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:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adsorption of thrombin to fibrin during clotting defines "Antithrombin I" activity. We confirmed that thrombin generation in afibrinogenemic or in Reptilase defibrinated normal plasma was higher than in normal plasma. Repletion of these fibrinogen-deficient plasmas with fibrinogen 1 (gamma A/gamma A), whose fibrin has two "low affinity" non-substrate thrombin binding sites, resulted in moderately reduced thrombin generation by 29-37%. Repletion with fibrinogen 2 (gamma'/gamma A), which in addition to low affinity thrombin-binding sites in fibrin, has a "high affinity" non-substrate thrombin binding site in the carboxy-terminal region of its gamma' chain, was even more effective and reduced thrombin generation by 57-67%. Adding peptides that compete for thrombin binding to fibrin [S-Hir53-64 (hirugen) or gamma'414-427] caused a transient delay in the onset of otherwise robust thrombin generation, indicating that fibrin formation is necessary for full expression of Antithrombin I activity. Considered together, 1) the increased thrombin generation in afibrinogenemic or fibrinogen-depleted normal plasma that is mitigated by fibrinogen replacement; 2) evidence that prothrombin activation is increased in afibrinogenemia and normalized by fibrinogen replacement; 3) the severe thrombophilia that is associated with defective thrombin-binding in dysfibrinogenemias Naples I and New York I, and 4) the association of afibrinogenemia or hypofibrinogenemia with venous or arterial thromboembolism, indicate that Antithrombin I (fibrin) modulates thromboembolic potential by inhibiting thrombin generation in blood.
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PMID:Inhibition of thrombin generation in plasma by fibrin formation (Antithrombin I). 1219 97

Specific cleavage of factor V at several P1Arg sites is critical for maintenance of hemostasis. While cleavage by procoagulant proteinases fXa and thrombin activates the cofactor, its cleavage by the anticoagulant proteinase activated protein C (APC) inactivates it. Antithrombin (AT), a specific serpin inhibitor of both thrombin and factor Xa, but not APC, was used as a model system to investigate molecular determinants of APC specificity in the inactivation reaction. Two mutants were prepared in which the P2 or the P3-P3' residues of the reactive site loop of the serpin were replaced with the corresponding residues of the APC cleavage site in factor V spanning residues 504-509 (Asp(504)-Arg-Arg-Gly-Ile-Gln(509)). Kinetic analysis showed that the reactivities of mutants were impaired by approximately 2-3 orders of magnitude with both factor Xa and thrombin, but improved by approximately 2 orders of magnitude with APC. The saturable dependence of the observed first-order rate constants on the concentrations of AT in complex with approximately 70-saccharide high-affinity heparin revealed that changes in the reactivity of the 504-509 mutant with proteinases are primarily due to an effect in the second reaction step in which a noncovalent serpin-proteinase encounter complex is converted to a stable, covalent complex. These results suggest that the P3-P3' residues of the APC cleavage site in factor Va, particularly P2Arg, confer specificity for the anticoagulant proteinase by improving the reactivity of the catalytic pocket with the transition state of the substrate in the second step of the reaction.
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PMID:Insight into the molecular basis of coagulation proteinase specificity by mutagenesis of the serpin antithrombin. 1235 19

Antithrombin (ATIII), heparin cofactor II (HCII) and protein C inhibitor (PCI; also named plasminogen activator inhibitor-3) are serine protease inhibitors (serpins) whose thrombin inhibition activity is accelerated in the presence of glycosaminoglycans. We compared the inhibition properties of PCI and HCII to ATIII using R93A/R97A/R101A thrombin, an anion-binding exosite-2 (exosite-2) mutant that has greatly reduced heparin-binding properties. Heparin-enhanced PCI inhibition of R93A/R97A/R101A thrombin was only approximately 2-fold compared to 40-fold enhancement with wild-type recombinant thrombin. Thrombomodulin (TM) (with or without the chondroitin sulfate moiety) accelerated PCI inhibition of both wild-type and R93A/R97A/R101A thrombins. HCII achieved the same maximum activity in the presence of heparin with both wild-type and R93A/R97A/R101A thrombins; however, the optimum heparin concentration was 20 times greater than the reaction with wild-type thrombin, indicative of a decrease in heparin affinity. Dermatan sulfate (DSO4)-catalyzed HCII thrombin inhibition was unchanged in R93A/R97A/R101A thrombin compared to wild-type recombinant thrombin. These results suggest that PCI is similar to ATIII and depends upon ternary complex formation with heparin and these specific thrombin exosite-2 residues to accelerate thrombin inhibition. In contrast, HCII does not require Arg(93), Arg(97) and Arg(101) of thrombin exosite-2 and further supports the hypothesis that HCII uses an allosteric process following glycosaminoglycan binding to inhibit thrombin.
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PMID:Inhibition of a thrombin anion-binding exosite-2 mutant by the glycosaminoglycan-dependent serpins protein C inhibitor and heparin cofactor II. 1241 92

