Academic literature on the topic 'Factor Xa Inhibitors'
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Journal articles on the topic "Factor Xa Inhibitors"
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Kunitada, Satoshi, and Takayasu Nagahara. "Factor Xa Inhibitors." Current Pharmaceutical Design 2, no. 5 (1996): 531–42. http://dx.doi.org/10.2174/1381612802666221004174926.
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Thrombin occupies a central position in thrombus formation and eventually has been a target to develop anticoagulant agents. Although both heparin and warfarin have been used as anticoagulants, a more useful, ideal anticoagulant is desired at bedside. Numerous efforts to develop a direct inhibitor of thrombin led to the discovery of improved anticoagulants including argatoroban. However, no orally available agent has been developed yet. FXa is responsible for prothrombin activation to generate thrombin and provides an alternative strategy to inhibit the coagulation cascade. In contrast with ATIII-dependent type FXa inhibitor, direct ATIII independent type inhibitors, such as tick anticoagulant peptide and antistasin, showed an inhibitory effect on arterial as well as venous thrombosis models, which was comparable to the effects of thrombin direct inhibitors or glycoprotein llb/Illa inhibitors. We synthesized a low molecular weight, orally active FXa inhibitor, DX- 9065l!, which also showed antithrombotic effect in various kind of thrombosis models. Further, FXa inhibitors have been known to have unique characteristics preferable to those of thrombin inhibitors. In this article, we review the pharmacological profile and structure-activity relationships of FXa inhibitors, ranging from naturally occuring to synthetic small molecular types.
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Perzborn, E. "Factor Xa inhibitors." Hämostaseologie 29, no. 03 (2009): 260–67. http://dx.doi.org/10.1055/s-0037-1617033.
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SummaryOral factor Xa (FXa) inhibitors are a promising alternative to current anticoagulants. This paper reviews the latest developments of oral direct FXa inhibitors and focuses on those which have been approved for the prevention of venous thromboembolism (VTE) after total hip or knee replacement or are in advanced development and have passed phase II (proof of principle) testing.The most advanced drugs are apixaban, betrixaban, edoxaban, eribaxaban, rivaroxaban, LY517717, TAK-442, and YM150. Rivaroxaban (Xarelto→) is the first direct FXa inhibitor which has recently been approved for the prevention of VTE in adult patients after elective hip or knee replacement in several countries, including the European Union and Canada. Rivaroxaban has a flat dose-dependent anticoagulant response with a wide therapeutic window and low potential for drug-drug and drug-food interactions. Rivaroxaban can be given in fixed doses without coagulation monitoring.This review describes the pharmacodynamic and pharmacokinetic profiles and the results of clinical trials with FXa inhibitors in the prevention and treatment of thromboembolic disorders.
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Kaiser, Brigitte. "State-of-the-Art Review: Factor Xa Versus Factor IIa Inhibitors." Clinical and Applied Thrombosis/Hemostasis 3, no. 1 (1997): 16–24. http://dx.doi.org/10.1177/107602969700300102.
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The development of specific inhibitors of blood coagulation enzymes has led to a number of new anticoagulant/antithrombotic agents that could be useful for prophylaxis and/or treatment of thromboembolic disorders. Because thrombin is the central bioregulatory enzyme in hemostasis, blocking of the active site of the enzyme by a fast reaction with an inhibitor may effectively prevent intravascular coagulation as well as other important biological effects of thrombin. For the direct inactivation of thrombin, several classes of compounds have been developed and characterized in vitro and in vivo as potential antithrombotic agents including naturally occurring as well as synthetic thrombin inhibitors such as hirudin, hirulog, arginine (argatroban), and benzamidine (NAPAP) derivatives as well as tripeptide-type inhibitors (efegatran, D-Phe-Pro-Arg-CH2Cl, boroarginine derivatives). Experimental findings suggest that directly acting thrombin inhibitors may be effective in a wide range of arterial and venous thrombotic events. The important role of factor Xa in the coagulation cascade at the stage of the conversion of extrinsic and intrinsic pathways and the amplification of its procoagulant action by prothrombinase complex formation makes factor Xa a promising target also for antithrombotic drugs. Experimental studies on highly effective and selective factor Xa inhibitors (antistasin, tick anticoagulant peptide, yagin, DX-9065a) showed that inhibition of coagulation at a relatively early stage is a very effective way for the prevention of thrombotic processes. Furthermore, it is assumed that factor Xa inhibitors selectively inhibit thrombus formation without compromising hemostasis. In conclusion, both thrombin and factor Xa inhibitors are promising drugs for the management of thrombotic disorders. However, besides the strong inhibitory potency against the target enzyme, other pharmacological aspects such as pharmacodynamics, pharmacokinetics, and toxic side effects must be included in the evaluation of the potential usefulness of thrombin and factor Xa inhibitors for clinical indications. Key Words: Anticoagulants—Antithrombotics—Factor Xa inhibitors—Thrombin inhibitors.
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Al-Obeidi, F., and JA Ostrem. "Factor Xa inhibitors." Expert Opinion on Therapeutic Patents 9, no. 7 (1999): 931–53. http://dx.doi.org/10.1517/13543776.9.7.931.
