scholarly journals Interleukin-1β Mediates Arterial Thrombus Formation via NET-Associated Tissue Factor

2019 ◽  
Vol 8 (12) ◽  
pp. 2072 ◽  
Author(s):  
Luca Liberale ◽  
Erik W. Holy ◽  
Alexander Akhmedov ◽  
Nicole R. Bonetti ◽  
Fabian Nietlispach ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Plasma Levels ◽  
Thrombus Formation ◽  
Mechanistic Explanation ◽  
Multicenter Trial ◽  
Coagulation Cascade ◽  
Reactive Protein ◽  
Arterial Thrombus ◽  
Activated Neutrophils ◽  
Potential Link

CANTOS reported reduced secondary atherothrombotic events in patients with residual inflammatory risk treated with the inhibitory anti-IL-1β antibody, Canakinumab. Yet, mechanisms that underlie this benefit remain elusive. Recent work has implicated formation of neutrophil extracellular traps (NETosis) in arterial thrombosis. Hence, the present study explored the potential link between IL-1β, NETs, and tissue factor (TF)—the key trigger of the coagulation cascade—in atherothrombosis. To this end, ST-elevation myocardial infarction (STEMI) patients from the Swiss multicenter trial SPUM-ACS were retrospectively and randomly selected based on their CRP levels. In particular, 33 patients with STEMI and high C-reactive protein (CRP) levels (≥ 10 mg/L) and, 33 with STEMI and low CRP levels (≤ 4 mg/L) were investigated. High CRP patients displayed elevated circulating IL-1β, NETosis, and NET-associated TF plasma levels compared with low CRP ones. Additionally, analysis of patients stratified by circulating IL-1β levels yielded similar results. Moreover, NETosis and NET-associated TF plasma levels correlated positively in the whole population. In addition to the above, translational research experiments provided mechanistic confirmation for the clinical data identifying IL-1β as the initial trigger for the release of the pro-coagulant, NET-associated TF. In conclusion, blunted TF presentation by activated neutrophils undergoing NETosis may provide a mechanistic explanation to reduced secondary atherothrombotic events as observed in canakinumab-treated patients in CANTOS.

scholarly journals Dietary α-Linolenic Acid Inhibits Arterial Thrombus Formation, Tissue Factor Expression, and Platelet Activation

2011 ◽  
Vol 31 (8) ◽  
pp. 1772-1780 ◽  
Author(s):  
Erik W. Holy ◽  
Marc Forestier ◽  
Eva K. Richter ◽  
Alexander Akhmedov ◽  
Florian Leiber ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Linolenic Acid ◽  
Platelet Activation ◽  
Thrombus Formation ◽  
Tissue Factor Expression ◽  
Arterial Thrombus ◽  
Factor Expression

scholarly journals Increased tissue factor expression on circulating monocytes in chronic HIV infection: relationship to in vivo coagulation and immune activation

Blood ◽  
2010 ◽  
Vol 115 (2) ◽  
pp. 161-167 ◽  
Author(s):  
Nicholas T. Funderburg ◽  
Elizabeth Mayne ◽  
Scott F. Sieg ◽  
Robert Asaad ◽  
Wei Jiang ◽  
...  
Keyword(s):  
Hiv Infection ◽  
Tissue Factor ◽  
Immune Activation ◽  
Interleukin 6 ◽  
Plasma Levels ◽  
Thrombus Formation ◽  
Hiv Replication ◽  
Increased Risk

Abstract HIV infection is associated with an increased risk of thrombosis; and as antiretroviral therapy has increased the lifespan of HIV-infected patients, their risk for cardiovascular events is expected to increase. A large clinical study found recently that all-cause mortality for HIV+ patients was related to plasma levels of interleukin-6 and to D-dimer products of fibrinolysis. We provide evidence that this elevated risk for coagulation may be related to increased proportions of monocytes expressing cell surface tissue factor (TF, thromboplastin) in persons with HIV infection. Monocyte TF expression could be induced in vitro by lipopolysaccharide and flagellin, but not by interleukin-6. Monocyte expression of TF was correlated with HIV levels in plasma, with indices of immune activation, and with plasma levels of soluble CD14, a marker of in vivo lipopolysaccharide exposure. TF levels also correlated with plasma levels of D-dimers, reflective of in vivo clot formation and fibrinolysis. Thus, drivers of immune activation in HIV disease, such as HIV replication, and potentially, microbial translocation, may activate clotting cascades and contribute to thrombus formation and cardiovascular morbidities in HIV infection.

scholarly journals Tissue factor–positive neutrophils bind to injured endothelial wall and initiate thrombus formation

