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)

Although D-dimer has gained widespread clinical use as a parameter for detection of in vivo fibrin formation, the issue of standardization of D-dimer assays remains to be resolved. The FACT study was performed to generate basic data for development of calibrators and standard preparations. A set of 86 samples, including plasma samples from patients with DIC, DVT. and other clinical conditions, serial dilutions of pooled plasma samples, and plasma samples containing fibrinogen- and fibrin derivatives, were distributed to 12 manufacturers of D-dimer assays. D-dimer assays differ concerning specificity for crosslinked fibrin, and preference for either high molecular weight fibrin complexes, or low molecular weight fibrin degradation products. Terminal plasmin digests of fibrin clots for calibration produce aberrant results in some assays, especially those with preference for high molecular weight crosslinked fibrin derivatives. The best conformity is achieved by the use of pooled plasma samples from patients with high levels of D-dimer antigen in plasma. In vitro preparations containing a comparable composition of fibrin derivatives to clinical plasma samples may also serve as reference material.
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PMID:The Fibrin Assay Comparison Trial (FACT): evaluation of 23 quantitative D-dimer assays as basis for the development of D-dimer calibrators. FACT study group. 1134 4

The aim of the following study was to evaluate the diagnostic value of selective hemostasis activation markers, prothrombin activation fragment 1 + 2 (F1 + 2), thrombin-antithrombin complex (TAT), plasmin-alpha 2-antiplasmin complex (PAP) and D-dimer in patients with acute deep venous thrombosis (DVT). The study was performed on 56 patients with freshly diagnosed acute DVT confirmed by venography. The study indicated that patients with acute venous thrombosis have increased concentrations of F1 + 2, TAT complex, PAP complex and D-dimer in blood plasma. The statistical analysis showed that F1 + 2 is the most sensitive test while the D-dimer measurement proved to be the most specific in diagnosing DVT. The conducted logistic regression showed that the most reliable parameter that confirms the existence of acute venous thrombosis is the D-dimer test. The measurement of both F1 + 2 and the D-dimer concentrations rises the reliability of the DVT up to 97%.
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PMID:[Diagnostic value of hemostasis activation markers in acute deep vein thrombosis]. 1210 82

Plasminogen activators (PA) are unique agents that are currently applied as thrombolytic therapy to achieve rapid vascular reperfusion. Regimens of PA plus anticoagulants and antiplatelet drugs have attained a high degree of sophistication and predictable rates of positive clinical outcomes for acute myocardial infarction (MI), ischemic stroke, pulmonary embolism (PE), deep vein thrombosis (DVT), and thrombosed catheters. Included in the repertoire are newly approved mutants of tissue plasminogen activator (TPA), which have biochemical advantages that allow for bolus administration. Yet, despite tremendous effort devoted to enormous trials to establish the clinical efficacy of these agents in acute MI, mortality results are not superior to those with native TPA or streptokinase (SK). Furthermore, all PAs have the potential for hemorrhagic complication, most critically intracranial hemorrhage (ICH), occurring in 0.9% of patients treated with native or mutant TPA. It is possible that a limit of clinical effectiveness has been reached, beyond which more potent PAs do not achieve greater benefit without a serious increase in risk of bleeding. A breakthrough is possible, however, if the risk of ICH could be avoided. One solution is the application of the direct-acting thrombolytic enzyme, plasmin. While intravenous plasmin is not effective when administered systemically, regional infusion to a thrombus induces local thrombolysis. Unlike the PAs, plasmin treatment should not cause hemorrhage from vascular trauma sites, as it is neutralized by antiplasmin in the blood. Animal studies are fully consistent with this approach, which offers potential for achieving a truly regional thrombolytic treatment.
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PMID:Towards safer thrombolytic therapy. 1212 83

