Mast cells enhance venous thrombus stability and lung fibrin deposition in murine sepsis.

abstractVenous thromboembolism is a serious complication of sepsis despite standard thromboprophylaxis. Mast cells (MCs) promote deep vein thrombosis (DVT) in sterile murine models, but their contribution during sepsis remains unknown. We explored the role of MCs in DVT in lipopolysaccharide (LPS)-induced sepsis in mice. We show that LPS treatment does not alter DVT prevalence or size in control C57BL/6 mice but increases intrathrombus inflammatory mediators, including interleukin-1β (IL-1β) and citrullinated histone 3 (CitH3), a hallmark of neutrophil extracellular traps (NETs). MC ablation (KITW-sh mice) protected animals from sterile DVT for up to 1 week, whereas in endotoxemia settings, KITW-sh mice produced thrombi similar to controls. Thrombi from KITW-sh mice were more susceptible to lysis by a combination of tissue plasminogen activator and DNase I and contained less CitH3 than controls. Septic DVT exacerbated pulmonary thromboinflammation characterized by large fibrin deposits and high levels of CitH3 and IL-1β in control but not KITW-sh mice. MC deficiency during septic DVT was associated with decreased plasma angiopoietin-2 levels, suggesting improved endothelial stability and reduced vascular inflammation. Thus, in septic conditions, MCs are dispensable for thrombus initiation but promote NET-rich thrombus stability, resistance to lysis, and pulmonary thromboinflammation, the major life-threatening complication of DVT.