High thrombin activatable fibrinolysis inhibitor levels are associated with an increased risk of premature peripheral arterial disease

Bruijne, E.L.E. de; Gils, Ann; Rijken, D.C.; Maat, Moniek P.M. de; Guimarães, Ana H.C.; Poldermans, Don; Declerck, Paul; Leebeek, Frank W.G.

doi:10.1016/j.thromres.2010.11.026

Cited by 16 publications

(16 citation statements)

References 35 publications

(54 reference statements)

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“…Therefore, we selected for platelet stimulation ADP, collagen, thrombin and collagen/thrombin, where thrombin was used as control due to its frequent use to generate MPs in vitro [26]. Moreover, thrombin plays a key role in myocardial infarction [29], ischemic stroke [30] and peripheral arterial vascular disease [31]. Understanding how platelet interacts with thrombin has raised great interest also for the development of anti-platelet drugs [32].…”

Section: Introductionmentioning

confidence: 99%

Quantitative proteomics analysis of platelet-derived microparticles reveals distinct protein signatures when stimulated by different physiological agonists

Milioli

Ibáñez-Vea

Palmisano³

et al. 2015

Journal of Proteomics

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Section: Introductionmentioning

confidence: 99%

Quantitative proteomics analysis of platelet-derived microparticles reveals distinct protein signatures when stimulated by different physiological agonists

Milioli

Ibáñez-Vea

Palmisano³

et al. 2015

Journal of Proteomics

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“…Plasma TAFI levels have been reported to be elevated in several disease conditions, including acute pancreatitis, type 2 diabetes, rheumatoid arthritis, coronary heart disease, deep venous thrombosis and neoplastic diseases (3,(6)(7)(8)(9)14). In addition, several reports suggested alterations in the TAFI levels in IBD, in which the degree of intestinal inflammation and changes in the TAFI levels appears to be correlated (15,16).…”

Section: Discussionmentioning

confidence: 99%

“…Although hyperfibrinolysis and hypofibrinolysis have been demonstrated in patients with UC and CD, the role of the fibrinolytic system in patients with IBD remains controversial (22,23). In this context, TAFI is an important inhibitor of this system, which cleaves the lysine binding sites of partially degraded fibrin, interfering with the interaction between plasminogen and fibrin (6). Furthermore, TAFIa plays an important role in modulating inflammation with its ability to downregulate pericellular plasminogen activation and inactivation of bradykinin, thrombincleaved osteopontin and the anaphylatoxins C3a and C5a (24).…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have been performed to determine the TAFI levels in distinct disease states. Increased TAFI levels have been determined in conditions such as stable coronary artery disease, venous thrombosis, peripheral arterial disease, type 2 diabetes and acute pancreatitis (3,(6)(7)(8)(9), and decreased TAFI plasma levels have been described during acute promyelocytic leukemia and in chronic liver disease (10,11). Apart from its well-known effects on suppressing fibrinolysis, TAFIa may also be involved in inflammation by inactivating the anaphylatoxins C3a and C5a, thrombin-cleaved osteopontin and bradykinin (5).…”

Section: Introductionmentioning

confidence: 99%

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Plasma Thrombin-activatable Fibrinolysis Inhibitor Levels Correlate with the Disease Activity of Ulcerative Colitis

et al. 2016

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Objective Patients with ulcerative colitis (UC) are at an increased risk for thromboembolic events, particularly in patients with extensive and active disease. To date, a few studies have been published on the role of thrombin-activatable fibrinolysis inhibitor (TAFI) in UC. However, there are no reports in the literature investigating the effect of UC treatment on plasma TAFI levels. Methods The plasma TAFI antigen levels were quantitatively determined using ELISA kits for 20 UC patients at activation and remission, along with 17 healthy controls. The association between the TAFI levels and inflammatory markers was assessed to determine UC activation. To predict and determine the activation of UC, the Truelove-Witts index and the endoscopic activation index (EAI) were used for each subject. Results The plasma TAFI levels were higher in UC patients at activation of the disease compared with the remission state and in healthy controls. Spearman's correlation analyses revealed that the WBC (r: 0.586, p< 0.001), hsCRP (r: 0.593, p<0.001) and EAI (r: 0.721, p<0.001) were significantly correlated with the TAFI levels. The overall accuracy of TAFI in determining UC activation was 82.5% with a sensitivity, specificity, NPV and PPV of 80%, 85%, 81% and 84.2%, respectively (cut-off value: 156.2% and AUC: 0.879). Conclusion The present study demonstrates that the TAFI levels are elevated in the active state of UC. The assessment of TAFI levels in patients with UC in conjunction with other markers of inflammation may provide additional information for estimating UC activation and severity.