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&NA;. "Factor Xa inhibitors." Inpharma Weekly &NA;, no. 867 (1992): 11. http://dx.doi.org/10.2165/00128413-199208670-00024.
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Mao, Shi-Shan. "Factor Xa inhibitors." Perspectives in Drug Discovery and Design 1, no. 3 (1994): 423–30. http://dx.doi.org/10.1007/bf02171857.
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Hérault, J. P., B. Perrin, C. Jongbloet, A. M. Pflieger, A. Bernat, and J. M. Herbert. "Effect of Factor Xa Inhibitors on the Platelet-derived Microparticles Procoagulant Activity In Vitro> and In Vivo in Rats." Thrombosis and Haemostasis 84, no. 10 (2000): 668–74. http://dx.doi.org/10.1055/s-0037-1614085.
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SummaryThe aim of this study was to investigate the effect of factor Xa inhibitors on the prothrombinase activity of platelet-derived microparticles in vitro and in vivo. The factor Xa inhibitors studied were DX9065A (a direct factor Xa inhibitor) and Sanorg34006 (an antithrombin (AT)-mediated factor Xa inhibitor). Microparticles formed from the platelet surface following activation were isolated by size exclusion gel chromatography. After purification, their presence was detected by their procoagulant activity and by flow cytometry. Our results show that factor Xa and/or factor Va were present at the surface of the platelet-derived microparticles. Prothrombinase formed on the microparticles was inhibited by factor Xa inhibitors at IC50 values of 0.45 ± 0.05 and 0.045 ± 0.005 µM for DX9065A and AT-Sanorg34006 respectively. In an experiment aimed at determining the kinetics of microparticles formation we demonstrated that thrombin traces were sufficient to induce the formation of a significant quantity of microparticles. Both factor Xa inhibitors delayed the formation of microparticles by delaying thrombin generation. The thrombogenic effect of the microparticles were studied in vivo in a modified arterio-venous shunt model in the rat. In this model, the increase in the thrombus weigh due to microparticles or phospholipids did not differ significantly (33% and 23% respectively). In these conditions, prothrombinase activity seemed to play a lesser role in the thrombogenic effect than phospholipids. Nevertheless, factor Xa inhibitors were efficient and inhibited thrombus formation in a dose-dependent manner.These results demonstrate that platelet-derived microparticles display a potent prothrombotic effect in vivo and show that factor Xa inhibitors are potent antithrombotic compounds when thrombosis was induced by microparticles.
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Friedberg, RC, PO Hagen, and SV Pizzo. "The role of endothelium in factor Xa regulation: the effect of plasma proteinase inhibitors and hirudin." Blood 71, no. 5 (1988): 1321–28. http://dx.doi.org/10.1182/blood.v71.5.1321.bloodjournal7151321.
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The role of endothelium in the inhibition of human factor Xa was studied in a plasma environment. Human factor Xa can bind to and function on bovine aortic endothelium in a manner similar to that of bovine factor Xa. Approximately 70% of the bound factor Xa is subject to inhibition by plasma proteinase inhibitors, and the remaining 30% is irreversibly bound as part of a 125 Kd membrane-associated complex not subject to proteolytic degradation. The proportion reversibly bound and its rate of release do not alter with changes in calcium, citrate, heparin, or active proteinase inhibitor concentrations. The principal plasma proteinase inhibitor of human factor Xa was antithrombin III, which accounted for 60% to 65% of factor Xa released from endothelium, with alpha 1-proteinase inhibitor inactivating 20% to 25% and alpha 2- macroglobulin approximately 15%. All of the reversibly bound factor Xa was identified in complex with one of these three proteinase inhibitors. The thrombin active-site inhibitor hirudin was found to markedly accelerate the displacement of reversibly bound factor Xa from the endothelium and to associate specifically with factor Xa without a loss of activity toward chromogenic substrates, perhaps accounting for a novel mechanism of anticoagulation.
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Stubbs II, Milton T. "Structural Aspects of Factor Xa Inhibition." Current Pharmaceutical Design 2, no. 5 (1996): 543–52. http://dx.doi.org/10.2174/1381612802666221004181847.
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Factor Xa is responsible for both extrinsic and intrinsic generation of active thrombin. The recent structure determination of human factor Xa provides a basis for structure based drug design. Until very recently, however, it .has not been possible to analyse factor Xa - ligand interactions directly. A semi-conservative modelling approach, in which the interaction of factor Xa inhibitors with related serine proteinases is investigated, has yielded valuable information on the structural determinants for factor Xa inhibition. The interactions of factor Xa with DX9065a, tissue factor pathway inhibitor (TFPI), variants of basic pancre tic trypsin inhibitor (BPTI) and tick anticoagulant peptide (TAP) are discussed.
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Friedberg, RC, PO Hagen, and SV Pizzo. "The role of endothelium in factor Xa regulation: the effect of plasma proteinase inhibitors and hirudin." Blood 71, no. 5 (1988): 1321–28. http://dx.doi.org/10.1182/blood.v71.5.1321.1321.
