Structure‐function relationships in thrombin‐activatable fibrinolysis inhibitor

Plug, T.; Meijers, Joost C. M.

doi:10.1111/jth.13261

Cited by 54 publications

(47 citation statements)

References 83 publications

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“…In the model in Figure 1, fXI is activated by thrombin after the VIIa/tissue factor complex initiates coagulation, with fXIa sustaining thrombin generation through factor IX activation [15]. In addition to promoting fibrin formation, fXI-dependent thrombin generation may promote activation of TAFI (thrombin-activatable fibrinolysis inhibitor), a metalloproteinase that modifies fibrin by removing binding sites for fibrinolytic proteins, rendering it resistant to fibrinolytic degradation [16]. While severe fXI deficiency delays clot formation in surface-dependent assays such as the activated partial thromboplastin time (aPTT), the magnitude of the abnormality correlates poorly with symptoms, and some patients with severe deficiency may not bleed abnormally, even with trauma.…”

Section: Factor XI In Hemostasismentioning

confidence: 99%

Factor XI as a Therapeutic Target

Gailani

Gruber

2016

ATVB

101

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Factor XIa is a plasma serine protease that contributes to thrombin generation primarily through proteolytic activation of factor IX. Traditionally considered part of the intrinsic pathway of coagulation, several lines of evidence now suggest that factor XIa serves as an interface between the vitamin-K dependent thrombin generation mechanism and the pro-inflammatory kallikrein-kinin system, allowing the two systems to influence each other. Work with animal models and results from epidemiologic surveys of human populations support a role for factor XIa in thromboembolic disease. These data, and the clinical observation that deficiency of factor XI, the zymogen of factor XIa, produces a relatively mild bleeding disorder suggest that drugs targeting factor XI or XIa could produce an antithrombotic effect while leaving hemostasis largely intact. Results of a recent trial comparing antisense-induced factor XI reduction to standard dose low molecular weight heparin as prophylaxis for venous thrombosis during knee replacement are encouraging in these regards. Here we discuss recent findings on the biochemistry, physiology and pathology of factor XI as they relate to thromboembolic disease.

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Section: Factor XI In Hemostasismentioning

confidence: 99%

Factor XI as a Therapeutic Target

Gailani

Gruber

2016

ATVB

101

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“…In a complex with Thbd, thrombin’s substrate selectivity is redirected toward activation of protein C (PC), the key effector protease of the cytoprotective and anticoagulant PC pathway, 1,2 and activation of thrombin-activatable fibrinolysis inhibitor. 3 In addition, Thbd exerts thrombin- and PC-independent functions to regulate complement activity and inflammatory signaling. 4,5 …”

Section: Introductionmentioning

confidence: 99%

Variable phenotypic penetrance of thrombosis in adult mice after tissue-selective and temporally controlled Thbd gene inactivation

et al. 2017

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Thrombomodulin (Thbd) exerts pleiotropic effects on blood coagulation, fibrinolysis, and complement system activity by facilitating the thrombin-mediated activation of protein C and thrombin-activatable fibrinolysis inhibitor and may have additional thrombin- and protein C (pC)-independent functions. In mice, complete Thbd deficiency causes embryonic death due to defective placental development. In this study, we used tissue-selective and temporally controlled Thbd gene ablation to examine the function of Thbd in adult mice. Selective preservation of Thbd function in the extraembryonic ectoderm and primitive endoderm via the Meox2Cre-transgene enabled normal intrauterine development of Thbd-deficient (Thbd−/−) mice to term. Half of the Thbd−/− offspring expired perinatally due to thrombohemorrhagic lesions. Surviving Thbd−/− animals only rarely developed overt thrombotic lesions, exhibited low-grade compensated consumptive coagulopathy, and yet exhibited marked, sudden-onset mortality. A corresponding pathology was seen in mice in which the Thbd gene was ablated after reaching adulthood. Supplementation of activated PC by transgenic expression of a partially Thbd-independent murine pC zymogen prevented the pathologies of Thbd−/− mice. However, Thbd−/− females expressing the PC transgene exhibited pregnancy-induced morbidity and mortality with near-complete penetrance. These findings suggest that Thbd function in nonendothelial embryonic tissues of the placenta and yolk sac affects through as-yet-unknown mechanisms the penetrance and severity of thrombosis after birth and provide novel opportunities to study the role of the natural Thbd-pC pathway in adult mice and during pregnancy.

