scholarly journals Thrombin Activatable Fibrinolysis Inhibitor (TAFI): An Updated Narrative Review

2021 ◽  
Vol 22 (7) ◽  
pp. 3670
Author(s):  
Machteld Sillen ◽  
Paul J. Declerck
Keyword(s):  
Potential Role ◽  
Biochemical Properties ◽  
Narrative Review ◽  
Fibrinolytic System ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
General Overview ◽  
Physiologic Function ◽  
Fibrinolysis Inhibitor ◽  
Thrombotic Diseases ◽  
Coagulation And Fibrinolysis

Thrombin activatable fibrinolysis inhibitor (TAFI), a proenzyme, is converted to a potent attenuator of the fibrinolytic system upon activation by thrombin, plasmin, or the thrombin/thrombomodulin complex. Since TAFI forms a molecular link between coagulation and fibrinolysis and plays a potential role in venous and arterial thrombotic diseases, much interest has been tied to the development of molecules that antagonize its function. This review aims at providing a general overview on the biochemical properties of TAFI, its (patho)physiologic function, and various strategies to stimulate the fibrinolytic system by interfering with (activated) TAFI functionality.

Evaluation of the profibrinolytic properties of an anti-TAFI monoclonal antibody in a mouse thromboembolism model

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4615-4622 ◽  
Author(s):  
Ellen Vercauteren ◽  
Jan Emmerechts ◽  
Miet Peeters ◽  
Marc F. Hoylaerts ◽  
Paul J. Declerck ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Clot Lysis ◽  
Fibrin Deposition ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
First Report ◽  
Fibrinolysis Inhibitor ◽  
Thrombotic Diseases

Abstract The enhancement of fibrinolysis constitutes a promising approach to treat thrombotic diseases. Activated thrombin activatable fibrinolysis inhibitor (TAFIa) attenuates fibrinolysis and is an attractive target to develop profibrinolytic drugs. TAFI can be activated by thrombin, thrombin/thrombomodulin, or plasmin, but the in vivo physiologic TAFI activator(s) are unknown. Here, we generated and characterized MA-TCK26D6, a monoclonal antibody raised against human TAFI, and examined its profibrinolytic properties in vitro and in vivo. In vitro, MA-TCK26D6 showed a strong profibrinolytic effect caused by inhibition of the plasmin-mediated TAFI activation. In vivo, MA-TCK26D6 significantly decreased fibrin deposition in the lungs of thromboembolism-induced mice. Moreover, in the presence of MA-TCK26D6, plasmin-α2-antiplasmin complexes in plasma of thromboembolism-induced mice were significantly increased compared with a control antibody, indicative of an acceleration of fibrinolysis through MA-TCK26D6. In this study, we show that plasmin is an important TAFI activator that hampers in vitro clot lysis. Furthermore, this is the first report on an anti-TAFI monoclonal antibody that demonstrates a strong profibrinolytic effect in a mouse thromboembolism model.

Thrombin activatable fibrinolysis inhibitor

2011 ◽  
Vol 31 (03) ◽  
pp. 165-173 ◽  
Author(s):  
P. J. Declerck
Keyword(s):  
Elevated Level ◽  
Fibrin Clot ◽  
Temperature Dependent ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Endogenous Inhibitors ◽  
Level Of Activity ◽  
Fibrinolysis Inhibitor ◽  
Thrombin Activation ◽  
Pharmacologically Active ◽  
Thrombotic Diseases

SummaryThrombin activatable fibrinolysis inhibitor (TAFI) was discovered two decades ago as a consequence of the identification of an unstable carboxypeptidase (CPU), which was formed upon thrombin activation of the respective pro-enzyme (proCPU). The antifibrinolytic function of the activated form (TAFIa, CPU) is directly linked to its capacity to remove C-terminal lysines from the surface of the fibrin clot. No endogenous inhibitors have been identified, but TAFIa activity is regulated by its intrinsic temperature-dependent instability with a half-life of 8 to 15 min at 37 °C. A variety of studies have demonstrated a role for TAFI/TAFIa in venous and arterial diseases. In addition, a role in inflammation and cell migration has been shown. Since an elevated level of TAFIa it is a potential risk factor for thrombotic disorders, many inhibitors, both at the level of activation or at the level of activity, have been developed and were proven to exhibit a profibrinolytic effect in animal models. Pharmacologically active inhibitors of the TAFI/TAFIa system may open new ways for the prevention of thrombotic diseases or for the establishment of adjunctive treatments during thrombolytic therapy.