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Abstract The role of endothelium in the inhibition of human factor Xa was studied in a plasma environment. Human factor Xa can bind to and function on bovine aortic endothelium in a manner similar to that of bovine factor Xa. Approximately 70% of the bound factor Xa is subject to inhibition by plasma proteinase inhibitors, and the remaining 30% is irreversibly bound as part of a 125 Kd membrane-associated complex not subject to proteolytic degradation. The proportion reversibly bound and its rate of release do not alter with changes in calcium, citrate, heparin, or active proteinase inhibitor concentrations. The principal plasma proteinase inhibitor of human factor Xa was antithrombin III, which accounted for 60% to 65% of factor Xa released from endothelium, with alpha 1-proteinase inhibitor inactivating 20% to 25% and alpha 2- macroglobulin approximately 15%. All of the reversibly bound factor Xa was identified in complex with one of these three proteinase inhibitors. The thrombin active-site inhibitor hirudin was found to markedly accelerate the displacement of reversibly bound factor Xa from the endothelium and to associate specifically with factor Xa without a loss of activity toward chromogenic substrates, perhaps accounting for a novel mechanism of anticoagulation.
Dissertations / Theses on the topic "Factor Xa Inhibitors"
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Al-Horani, Rami. "Designing Direct and Indirect Factor Xa Inhibitors." VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/329.
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Anticoagulants are the basis for treatment and prevention of thrombotic diseases. The currently available medicines are associated with a wide range of adverse reactions that mandates developing new anticoagulants. Several lines of evidence support the superiority of factor Xa (FXa) as a promising target to develop novel anticoagulants. This work focuses on the design of direct and indirect FXa inhibitors using an interdisciplinary approach. As indirect FXa inhibitors, a focused library of tetrasulfated N–arylacyl tetrahydroisoquinoline (THIQ) nonsaccharide allosteric antithrombin activators was designed, synthesized, and biochemically evaluated to establish their structure–activity relationship (SAR). An N–arylacyl THIQ analog having carboxylate at position–3, two sulfate groups at positions–5 and –8 of THIQ moiety, butanoyl linker, and two sulfate groups at positions–2 and –5 of the phenolic monocyclic moiety was identified as the most promising nonsaccharide antithrombin activator with KD of 1322 ± 237 μM and acceleration potential of 80–fold. Its biochemical profile indicates a strong possibility that it activates antithrombin by the pre–equilibrium pathway rather than the induced–fit mechanism utilized by heparin analogs. A similar interdisciplinary approach was exploited to design direct FXa inhibitors that possess high selectivity and are potentially orally bioavailable. Structurally, the designed direct FXa inhibitors are neutral THIQ dicarboxamides. THIQ dicarboxamide is a privileged structure with a semi–rigid character, a structural feature that potentially offers high selectivity for targeting FXa over other coagulation and digestive proteases. It can also be thought of as an amino acid–like structure, which affords accessibility to a large number of compounds using well established peptide chemistry. Mechanistically, the designed inhibitors were expected to bind to FXa in the active site and function as orthosteric inhibitors. These direct FXa active site inhibitors are also likely to inhibit clot–bound enzyme. Nearly 60 THIQ dicarboxamides were synthesized and biochemically evaluated. Through detailed SAR analysis, the most potent analog was designed and found to exhibit an IC50 of 270 nM (Ki = 135 nM), an improvement of more than 207–fold over the first inhibitor synthesized in the study. The most potent inhibitor displayed at least 1887–fold selectivity for FXa over other coagulation enzymes and a selectivity index of at least 279–fold over the digestive serine proteases. This analog doubled plasma clotting times at 17–20 μM, which are comparable to those of agents being currently studied in clinical trials. Overall, allosteric and orthosteric approaches led to the design of indirect and direct small molecule inhibitors of FXa based on the THIQ scaffold. This work introduces two promising molecules, a tetrasulfated N–arylacyl THIQ analog as a heparin mimetic and a neutral THIQ dicarboxamide as a potent, selective, and potentially bioavailable peptidomimetic, for further advanced medicinal chemistry studies.
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Imaeda, Yasuhiro. "Studies on Sulfonylalkylamides as a New Class of Orally Active Factor Xa Inhibitors." Kyoto University, 2009. http://hdl.handle.net/2433/124028.
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Moulin, Paccaly Anne J. "Approches pharmacocinétiques/pharmacodynamiques appliquées au développement d'un nouvel inhibiteur direct du facteur Xa pour le traitement de la thrombose artérielle." Paris 5, 2005. http://www.theses.fr/2005PA05P630.