Thrombolytic agents are in widespread use for the dissolution of arterial and venous pathologic thrombi. Clinical settings where thrombolysis has played an important role include the acute coronary syndromes, peripheral arterial occlusion, ischemic stroke, deep venous thrombosis, and pulmonary embolism. Thrombolytic agents have been successfully employed in each of these areas, achieving dissolution of the occluding thrombus, reconstitution of blood flow, and improvement in the status of the tissue bed supplied or drained by the involved vascular segment. All clinically available thrombolytic agents act through cleavage of the plasminogen molecule to its active form, plasmin. Despite this similar mechanism of action, the thrombolytic agents differ in several biochemical parameters, including fibrin specificity, fibrin affinity, and relative resistance to inactivating factors in the plasma. Whether these differences account for significant differences in clinical outcome is a matter of some dispute. It is quite possible that in vitro biochemical differences do not have meaningful clinical correlates. However, there exists some evidence to suggest that differences in the risk of distant hemorrhage, idiosyncratic reactions, and the rapidity of clot dissolution do exist. An ideal agent for peripheral vascular thrombolysis would be one that was specific in its actions at the site of pathologic thrombi yet left the important and desirable pathologic thrombi that seal vascular defects unscathed. Although such an agent has not yet been identified, an understanding of the mechanism of action and principles underlying pharmacologic thrombolysis provides the necessary foundation of knowledge to choose a particular thrombolytic agent for a given clinical scenario.
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PMID:Comparison of safety and efficacy of the various thrombolytic agents. 1255 39

Thrombin inhibitors are potentially useful in medicine for their anticoagulant and antithrombotic effects. We synthesized and evaluated diverse heterocycle-activated ketones based on the d-Phe-Pro-Arg, and related thrombin active-site recognition motifs, as candidate inhibitors. The peptide-based alpha-ketoheterocycles were typically prepared by either an imidate or a Weinreb amide route (Schemes 1 and 2), the latter of which proved to be more general. Test compounds were generally assayed for inhibition of human alpha-thrombin and bovine trypsin. From a structure-based design standpoint, the heterocycle allows one to explore and adjust interactions within the S1' subsite of thrombin. The preferred alpha-ketoheterocycle is a pi-rich 2-substituted azole with at least two heteroatoms proximal to the carbon bearing the keto group, and a preferred thrombin inhibitor is 2-ketobenzothiazole 3, with a potent K(i) value of 0.2 nM and ca. 15-fold selectivity over trypsin. 2-Ketobenzothiazole 13 exhibited exceedingly potent thrombin inhibition (K(i) = 0.000 65 nM; slow tight binding). Several alpha-ketoheterocycles had thrombin K(i) values in the range 0.1-400 nM. The "Arg" unit in the alpha-ketoheterocycles can be sensitive to stereomutation under mildy basic conditions. For example, 2-ketothiazoles 4 and 59 readily epimerize at pH 7.4, although they are fairly stable stereochemically at pH 3-4; thus, suitable conditions had to be selected for the enzymatic assays. Lead d-Phe-Pro-Arg 2-benzothiazoles 3, 4, and 68 displayed good selectivity for thrombin over other key coagulation enzymes (e.g., factor Xa, plasmin, protein Ca, uPA, tPA, and streptokinase); however, their selectivity for thrombin over trypsin was modest (<25-fold). Compounds 3, 4, and 68 exhibited potent in vitro antithrombotic activity as measured by inhibition of gel-filtered platelet aggregation induced by alpha-thrombin (IC(50) = 30-40 nM). They also proved to be potent anticoagulant/antithrombotic agents in vivo on intravenous administration, as determined in the canine arteriovenous shunt (ED(50) = 0.45-0.65 mg/kg) and the rabbit deep vein thrombosis (ED(50) = 0.1-0.4 mg/kg) models. Intravenous administration of 3, and several analogues, to guinea pigs caused hypotension and electrocardiogram abnormalities. Such cardiovascular side effects were also observed with some nonguanidine inhibitors and inhibitors having recognition motifs other than d-Phe-Pro-Arg. 2-Benzothiazolecarboxylates 4 and 68 exhibited significantly diminished cardiovascular side effects, and benzothiazolecarboxylic acid 4 had the best profile with respect to therapeutic index. The X-ray crystal structures of the ternary complexes 3-thrombin-hirugen and 4-thrombin-hirugen depict novel interactions in the S(1)' region, with the benzothiazole ring forming a hydrogen bond with His-57 and an aromatic stacking interaction with Trp-60D of thrombin's insertion loop. The benzothiazole ring of 3 displaces the Lys-60F side chain into a U-shaped gauche conformation, whereas the benzothiazole carboxylate of 4 forms a salt bridge with the side chain of Lys-60F such that it adopts an extended anti conformation. Since 3 has a 10-fold greater affinity for thrombin than does 4, any increase in binding energy resulting from this salt bridge is apparently offset by perturbations across the enzyme (viz. Figure 4). The increased affinity and selectivity of 2-ketobenzothiazole inhibitors, such as 3, may be primarily due to the aromatic stacking interaction with Trp-60D. However, energy contour calculations with the computer program GRID also indicate a favorable interaction between the benzothiazole sulfur atom and a hydrophobic patch on the surface of thrombin.
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PMID:In-depth study of tripeptide-based alpha-ketoheterocycles as inhibitors of thrombin. Effective utilization of the S1' subsite and its implications to structure-based drug design. 1577 42

