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:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue factor pathway inhibitor (TFPI) is a plasma proteinase inhibitor. It is a 42 kD glycoprotein that consists of 276 amino acid residues which sequence is known. TFPI is synthesized by vascular endothelial cells and part of it is associated with glycosaminoglycans of these cells. In blood TFPI is found in a free-form (active) and in an associated with lipoprotein form (nonactive). TFPI directly inhibits activated factor Xa and then factor VIIa/TF complex. Decreasing TFPI activity facilitates an activation of blood coagulation and fibrin forming, increasing TFPI activity inhibits these processes.
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PMID:Tissue factor pathway inhibitor (TFPI). 933 30

Factor V is a single chain glycoprotein that plays an essential role in the regulation of blood coagulation. After initiation of coagulation, factor V is converted into factor Va through limited proteolysis. Factor Va acts as protein cofactor in the prothrombin-activating complex, which is comprised of the serine protease factor Xa, Ca2+ ions and a procoagulant membrane surface. Factor Va accelerates factor Xa-catalysed conversion of prothrombin into thrombin more than 10(4)-fold. The cofactor activity of factor Va in prothrombin activation is down-regulated by activated protein C (APC). The physiological importance of this regulatory pathway is demonstrated by the occurrence of hereditary thrombophilia in individuals with a genetic defect that makes factor Va less sensitive to proteolytic inactivation by APC (APC resistance).
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PMID:Factor V. 943 74

Tissue factor pathway inhibitor (TFPI) is an important regulator of blood coagulation. It was described as antyconwertin (AC), extrinsic pathway inhibitor (EPI) and lipoprotein-associated coagulation inhibitor (LACI). TFPI is a glycoprotein, which is mainly synthesized by vascular endothelial cells. The concentration of this enzyme in plasma is low (100 ng/ml). TFPI inhibits activity of factor Xa and complex FVIIa/TF. Changes TFPI activity play an important role in coagulation disorders and presently the function of TFPI in various kinds of diseases is discussed.
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PMID:[Tissue factor pathway inhibitor (TFPI) and its role in pathology]. 944 3

The carbohydrate-deficient glycoprotein syndromes are a group of recently described autosomal recessive, metabolic defects affecting multiple systems. The disorder is caused by inefficient posttranslational glycosylation of glycoproteins. Patients with the syndrome present early in life with psychomotor retardation, seizures, hypotonia, and stroke-like episodes. They also have dysmorphic features including almond-shaped eyes, constant squint, inverted nipples, and buttock fat pads. One of the features of the syndrome is coagulopathy, and we report here a patient who presented with a prolonged activated partial thromboplastin time, and was subsequently diagnosed with the carbohydrate-deficient glycoprotein syndrome. We also summarize the results of five previously published studies of the coagulation system in these patients. Most of the reported patients are deficient in factor XI, protein C, antithrombin III, and protein S. Other coagulation proteins are less frequently affected. Both bleeding and thrombosis have been observed, yet the cause of the stroke-like episodes remains speculative. The carbohydrate-deficient glycoprotein syndrome is an increasingly recognized multisystem disorder affecting hemostasis, and thus will involve clinical hematologists as part of a multidisciplinary team caring for patients with the syndrome.
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PMID:Coagulation abnormalities in the carbohydrate-deficient glycoprotein syndrome: case report and review of the literature. 988 8

