Thrombus resolution of DVT hampered by IFN-gamma
MedWire News: Interferon (IFN)-gamma may be associated with increased thrombus size and may delay thrombus resolution in deep vein thrombosis (DVT), say Japanese scientists who suggest it may represent a molecular target for the prevention of thromboembolism.
Previous studies have implied that proinflammatory cytokines such as tumor necrosis factor-α are linked to thrombus formation and resolution in DVT, but there has been little evidence on the potential role of IFN-γ, which is known to be involved in skin wound healing.
Mizuho Nosaka, from Wakayama Medical University, and colleagues therefore studied six wild type (WT) and six age- and gender-matched IFN-gamma-deficient mice, performing ligation of the inferior vena cava to induce DVT. The experiment was repeated at least three times.
As the postligation interval continued, intrathrombotic IFN- γ levels increased progressively in WT mice. WT mice had substantially larger thrombus sizes at 10 and 14 days, compared with IFN-γ-deficient mice, and intrathrombotic collage content was markedly increased beyond 10 days.
Interestingly, the team reports in the Journal of Clinical Investigation that the expression and activity of matrix metalloproteinase (MMP)-9 was higher in the late phase in IFN-γ-deficient mice compared with WT mice, although MMP-2 was unaffected. Compared with WT mice, IFN-γ-deficient mice had increased intrathrombotic recanalization, coupled with increased vascular endothelial growth factor (VEGF) gene expression.
It was also observed that IFN-γ/Stat1 pathway activation suppressed phorbol 12-myristate 13-acetate-induced MMP-9 and VEGF gene expression in peritoneal macrophages. Importantly, thrombus resolution in WT mice was enhanced by administration of anti-IFN-γ monoclonal antibodies.
The team writes: "At present, warfarin is mainly employed against DVT to prevent pulmonary thromboembolism, but this anticoagulation therapy increases the risk of bleeding."
They add: "IFN-γ blockade… accelerated thrombus resolution without any effects on coagulation function, even if given after thrombus formation. Thus, IFN-γ may be a novel molecular target for the development of therapies that accelerate thrombus resolution in patients with DVT."
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By Liam Davenport