Basic mechanisms and regulation of fibrinolysis

Longstaff, Colin; Kolev, Krasimir

doi:10.1111/jth.12935

Cited by 192 publications

(186 citation statements)

References 63 publications

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“…539 A10255 activates plasminogen, which is involved in fibrinolysis and other cell surface interactions. 540, 541 Overall, the unique and constrained structure of thiopeptides enables them to effect multiple biological processes, but their poor solubility and large size limits their ability to be used directly as therapeutics. Nonetheless, thiopeptides have recently emerged as drugs leads.…”

Section: Thiopeptidesmentioning

confidence: 99%

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

et al. 2017

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With advances in sequencing technology, uncharacterized proteins and domains of unknown function (DUFs) are rapidly accumulating in sequence databases and offer an opportunity to discover new protein chemistry and reaction mechanisms. The focus of this review, the formerly enigmatic YcaO superfamily (DUF181), has been found to catalyze a unique phosphorylation of a ribosomal peptide backbone amide upon attack by different nucleophiles. Established nucleophiles are the side chains of Cys, Ser, and Thr which gives rise to azoline/azole biosynthesis in ribosomally synthesized and posttranslationally modified peptide (RiPP) natural products. However, much remains unknown about the potential for YcaO proteins to collaborate with other nucleophiles. Recent work suggests potential in forming thioamides, macroamidines, and possibly additional post-translational modifications. This review covers all knowledge through mid-2016 regarding the biosynthetic gene clusters (BGCs), natural products, functions, mechanisms, and applications of YcaO proteins and outlines likely future research directions for this protein superfamily.

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Section: Thiopeptidesmentioning

confidence: 99%

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

et al. 2017

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“…Activated TAFI cleaves C-terminal lysine residues from partially degraded fibrin, which are critical for the binding of plasminogen and as a result, plasmin generation is reduced [146]. …”

Section: Current Approaches To Reduce Hypofibrinolysis In Diabetesmentioning

confidence: 99%

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

Kearney

Tomlinson

Smith

et al. 2017

Cardiovasc Diabetol

105

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An enhanced thrombotic environment and premature atherosclerosis are key factors for the increased cardiovascular risk in diabetes. The occlusive vascular thrombus, formed secondary to interactions between platelets and coagulation proteins, is composed of a skeleton of fibrin fibres with cellular elements embedded in this network. Diabetes is characterised by quantitative and qualitative changes in coagulation proteins, which collectively increase resistance to fibrinolysis, consequently augmenting thrombosis risk. Current long-term therapies to prevent arterial occlusion in diabetes are focussed on anti-platelet agents, a strategy that fails to address the contribution of coagulation proteins to the enhanced thrombotic milieu. Moreover, antiplatelet treatment is associated with bleeding complications, particularly with newer agents and more aggressive combination therapies, questioning the safety of this approach. Therefore, to safely control thrombosis risk in diabetes, an alternative approach is required with the fibrin network representing a credible therapeutic target. In the current review, we address diabetes-specific mechanistic pathways responsible for hypofibrinolysis including the role of clot structure, defects in the fibrinolytic system and increased incorporation of anti-fibrinolytic proteins into the clot. Future anti-thrombotic therapeutic options are discussed with special emphasis on the potential advantages of modulating incorporation of the anti-fibrinolytic proteins into fibrin networks. This latter approach carries theoretical advantages, including specificity for diabetes, ability to target a particular protein with a possible favourable risk of bleeding. The development of alternative treatment strategies to better control residual thrombosis risk in diabetes will help to reduce vascular events, which remain the main cause of mortality in this condition.

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“…Formation of covalent cross-links formed by activated factor (F)XIII improves elasticity of fibrin clots and resistance to enzymatic degradation [3]. Dissolution of a fibrin clot is mediated by the interaction of tissue plasminogen activator (tPA) and plasminogen on fibrin fibers, which enhances the conversion of plasminogen to plasmin by tPA.…”

Section: Introductionmentioning

confidence: 99%

Prothrombotic Fibrin Clot Phenotype in Patients with Deep Vein Thrombosis and Pulmonary Embolism: A New Risk Factor for Recurrence

Undas

2017

BioMed Research International

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Prothrombotic fibrin clot phenotype, involving faster formation of dense meshwork composed of thinner and highly branched fibers that are relatively resistant to plasmin-induced lysis, has been reported in patients with not only myocardial infarction or stroke, but also venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT), and/or pulmonary embolism (PE). Prothrombotic fibrin clot phenotype, in particular prolonged clot lysis time, is considered a novel risk factor for VTE as well as venous thrombosis at unusual location, for example, cerebral sinus venous thrombosis, retinal vein obstruction, and Budd-Chiari syndrome. Growing evidence from observational studies indicates that abnormal fibrin clot properties can predict recurrent DVT and PE and they are involved in serious complications of VTE, for example, thromboembolic pulmonary hypertension and postthrombotic syndrome. The purpose of this article is to review our current understanding of the role of fibrin clot structure and function in venous thrombosis with emphasis on clinical issues ranging from prognosis to therapy.

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Basic mechanisms and regulation of fibrinolysis

Cited by 192 publications

References 63 publications

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

YcaO-Dependent Posttranslational Amide Activation: Biosynthesis, Structure, and Function

Hypofibrinolysis in diabetes: a therapeutic target for the reduction of cardiovascular risk

Prothrombotic Fibrin Clot Phenotype in Patients with Deep Vein Thrombosis and Pulmonary Embolism: A New Risk Factor for Recurrence

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