Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Activated thrombin-activable fibrinolysis inhibitor (TAFIa) is a carboxypeptidase B-like plasma enzyme that can slow clot lysis by removing lysine residues exposed on fibrin as it is cleaved by plasmin. Previously, it was shown that fibrin treated with TAFIa is less able to promote plasminogen activation by tissue-type plasminogen activator. In this study, the effect of TAFIa modification of a fibrin surface on the rate of plasmin inhibition by antiplasmin was studied using high molecular weight fibrin degradation products (HMw-FDPs) as a soluble model for intact plasmin-modified fibrin. To quantify the inhibition, a novel end point assay was employed where plasmin, antiplasmin, and cofactors were mixed in the presence of a chromogenic substrate and the end point in the substrate hydrolysis reaction was used to measure the second order rate constant of inhibition. When HMw-FDPs were titrated in the presence of plasmin and antiplasmin, the rate constant for inhibition decreased by 16-fold at saturation (9.6 x 10(6) m(-1) s(-1) to 0.59 x 10(6) m(-1) s(-1)). When HMw-FDPs were pretreated with TAFIa, nearly two-thirds of the protective effect was lost. When 730 nm HMw-FDPs were treated for 20 min with TAFIa, the rate constant for plasmin inhibition was increased 3-fold from 1.9 x 10(6) m(-1) s(-1) to 6.2 x 10(6) m(-1) s(-1). Therefore, a novel mechanism was identified whereby TAFIa can modulate plasmin levels by increasing the susceptibility of plasmin to inhibition by antiplasmin.
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PMID:Activated thrombin-activatable fibrinolysis inhibitor reduces the ability of high molecular weight fibrin degradation products to protect plasmin from antiplasmin. 1471 54

Previous work using soluble fibrin surrogates or very dilute fibrin indicate that inhibition of plasmin by antiplasmin is attenuated by fibrin surrogates; however, this phenomenon has not been quantified within intact fibrin clots. Therefore, a novel system was designed to measure plasmin inhibition by antiplasmin in real time within an intact clot during fibrinolysis. This was accomplished by including the plasmin substrate S2251 and a recombinant fluorescent derivative of plasminogen (S741C-fluorescein) into clots formed from purified components. Steady state plasmin levels were estimated from the rates of S2251 hydrolysis, the rates of plasminogen activation were estimated by fluorescence decrease over time, and residual antiplasmin was deduced from residual fluorescence. From these measurements, the second order rate constant could be inferred at any time during fibrinolysis. Immediately after clot formation, the rate constant for inhibition decreased 3-fold from 9.6 x 10(6) m(-1) s(-1) measured in a soluble buffer system to 3.2 x 10(6) m(-1) s(-1) in an intact fibrin clot. As the clot continued to lyse, the rate constant for inhibition continued to decrease by 38-fold at maximum. To determine whether this protection was the result of plasmin exposure of carboxyl-terminal lysine residues, clots were formed in the presence of activated thrombin-activatable fibrinolysis inhibitor (TAFIa). In the presence of TAFIa, the initial protective effect associated with clot formation occurred; however, the secondary protective effect associated with lysine residue exposure was delayed in a TAFIa concentration-dependent manner. This latter effect represents another mechanism whereby TAFIa attenuates fibrinolysis.
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PMID:A study of the protection of plasmin from antiplasmin inhibition within an intact fibrin clot during the course of clot lysis. 1471 55

The fate of a forming thrombus is determined through the delicate balance between the coagulation cascade, favouring clot formation, and the fibrinolytic system, favouring clot lysis. These processes occur simultaneously, and enhancement of fibrinolysis has been shown to reduce occlusive thrombus formation in animal models. This review examines the roles of the major fibrinolytic factors involved in clot lysis. The regulation of plasmin activity by plasminogen activators, alpha-2-antiplasmin, plasminogen activator inhibitor 1, and thrombin-activatable fibrinolysis inhibitor, and their effects on thrombus formation in vivo are discussed. Since alterations in fibrinolytic capacity appear to affect thrombus formation in animal models, there is considerable interest in the pharmacological manipulation of fibrinolysis.
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PMID:Recent advances in understanding endogenous fibrinolysis: implications for molecular-based treatment of vascular disorders. 1498 91

In an in vitro clot lysis model in human plasma, carboxypeptidase U (CPU) is generated by thrombin following the coagulation and by plasmin at the later stage of clot lysis. CPU is able to slow down clot lysis by suppressing the cofactor activity of partially degraded fibrin in the plasminogen activation by tissue-type plasminogen activator (t-PA). Making use of thrombomodulin and a thrombin inhibitor, the generation of CPU during the in vitro clot lysis can be manipulated both in terms of magnitude and time course. The data obtained demonstrate that CPU affects the clot dissolution through a threshold-dependent mechanism: as long as the CPU activity remains above the threshold value, lysis is prevented from proceeding into the propagation phase. From the moment the CPU activity drops below this threshold value, the rate of lysis accelerates. This threshold value for CPU activity is dictated by the t-PA concentration: increasing the t-PA concentration increases the CPU threshold and vice versa. This implies that the effect of the CPU pathway will become more apparent at a lower fibrinolytic capacity. Our threshold-based hypothesis indicates that the time course of proCPU activation, the stability of CPU and the t-PA concentration all play a crucial role in determining the result of the in vitro clot lysis experiment. Furthermore, this hypothesis provides us with new insights into previously published data on the effects of CPU on in vitro clot lysis by high and low t-PA concentrations.
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PMID:Carboxypeptidase U (TAFIa) prevents lysis from proceeding into the propagation phase through a threshold-dependent mechanism. 1740 10