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“…Deficiencies in α2AP are linked to rare bleeding disorders and increased mortality in models of PE [189,190]. Thrombin-activatable fibrinolysis inhibitor (TAFI) operates primarily by removing the C-terminal lysine from fibrin polymers, thereby preventing several amplification mechanisms of fibrinolysis that occur when plasminogen binds to fibrin [181,191,192]. Although TAFI deficiency lacks a murine phenotype [193,194], human genetic and microscopic imaging studies demonstrate a hemostatic role [195,196].…”

Section: Fibrinolysismentioning

confidence: 99%

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

Nicklas

Gordon

Henke

2020

IJMS

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Venous thromboembolism (VTE) is a pathology encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE) associated with high morbidity and mortality. Because patients often present after a thrombus has already formed, the mechanisms that drive DVT resolution are being investigated in search of treatment. Herein, we review the current literature, including the molecular mechanisms of fibrinolysis and collagenolysis, as well as the critical cellular roles of macrophages, neutrophils, and endothelial cells. We propose two general models for the operation of the immune system in the context of venous thrombosis. In early thrombus resolution, neutrophil influx stabilizes the tissue through NETosis. Meanwhile, macrophages and intact neutrophils recognize the extracellular DNA by the TLR9 receptor and induce fibrosis, a complimentary stabilization method. At later stages of resolution, pro-inflammatory macrophages police the thrombus for pathogens, a role supported by both T-cells and mast cells. Once they verify sterility, these macrophages transform into their pro-resolving phenotype. Endothelial cells both coat the stabilized thrombus, a necessary early step, and can undergo an endothelial-mesenchymal transition, which impedes DVT resolution. Several of these interactions hold promise for future therapy. already progressed past the point of anticoagulant efficacy [12,13]. Thus, there is potential clinical utility in investigating and controlling the process by which DVTs resolve in order to provide better care to these later-stage patients, with less bleeding risk. Overview of Venous Thrombus Development in HumansThe time sequence of DVT development and resolution was correctly suggested as early as 1962, based on empirical stains that detected changes in the nanoscopic roughness of clotted material [14]. As Lendrum et. al. remarked, "we consider that the intracytoplasmic granules, which we think are engulfed fibrin, seen in pulmonary phagocytes and in the endothelium of arteries and veins containing thrombus, are better shown by this (methyl-scarlet-blue) method than by any of the others." In fresh clot (whether in deep veins or in diabetic kidneys), platelets and erythrocytes are initially linked in a fine mesh yielding a relatively smooth surface (stage 1). A mat of the medium-textured fibrin replaces the initial thrombus (stage 2), which is gradually replaced by much coarser collagen (stage 3). This staging of clot development quickly became the basis of a pathological guide to grade thrombi [15]. The current three-stage refinement of the DVT grading scheme indicates that the turnover of erythrocyte-rich to fibrin-rich clot in humans is complete approximately seven days after the initial thrombotic event [16], whereas fibrin deposition commences after one day [17]. Various leukocytes, initially neutrophils and later macrophages, are believed to control this progression of DVTs development from a mass of erythrocytes, to fibrin, and finally to collagen [18]. Infiltrating T-lymphocytes and macrophages conta...

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Structure‐function relationships in thrombin‐activatable fibrinolysis inhibitor

Cited by 54 publications

References 83 publications

Factor XI as a Therapeutic Target

Factor XI as a Therapeutic Target

Variable phenotypic penetrance of thrombosis in adult mice after tissue-selective and temporally controlled Thbd gene inactivation

Resolution of Deep Venous Thrombosis: Proposed Immune Paradigms

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