Antithrombin (AT) is a plasma-derived, single-chain glycoprotein with a molecular weight of 58 kDa. It is a serine protease inhibitor (serpin), sharing about 30% homology in amino acid sequence with other serpins. AT is a complex molecule with multiple biologically important properties. It is a potent anticoagulant that has been demonstrated to provide benefit in animal models and small cohorts of patients with coagulation disorders. AT also has remarkable anti-inflammatory properties, several of which result from its actions in the coagulation cascade. Activated coagulation proteases like activated factor X and thrombin contribute to inflammation; for instance, by the release of pro-inflammatory mediators. Inhibition of these proteases by AT prevents their specific interaction with cells and subsequent reactions. Anti-inflammatory properties of AT independent of coagulation involve direct interactions with cells leading to the release of, for instance, prostacyclin. Binding of AT to a recently identified cellular receptor, syndecan-4, leads to the interference with the intracellular signal induced by mediators like lipopolysaccharides and, thereby, to a down-modulation of the inflammatory response. AT has been shown to be effective in prospective and well-controlled small-scale studies of patients with inflammatory conditions, including sepsis. Although AT did not decrease overall patient mortality in a double-blind, placebo-controlled, phase III trial of patients with sepsis, it is important to note that AT improved the survival of individuals in this study not receiving heparin as a prophylactic regimen, which can be explained by the impaired interaction of AT with its cellular receptor in the presence of heparin, resulting in the reduction of the anti-inflammatory properties. Accordingly, the supplementation of AT without concomitant heparin may be beneficial in disorders with inflammatory characteristics, which has to be demonstrated in further clinical studies. Finally, recent results suggest that latent AT can induce apoptosis of endothelial cells by disrupting cell-matrix interactions. Further investigations will have to demonstrate whether latent and/or cleaved AT are physiological means to control angiogenesis. A potential prophylactic or therapeutic use as an anti-angiogenic and antitumor agent merits further exploration, including whether the growth of vessels in tumor tissues or close to tumors can be controlled by latent AT without affecting the formation of blood vessels during wound healing processes.
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PMID:Antithrombin: a new look at the actions of a serine protease inhibitor. 1244 4

Antithrombin (AT) supplementation in patients with severe sepsis has been shown to improve organ failures in which activated leukocytes are critically involved. However, the precise mechanism(s) for the therapeutic effects of AT is not well understood. We examined in rats whether AT reduces ischemia/reperfusion (I/R)-induced renal injury by inhibiting leukocyte activation. AT markedly reduced the I/R-induced renal dysfunction and histologic changes, whereas neither dansyl glutamylglycylarginyl chloromethyl ketone-treated factor Xa (DEGR-F.Xa), a selective inhibitor of thrombin generation, nor Trp49-modified AT, which lacks affinity for heparin, had any effect. Renal tissue levels of 6-keto-PGF(1 alpha), a stable metabolite of prostacyclin (PGI(2)), increased after renal I/R. AT enhanced the I/R-induced increases in renal tissue levels of 6-keto-PGF(1 alpha), whereas neither DEGR-F.Xa nor Trp49-modified AT had any effect. AT significantly inhibited I/R-induced decrease in renal tissue blood flow and the increase in the vascular permeability. Ischemia/reperfusion-induced increases in renal tissue levels of tumor necrosis factor-alpha, cytokine-induced neutrophil chemoattractant, and myeloperoxidase were significantly inhibited in animals given AT. Pretreatment of animals with indomethacin reversed the effects induced by AT. Iloprost, an analog of PGI(2), produced effects similar to those induced by AT. These observations strongly suggest that AT reduces the I/R-induced renal injury by inhibiting leukocyte activation. The therapeutic effects of AT might be mainly mediated by PGI(2) released from endothelial cells through interaction of AT with cell surface glycosaminoglycans.
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PMID:Antithrombin reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation through promotion of prostacyclin production. 2354 58