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L'otamixaban est un nouvel inhibiteur direct du FXa, en développement pour le traitement intraveineux de la thrombose artérielle. L'objectif de ce travail de pharmacologie clinique vise l'étude des propriétés pharmacocinétiques (PK) et pharmacodynamiques (PD) de l'otamixaban ainsi que l'élaboration de modélisations et simulations (M&S) en support des études de Phase II/III à partir des données chez le sujet sain et chez le patient coronarien chronique. Une "empreinte PK/PD des marqueurs de l'effet anticoagulant" a été genérée, incluant les mesures d'activité anti-FXa, des temps de coagulation (aPTT, PT, dPT, RVVT et HCT), et de l'inhibition de la génération de thrombine. La non-proportionalité de la pharmacocinétique de l'otamixaban à la dose a été explorée et intégrée dans les modèles pharmacocinétiques. L'absence d'effet majeur sexe et age sur les paramètres PK et PD a été démontrée. Enfin, l'absence d'interaction médicamenteuse et la complémentarité des effets anticoagulants de l'otamixaban et des effets anti-plaquettaires des modificateurs de la fonction plaquettaires a été demontrée pour le tirofiban et pour l'acide acétyle salicylique.<br>Otamixaban, is a novel direct FXa inhibitor for the treatment of arterial thrombosis. This clinical pharmacology work aims the study of the pharmacokinetic (PK) and pharmacodynamic (PD) properties of otamixaban as well as the development of modeling and simulations (M&S) to support the Phase II/III studies using data in healthy subjects and in chronic coronary patients. A “fingerprint of PK/PD markers for anticoagulant effect” was generated, including the measurements of anti-FXa activity, of clotting times (aPTT, PT, dPT, RVVT et HCT) and of the inhibition of thrombin generation. The non-dose proportional pharmacokinetics of otamixaban was investigated and built into the pharmacokinetic models. The lack of a major gender and age effect on the PK and PD parameters was demonstrated. Finally, the absence of any drug-drug interactions and the complementarities of the anticoagulant effect of OTAM and of the anti-platelet effects of modifiers of the platelet function has been reported for tirofiban and acetyl salicylic acid
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Sun, Wei. "A New Look into Protein C Inhibitor : Posttranslational Modifications and their Functions." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-131126.
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The influences of posttranslational modifications on the functions of the versatile serpin protein C inhibitor (PCI) were studied. PCI is a serine protease inhibitor that is expressed in many tissues and secreted to various fluids in human, including blood plasma, seminal plasma, and urine. PCI in blood can act both as an anticoagulant and a procoagulant and is believed to play a role in pathogen defence. PCI in reproductive tissues is believed to regulate human reproduction at several steps, including the fertilization process. Due to the broad protease specificity and the contradictory activities, the physiological role of PCI is elusive. In this work the inhibitor was purified from blood and seminal plasma by immunoaffinity chromatography. Blood-derived PCI was found to be highly heterogeneous, due to variations in posttranslational modifications. The occupancy and structures of N- and O-glycans attached to blood plasma PCI and N-glycans of seminal plasma PCI were determined by mass spectrometry. An O-glycosylation site at Thr 20 was identified in PCI derived from blood. N-glycan structures of PCI isolated from blood and seminal plasma differed markedly, demonstrating that they are expressed in a tissue-specific manner. Proteolytic processing also appeared to be tissue-specific, since N-terminally cleaved PCI was found in PCI isolated both from blood and seminal plasma, but the length of the lacking segment differed. The effects of the N-linked glycans and the N-terminus of PCI on protease inhibition were determined using enzymatic measurements with chromogenic substrates. The N-glycans and the N-terminus had different effects on the inhibition of thrombin, factor Xa and prostate specific antigen, demonstrating that posttranslational modifications of PCI affect its functional specificity. These findings enhance the understanding of the regulation of the various functions of PCI and may potentially be used for the production of specialized PCI variants for medical purposes.
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Bonfadini, Marcos Roberto. "Estrutura cristalográfica do inibidor de tripsina purificada de sementes de Enterolobium contortisiloquum e modelagem molecular de seus complexos com tripsina, trombina e fator Xa." Universidade de São Paulo, 2003. http://www.teses.usp.br/teses/disponiveis/76/76132/tde-10092008-101315/.
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Esse trabalho teve como objetivo a determinação da estrutura tridimensional do inibidor de tripsina purificado de sementes de Enterolobium contortisiliquum (EcTI) e a modelagem molecular dos complexos EcTItripsina, EcTI-quimotripsina , EcTI-trombina, EcTI-fator Xa, e suas análises. O EcTI possui 19kDa de peso molecular inibe tripsina, quimotripsina, calicreína plasmática humana, plasmina humana e fator Xlla, mas não inibe fator Xa e ativador de plasminogênio. Monocristais apropriados à coleta de dados de difração de raios-X foram obtidos na condição 50 do fatorial da Hampton (PEG8000 - 0,5M, LiSO4 - 0,5M) através da técnica de acupuntura em gel à temperatura constante de 15°C após três semanas. O grupo espacial encontrado foi o P21 com uma molécula na unidade assimétrica. Os dados de difração foram coletados num detetor de placas de imagem MAR345 na linha de Cristalografia de Proteínas (PCr) no Laboratório Nacional de Luz Síncrotron (LNLS) em Campinas até uma resolução de 1,96Å, completeza de 87% e Rsym=10,3%. A estrutura foi resolvida por Substituição Molecular tendo-se como molde a estrutura do inibidor de tripsina proveniente de Erythrina caffra que apresenta 39% de identidade seqüencial com a seqüência primária do EcTI. Divergências entre a seqüência primária esperada e a observada no mapa de densidade eletrônica levaram à suposição da existência de isoformas para este inibidor. Acatando esta hipótese e supondo que a isoforma cristalizada era diferente da isoforma cuja seqüência foi publicada, mudanças na seqüência guiadas pelo mapa de densidades foram realizadas. Um total de 33 substituições e 1 inserção foram feitos. Diferentemente das tentativas de refinamento com a seqüência original, após as substituições o refinamento convergiu para valores aceitáveis de Rfactor=17% e Rfree=25%. A estrutura apresenta o enovelamento β-trefoil com uma pseudo simetria de ordem 3. Os grampos de cabelo presentes na estrutura são espiralados mas isto não é resultado de repetições sistemáticas nos ângulo Φ/Ψ como esperado. Baseado nesta estrutura cristalográfica, um modelo da seqüência original foi construído por modelagem por homologia. A avaliação do modelo em termos de estereoquímica e compatibilidade estrutura-seqüência mostra uma boa qualidade, mesmo existindo a formação de uma ponte salina enterrada no núcleo hidrofóbico da molécula. Estruturas cristalográficas de complexos entre tripsina, quimotripsina, fator Xa e trombina foram usados para gerar modelos de complexos entre as serinoproteases correspondentes e o EcTI. A falta de atividade de EcTI contra fator Xa e trombina pode ser atribuída à incompatibilidade química e estrutural na interface do complexo.