Many types of solid tumors are known to be procoagulant environments. This is partly because a hyperpermeable vascular system within the tumor allows plasma hemostatic factors to accumulate in relatively high concentrations in the stroma, and many solid-tumor cells express tissue factor or a procoagulant factor. These circumstances appear to exist in the VX-2 lung tumor of the New Zealand White (NZW) rabbit, and they sustain a measurable turnover of stromal deposits of fibrin(ogen). We have measured the turnover of fibrinogen within tumors of the VX-2 tumor-burdened rabbit and analysed the catabolic products of fibrin(ogen) and the status of fibrinolysis in tumor-derived interpleural effusate. Using intravenously injected (125)I-labeled rabbit fibrinogen as a marker, we found that fibrinogen (approximate blood concentration 1740 microg/mL) passed from blood to VX-2 tumor stroma, saturating the tumor at a concentration of approximately 348 microg fibrinogen/g in approximately 12 hours. We measured fibrin(ogen) fragments, at a concentration of approximately 292 microg/mL, in interpleural effusates that we recovered from 13% of the VX-2-burdened rabbits. Unreduced fibrin(ogen) fragments consisted of 4 major components with a relative molecular mass of approximately 250,000 (assumed to be fragment X; approximately 9% of total fragments from densitometry of immunoblots), 200,000 (d-dimer; 41%), 110,000 (fragment D; 49%), and 50,000 to 55,000 (fragment E; 1%-2%) kD. Total fibrin(ogen) fragments immunopurified from effusates exhibited an antiangiogenic effect when subjected to a chick embryo chorioallantoic membrane procedure. Interpleural effusates were devoid of plasmin activity or active plasminogen activator inhibitor-1 but contained plasmin complexes and active urokinase-like plasminogen activator (uPA), alpha(2)-antiplasmin, and thrombin-activatable fibrinolysis inhibitor. We speculate that VX-2 cells release uPA to activate fibrinolysis within the tumor stroma. Catabolic products of hemostasis (eg, fibrinolytic fragments, angiostatin) flux from the stroma into the interpleural space, thereby providing a net antiangiogenic property to the effusate and ultimately to the lymphatic and circulatory systems.
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PMID:Fibrinogen catabolism within the procoagulant VX-2 tumor of rabbit lung in vivo: Effluxing fibrin(ogen) fragments contain antiangiogenic activity. 1508 83

Many studies have indicated that the plasminogen activation system may have a prominent role in cancer. Activation of the zymogen plasminogen into the serine protease plasmin by plasminogen activator is mediated by carboxyterminal basic amino acids in fibrin, including lysines and arginines. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a circulating carboxypeptidase B-type proenzyme that, after activation, removes carboxyterminal lysine or arginine residues in fibrin, resulting in decreased plasminogen activation and attenuated fibrinolysis. To determine directly whether TAFI is involved in primary tumor growth and metastasis formation, we examined the effects of TAFI deficiency on subcutaneous growth and experimentally or spontaneously induced pulmonary metastasis formation of different tumor cell types in mice. In all tumor models TAFI deficiency did not affect the formation and growth of primary and metastasized tumors.
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PMID:Tumor growth and metastasis are not affected in thrombin-activatable fibrinolysis inhibitor-deficient mice. 1509 84

Activated thrombin-activable fibrinolysis inhibitor (TAFIa) is intrinsically unstable, a property that complicates the study of its role in regulating fibrinolysis. To investigate the effect of basic carboxypeptidases on fibrinolysis under conditions of constant carboxypeptidase activity, we employed pancreatic carboxypeptidase B (CPB), a homologous, stable basic carboxypeptidase, as a surrogate for TAFIa. Clots formed from TAFI-depleted plasma or from purified components were supplemented with tissue-type plasminogen activator and either CPB or TAFIa. The clot lysis data indicate that the down-regulation of fibrinolysis mediated by basic carboxypeptidases involves a threshold mechanism. At carboxypeptidase concentrations above the threshold, plasminogen activation is maintained in a fully down-regulated state; experiments in plasma showed that fibrinolysis is essentially halted by saturating concentrations of TAFIa and that fibrinolysis can be prolonged more than 45-fold by a stable carboxypeptidase. The threshold carboxypeptidase concentration was dependent on tissue-type plasminogen activator and antiplasmin concentrations, indicating that the threshold is determined by the steady-state plasmin concentration. Although obvious with CPB, the threshold was masked by the intrinsic instability of TAFIa and became apparent only when the effect of TAFIa was investigated over the picomolar concentration range. Because of the threshold effect and the instability of TAFIa, exponential increases in TAFIa concentration generate linear increases in lysis time. A model relating lysis time to TAFIa concentration, TAFIa half-life, and the threshold concentration of TAFIa is provided. The threshold effect has potentially important implications regarding the role of TAFIa and the regulation of clot lysis in vivo.
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PMID:The intrinsic threshold of the fibrinolytic system is modulated by basic carboxypeptidases, but the magnitude of the antifibrinolytic effect of activated thrombin-activable fibrinolysis inhibitor is masked by its instability. 1512 44

