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 4

Endotoxemic mice develop increased thrombotic response before the onset of overt DIC.

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Endotoxemic mice develop increased thrombotic response before the onset ...
(A) Representative binarized images of thrombus formation in response to laser injury in cremaster arterioles of mice exposed to saline or LPS (10 mg/kg) for 1–3 hours. Platelet accumulation (red, Dylight 649) and fibrin generation (green, Dylight 488) were visualized for 180 seconds following injury. Scale bar: 10 μm. Median integrated fluorescence intensity and area under the curve (AUC) were calculated for platelets (B and C) and fibrin (D and E). (C and E) Data are represented as the median AUC of individual thrombi (saline n = 36; LPS n = 34). *P < 0.05; ***P < 0.001, Mann-Whitney U test. PAR4-mediated platelet aggregation was measured in platelet-rich plasma obtained from C57BL/6J mice 3 hours after saline or LPS injection showing (F) quantification of aggregation and (G) a representative aggregation experiment of 3 independent experiments (saline = gray tracing; LPS = red tracing). (H) Platelet-factor 4 (PF4) levels were measured in plasma of C57BL/6J mice at 0 or 3 hours after LPS (10 mg/kg) (n = 9–11). Mann-Whitney U test.