<br>The principal objective of this work was the 3D structural determination of a Trypsin inhibitor from Enterolobium contortisiliquum (EcTI) seeds as well as the modeling of the complexes between EcTI and trypsin, chymotrypsin, thrombin and factor Xa and their subsequent analysis. The inhibitor has a molecular weight of 19.5 kDa and inhibits trypsin, chymotrypsin, human plasma kallikrein, human plasmin and factor Xlla but not factor Xa and tissue type plasminogen activator. A single crystal appropriate for X-ray data collection was grown using condition 50 of Hampton\'s Research fatorial (PEG8000 - 15%, LiSO4 - 0.5mM) by the gel acupuncture technique at 15°C. The crystal grew in three weeks in the space group P21 with one molecule in the assymetric unit. Crystallographic data were acquired using an image plate detector MAR345 on the Protein Crystallography beam line at the Laboratório Nacional de Luz Síncrotron (LNLS), Campinas, out to 1,96Å resolution, with a completeness of 87% and Rsym= 10.3%. The structure was solved by the Molecular Replacement method using the previous determined structure of the trypsin inhibitor from Erythrina caffra which presented 39% sequence identity to EcTI. Discrepancies in the primary structure, as observed in the electron density map led to the supposition of the existence of isoforms for this particular inhibitor. In total 33 substitutions and 1 insertion were made. In contrast with the attempts made with the original sequence, after the amino acids were substituted the refinement converged to acceptable values for Rfactor=17% and Rfree=25%. The 3D fold of EcTI is a β-trefoil as expected. The hairpins present in this fold are coiled coils, but not as a result of the systematic alternation of the Φ/Ψ angles as expected. Using the crystallographic structure as a template a homology model for the original sequence was built. The model evaluation in terms of stereochemistry and structure-sequence compatibility showed it to be of generally good quality, despite the presence of a salt bridge buried in the hydrophobic core. Docking experiments using crystallographic structures of trypsin, chymotripsin, factor Xa and thrombin complexed with their respective inhibitors were undertaken. The lack of EcTI activity against factor Xa and thrombin is predicted to be due to chemical and structural incompatibility at the complex interface.
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Duarte, Beatriz Maria Pinto. "Terapêutica anticoagulante: Novos anticoagulantes orais." Master's thesis, 2019. http://hdl.handle.net/10316/88298.
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Relatório de Estágio do Mestrado Integrado em Ciências Farmacêuticas apresentado à Faculdade de Farmácia<br>O surgimento da varfarina, enquanto medicamento anticoagulante, veio solucionar em parte a profilaxia e o tratamento do tromboembolismo venoso. É uma terapia barata, porém tem desvantagens que são a necessidade de monitorização e o risco de hemorragia. A terapêutica anticoagulante foi facilitada pela descoberta e desenvolvimento dos novos anticoagulantes orais. Estes representam uma nova solução terapêutica, além de não necessitar de testes de monitorização, têm revelado menos efeitos hemorrágicos. Porém é fulcral, mais do que na terapêutica convencional com recurso à varfarina, uma elevada adesão à terapêutica, pois as consequências da não adesão são bem mais gravosas do que com a varfarina.Esta nova terapia não é elegível para todos os indivíduos. Para a sua utilização devem considerar-se todos os fatores relacionados com o doente para se realizar uma escolha criteriosa e direcionada da terapêutica anticoagulante em doentes de risco.O custo elevado, a curto prazo, continua a ser o grande motivo da não adesão. Mas quando se estuda os efeitos a longo prazo e se entendem as verdadeiras vantagens desta nova terapêutica em comparação com a varfarina, verifica-se que o benefício supera o custo. Por fim, importa ressalvar que a limitação quanto à existência de antídotos também começa a ser ultrapassada, uma vez que o dabigatrano já tem antídoto aprovado. E o apixabano e o rivaroxabano têm antídoto desenvolvido e aprovado, até à data, apenas nos Estados Unidos. Isto permite aumentar a segurança no uso dos novos anticoagulantes orais.Posto isto, importa conhecer as características de cada um dos anticoagulantes para se poder fazer um melhor ajuste da terapêutica.<br>The emergence of warfarin as na anticoagulante drug partially resolved the profilaxys and treatment of venous thromboembolism. It is a cheap terapy, but has its disadvantages, the need for monitoring or the risk of bleeding, this therapy was facilitated by the introduction of new oral anticoagulants. These represente a new therapeutic solution, in addition to not requiring monitoring tests have revealed fewer bleeding effects. However, i tis more importante than in conventional therapy with warfarin that get a high adherence to therapy, because the consequences of non-compliance imply far more severe consequences than in warfarin.This new anticoagulante therapy is not elible for all pacientes. For the use of this therapy, all factos related to the pacient should be considered in order to make a judicious and targeted choice of anticoagulante therapy in patients at risk.The high cost, in the short term, remains the major reason for non-adherence. But, once studied the long-term effects and understands the true advantages of this new therapy compared to warfarin, it turn out that the benefit outweighs the cost.Finally, it should be noted that the limitation of antidote also begins to be exceeded, since the dabigatran already has approved antidote. Apixaban and rivaroxaban have antidote developed, but only approved is use in the United States. This facts increases safety in the use of new oral anticoagulants.Having said this, it is importante to know the characteristics of each anticoagulante in order to make a better adjustment of the therapeutics choice.
