impairs Deep Vein Thombosis Resolution in a Mouse Model

Henke

Pearce

Moaveni

et al. 2006

The Journal of Immunology

111

177

View full text Add to dashboard Cite

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“…Monocytes enter the thrombus as resolution proceeds, and injection of monocyte chemotactic protein-1 into the thrombus results in enhanced resolution. 13 We have also shown that the thrombus contains increasing quantities of both tPA and uPA activity as it resolves 14 and that this activity is expressed by invading monocytes. 15 These findings led us to speculate that monocytes orchestrate thrombus resolution and that this process is facilitated by the expression of both uPA and tPA.…”

mentioning

confidence: 81%

Failure of Thrombus to Resolve in Urokinase-Type Plasminogen Activator Gene–Knockout Mice

et al. 2003

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Background— Monocytes may have an important role in the resolution of venous thrombosis. Increased expression of tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) is associated with an ingress of monocytes into the thrombus. This study was designed to evaluate the importance of these activators in thrombus resolution. Methods and Results— Inferior caval vein thrombosis was induced in cohorts of adult wild-type, uPA gene-knockout (uPA −/− ), and tPA gene-knockout (tPA −/− ) mice in a flow model. Thrombi were harvested from wild-type and uPA −/− mice (n=60 per group) between 1 and 60 days. Thrombi were also obtained from groups of wild-type and tPA −/− mice (n=24 per group) between 1 and 28 days. Thrombus size and macrophage content were measured by computer-assisted image analysis. Thrombus resolution was significantly impaired in the uPA −/− mice compared with wild-type controls ( P <0.0001) but was unaffected in tPA −/− mice. Monocyte content in wild-type mice was highest at 14 days after thrombus induction and was ≈4 times greater than in uPA −/− mice ( P =0.0043). Thrombus size in uPA −/− mice transplanted with wild-type marrow (0.29±0.06 mm 2 ) was significantly smaller than in uPA −/− mice given uPA −/− bone marrow (3.9±1.1 mm 2 ) ( P =0.0022). Donor bone marrow–derived cells expressing LacZ were present in the thrombus after transplantation. Conclusions— The resolution of experimental venous thrombus is dependent on uPA but is unaffected by the absence of tPA. Absence of uPA is also associated with delayed monocyte recruitment into the thrombus. Transplanting wild-type bone marrow restores thrombus resolution in uPA −/− animals, suggesting an important role for bone marrow–derived cells in this process.

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“…These included an article by Professor Burnand on "the response of the vein wall to thrombosis. 5 " Professor Smith says, "His serendipitous finding was the presence of large numbers of mononuclear cells in thrombus, which appeared to be a rich source of plasminogen activators, in particular urokinase. The subsequent programme of work that he developed on the mechanisms that regulate thrombus resolution came from this article.…”

mentioning

confidence: 99%

European Perspectives

2013

Circulation

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The tissue plasminogen activator and urokinase response in vivo during natural resolution of venous thrombus

Cited by 48 publications

References 36 publications

Targeted Deletion of CCR2 Impairs Deep Vein Thombosis Resolution in a Mouse Model

Targeted Deletion of CCR2 Impairs Deep Vein Thombosis Resolution in a Mouse Model

Failure of Thrombus to Resolve in Urokinase-Type Plasminogen Activator Gene–Knockout Mice

European Perspectives

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