Current antithrombotic therapy in acute coronary symptoms is only partially effective and exhibits bleeding complications. These experiments were designed to address the antithrombotic and hemorrhagic interactions of the novel glycoprotein (GP) IIb/IIIa antagonist SR121787 in combination with the indirect inhibitor of factor Xa, SR90107/ORG31540. Thrombogenesis was initiated by electrolytic injury of the intimal surface of the carotid artery, and thrombus formation was assessed by recording carotid blood flow and by measuring thrombus weight 45 min after electrical stimulation. SR121787 was an efficacious antithrombotic agent in this model (ED50 = 16.3+/-0.3 mg/kg, p.o.), whereas heparin (4.5 mg/kg, i.v.) and SR90107/ORG31540 [1 mg/kg (850 aXa anti-units/kg), i.v.] were only marginally effective (17 and 27% inhibition of carotid blood flow reduction, respectively). Coadministrations of heparin (4.5 mg/kg, i.v.) or SR90107/ORG31540 (0.5 mg/kg, i.v.) were found to potentiate the antithrombotic efficacy of threshold doses of SR121787 (5 or 10 mg/kg, p.o.). The enhancement of the antithrombotic efficacy of SR121787 by SR90107/ORG31540 was--contrary to the association of SR121787 with heparin--not accompanied by an increased blood loss from the incised rabbit ear. Coadministrations of heparin or SR90107/ORG31540 did not influence the ex vivo antiaggregatory activity of SR121787. SR121787 coadministration did not alter the systemic anticoagulant activities in heparin or SR90107/ORG31540-treated animals. These data suggest the potential for optimized antithrombotic treatment in acute coronary syndromes when a GP IIb/IIIa antagonist (SR121787) is combined with an antithrombin-dependent factor Xa inhibitor (SR90107/ORG31540).
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PMID:The antithrombotic efficacy of the GP IIb/IIIa antagonist SR121787 is potentiated by antithrombin-dependent factor Xa inhibition without an increase in the bleeding risk in the rabbit. 1021 27

Orgaran, a heparinoid, has been used successfully in patients with heparin-induced thrombocytopenia. We report three cases in which Orgaran was combined with the glycoprotein IIbIIa receptor antagonist Reopro during coronary angioplasty. Orgaran was given as a single intravenous bolus of 1500 anti-factor Xa units. No ischemic or hemorrhagic complications occurred during or following the procedure.
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PMID:Combined use of Orgaran and Reopro during coronary angioplasty in patients unable to receive heparin. 1034 40

Beta2-glycoprotein I (beta2GPI) is a plasma glycoprotein with unknown physiological function(s). In in vitro experiments it has been demonstrated that beta2GPI has both anticoagulant properties, such as the inhibition of factor X and prothrombin activation and procoagulant properties, such as the inhibition of the anticoagulant activity of activated protein C. Besides this, beta2GPI bound to cardiolipin is recognized by antiphospholipid antibodies (aPL). In this study we demonstrate that beta2GPI is very sensitive for cleavage between Lys317 and Thr318 by plasmin, resulting in two immunologically different cleaved forms. In vitro experiments show that these plasmin cleaved forms of beta2GPI bind to negatively charged phospholipids with much lower affinity compared to intact beta2GPI. Similar to plasmin, trypsin and elastase can also induce this proteolytical cleavage in beta2GPI, whereas thrombin and factor Xa do not cleave beta2GPI. The in vivo occurrence of the proteolytical cleavage was demonstrated by the finding that in plasmas of patients with disseminated intravascular coagulation (DIC) and in plasmas of patients treated with streptokinase, significant amounts of cleaved beta2GPI (up to 12 microg/ml) are present. During the development of DIC, the increase in levels of cleaved beta2GPI is accompanied by a 70% decrease in the levels of intact beta2GPI, whereas in streptokinase treated patients levels of intact beta2GPI stay within the normal range. This study demonstrates for the first time that during in vivo activation of fibrinolysis beta2GPI is cleaved. which results in the formation of a form of beta2GPI with much lower affinity for negatively charged phospholipids. Plasmin is most likely responsible for this modification.
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PMID:Beta2-glycoprotein I is proteolytically cleaved in vivo upon activation of fibrinolysis. 1034 17

Among snake venom procoagulant proteins, group II prothrombin activators are functionally similar to blood coagulation factor Xa. We have purified and partially characterized the enzymatic properties of trocarin, the group II prothrombin activator from the venom of the Australian elapid, Tropidechis carinatus (rough-scaled snake). Prothrombin activation by trocarin is enhanced by Ca2+, phospholipids, and factor Va, similar to that by factor Xa. However, its amidolytic activity on peptide substrate S-2222 is significantly lower. We have determined the complete amino acid sequence of trocarin. It is a 46,515-Dalton glycoprotein highly homologous to factor Xa and shares the same domain architecture. The light chain possesses an N-terminal Gla domain containing 11 gamma-carboxyglutamic acid residues, followed by two epidermal growth factor (EGF)-like domains; the heavy chain is a serine proteinase. Both chains are likely glycosylated: the light chain at Ser 52 and the heavy chain at Asn 45. Unlike other types of venom procoagulants, trocarin is the first true structural homologue of a coagulation factor. It clots snake plasma and thus may be similar, if not identical, to snake blood coagulation factor Xa. Unlike blood factor Xa, it is expressed in high quantities and in a nonhepatic tissue, making snake venom the richest source of factor Xa-like proteins. It induces cyanosis and death in mice at 1 mg/kg body weight. Thus, trocarin acts as a toxin in venom and a similar, if not identical, protein plays a critical role in hemostasis.
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PMID:Amino acid sequence of trocarin, a prothrombin activator from Tropidechis carinatus venom: its structural similarity to coagulation factor Xa. 1039 29