Thrombotic occlusive diseases are manifested in several disorders that have significant morbidity and mortality, including acute myocardial infarction, pulmonary embolism, deep venous thrombosis, and cerebrovascular accidents. This review summarizes the recently published literature covering thrombolytic therapies in these diseases, with particular attention to comparisons between the fibrin-specific tissue plasminogen activators (alteplase, reteplase, and tenecteplase) and the nonfibrin-specific activators (streptokinase or urokinase plasminogen activator). These agents act to convert plasminogen to plasmin, which in turn cleaves fibrin as part of the lysis process. Fibrin-specific activators were anticipated to be more efficacious and safer than nonspecific agents in thrombolytic occlusive diseases because of their pathophysiologically restricted mechanism of action. However, the fibrin-specific activators also lyse physiological hemostatic plugs, which can result in costly adverse events. Efficacy of fibrin-specific tissue plasminogen activators has been shown to be generally equivalent, with similar mortality rates compared with nonspecific agents; however, fibrin-specific agents may be associated with an increased incidence of intracerebral hemorrhage and with increased costs. Therefore, it appears that given equivalent efficacy, nonfibrin-specific activators, such as streptokinase or urokinase, may be a safer choice in many thrombotic situations.
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PMID:Thrombolytic therapies: the current state of affairs. 1582 70

Pre-eclampsia (P-Ec) is a complex multisystem disorder of unknown aetiology reported to occur in about 6% to 8% of all pregnancies throughout the world. This disease is associated with fibrin deposition and occlusive lesions in placental vessels. Pro-thrombin activatable fibrinolysis inhibitor (pro-TAFI) is a relatively recently described glycoprotein that can be converted into its active form (TAFIa) by thrombin, thrombin-thrombomodulin and plasmin. TAFIa potentially inhibits fibrinolysis by removing C-terminal lysine and arginine residues from fibrin. These residues are required for adsorption of tissue-type plasminogen activator (t-PA) and plasminogen to fibrin. Therefore, TAFIa decreases plasmin formation and protects the fibrin clot against lysis. An increased of pro-TAFI/TAFIa levels has been reported in some clinical conditions associated with thrombotic tendency, as type II diabetes mellitus, deep vein thrombosis and symptomatic artery disease. Few studies have investigated pro-TAFI/TAFIa in normal or complicated pregnancy but contrasting results were reported. Understanding the role of pro-TAFI/TAFIa in the pathogenesis of P-Ec can hold great promise for improving P-Ec management. In this context, a large-scale study evaluating plasma TAFI antigen and activity, its synthesis and metabolism in pre-eclamptic women is required. Recently new selective TAFIa inhibitors have been developed. The design of a new therapy to treat and/or prevent P-Ec, based on successful use of TAFIa inhibitors, may have significant clinical ramifications.
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PMID:Thrombin activatable fibrinolysis inhibitor (TAFI): a role in pre-eclampsia? 1718 58