Books on the topic "Factor Xa Inhibitors"
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Burger, Christina F., Melissa L. Bellomy, and Joseph J. Schlesinger. Coagulation System. Edited by Matthew D. McEvoy and Cory M. Furse. Oxford University Press, 2017. http://dx.doi.org/10.1093/med/9780190226459.003.0091.
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Anticoagulation is increasingly prevalent in the general population and poses a significant risk of increased bleeding in patients needing urgent or emergent surgical procedures. There are two main classes of direct or anticoagulants: direct thrombin inhibitors and factor Xa inhibitors. Management of these patients requires assessment of bleeding risk, possible reversal of anticoagulation, and subsequent management after surgery to prevent postoperative complications associated with either bleeding or clot formation (due to cessation of anticoagulants). This chapter covers the proper assessment and management of patients on oral direct thrombin inhibitor or oral Factor Xa inhibitor therapies.
Book chapters on the topic "Factor Xa Inhibitors"
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Shantsila, Eduard, and Gregory YH Lip. "Factor Xa Inhibitors." In Non-Vitamin K Antagonist Oral Anticoagulants. Springer International Publishing, 2016. http://dx.doi.org/10.1007/978-3-319-25460-9_3.
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Kunitada, S., T. Nagahara, and T. Hara. "Inhibitors of Factor Xa." In Antithrombotics. Springer Berlin Heidelberg, 1999. http://dx.doi.org/10.1007/978-3-642-59942-2_14.
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Schmaier, A. H. "Inhibitors of Thrombin and Factor Xa." In Handbook of Experimental Pharmacology. Springer Berlin Heidelberg, 2000. http://dx.doi.org/10.1007/978-3-642-57092-6_15.
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Husted, Steen, and Lars Wallentin. "Oral Direct Thrombin Inhibitors and Oral Factor Xa Inhibitors." In Therapeutic Advances in Thrombosis. Blackwell Publishing Ltd., 2012. http://dx.doi.org/10.1002/9781118410875.ch12.
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Khan, M. Gabriel. "Antiplatelet Agents, Anticoagulants, Factor Xa Inhibitors, and Thrombin Inhibitors." In Contemporary Cardiology. Humana Press, 2014. http://dx.doi.org/10.1007/978-1-61779-962-4_19.
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Muñiz-Lozano, Ana, Fabiana Rollini, Francesco Franchi, and Dominick J. Angiolillo. "Anticoagulation Therapy. Heparins, Factor II and Factor Xa Inhibitors." In Pharmacological Treatment of Acute Coronary Syndromes. Springer London, 2013. http://dx.doi.org/10.1007/978-1-4471-5424-2_3.
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Mousa, Shaker A. "Oral Direct Factor Xa Inhibitors, with Special Emphasis on Rivaroxaban." In Anticoagulants, Antiplatelets, and Thrombolytics. Humana Press, 2010. http://dx.doi.org/10.1007/978-1-60761-803-4_6.
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Malmström, Rickard E. "New Anticoagulants: Focus on Currently Approved Oral Factor Xa and Factor IIa Inhibitors." In Essential Guide to Blood Coagulation. Wiley-Blackwell, 2010. http://dx.doi.org/10.1002/9781444314465.ch9.
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Malmström, Rickard E., and Hans Johnsson. "New oral anticoagulants: focus on currently approved oral factor Xa and thrombin inhibitors." In Essential Guide to Blood Coagulation. John Wiley & Sons Ltd, 2013. http://dx.doi.org/10.1002/9781118327517.ch11.
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Yang, Xue-Gang, Duan Chen, and Ying Xue. "Integration of Ligand-Based and Structure-Based Approaches for Virtual Screening of Factor Xa Inhibitors." In Quantum Simulations of Materials and Biological Systems. Springer Netherlands, 2012. http://dx.doi.org/10.1007/978-94-007-4948-1_8.