It is known that low-dose aspirin is effective in coronary artery therapy, although it has not yet been clarified how it exerts its action. Here, we report that treatment of coronary artery patients with 100 mg/day of aspirin does not attenuate thrombin generation, but reduces free thrombin by favouring the formation of thrombin/antithrombin (TAT) complexes. Antithrombin hyperactivation is mediated by inhibition of platelet factor 4 release from alpha-granules, leading to higher heparin availability.
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PMID:Anti-thrombin action of low-dose acetylsalicylic acid. 1253 60

The purpose of this study was to establish a new coagulation index to distinguish severe preeclampsia from normal pregnancy using optimal coagulation parameters. The difference between platelet counts in early gestation and before delivery (DeltaPlt = [platelet counts before delivery] - [platelet counts in early gestation]) was calculated as an index of changes in platelet counts. Antithrombin (AT) activity, thrombin-antithrombin (TAT) complex, fibrin degradation products (FDP) D-dimer, and DeltaPlt were investigated in 72 cases of normal pregnant women in the third trimester of pregnancy and 56 cases of severe preeclampsia. The new coagulation index was calculated using multivariate logistic regression analysis. As a result, in a case using four parameters, the following formula was obtained: Y = (-0.019 x AT activity) + (0.067 x TAT) + (0.067 x D-dimer) + (-0.064 x DeltaPlt) + 0.706. According to this formula, coagulation indices in normal pregnant women and in patients with severe preeclampsia were -0.77 +/- 0.51 and 1.41 +/- 1.56, respectively (p < 0.0001). Among patients with severe preeclampsia, coagulation and fibrinolysis disorders before delivery were typical in patients terminated by cesarean section (coagulation index = 1.62 +/- 1.66) compared with those with successful vaginal delivery (coagulation index = 0.52 +/- 0.34) (p < 0.05). These facts suggest that an excessive hypercoagulable state is associated with the termination of pregnancy resulting from the aggravation of preeclampsia. From the viewpoint of coagulation and fibrinolysis disorders, the predictive value in order to decide the optimal time for the termination of pregnancy could be recommended when the coagulation index exceeded 1.20.
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PMID:Coagulation index to distinguish severe preeclampsia from normal pregnancy. 1253 38

Thrombin substrate binding is mediated through fibrinogen recognition "exosite 1" in thrombin, resulting in fibrinopeptide cleavage to form fibrin. In addition, thrombin exhibits "non-substrate" binding to fibrin, an activity termed "Antithrombin I". Antithrombin I (AT-I) is characterized by two classes of thrombin binding sites, the first of "low affinity" in the fibrin E domain, and the other of high affinity, that is situated between C-terminal residues 414 and 427 of a variant gamma chain termed gamma'(1-427L), Plasma fibrinogen molecules containing gamma' chains ("fibrinogen 2") are virtually all heterodimers containing one gamma(A) chain (platelet-binding) and one gamma' chain. The remaining fibrinogen (approximately 85%) is homodimeric, lacks high affinity thrombin-binding potential, and is termed " fibrinogen 1" (gamma(A)/gamma(A)). Thrombin generation in recalcified fibrinogen-depleted or congenital afibrinogenemic plasma is increased. Repletion with fibrinogen 1 has a modest effect in normalizing thrombin generation, whereas repletion with fibrinogen 2 (gamma(A)/gamma') has a more marked effect. A post-translational gamma' chain derivative, gamma'(1-423P), accounts for 3%-34% of the gamma' chain population, lacks thrombin binding potential, and arises by proteolytic processing at the expense of gamma' (1-427L) chains. Little is known about its effect on plasma AT-I activity under normal or pathological circumstances. In summary, fibrin formation (Antithrombin I) inhibits thrombin generation in clotting blood by sequestering thrombin, and "high-affinity" thrombin-binding (i.e., via gamma' chains) plays a dominant role in this process. AT-1 should be considered when assessing the pathogenesis of thromboembolic disease.
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PMID:Antithrombin I. Inhibition of thrombin generation in plasma by fibrin formation. 1254 Sep 47

