Urokinase plasminogen activator independent early experimental thrombus resolution: MMP2 as an alternative mechanism

• DOI: 10.1160/th10-03-0184
• Publication Date: 2010-10-01T09:22:13Z
• Authors: Vikram Sood; Catherine E. Luke; Joseph Baldwin; Erin M. Miller; Megan Elfline; Gilbert R. Upchurch; Thomas W. Wakefield; Peter K. Henke
• Keywords: MMP2

Summary Deep-vein thrombosis (DVT) resolution is thought to be primarily a urokinase plasminogen activator (uPA) -dependent mechanism, although observations suggest other non-fibrinolytic mechanisms may exist. We explored the role of matrix metalloproteinase (MMP) -2 and –9 in early DVT uPA-deficient mice. Male B6/SVEV (WT) genetically matched uPA -/- mice underwent inferior vena cava (IVC) ligation create stasis venous thrombi, with IVC thrombus harvest. Thrombus size was similar between WT at day 4, suggesting non uPA-dependent resolution. Intrathrombus neutrophils monocytes were reduced 3- 3.5-fold as compared WT. By ELISA, tumour necrosis factor α interleukin 1β not altered, while interferon (IFN)γ significantly elevated A compensatory increase tPA observed, plasmin activity PAI-1 2.5-fold Active MMP2, but MMP9, 3-fold uPA-/- well MMP-14, an MMP2 activator. Collagen type IV fibrinogen thrombi IFNγ induces blockade associated larger active Consistently, had VT controls, despite normal levels. Taken together, experimental independent uPA, and, part, inflammatory cell influx. MMP2-dependent thrombolysis important mechanism resolution, possibly by collagen metabolism, represent exploitable therapeutic avenue.