Premium
Activated protein C accelerates venous thrombus resolution through heme oxygenase‐1 induction
Author(s) -
Gabre J.,
Chabasse C.,
Cao C.,
Mukhopadhyay S.,
Siefert S.,
Bi Y.,
NetzelArnett S.,
Sarkar R.,
Zhang L.
Publication year - 2014
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12424
Subject(s) - thrombus , medicine , plasminogen activator , thrombosis , post thrombotic syndrome , thrombolysis , inferior vena cava , ligation , venous thrombosis , protein c , myocardial infarction
Summary Background 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. Aim 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 ). Methods The IVC s of C57 BL /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 (Sn PP ), Sn PP alone, or vehicle control. At different time points following surgery, the thrombus‐containing IVC s were weighed and then analyzed by use of biochemical assays and histology. Results 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 Sn PP abolished the ability of APC to enhance thrombus resolution. Conclusions 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.