As a result of advanced technology, dramatic developments in the area of new anticoagulant and antithrombotic drugs appear to have made a profound impact on the use of LMWHs. Furthermore, because porcine mucosal heparin is used for the preparation of these agents, it is likely that alternative drugs with comparable pharmacologic and clinical efficacy are sought. Antithrombin drugs such as argatroban and hirudin are already approved for alternative management of heparin-compromised patients. Their efficacy in other indications is less superior. The development of specific anti-Xa drugs is slow. Although these agents may inhibit factor Xa and thrombin generation, none of them are capable of mimicking the polytherapeutic effects of LMWHs and thus can only be given in drug combinations. Synthetic and recombinant protein-derived anti-tissue factor agents have also been developed. These drugs only inhibit the tissue factor-mediated process and are limited in their therapeutic spectrum. Plasma-derived and recombinant serine protease inhibitors (serpins) are also available for the management of thrombotic and inflammatory disorders, but these agents cannot be given subcutaneously. Furthermore, because they are proteins, antibodies to these agents are generated. Nucleic acid derivatives (natural and synthetic aptomers) are developed for intravenous administration, but they are relatively weak antithrombotic agents. Dermatans, heparans, and chondroitin sulfates represent nonheparin GAGs, and, in mono-compositional and polycompositional form, these drugs are mainly used for the intravenous management of DVT prophylaxis. They can be given to patients who are heparin compromised. Synthetic heparinomimetics include heparin consensus-binding oligosaccharides and synthetic oligosaccharides with non-serpin affinity. In addition, binding oligosaccharides are conjugated with antithrombin agents to mimic the anti-Xa/anti-IIa activities of heparin. Biotechnology using bacterial and yeast cultures, aqua cultures for marine products, and plant carbohydrates have been the focus of developing heparin analogues. Development of these agents is in the early phase; however, it is likely that this approach may provide a reasonable alternative to LMWHs. Despite these developments, it is unlikely that any of these drugs will have a profound impact on the use of LMWHs in the near future. Unfractionated heparin and LMWHs collectively represent an important group of polypharmacologic drugs without which the management of thrombosis and vascular disorders would not be possible. The continual development of LMWHs in expanded indications did not comprise the use of unfractionated heparin in surgical and interventional cardiovascular indications. Ever since their introduction in the 1980s, the use of LMWHs has continually increased. This is primarily because of expanded indications and growing awareness among the clinicians. It is likely that once an antidote is developed and additional information is available on the mechanism of action of LMWHs, these drugs may gradualty be used for surgery patients. Despite these developments, it is likely that unfractionated heparin will continue to be used for specific indications. Drug combinations with heparins may necessitate dose adjustments, but it is unclear whether unilateral reduction of heparins will be optimal. The coming years will provide useful clinical and applied data on the improved use of unfractionated heparin. LMWHs, and pentasaccharide in the management of thrombotic and cardiovascular disorders. In addition, use of these drugs will be extended to many conditions, including cancer, inflammation, sepsis, and autoimmune diseases. Polytherapeutic approaches emphasizing LMWHs as primary and secondary drugs will also have an impact on the management of thrombotic and nonthrombotic disorders. Ultra-LMWHs and synthetic heparinomimetics, such as fondaparinux, that exhibit a narrow pharmacologic spectrum will only be useful in specific indications and in combination with other drugs.
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PMID:Heparin, low-molecular-weight heparins, and heparin pentasaccharide: basic and clinical differentiation. 1262 73

Blood coagulation can be initiated by two pathways: the extrinsic pathway, which is triggered by release of tissue factor from the site of injury, and the intrinsic system, which is stimulated by contact with a negatively charged surface. Following initial triggering, a series of serine proteases are sequentially activated, culminating in the formation of thrombin, the enzyme responsible for the conversion of soluble fibrinogen to the insoluble fibrin clot. Activation of coagulation is tightly regulated. Initiation by tissue factor is inhibited by tissue factor pathway inhibitor. Antithrombin can inactivate many of the serine proteases, including thrombin, by forming stable complexes which are rapidly cleared from the circulation. Protein C and protein S combine to inactivate coagulation factors V and VIII. The deposition of excess fibrin is prevented by the fibrinolytic system which can lyse fibrin into fibrin degradation products. Both genetic and environmental factors can influence the activation of coagulation and may predispose affected individuals to thrombosis.
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PMID:Blood coagulation. 1278 32


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