Full textConference papers on the topic "Factor Xa Inhibitors"
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Gadi, I., S. Fatima, S. Kohli, A. Elwakiel, B. Isermann, and K. Shahzad. "Factor Xa and factor IIa inhibitors differentially regulate inflammation in myocardial ischemia reperfusion injury." In 65th Annual Meeting of the Society of Thrombosis and Haemostasis Research. Georg Thieme Verlag KG, 2021. http://dx.doi.org/10.1055/s-0041-1728112.
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Kato, H., K. Uchida, Y. Okada, and T. Yamaguchi. "ANALYSIS OF HYPERCOAGULABILITY BY AUTOMATED FLUOROGENIC METHODS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643053.
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In order to detect hypercoagulable state due to the increase or decrease of coagulation factors and inhibitors concentrations or the presence of active coagulation factors or tissue factor in plasma, highly sensitive automated methods were developed using fluorogenic substrate for thrombin. Coagulability of human plasma was measured by mixing 3 yl of plasma with Thromborel S (TF), calcium and Boc-Val-Pro-Arg-MCA(MCA) (Fluorogenic PT, FPT). FPT of normal plasma was shortened by the addition of purified X or VII (Final conc. 1-5 U per ml), and of thrombin (0.3-1 ng) or Xa (10500 pg). Factors VII and X contents in plasma were measured by mixing 3 yl of diluted plasma with each factor deficient plasma, TF, calcium and MCA in which 10 %-800 % of each factor was quantitatively measured. TF and Xa were measured by mixing with XII or X deficient plasma, phospholipid, calcium and MCA. By this method, 5-500 pg of Xa or 1-1000 units of TF (assuming that one vial of Thromborel S contains 2,000,000 U TF per ml) was quantitatively measured. All the experiments were performed using a centrifugal autoanalyzer (Cobas Bio) with FIA module. The reaction time to reach 0.1 relative fluorescence was calculated by a computer using a program developed by us.These automated methods were applied to examine the hypercoagulability of plasmas from patients with cerebral infarction. Sixty five samples out of 75 showed shorter FPT than control plasma. Xa was detected with the conc. of 3-13 ng Xa per ml. FPT of patient plasmas correlated with Xa content (r=0.70) and X (r=0.63). Xa activity of patient plasma was eluted in the same peak as purified X on gel-filtration of Sephacryl S-200 column and completely inhibited by anti X rabbit IgG. Xa activity was also found in normal serum. The conventional PT or chromogenic PT methods are sensitive to hypocoagulable state but not to hypercoagulab le state. The present automated methods were proved to be sensitive to hypercoagulable state and demonstrated that the presence of Xa or the increase of X concentration in plasma contributes in part to the hypercoagulable state of cerebral infarction.
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Kloss, S., H. Bonnemeier, D. Häckl, T. Vaitsiakhovich, N. Schmedt, and D. Enders. "Comparative safety and effectiveness of factor-xa inhibitors vs. phenprocoumon in patients with non-valvular atrial fibrillation and diabetes." In Diabetes Kongress 2019 – 54. Jahrestagung der DDG. Georg Thieme Verlag KG, 2019. http://dx.doi.org/10.1055/s-0039-1688302.
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Rodzynek, J. J., C. Van Rissenghem, P. Leautaud, and A. Delcourt. "STUDY OF THE PROCOAGULANT ACTIVITY OF ASCITIC FLUID." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643060.
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The aims of the study were to determine the nature of the procoagulant activity present in the ascitic fluid and the means to inhibit the thrombotic complications appearing after peritoneovenous shunting. In a prospective study, 10 ascitic fluids (5 exsudates, 5 transsudates) were studied. The procoagulant activity was defined as the capacity of ascitic fluid to shorten the recalcification time of a control plasma.Our results showed :1. All the ascitic fluids exhibited a procoagulant activity.2. The procoagulant activity of the cellular fraction was related to the presence of platelet factor 3 (PF3) and polymorphonuclear elastase and may be inhibited by the combination of inhibitors of PF3 (phospholipase A inhibitor calbio-chem) and elastase antibody.3. The procoagulant activity of the free cellular fraction was related to the presence of thrombin, factor Xa, PF3 and tissular thromboplastin, and may be inhibited by a combination of Antithrombin III, phospholipase A and Diisopropyl-fluorophosphate.Conclusion :1. The important procoagulant activity of ascitic fluid is present in both cellular and acellular fractions and is related to the presence of different coagulation activators (PF3, elastase, Xa, thrombin, tissular thromboplastin).2. The administration of a combination of AT III and phospholipase A in the ascitic fluid before the contact with the whole blood allows to inhibit the procoagulant activity of ascitic fluid and could prevent the thrombotic complications appearing after peritoneovenous shunt.
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Bowen-Pope, D. F., C. Gajdusek, J. Harlan, et al. "REGULATION OF GROWTH FACTOR PRODUCTION BY ENDOTHELIAL CELLS IN RESPONSE TO COAGULATION AND INFLAMATORY FACTORS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642947.
