Activity of thrombin-activatable fibrinolysis inhibitor in the plasma of patients with abdominal aortic aneurysm

Dubis, Joanna; Żuk, Natalia; Grendziak, Ryszard; Zapotoczny, Norbert; Pfanhauser, Monika; Witkiewicz, Wojciech

doi:10.1097/mbc.0000000000000028

Cited by 9 publications

(8 citation statements)

References 46 publications

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“…Previous studies have suggested that the activities of thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) play crucial roles in the initiation and development of deep venous thrombus ( 11 – 13 ). TAFI is an anti-fibrinolytic factor, lower levels of which have been associated with certain comorbidities, such as CVD ( 14 , 15 ). However, previous studies have demonstrated that the influence of genetic variations in the TAFI gene on the risk of CVD is inconclusive.…”

Section: Introductionmentioning

confidence: 99%

Rivaroxaban attenuates thrombosis by targeting the NF-κB signaling pathway in a rat model of deep venous thrombus

Wang

et al. 2017

Int J Mol Med

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Anticoagulant therapy is commonly used for the prevention and treatment of patients with deep venous thrombus. Evidence has shown that rivaroxaban is a potential oral anticoagulant drug for the acute treatment of venous thromboembolism. However, the rivaroxaban-mediated molecular mechanism involved in the progression of deep venous thrombosis has not been investigated. In the present study, we investigated the efficacy of rivaroxaban and the underlying signaling pathways in the prevention and treatment of rats with deep venous thrombosis. A rat model with deep vein thrombus formation was established and received treatment with rivaroxaban or PBS as control. The thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) were analyzed both in vitro and in vivo. The progression of thrombosis and stroke was evaluated after treatment with rivaroxaban or PBS. Nuclear factor-κB (NF-κB) signaling pathway in venous endothelial cells and in the rat model of deep venous thrombus was assessed. The therapeutic effects of rivaroxaban were evaluated as determined by changes in deep venous thrombosis in the rat model. Our results showed that rivaroxaban markedly inhibited TAFI and PAI-1 expression levels, neutrophils, tissue factor, neutrophil extracellular traps (NETs), myeloperoxidase and macrophages in venous endothelial cells and in the rat model of deep venous thrombus. Expression levels of ADP, PAIs, von Willebrand factor (vWF) and thromboxane were downregulated in vein endothelial cells and in serum from the experimental rats. Importantly, the incidences of inferior vena cava filter thrombus were protected by rivaroxaban during heparin-induced thrombolysis deep venous thrombosis in the rat model. We observed that activity of the NF-κB signaling pathway was inhibited by rivaroxaban in vein endothelial cells both in vitro and in vivo. Notably, immunohistology indicated that rivaroxaban attenuated deep venous thrombosis and the accumulation of inflammatory factors in the lesions in venous thrombus. Matrix metalloproteinase (MMP) expression and activity were downregulated in rivaroxaban-treated rats with deep venous thrombus. Rivaroxaban inhibited the elasticity of the extracellular matrix and collagen-elastin fibers. On the whole, these results indicate that rivaroxaban attenuates deep venous thrombus through MMP-9-mediated NF-κB signaling pathway.

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Section: Introductionmentioning

confidence: 99%

Rivaroxaban attenuates thrombosis by targeting the NF-κB signaling pathway in a rat model of deep venous thrombus

Wang

et al. 2017

Int J Mol Med

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“…Tissue plasminogen activator (tPA) is an effective drug approved by US FDA for the treatment of ischemic stroke, and it exhibits pleiotropic effects in addition to thrombolysis (10). Thrombin-activatable fibrinolysis inhibitor (TAFI) is also an anti-fibrinolytic factor with an increased risk of cerebral infarction as the levels of plasma TAFI increase (11,12). Previous studies have suggested that TAFI and plasminogen activator inhibitor (PAI)-1serve crucial roles in the initiation and development of deep cerebral infarction (13,14).…”