The objectives were to investigate whether activation of the extrinsic coagulation cascade by recombinant factor VIIa (rFVIIa) reverses the inhibition of thrombin generation and platelet activation by melagatran, the active form of the oral direct thrombin inhibitor ximelagatran. In a single-blind, randomized, parallel-group study, volunteers (20 per group) received a 5-hour intravenous (i.v.) infusion to achieve steady-state melagatran plasma concentrations of approximately 0.5 micromol/L, with a single i.v. bolus of rFVIIa (90 microg/kg) or placebo at 60 minutes. Prothrombin fragment 1+2, thrombin-anti-thrombin complex, fibrinopeptide A, beta-thromboglobulin, and thrombin-activatable fibrinolysis inhibitor were quantified for venous and shed blood. Activated partial thromboplastin time (APTT), prothrombin time (PT), endogenous thrombin potential, thrombus precursor protein (TpP), and plasmin-alpha(2)-antiplasmin complex concentrations were determined in venous blood. Shed blood volume was measured. Melagatran reduced markers of thrombin generation and platelet activation in shed blood and prolonged APTT. rFVIIa increased FVIIa activity, PT, and TpP in venous blood. All other parameters were unaffected. In conclusion, rFVIIa did not reverse the anticoagulant effects of high constant concentrations of melagatran. However, the potential value of higher, continuous or repeated doses of rFVIIa or its use with lower melagatran concentrations has not been excluded.
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PMID:Effect of recombinant factor VIIa on melagatran-induced inhibition of thrombin generation and platelet activation in healthy volunteers. 1517 94

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a procarboxypeptidase found in plasma that is activated by thrombin, the thrombin-thrombomodulin complex, or plasmin. The active carboxypeptidase, TAFIa, attenuates fibrinolysis by removing newly exposed carboxy-terminal lysine residues on fibrin. The half-maximal effect of TAFIa on clot lysis occurs at 1 nM and the maximal effect occurs at 20 nM. Since the circulating concentration of the procarboxypeptidase is approximately 75 nM, only a small portion needs to be activated to have a significant effect on clot lysis. Several assays to measure total plasma TAFI levels and plasma TAFIa levels after it is fully activated exist. However, no currently available assay is sufficiently sensitive and specific to measure endogenous TAFIa in plasma. We have devised a new sensitive and specific assay for TAFIa in plasma that is based on physiologic function. This assay is based on the fact that TAFIa decreases the cofactor activity of high-molecular-weight fibrin degradation products in the stimulation of plasminogen cleavage in a concentration-dependent fashion. With this assay, we can measure TAFIa concentrations as low as 10 pM in plasma and it is not affected by variability in other hemostatic factors. This assay is reliable and repeatable with intra- and interassay variabilities of 6.5 and 6.1%, respectively.
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PMID:A functional assay for measuring activated thrombin-activatable fibrinolysis inhibitor in plasma. 1520 40

The hemostatic system comprises platelet aggregation, coagulation and fibrinolysis also termed primary, secondary and tertiary hemostasis. From the platelet transcriptome 6000 mRNA species and represent receptors, ion channels, signalling molecules, kinases, phosphatases, and structural, metabolic and regulatory proteins. This abundance of regulatory proteins points towards the importance of signal transduction in platelet function. First platelets adhere to collagen, this induces activation signals such as TXA(2) that induces further Ca(2+) increase. Consecutively, fibrinogen binds to the integrin alpha(IIb)beta(3) resulting in aggregation.This self-amplifying process is controlled by signals, from endothelial cells, to restrict the platelet plug to the site of vessel injury. Secondary hemostasis (coagulation) consists of an extrinsic and intrinsic pathway. Thrombin is generated via Factor Xa resulting from the extrinsic tenase reaction that is turned of by tissue factor pathway inhibitor. While thrombin generation is maintained via positive feedback mechanisms activating factors V, VIII and XI. Excess thrombin is inhibited by antithrombin or by autodownregulation via activation of protein C. Since minor injuries are common, platelets and plasma clotting factors constantly produce clots to stop bleeding. If clots remained after the tissue healing, the vascular bed would become obstructed with clots therefore this is regulated by fibrinolysis, tertiary hemostasis. Tissue-type plasminogen activator synthesised by the endothelium, converts plasminogen to plasmin, the clot lysis enzyme. Plasmin clears the blood vessels by degrading fibrin. Fibrinolysis is controlled by plasminogen activators inhibitor (PAI-1), alpha2-antiplasmin and alpha2-macroglobulin, and thrombin-activatable fibrinolysis inhibitor (TAFI).
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PMID:The hemostatic system. 1537 10


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