scholarly journals Structure of Activated Thrombin-Activatable Fibrinolysis Inhibitor, a Molecular Link between Coagulation and Fibrinolysis

2008 ◽  
Vol 31 (4) ◽  
pp. 598-606 ◽  
Author(s):  
Laura Sanglas ◽  
Zuzana Valnickova ◽  
Joan L. Arolas ◽  
Irantzu Pallarés ◽  
Tibisay Guevara ◽  
...  
Keyword(s):  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor ◽  
Coagulation And Fibrinolysis

scholarly journals Thrombin activatable fibrinolysis inhibitor (TAFI): A molecular link between coagulation and fibrinolysis

2010 ◽  
Vol 138 (suppl. 1) ◽  
pp. 74-78 ◽  
Author(s):  
Predrag Miljic ◽  
Evelien Heylen ◽  
Johan Willemse ◽  
Valentina Djordjevic ◽  
Dragica Radojkovic ◽  
...  
Keyword(s):  
Half Life ◽  
Thrombin Generation ◽  
Blood Clot ◽  
Thromboembolic Complications ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Two Systems ◽  
Lysine Residues ◽  
Fibrinolysis Inhibitor ◽  
Thrombotic Tendency ◽  
Coagulation And Fibrinolysis

Although the maintenance of precise balance between coagulation and fibrinolysis is of utmost importance for normal haemostasis, until recently these two systems were considered as completely separate mechanisms involved in the process of formation and dissolution of blood clot. Thrombin activatable fibrinolysis inhibitor (TAFI) is a recently described attenuator of the fibrinolytic rate and is considered to be the molecular link between coagulation and fibrinolysis. TAFI circulates in plasma as an inactive precursor and its conversion in active enzyme (TAFIa) occurs by the action of thrombin or plasmin, but most efficiently by thrombin in the presence of its cofactor thrombomodulin. Once generated, TAFI down-regulates fibrinolysis by removing C-terminal lysine residues from partially degraded fibrin; thereby preventing the upregulation of plasminogen binding and activation. Because TAFI is activated by thrombin on one side, and acts as the attenuator of fibrinolysis on another side, it enables fine synchronization between these two systems. The antifibrinolytic function of TAFI mostly depends on TAFI concentration, the rate of its activation and the half-life of TAFIa in plasma. Changes in thrombin generation can have a profound effect on the rate of TAFI activation, and consequently on the rate of fibrinolysis. Therefore, it has been hypothesized that increased thrombin generation seen in thrombophilia patients may enhance TAFI activation, leading to a hypofibrinolytic state, which may further contribute to the thrombotic tendency. However, the results of several studies, in which relation between TAFI level and the occurrence of thromboembolic complications in carriers of hereditary thrombophilia have been investigated, were not consistent.

TAFI Meets the Sticky Ends

2001 ◽  
Vol 85 (01) ◽  
pp. 1-2 ◽  
Author(s):  
Nuala Booth
Keyword(s):  
Fibrinolytic Activity ◽  
Potential Role ◽  
Thromboembolic Disease ◽  
Fibrinolytic System ◽  
The Other ◽  
Pivotal Role ◽  
Plasmin Activity ◽  
Carboxypeptidase B ◽  
Fibrinolysis Inhibitor

SummaryThe coagulation and fibrinolytic system are often considered as separate entities, despite the obvious connection that one produces fibrin, the substrate for the other. A potent example of a more subtle and yet important connection lies in thrombin’s ability to generate an inhibitor of fibrinolysis. This exemplifies the pivotal role of thrombin in haemostasis, a consequence of its broad range of activities. Thrombin activates the zymogen form of a basic carboxypeptidase, generating an active enzyme called carboxypeptidase U, carboxypeptidase R, plasma carboxypeptidase B or TAFIa, thrombin activable fibrinolysis inhibitor (reviewed in 1-4; references from the reviews are not cited here). The activated carboxypeptidase removes C-terminal basic residues from fibrin. C-terminal Lys residues are key to binding t-PA and plasminogen, and thus to generating plasmin activity, a mechanism by which partially-lysed fibrin amplifies plasmin formation. The removal of these C-terminal Lys residues therefore decreases local fibrinolytic activity (Fig. 1). Several recent studies, two of which appear in this issue of Thrombosis and Haemostasis (5, 6), add to our knowledge of this activity and its potential role in thromboembolic disease.