Section: Introductionmentioning

confidence: 99%

Aspirin ameliorates cerebral infarction through regulation of TLR4/NF‑κB‑mediated endoplasmic reticulum stress in mouse model

et al. 2017

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Cerebral infarction is a cerebrovascular disease caused by local brain ischemic necrosis or softening, which is associated with diabetes, obesity, hypertension and rheumatic heart arrhythmia. Previous studies have indicated that aspirin is a potential oral anticoagulant in the treatment of cerebral ischemic stroke. However, the potential mechanism mediated by aspirin in cerebral infarction therapy is not well understood. The present study analyzed the therapeutic effects of aspirin on cerebral infarction and investigated the underlying molecular mechanism of aspirin‑ameliorated benefits for thrombolysis. The results demonstrated that aspirin inhibited inflammation and apoptosis of cerebrovascular endothelial cells in a mouse model of cerebral infarction. Aspirin treatment suppressed toll‑like receptor (TLR)4 and nuclear factor (NF)‑κB expression in cerebrovascular endothelial cells. Endoplasmic reticulum (ER) stress was suppressed by aspirin treatment through the downregulation of protein kinase R‑like endoplasmic reticulum kinase, eukaryotic translation initiation factor 2 subunit 1 and C/EBP homologous protein expression levels in cerebrovascular endothelial cells. It was identified that knockdown of TLR4 inhibited aspirin‑mediated downregulation of NF‑κB signaling pathway and ER stress in cerebrovascular endothelial cells. Expression levels of adenosine diphosphate plasminogen activator inhibitors, von Willebrand factor and thromboxane were downregulated in cerebrovascular endothelial cells and in serum in experimental mice. The results demonstrated that aspirin was beneficial forthrombolysis by decreasing thrombin‑activatable fibrinolysis inhibitor and plasminogen activator inhibitor‑1 expression in a mouse model of cerebral infarction. These results suggested that aspirin may improve cerebral infarction by downregulating TLR4/NF‑κB‑mediated ER stress in a mouse model.

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“…There are only two previous studies on TAFI in human AAA disease. In a small cohort study, Dubis et al demonstrated decreased TAFI activity in AAA patients [26]. In another study, TAFIa levels were high in patients with ruptured and non-ruptured AAA, although no control group was included [27].…”

Section: Introductionmentioning

confidence: 98%

Thrombin‐activatable fibrinolysis inhibitor in human abdominal aortic aneurysm disease

Bridge

Bollen

Zhong

et al. 2017

Journal of Thrombosis and Haemostasis

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Patients with abdominal aortic aneurysms (AAA) develop dense clots that are resistant to lysis. This study explores the role of thrombin‐activatable fibrinolysis inhibitor (TAFI) in human AAA. There is evidence of chronically increased TAFI activation in patients with AAA. TAFI may represent a pharmacological target for cardiovascular risk reduction in AAA. Summary BackgroundIntra‐luminal thrombosis is a key factor in growth of abdominal aortic aneurysms (AAAs). Patients with AAA form dense clots that are resistant to fibrinolysis. Thrombin‐activatable fibrinolysis inhibitor (TAFI) has been shown to influence AAA development in murine models. ObjectiveThe aim of this study is to characterize the role of TAFI in human AAA. MethodsPlasma levels of TAFI, TAFI activation peptide (TAFI‐AP), activated/inactivated TAFI (TAFIa/ai) and plasmin‐α2‐antiplasmin complex were measured by ELISAs in patients with AAA (n = 202) and controls (n = 188). ResultsTAFIa/ai and TAFI‐AP levels were higher in patients than controls (median [IQR], 20.3 [14.6–32.8] ng mL−1 vs. 14.2 [11.2–19.3] ng mL−1 and 355.0 [232.4–528.1] ng mL−1 vs. 248.6 [197.1–328.1] ng mL−1). TAFIa/ai was positively correlated with TAFI‐AP (r = 0.164). Intact TAFI levels were not different between patients and controls (13.4 [11.2–16.1] μg mL−1 vs. 12.8 [10.6–15.4] μg mL−1). Plasmin‐α2‐antiplasmin was higher in AAA patients than controls (690.0 [489.1–924.3] ng mL−1 vs. 480.7 [392.6–555.3] ng mL−1). ConclusionsThe increase in TAFIa/ai and TAFI‐AP suggests an increased TAFI activation in patients with AAA. Prospective studies are required to further elucidate the role of TAFI and fibrinolysis in AAA pathogenesis.

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Activity of thrombin-activatable fibrinolysis inhibitor in the plasma of patients with abdominal aortic aneurysm

Cited by 9 publications

References 46 publications

Rivaroxaban attenuates thrombosis by targeting the NF-κB signaling pathway in a rat model of deep venous thrombus

Rivaroxaban attenuates thrombosis by targeting the NF-κB signaling pathway in a rat model of deep venous thrombus

Aspirin ameliorates cerebral infarction through regulation of TLR4/NF‑κB‑mediated endoplasmic reticulum stress in mouse model

Thrombin‐activatable fibrinolysis inhibitor in human abdominal aortic aneurysm disease

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