Antiphospholipid syndrome is characterized by the presence of high titers of anti-beta(2)-glycoprotein I (beta(2)GPI) antibodies, lupus anticoagulant associated with thromboembolic phenomena, thrombocytopenia and recurrent fetal loss. Single-chain Fv (scFv) were prepared from four anti-beta(2)GPI mAb, CAM, CAL, CAR and 2C4C2, and one anti-ssDNA. All five scFv showed the same antigen binding properties as the original mAb. Replacement of the pathogenic CAM V(H) domain with the non-pathogenic CAL V(H) or anti-ssDNA V(H) decreased the binding affinity of the scFv to beta(2)GPI and completely abrogated the anticoagulant activity. Exchanging the CAM V(H) with anti-DNA V(H) resulted in a shift from anti-beta(2)GPI to anti-ssDNA binding of the scFv. Replacement of the CAM V(L) with CAL V(L) did not affect the binding and activity. BALB/c mice were immunized with the anti-beta(2)GPI scFv, and the scFv resulting from the substitution of the heavy (H) and light (L) chains. The mice which were immunized with CAM, 2C4C2 and CAR scFv developed clinical manifestations of experimental anti-phospholipid syndrome. Elevated titers of mouse anti-cardiolipin (aCL), anti-beta(2)GPI, associated with lupus anticoagulant activity, thrombocytopenia, prolonged activated partial thromboplastin time and a high percentage of fetal resorptions were detected, in the CAM scFv group and in the scFv composed of CAM V(H) groups. High titers of aCL, anti-beta(2)GPI, anti-ss/dsDNA and anti-histone associated with lupus findings were observed in the sera of the 2C4C2 scFv-immunized mice. Immunization with CAL scFv did not lead to any clinical findings. The current study shows that scFv of pathogenic antibodies are capable of inducing the same clinical manifestations as the whole antibody molecule upon active immunization. Replacement of H/L chains point to the importance of the V(H) domains in the pathogenic potential of anti-beta(2)GPI.
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PMID:Characteristics and pathogenic role of anti-beta2-glycoprotein I single-chain Fv domains: induction of experimental antiphospholipid syndrome. 1059 Feb 57

The GUSTO-I trial provided definitive evidence that early and complete thrombolysis are closely associated with clinical outcome. However, in this trial the best thrombolytic strategy, consisting of accelerated t-PA, aspirin, and heparin, only yielded restoration of brisk flow (TIMI 3) in 54% of patients at 90 minutes after therapy. There are a variety of new strategies aimed at improving the rate of early TIMI flow, consisting of new plasminogen activators, anticoagulants, and platelet inhibitors, The third generation plasminogen activators include reteplase (r-PA), n-PA, bat-PA, staphylokinase, and TNK. To date, none of these molecules have been clearly associated with superior rates of infarct vessel patency, but comparative trials are in progress. Potent inhibitors of thrombin are recombinant hirudin, the most potent naturally occurring anticoagulant known, and synthetic direct thrombin inhibitors such as hirulog and argatroban. In the years ahead, agents that block the generation of thrombin, a step higher up in the coagulation cascade, such as factor Xa inhibitors, will be clinically pursued. The platelet glycoprotein Ilb/Illa inhibitors are a potent class of agents directed against the final common pathway for platelet aggregation, and pilot studies suggest excellent potential for facilitating early thrombolysis. Accordingly, a multitiered strategy of improved plasminogen activators, thrombin inhibitors, and antiplatelets is likely to result in far better clinical outcomes for myocardial reperfusion therapy in the future.
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PMID:Potential for a New Coronary Thrombolytic Plateau. 1060 53


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