Thrombin-Activatable Fibrinolysis Inhibitor (TAFI, Plasma Procarboxypeptidase B, Procarboxypeptidase R, Procarboxypeptidase U)

Bouma, Bonno N.; Marx, Pauline F.; Mosnier, Laurent O.; Meijers, Joost C. M.

doi:10.1016/s0049-3848(00)00411-4

Cited by 180 publications

(157 citation statements)

References 113 publications

Supporting

Mentioning

150

Contrasting

Unclassified

Order By: Relevance

“…Because activation of TAFI in our model is largely due to thrombin, 13,27 we also determined the profile of thrombin generation during clot lysis using a fibrinogen clotting assay. As shown in Fig.…”

Section: Tafi Levels Are Reduced In Cirrhotic Patientsmentioning

confidence: 99%

“…10,11 In so doing, TAFIa reduces the cofactor function of fibrin in the plasminogen activation catalyzed by t-PA, thereby decreasing plasmin generation. The most likely physiologic activator of TAFI is thrombin, 12,13 which can work either alone, provided it is present at high concentrations, or in complex with thrombomodulin, in which case its efficiency is increased by more than 1,000-fold. 14 It is believed that TAFI activation by thrombin/thrombomodulin complex occurs on the endothelial surface adjacent to the hemostatic plug and protects the outside of the fibrin matrix from fibrinolysis, whereas TAFI activation by thrombin alone takes place within the hemostatic plug and serves to down-regulate fibrinolysis induced by t-PA incorporated into the fibrin plug.…”

mentioning

confidence: 99%

“…14 It is believed that TAFI activation by thrombin/thrombomodulin complex occurs on the endothelial surface adjacent to the hemostatic plug and protects the outside of the fibrin matrix from fibrinolysis, whereas TAFI activation by thrombin alone takes place within the hemostatic plug and serves to down-regulate fibrinolysis induced by t-PA incorporated into the fibrin plug. 13 Under the latter condition, antifibrinolytic amounts of TAFIa are generated only if high amounts of thrombin are formed, likely via a FXI-dependent feedback mechanism, 15 and any impairment of TAFIa formation will translate in highly accelerated fibrinolysis because plasmin generated within a fibrin clot has a much higher impact on fibrinolysis than plasmin generated at the clot surface. 16,17 The potential physiologic role of TAFI in the fibrinolytic process is underscored by several in vitro and in vivo data, 7,10,[18][19][20][21] and evidence is accumulating suggesting that alterations in the TAFI pathway, either because of derangements in the TAFI activating capacity or because of changes in TAFI levels, may contribute to bleeding or thrombosis.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Deficiency of Thrombin Activatable Fibrinolysis Inhibitor in Cirrhosis Is Associated With Increased Plasma Fibrinolysis

et al. 2003

View full text Add to dashboard Cite

Hyperfibrinolysis is thought to contribute to bleeding associated with advanced cirrhosis. Thrombin activatable fibrinolysis inhibitor (TAFI) is a plasma precursor of a carboxypeptidase (TAFIa) with antifibrinolytic activity and was recently shown to be reduced in cirrhosis. In this study, we evaluated the influence of TAFI deficiency on in vitro fibrinolysis in cirrhotic patients. Fifty-three patients with cirrhosis and 43 healthy controls were studied. TAFI antigen was measured by enzyme-linked immunosorbent assay and TAFI activity by chromogenic assay. Fibrinolysis was evaluated as tissue plasminogen activator-induced plasma clot lysis time in the absence and in the presence of a specific inhibitor of TAFIa. TAFI antigen and activity levels were markedly reduced in cirrhotic patients (P < .0001). In these patients, the lysis time of plasma clots was shorter than in controls (median, interquartile range: 25 minutes, 21-36 minutes vs. 48 minutes, 40-60 minutes, respectively; P < .0001) and was poorly influenced by the TAFIa inhibitor. Accordingly, TAFIa and thrombin activity, generated in cirrhotic samples during clot lysis, were significantly lower than in control samples. Addition of purified TAFI to cirrhotic plasma prolonged the lysis time and enhanced the response to TAFIa inhibitor in a dose-dependent manner. In conclusion, our results indicate that in vitro plasma hyperfibrinolysis in cirrhosis is largely due to a defective TAFIa generation resulting from low TAFI levels and probably from impaired thrombin generation. Impairment of the antifibrinolytic TAFI pathway might contribute to bleeding associated with this disease. (HEPATOLOGY 2003;38:230-237.) H yperfibrinolysis is a common finding in cirrhosis and is thought to contribute to the bleeding tendency associated with this disease by causing a premature removal of the hemostatic plug at sites of vascular injury. The abnormalities of the fibrinolytic system encountered in cirrhosis are complex and result from both impaired synthesis and altered clearance of the fibrinolytic factors. 1 Of particular relevance to hyperfibrinolysis are the imbalance between tissue plasminogen activator (t-PA) and its specific inhibitor (PAI-1), which results in an enhancement of free t-PA in the circulation and the reduction of ␣ 2 -plasmin inhibitor (␣ 2 -PI). [2][3][4][5][6] In recent years, a new plasma protein has been identified that may play an important regulatory role in fibrinolysis. It is a procarboxypeptidase synthesized by the liver and named thrombin activatable fibrinolysis inhibitor (TAFI) or procarboxypeptidase B or U. 7-9 Upon activation by thrombin or plasmin, it is converted to an enzyme (TAFIa) with carboxypeptidase B-like activity that inhibits fibrinolysis through the removal of C-terminal lysines from partially degraded fibrin. 10,11 In so doing, TAFIa reduces the cofactor function of fibrin in the plasminogen activation catalyzed by t-PA, thereby decreasing plasmin generation. The most likely physiologic activator of TAFI is thrombin, 12,13 whi...