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“…7,8) Recent reports showed that a high level of TAFI expression in circulating plasma was a risk factor for thrombotic disorders. Thus, it was shown that elevated TAFI antigen in circulating plasma was a risk factor for premature peripheral arterial disease 9) and recurrent venous thromboembolism. 10) Moreover, TAFI antigen and functional protein levels in human plasma are significantly higher in the acute phase of ischemic stroke.…”

Section: )mentioning

confidence: 99%

PI3-Kinase Inhibitor LY294002 Repressed the Expression of Thrombin-Activatable Fibrinolysis Inhibitor in Human Hepatoma HepG2 Cells

Masuda

Yazawa

Makino

et al. 2015

Biological & Pharmaceutical Bulletin

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Thrombin-activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B-like proenzyme biosynthesized in the liver and released into the blood circulation. Activated TAFI (TAFIa) has been implicated as an important player in maintaining the balance between blood coagulation and fibrinolysis. In the present study, regulation of TAFI (CPB2) gene expression was investigated using cultured human hepatoma HepG2 cells. HepG2 cells were treated with the phosphoinositide 3-kinase (PI3K) inhibitor LY294002, and the levels of TAFI antigen and CPB2 mRNA were measured. HepG2 cells treated with LY29400 decreased their release of TAFI antigen into the conditioned medium (CM). In parallel, there were decreased levels of CPB2 mRNA and TAFI antigen in the cells. However, CPB2 gene promoter activity was not influenced by treatment of the cells with LY294002. The half-life of the CPB2 transcript was shortened by treatment with LY294002 compared with control. The present results suggest that the PI3K inhibitor LY294002 suppresses expression of TAFI, a prothrombotic factor, by decreasing the stability of CPB2 transcripts.Key words thrombin-activatable fibrinolysis inhibitor (TAFI); carboxypeptidase; LY294002; Akt; HepG2 cell Thrombin-activatable fibrinolysis inhibitor (TAFI) is a zymogen of carboxypeptidase B (CPB)-like proenzyme that is synthesized in the liver and released into circulating plasma. 1)The active form of TAFI (TAFIa) is generated by cleavage at Arg92 of the proenzyme by the proteolytic activity of thrombin, plasmin, and trypsin. TAFIa exhibits CPB-like activity that specifically cleaves basic amino acids such as arginine and lysine residues located in the carboxyl (C)-termini of peptides. One of the TAFIa substrates is a partially degraded fibrin that contains a C-terminal lysine that provides a high affinity binding sites for tissue type plasminogen activator (tPA) and plasminogen in tPA-dependent plasminogen activation. Thus, TAFIa inhibits fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin, thereby inhibiting development of the positive feedback mechanism in the fibrinolytic cascade.2,3) Indeed, TAFIa attenuates spontaneous fibrinolysis of batroxobin-induced fibrin deposition in rat lungs. 4) TAFIa inhibitors enhance endogenous fibrinolysis, resulting in antithrombotic effects.5,6) Additionally, TAFIa has been shown to remove the C-terminal arginine residues from bradykinin as well as the anaphylatoxins C3a and C5a, thus indicating a role for the TAFI pathway in the vascular response to inflammation and the regulation of fibrinolysis. 7,8)Recent reports showed that a high level of TAFI expression in circulating plasma was a risk factor for thrombotic disorders. Thus, it was shown that elevated TAFI antigen in circulating plasma was a risk factor for premature peripheral arterial disease 9) and recurrent venous thromboembolism. 10) Moreover, TAFI antigen and functional protein levels in human plasma are significantly higher in the acute phase of ischemic stroke.11,12) Importantly,...

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High thrombin activatable fibrinolysis inhibitor levels are associated with an increased risk of premature peripheral arterial disease

Abstract: High TAFI levels are associated with increased risk of premature peripheral arterial disease.

Cited by 16 publications

References 35 publications

Quantitative proteomics analysis of platelet-derived microparticles reveals distinct protein signatures when stimulated by different physiological agonists

Quantitative proteomics analysis of platelet-derived microparticles reveals distinct protein signatures when stimulated by different physiological agonists

Plasma Thrombin-activatable Fibrinolysis Inhibitor Levels Correlate with the Disease Activity of Ulcerative Colitis

PI3-Kinase Inhibitor LY294002 Repressed the Expression of Thrombin-Activatable Fibrinolysis Inhibitor in Human Hepatoma HepG2 Cells

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