Blood ◽  
2012 ◽  
Vol 120 (10) ◽  
pp. 2133-2143 ◽  
Author(s):  
Roxane Darbousset ◽  
Grace M. Thomas ◽  
Soraya Mezouar ◽  
Corinne Frère ◽  
Rénaté Bonier ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Blood Coagulation ◽  
Thrombus Formation ◽  
Coagulation Cascade ◽  
Factor Xii ◽  
Long Time ◽  
Platelet Accumulation

AbstractFor a long time, blood coagulation and innate immunity have been viewed as interrelated responses. Recently, the presence of leukocytes at the sites of vessel injury has been described. Here we analyzed interaction of neutrophils, monocytes, and platelets in thrombus formation after a laser-induced injury in vivo. Neutrophils immediately adhered to injured vessels, preceding platelets, by binding to the activated endothelium via leukocyte function antigen-1–ICAM-1 interactions. Monocytes rolled on a thrombus 3 to 5 minutes postinjury. The kinetics of thrombus formation and fibrin generation were drastically reduced in low tissue factor (TF) mice whereas the absence of factor XII had no effect. In vitro, TF was detected in neutrophils. In vivo, the inhibition of neutrophil binding to the vessel wall reduced the presence of TF and diminished the generation of fibrin and platelet accumulation. Injection of wild-type neutrophils into low TF mice partially restored the activation of the blood coagulation cascade and accumulation of platelets. Our results show that the interaction of neutrophils with endothelial cells is a critical step preceding platelet accumulation for initiating arterial thrombosis in injured vessels. Targeting neutrophils interacting with endothelial cells may constitute an efficient strategy to reduce thrombosis.

Sirtuin 5 promotes arterial thrombosis by blunting the fibrinolytic system

2020 ◽  
Author(s):  
Luca Liberale ◽  
Alexander Akhmedov ◽  
Nikolaos I Vlachogiannis ◽  
Nicole R Bonetti ◽  
Vanasa Nageswaran ◽  
...  
Keyword(s):  
Arterial Thrombosis ◽  
Mononuclear Cells ◽  
Thrombus Formation ◽  
Fibrinolytic System ◽  
Coagulation Cascade ◽  
Total N ◽  
Coronary Syndrome ◽  
Arterial Thrombus ◽  
Gene And Protein Expression ◽  
Pai 1

Abstract Aims Arterial thrombosis as a result of plaque rupture or erosion is a key event in acute cardiovascular events. Sirtuin 5 (SIRT5) belongs to the lifespan-regulating sirtuin superfamily and has been implicated in acute ischaemic stroke and cardiac hypertrophy. This project aims at investigating the role of SIRT5 in arterial thrombus formation. Methods and results Sirt5 transgenic (Sirt5Tg/0) and knock-out (Sirt5−/−) mice underwent photochemically induced carotid endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) were treated with SIRT5 silencing-RNA (si-SIRT5) as well as peripheral blood mononuclear cells from acute coronary syndrome (ACS) patients and non-ACS controls (case–control study, total n = 171) were used to increase the translational relevance of our data. Compared to wild-type controls, Sirt5Tg/0 mice displayed accelerated arterial thrombus formation following endothelial-specific damage. Conversely, in Sirt5−/− mice, arterial thrombosis was blunted. Platelet function was unaltered, as assessed by ex vivo collagen-induced aggregometry. Similarly, activation of the coagulation cascade as assessed by vascular and plasma tissue factor (TF) and TF pathway inhibitor expression was unaltered. Increased thrombus embolization episodes and circulating D-dimer levels suggested augmented activation of the fibrinolytic system in Sirt5−/− mice. Accordingly, Sirt5−/− mice showed reduced plasma and vascular expression of the fibrinolysis inhibitor plasminogen activator inhibitor (PAI)-1. In HAECs, SIRT5-silencing inhibited PAI-1 gene and protein expression in response to TNF-α. This effect was mediated by increased AMPK activation and reduced phosphorylation of the MAP kinase ERK 1/2, but not JNK and p38 as shown both in vivo and in vitro. Lastly, both PAI-1 and SIRT5 gene expressions are increased in ACS patients compared to non-ACS controls after adjustment for cardiovascular risk factors, while PAI-1 expression increased across tertiles of SIRT5. Conclusion SIRT5 promotes arterial thrombosis by modulating fibrinolysis through endothelial PAI-1 expression. Hence, SIRT5 may be an interesting therapeutic target in the context of atherothrombotic events.

