See also Deguchi H, Elias DJ, Griffin JH. Gain in translation: heme oxygenase-1 induced by activated protein C promotes thrombus resolution. This issue, pp 90–2.
Activated protein C accelerates venous thrombus resolution through heme oxygenase-1 induction
Article first published online: 9 JAN 2014
© 2013 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 12, Issue 1, pages 93–102, January 2014
How to Cite
Activated protein C accelerates venous thrombus resolution through heme oxygenase-1 induction. J Thromb Haemost 2014; 12: 93–102., , , , , , , , .
Manuscript handled by: W. Ruf
Final decision: P. H. Reitsma, 22 September 2013
- Issue published online: 9 JAN 2014
- Article first published online: 9 JAN 2014
- Accepted manuscript online: 3 OCT 2013 10:21AM EST
- Manuscript Received: 8 MAY 2013
- National Institutes of Health. Grant Numbers: HL054710, AI078365, HL083917
- heme oxygenase-1;
- protein C;
- thrombolytic therapy;
- venous thrombosis
Thrombus resolution is a complex process that involves thrombosis, leukocyte-mediated thrombolysis, and the final resolution of inflammation. Activated protein C (APC) is an anticoagulant that also possesses immunoregulatory activities.
In this study, we sought to examine the effects of APC administration on thrombus resolution using a mouse model of deep vein thrombosis by ligating the inferior vena cava (IVC).
The IVCs of C57BL/6 mice were ligated. Beginning on day 4 post IVC ligation, mice were injected intraperitoneally daily with APC, APC plus an heme oxygenase-1 (HO-1) inhibitor Sn-protoporphyrin IX (SnPP), SnPP alone, or vehicle control. At different time points following surgery, the thrombus-containing IVCs were weighed and then analyzed by use of biochemical assays and histology.
Venous thrombi reached maximum size on day 4 post ligation. The APC-treated group exhibited a significant reduction in thrombus weights on day 12 but not on day 7 compared with control mice. The enhanced thrombus resolution in APC-treated mice correlated with an increased HO-1 expression and a reduced interleukin-6 production. No significant difference was found in urokinase-type plasminogen activator, plasminogen activator inhibitor-1, or matrix metalloproteinase-2 and -9 between APC-treated and control mice. Coinjection of the HO-1 inhibitor SnPP abolished the ability of APC to enhance thrombus resolution.
Our data show that APC enhances the resolution of existing venous thrombi via a mechanism that is in part dependent on HO-1, suggesting that APC could be used as a potential treatment for patients with deep vein thrombosis to accelerate thrombus resolution.