Tie2 protects the vasculature against thrombus formation in systemic inflammation
Sarah J. Higgins, … , Robert Flaumenhaft, Samir M. Parikh
Sarah J. Higgins, … , Robert Flaumenhaft, Samir M. Parikh
Published January 23, 2018
Citation Information: J Clin Invest. 2018;128(4):1471-1484. https://doi.org/10.1172/JCI97488.
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Research Article Hematology Vascular biology

Tie2 protects the vasculature against thrombus formation in systemic inflammation

Abstract

Disordered coagulation contributes to death in sepsis and lacks effective treatments. Existing markers of disseminated intravascular coagulation (DIC) reflect its sequelae rather than its causes, delaying diagnosis and treatment. Here we show that disruption of the endothelial Tie2 axis is a sentinel event in septic DIC. Proteomics in septic DIC patients revealed a network involving inflammation and coagulation with the Tie2 antagonist, angiopoietin-2 (Angpt-2), occupying a central node. Angpt-2 was strongly associated with traditional DIC markers including platelet counts, yet more accurately predicted mortality in 2 large independent cohorts (combined N = 1,077). In endotoxemic mice, reduced Tie2 signaling preceded signs of overt DIC. During this early phase, intravital imaging of microvascular injury revealed excessive fibrin accumulation, a pattern remarkably mimicked by Tie2 deficiency even without inflammation. Conversely, Tie2 activation normalized prothrombotic responses by inhibiting endothelial tissue factor and phosphatidylserine exposure. Critically, Tie2 activation had no adverse effects on bleeding. These results mechanistically implicate Tie2 signaling as a central regulator of microvascular thrombus formation in septic DIC and indicate that circulating markers of the Tie2 axis could facilitate earlier diagnosis. Finally, interventions targeting Tie2 may normalize coagulation in inflammatory states while averting the bleeding risks of current DIC therapies.

Authors

Sarah J. Higgins, Karen De Ceunynck, John A. Kellum, Xiuying Chen, Xuesong Gu, Sharjeel A. Chaudhry, Sol Schulman, Towia A. Libermann, Shulin Lu, Nathan I. Shapiro, David C. Christiani, Robert Flaumenhaft, Samir M. Parikh

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Figure 7

Tie2 activation normalizes the septic thrombotic response to injury without increasing bleeding risk.

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Tie2 activation normalizes the septic thrombotic response to injury with...
Representative binarized images of thrombus formation (A) following laser injury in mice injected with control adenovirus (CtlAdv) (top) or an adenovirus expressing Angpt-1 (AdAngpt-1) after LPS injection (1–3 hours) (platelets = red; fibrin = green). Scale bar: 10 μm. Median integrated platelet (B) and fibrin (D) fluorescence intensities and AUC (C and E) were calculated for individual thrombi, CtlAdv (n = 2; 33 thrombi), CtlAdv plus LPS (n = 3; 37 thrombi), AdAngpt-1 (n = 3; 38 thrombi), and Angpt-1 plus LPS (n = 3; 37 thrombi). (F) Time to bleeding cessation (seconds) in CtlAdv and AdAngpt-1 mice 3 hours after LPS challenge (n = 18 or 19 mice). (G) The number of re-bleeding events during 10-minute observation window stratified as follows: 0, 1–3, or 4 or more events. Representative immunoblot (H) and quantification (I) of fibrin in liver isolates relative to pan cadherin. (J) Relative change in TAT complex levels at 3 hours after LPS challenge in CtlAdV- and AdAngpt-1–treated mice. Angpt-2 levels in (K) plasma and (L) lungs of CtlAdV or AdAngpt-1 mice after LPS (n = 5 per group). *P < 0.05, **P < 0.01 by 1-way ANOVA. (M) Representative immunoblots of p-Tie2 (p-Tie2Y992) and total Tie2 levels in lung isolates.