The impact of factor Xa inhibition on axial dependent arterial thrombus formation triggered by a tissue factor rich surface

2011 ◽  
Vol 33 (1) ◽  
pp. 6-15 ◽  
Author(s):  
Nicholas Pugh ◽  
Gavin E. Jarvis ◽  
Annelize Koch ◽  
Kjell S. Sakariassen ◽  
Bill Davis ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Thrombus Formation ◽  
Factor Xa ◽  
Arterial Thrombus ◽  
Factor Xa Inhibition ◽  
The Impact

scholarly journals Amiodarone Inhibits Arterial Thrombus Formation and Tissue Factor Translation

2008 ◽  
Vol 28 (12) ◽  
pp. 2231-2238 ◽  
Author(s):  
A. Breitenstein ◽  
S.F. Stämpfli ◽  
G.G. Camici ◽  
A. Akhmedov ◽  
H.R. Ha ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Thrombus Formation ◽  
Arterial Thrombus

scholarly journals Tissue Factor Pathway Inhibitor and Thrombin Activatable Fibrinolytic Inhibitor Plasma Levels following Burnand Septic Injuries in Rats

2004 ◽  
Vol 10 (4) ◽  
pp. 379-385 ◽  
Author(s):  
Thyyar M. Ravindranath ◽  
Masakatsu Goto ◽  
Muzaffer Demir ◽  
Mahmut Tobu ◽  
M. Florian Kujawski ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Plasma Levels ◽  
Tissue Factor Pathway Inhibitor ◽  
Burn Injury ◽  
Coagulation Cascade ◽  
Clinical Model ◽  
Coagulation Status ◽  
Tissue Factor Pathway ◽  
Caecal Ligation And Puncture ◽  
Combined Injuries

Burn and septic injuries induce profound changes in coagulation status. This study examined the changes in plasma tissue factor pathway inhibitor (TFPI) and thrombin activatable fibrinolytic inhibitor (TAFI) levels in a rat model of burn and septic injuries. Rats underwent 30% TBSA cutaneous scald burn injury and septic insult was induced by caecal ligation and puncture (CLP). CLP was superimposed on burn injury to mimic the clinical model of sepsis complicating burn injury. Rats were pretreated with Cprofloxacin orally to colonize their gut with Enterococcus faecalis. TFPI and TAFI plasma levels were measured using functional activity assay kit with a chromogenic method at 24 and 72 hours following the injuries. TFPI levels decreased significantly at 24 hours in burn, CLP, and burn+CLP groups, followed by incomplete rebound recovery at 72 hours in all three groups. On the other hand, TAFI levels increased significantly at 24- and 72-hour time points in all three groups. These results suggest that burn, septic, and their combined injuries perturb coagulation cascade and thrombotic process toward the procoagulant pathway by impairing fibrinolysis.

Iohexol, platelet activation and thrombosis

1998 ◽  
Vol 39 (4) ◽  
pp. 355-361 ◽  
Author(s):  
K. S. Sakariassen ◽  
M. Buchmann ◽  
M. J. A. G. Hamers ◽  
H. Stormorken
Keyword(s):  
Tissue Factor ◽  
Platelet Activation ◽  
Thrombus Formation ◽  
Initial Study ◽  
Human Model ◽  
Thrombotic Risk ◽  
Arterial Thrombus ◽  
Radiographic Contrast ◽  
Radiographic Contrast Media

Background: There is a dispute about the potential effects of radiographic contrast media (CM) on thrombogenesis. The nonionic CM iohexol triggers platelet β-thromboglobulin (β-TG) secretion, and thus may activate the platelets and promote thrombosis. We addressed this topic in a study employing a human model of arterial thrombus formation in the presence of aspirin and heparin. This was a follow-up to our initial study (on thrombus formation in native blood) which did not include antithrombotic drugs. The nonionic CM iohexol (monomer) and iodixanol (dimer) and the ionic CM ioxaglate (dimer) were compared. Methods and Results: Thrombus formation was triggered by a surface rich in either collagen or tissue factor, positioned in a parallel-plate perfusion chamber device at an arterial wall shear rate of 2600 s−1. Blood from healthy volunteers, following ingestion of 1 g aspirin, was mixed with 40 vol% CM and 2.0 IU/ml heparin and passed over the surfaces. Thrombus formation in the presence of either CM showed no difference, despite the fact that iohexol triggered a pronounced platelet β-TG secretion; iodixanol or ioxaglate were virtually inert. Conclusion: There was no association between iohexol-induced β-TG secretion and thrombus formation on collagen (platelet-driven) or on tissue factor (thrombin-driven) in the presence of a standard antithrombotic regimen of aspirin and heparin as used in the clinic. The notion of a thrombotic risk due to platelet activation by iohexol was thus not substantiated by this study.

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