show abstract

Section: Tafi Levels Are Reduced In Cirrhotic Patientsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Deficiency of Thrombin Activatable Fibrinolysis Inhibitor in Cirrhosis Is Associated With Increased Plasma Fibrinolysis

et al. 2003

View full text Add to dashboard Cite

show abstract

“…During coagulation, TAFI is proteolytically activated by thrombin in a TM-dependent manner to its active form, TAFIa, which inhibits fibrinolysis by removing the carboxyl-terminal lysine and arginine residues from partially degraded fibrin (5,6). As activation of TAFI requires exposure to relatively high concentrations of thrombin, the intrinsic pathway-mediated thrombin generation plays a pivotal role in the regulation of fibrinolysis (7).…”

Section: Tafimentioning

confidence: 99%

Studies on the Different Modes of Action of the Anticoagulant Protease Inhibitors DX-9065a and Argatroban

Nagashima¹

2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

The accompanying paper (Nagashima, H. (2002) J. Biol. Chem. 277, 50439 -50444) has demonstrated that argatroban can yield a stronger inhibitory effect on thrombin generation than DX-9065a during extrinsic pathway-stimulated human plasma coagulation, while these anticoagulant compounds have comparable abilities to prolong clot time. Since thrombin generation is known to be an important determinant for fibrinolytic resistance of clots formed during coagulation, the two compounds are compared by tissue plasminogen activator-induced clot lysis assays. The results demonstrated that, in the presence of thrombomodulin, argatroban dose dependently accelerated fibrinolysis of the clots, whereas DX-9065a did not. The activation of thrombin activatable fibrinolysis inhibitor (TAFI) determined in separate assays reflected the differential influence on thrombin generation by these compounds. Moreover, TAFI activation correlated closely with the fibrinolytic resistance observed during tissue plasminogen activator-induced clot lysis. This study demonstrates the differential effects of DX-9065a and argatroban on thrombin generation, which in turn results in a differential acceleration of fibrinolysis as well as TAFI activation in the clots formed under the influence of these compounds. The data implicate a possible difference in the antifibrinolytic properties of clots formed during treatment with these compounds.Thrombin plays a central role in thrombosis and hemostasis. While only a small amount of prothrombin is activated at the moment of clotting, the remaining prothrombin is activated predominantly after clot formation (1). These observations are consistent with the recently proposed notion (2) that activation of the extrinsic pathway is responsible for the rapid generation of a small amount of thrombin, which is sufficient for clot formation; however, activation of the intrinsic pathway is responsible for a massive production of thrombin mostly after clot formation, which effectively augments the antifibrinolytic properties of the clot. Such an intrinsic pathway-mediated thrombin burst is critically dependent on a feedback activation mechanism mediated by thrombin-catalyzed activation of factor XI (3, 4). TAFI1 is a zymogen that plays a key role in the regulation of fibrinolysis. During coagulation, TAFI is proteolytically activated by thrombin in a TM-dependent manner to its active form, TAFIa, which inhibits fibrinolysis by removing the carboxyl-terminal lysine and arginine residues from partially degraded fibrin (5, 6). As activation of TAFI requires exposure to relatively high concentrations of thrombin, the intrinsic pathway-mediated thrombin generation plays a pivotal role in the regulation of fibrinolysis (7).The accompanying paper (8) demonstrates the differential actions on thrombin generation by two different anticoagulant protease inhibitors DX-9065a (9) and argatroban (10). Both theoretical and experimental approaches (8) revealed that the thrombin inhibitor, argatroban, yielded a stronger inhibitory effect on...

