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Resolving deep vein thrombosis

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Science Translational Medicine  07 Aug 2019:
Vol. 11, Issue 504, eaay7696
DOI: 10.1126/scitranslmed.aay7696

Abstract

Inflammation-resolving lipid mediator resolvin D4 attenuates murine venous thrombosis.

Deep vein thrombosis (DVT) is a thromboinflammatory disease and a leading cause of disability and mortality due to the development of life-threatening pulmonary embolism. Delayed or incomplete thrombus resolution promotes the development of post-thrombotic syndrome (PTS), characterized by vascular thrombosis and lower extremity swelling. Management of acute DVT involves anticoagulation and thrombolysis; however, strategies to resolve persistent venous thrombi and restore blood flow to prevent PTS are limited. Current anticoagulants prevent recurrent thrombosis, but they are associated with an increased bleeding risk, do not lyse established thrombi, and cannot prevent PTS.

Specialized proresolving mediators (SPMs) are endogenous inflammation-resolving lipids associated with dampening inflammation, tissue remodeling, organ protection, host defense, and microbial clearance. SPMs are biologically active in the vasculature, yet their potential role(s) in venous thrombosis (VT) remain underinvestigated. Cherpokova and colleagues used a murine model of VT, surgically restricting blood flow to the inferior vena cava to identify SPMs biosynthesized during the progression of DVT. A second objective was to determine whether selected SPMs reduced VT burden, a key determinant of PTS development.

Using a targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS)–based metabololipidomics approach, the authors identified temporal clusters of endogenously biosynthesized SPMs, as well as proinflammatory and prothrombotic lipid mediators during DVT progression. Intravenous administration of resolvin D4 (RvD4), an SPM that was enriched at the natural onset of thrombus resolution, reduced thrombus burden and neutrophil infiltration, increasing proresolving monocytes in the thrombus. RvD4 further promoted the biosynthesis of other D-series resolvins implicated in resolving inflammation. Neutrophils from RvD4-treated mice showed reduced susceptibility to ionomycin-induced release of neutrophil extracellular traps (NETs), a meshwork of decondensed chromatin lined with histones and neutrophil proteins critical for DVT development.

The results of this study indicate that delivery of SPMs, specifically RvD4, can modulate the severity of thromboinflammatory disease, improving thrombus resolution. These findings have so far been limited to murine models, but they suggest the potential for development of proresolving therapies for human thromboinflammatory disease. Future studies will be required to investigate resolution biology in human DVT and assess for common mechanisms in vascular pathobiology between mice and humans. Researchers may also be able to identify clinical strategies harnessing endogenous resolution mechanisms for thromboinflammatory disease.

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