Imaging analyses of coagulation-dependent initiation of fibrinolysis on activated platelets and its modification by thrombin-activatable fibrinolysis inhibitor

2017 ◽  
Vol 117 (04) ◽  
pp. 682-690 ◽  
Author(s):  
Tomasz Brzoska ◽  
Yuko Suzuki ◽  
Hideto Sano ◽  
Seiichirou Suzuki ◽  
Martyna Tomczyk ◽  
...  
Keyword(s):  
Tissue Factor ◽  
Network Formation ◽  
Laser Scanning Microscopy ◽  
Tissue Type ◽  
Confocal Laser ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Activated Platelets ◽  
Fibrin Network ◽  
Fibrinolysis Inhibitor ◽  
Coagulation And Fibrinolysis

SummaryUsing intravital confocal microscopy, we observed previously that the process of platelet phosphatidylserine (PS) exposure, fibrin formation and lysine binding site-dependent plasminogen (plg) accumulation took place only in the centre of thrombi, not at their periphery. These findings prompted us to analyse the spatiotemporal regulatory mechanisms underlying coagulation and fibrinolysis. We analysed the fibrin network formation and the subsequent lysis in an in vitro experiment using diluted platelet-rich plasma supplemented with fluorescently labelled coagulation and fibrinolytic factors, using confocal laser scanning microscopy. The structure of the fibrin network formed by supplemented tissue factor was uneven and denser at the sites of coagulation initiation regions (CIRs) on PS-exposed platelets. When tissue type plasminogen activator (tPA; 7.5 nM) was supplemented, labelled plg (50 nM) as well as tPA accumulated at CIRs, from where fibrinolysis started and gradually expanded to the peripheries. The lysis time at CIRs and their peripheries (50 µm from the CIR) were 27.9 ± 6.6 and 44.4 ± 9.7 minutes (mean ± SD, n=50 from five independent experiments) after the addition of tissue factor, respectively. Recombinant human soluble thrombomodulin (TMα; 2.0 nM) attenuated the CIR-dependent plg accumulation and strongly delayed fibrinolysis at CIRs. A carboxypeptidase inhibitor dose-dependently enhanced the CIR-de- pendent fibrinolysis initiation, and at 20 µM it completely abrogated the TMα-induced delay of fibrinolysis. Our findings are the first to directly present crosstalk between coagulation and fibrinolysis, which takes place on activated platelets’ surface and is further controlled by thrombin-activatable fibrinolysis inhibitor (TAFI).Supplementary Material to this article is available online at www.thrombosis-online.com.

scholarly journals PENGUKURAN DAN APLIKASI KLINIK THROMBIN ACTIVATABLE FIBRINOLYSIS INHIBITOR

2018 ◽  
Vol 16 (1) ◽  
pp. 42
Author(s):  
Mansyur Arif
Keyword(s):  
Blood Loss ◽  
Clinical Application ◽  
Coagulation System ◽  
Fibrin Deposition ◽  
Thrombin Activatable Fibrinolysis Inhibitor ◽  
Fibrinolysis Inhibitor ◽  
Coagulation And Fibrinolysis ◽  
Excessive Blood Loss

Cross regulation of coagulation and fibrinolysis plays an important role in preserving a balanced hemostatic process. These process are exquisitely regulated and protect the organism from excessive blood loss or excessive fibrin deposition. Identification of ThrombinActivatable Fibrinolysis Inhibitor (TAFI) as an inhibitor of fibrinolysis and one of the main intermediates between coagulation andfibrinolysis, greatly improved our understanding of cross regulation of coagulation and fibrinolysis. As TAFI is an enzyme that is activatedby thrombin generated by the coagulation system, its activation is sensitive to the dynamics of the coagulation system. This review willdiscuss the role of TAFI and characterize it with respect to its activation, regulation, and clinical application.

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