show abstract

“…It was shown that plasma CPU and CPN cleave C-terminal Lys residues on these plasminogen "receptors" and thereby downregulate plasminogen activation [77,78]. CPU (also called TAFI) exists in blood as a proenzyme and once activated by thrombin/thrombomodulin during coagulation has a short half-life [79,80]. Although CPU reduces plasminogen binding to both cells and in fibrin clots, the effect of CPN is largely restricted to removal of C-terminal Lys residues of plasma CPN also cleaves off C-terminal Lys residues from other large protein substrates; it is the "creatine kinase conversion factor" in blood that liberates the C-terminal Lys from both the M and B subunits of creatine kinase, released from the heart after myocardial infarction [84,85].…”

mentioning

confidence: 99%

Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Skidgel

Erdös

2007

International Immunopharmacology

View full text Add to dashboard Cite

Human carboxypeptidase N (CPN) was discovered in the early 1960s as a plasma enzyme that inactivates bradykinin and was identified 8 years later as the major "anaphylatoxin inactivator" of blood. CPN plays in important role in protecting the body from excessive buildup of potentially deleterious peptides that normally act as local autocrine or paracrine hormones. This review summarizes the structure, enzymatic properties and function of this important human enzyme, including insights gained by the recent elucidation of the crystal structure of the CPN catalytic subunit and structural modeling of the non-catalytic regulatory 83 kDa subunit. We also discuss its physiological role in cleaving substrates such as kinins, anaphylatoxins, creatine kinase, plasminogen receptors, hemoglobin and stromal cell-derived factor-1α (SDF-1α). HistoryCarboxypeptidases were initially isolated from pancreatic extracts and so were associated with protein and peptide degradation in the digestive tract [1][2][3][4]. However, work beginning in the early 1960's by Erdös and Sloane [5] revealed the presence of a novel carboxypeptidase in the blood that plays a regulatory role by inactivating bradykinin via removal of its C-terminal Arg residue. (Subsequent research some 2 decades later led to the discovery of a second kinin B 1 receptor activated by the carboxypeptidase metabolite that is its endogenous agonist -see below). Initially it was assumed that the enzyme represents a circulating form of pancreatic carboxypeptidase B, but this was disproved by the characterization of its enzymatic properties [5][6][7][8], which was later borne out by biochemical studies, sequence analysis [9][10][11][12][13][14][15] and ultimately X-ray crystallography [16]. To differentiate it from the pancreatic enzyme, it was named carboxypeptidase N (CPN; EC 3.4.17.3) and was the first member of a family of carboxypeptidases now known as the regulatory or CPN/E subfamily of metallocarboxypeptidases [17][18][19]. It has since been re-discovered many times as other substrates were found and so has acquired aliases such as creatine kinase conversion factor, plasma carboxypeptidase B, arginine carboxypeptidase, lysine carboxypeptidase and protaminase [8,17,20,21]. The most notable was the finding by Bokisch and Müller-Eberhard in 1969 -70 [22,23] that the human plasma "anaphylatoxin inactivator" is identical with CPN. This finding explains our interest in the work of Dr. Tony Hugli, who has made many seminal contributions to the understanding of the structure and function of anaphylatoxins [24][25][26][27]. In Send Correspondence and Proofs To: Randal A. Skidgel, PhD, Dept. of Pharmacology (M/C 868), Univ. of Illinois College of Medicine, 835 S. Wolcott, Chicago, IL 60612, Phone: 312-996-9179, FAX: 312-996-1648, EMAIL: E-mail: rskidgel@uic.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript w...

show abstract

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI, Plasma Procarboxypeptidase B, Procarboxypeptidase R, Procarboxypeptidase U)

Cited by 180 publications

References 113 publications

Deficiency of Thrombin Activatable Fibrinolysis Inhibitor in Cirrhosis Is Associated With Increased Plasma Fibrinolysis

Deficiency of Thrombin Activatable Fibrinolysis Inhibitor in Cirrhosis Is Associated With Increased Plasma Fibrinolysis

Studies on the Different Modes of Action of the Anticoagulant Protease Inhibitors DX-9065a and Argatroban

Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Contact Info

Product

Resources

About