Patients with inflammatory vascular disease caused by anti-neutrophil cytoplasmic autoantibodies (ANCA) can harbor antibodies not only to the autoantigen proteinase 3 (PR3) but also to complementary PR3 (cPR3(105-201)), a recombinant protein translated from the antisense strand of PR3 cDNA. The purpose of this study was to identify potential endogenous targets of anti-cPR3(105-201) antibodies. Patients' plasmapheresis material was tested for the presence of antigens reactive with affinity-purified rabbit and chicken anti-cPR3(105-201) polyclonal antibodies. Antigen-containing fractions were tested with patients' anti-cPR3(105-201) affinity-purified IgG, and putative protein targets were sequenced by mass spectrometry. Unexpectedly, plasminogen was identified as a target of anti-cPR3(105-201). Reactivity of affinity-purified antibodies from two patients was lost when plasminogen was converted to plasmin, indicating restricted specificity. Antiplasminogen antibodies from five patients bound plasminogen at a surface-exposed loop structure within the protease domain. This loop contains an amino acid motif that is also found in a portion of recombinant cPR3(105-201); site-directed mutagenesis of this sequence decreased antibody reactivity by 30%. Functionally, antiplasminogen antibodies delayed the conversion of plasminogen to plasmin and increased the dissolution time of fibrin clots. Serologically, antiplasminogen antibody levels were higher in PR3-ANCA patients (n = 72) than healthy control subjects (n = 63), myeloperoxidase-ANCA patients (n = 34), and patients with idiopathic thrombosis (n = 57; P = 0.001). Of the patients with PR3-ANCA, nine had documented deep venous thrombosis events, five of whom were positive for antiplasminogen antibodies. In summary, capitalizing on interactions with complementary proteins, specifically complementary PR3, this study identified plasminogen as a previously undescribed autoantigen in PR3-ANCA vasculitis.
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PMID:Antibodies with dual reactivity to plasminogen and complementary PR3 in PR3-ANCA vasculitis. 1870 7

This study investigated the relationship between right atrial SEC (RA-SEC) and silent pulmonary embolism (PE) in patients with nonvalvular atrial fibrillation (NVAF). Spontaneous echo contrast (SEC) within the cardiac chambers is associated with an increased risk of thromboembolism. However, most studies have examined the relationship between left atrial SEC and systemic thromboembolic disease. Transesophageal echocardiography (TEE) was performed in 210 patients with NVAF to assess a risk of thromboembolism. Right atrial SEC was detected in 37 patients, and 35 of these patients with RA-SEC and 29 patients without RA-SEC were enrolled in this study. However, patients with a history of symptomatic PE or deep vein thrombosis were excluded. Spontaneous echo contrast was diagnosed by TEE as the presence of smoke-like echoes that swirled in a circular pattern. PE was diagnosed by pulmonary scintigraphy. Thrombotic and thrombolytic parameters, including serum concentrations of plasmin-alpha-plasmin inhibitor complex (PIC), thrombin-antithrombin complex (TAT), D-dimer, and fibrinogen were measured in all patients. Left ventricular dimension, cardiac function, and hematologic parameters were similar in the two groups. Nevertheless, the incidence of perfusion defects in pulmonary scintigraphy was significantly higher in the group with RA-SEC (40%) than in the group without RA-SEC (7%; chi-square, P=0.006). The increased incidence of perfusion defects in pulmonary scintigraphy in patients with RA-SEC indicates that right atrial SEC may be a predictable factor at a high risk of PE.
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PMID:Right atrial spontaneous echo contrast indicates a high incidence of perfusion defects in pulmonary scintigraphy in patients with atrial fibrillation. 1916 66

Plasmin is the prototype of a distinct class of "direct-acting" fibrinolytic agents, with biochemical and physiological attributes that are favorable for catheter-delivered thrombolytic therapy. Our studies indicate that plasmin is superior to plasminogen activators for hemostatic safety and thrombolytic efficacy in experimental models, and that plasmin has potential to avoid the bleeding risk that accompanies therapy of deep vein thrombosis with currently-used thrombolytic agents.
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PMID:Thrombolytic therapy for deep vein thrombosis: potential application of plasmin. 1930 6


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