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Platelet-derived growth factor (PDGF) is a polypeptide growth factor first discovered in, and purified from, human blood platelets. As assayed by its ability to stimulate proliferation of cultured vascular smooth muscle cells, PDGF is the major mitogen in human whole blood serum. PDGF has also been reported to be chemotactic for fibroblasts, vascular smooth muscle cells, and leukocytes, and to be able to stimulate contraction of arterial smooth muscle. This, spectrum of activities suggests that PDGF could play a significant role in several vascular processes, including wound repair and the formation of atherosclerotic lesions (reviewed in Ross et al., 1986 Cell 46:155). Several cell types in addition to the platelet have now been shown to be capable of secreting PDGF-like molecules. In culture, vascular endothelial cells from many sources secrete significant levels of PDGF (DiCorleto and Bowen-Pope, 1983 PNAS 80:1919). Rates of secretion can be increased four fold and more bythe activated procoagulants thrombin (Harlan et al 1986 J. Cell Biol. 103:1129) and factor Xa (Gajdusek et al 1986 J. Cell Biol. 103:419). Thrombin stimulates secretion by the earliest times measurable (about 1.5hr) and this early response is not diminished by inhibitors of protein and RNA synthesis. Nevertheless, unlike secretion from the platelet, stimulated secretion does not represent release of sequestered active PDGF since no reservoir of active PDGF can be detected within the cells prior to stimulation. It is likely therefore that stimulation of secrtion involves the activation or unmasking of an inactive form of PDGF. The proteolytic activities of thrombin and Xa are necessary for activation of secretion but the mechanism does not seem to to involve direct proteolytic activation by thrombin of a precursor since thrombin treatment does not generate active PDGF in freeze-thawed preparations of endothelial cells. We have recently found that tumor necrosis factor alpha (TNF) and gamma interferon (IFN) can stimulate increased rates of secretion of PDGF by cultured human saphenous vein and umbilical vein endothelial cells. Stimulation by a combination of the two is more than additive. In contrast to the rapid kinetics of stimulation by thrombin and Xa, TNF and IFN do not measurably increase secretion for at lease four hrs. This delayed kinetics is paralleled by increases in mRNA encoding the two subunit chains of PDGF ("A" and "B") and it seems likely that in this case stimulation of secretion results from increased rates of mRNA and protein synthesis. Since evidence is accumulating that TNF and IFN are both present in human atherosclerotic lesions, it is possible that they help stimulate production of endothelial cell-derived mitogens, including PDGF and thus contribute to the development of the lesion.
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Hubbard, A. R., and C. A. Jennings. "TISSUE FACTOR-FACTOR VII INHIBITION REQUIRES FACTOR Xa AND PLASMA LIPOPROTEINS." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643291.
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Tissue factor rapidly loses procoagulant activity when incubated with defibrmated normal plasma and calcium ions. Inhibition is apparently directed against the tissue factor-Factor VII complex (TF-EVII) and requires Factor Xa and a component(s) found in A1 (OH)3-adsorbed plasma (AP). We have developed a two stage assay for the inhibitor which involves first, the incubation of a TF-FVII complex with test material in the presence of Factor Xa, followed by the amidolytic assay of residual TF-EVII activity.Our studies have indicated that the component of AP responsible for this effect is lipoprotein. Incubation of AP with antiserum to apo-lipoprotein B (apo B) reduced the inhibitory activity by 73%, whereas antisera to antithrombin III and a2-macroglobulin had no effect. Inhibition by AP does not appear to be caused by an artefact of adsorption, since the inhibitory-capacity of AP was 59% of normal, defibrinated plasma. This correlated well with the apo B antigen in AP, which was 64% of normal. Moreover, the dose/response lines of AP and normal plasma were parallel, suggesting that the inhibitor assay is not affected by the presence of normal levels of coagulation factors.Purified lipoprotein-rich fractions prepared from AP using density gradient ultracentrifugation all contained inhibitory activity. Incubation of these fractions with anti-apo B greatly reduced the inhibition by the very low density and low density lipoprotein-rich fractions (VLDL and LDL) but had essentially no effect on the high density lipoprotein-rich fractions (HDL). Incubation of LDL with Factor Xa produced an inhibitory component which eluted together with the apo B antigen during gel filtration. Inhibition appears to require the interaction of Factor Xa with plasma lipoproteins, particularly LDL. The product of this interaction is then able to bind and inhibit the TF EVII complex. The requirement of Factor Xa in order for inhibition to be expressed is indicative of a feedback anticoagulant response which may have physiological significance.
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Shen An Xiong and Yang Gen Sheng. "Synthesis a novel inhibitor of factor Xa." In 2011 International Conference on Remote Sensing, Environment and Transportation Engineering (RSETE). IEEE, 2011. http://dx.doi.org/10.1109/rsete.2011.5966029.
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Suzuki, Koji, Yoshihiro Deyashiki, Junji Nishioka, Kazunori Toma, and Shuji Yamamoto. "THE INHIBITOR OF ACTIVATED PROTEIN C: STRUCTURE AND FUNCTION." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642963.
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In the final step of protein C pathway, activated protein C (APC) is neutralized with a plasma inhibitor, termed protein C inhibitor (PCI). PCI was first described by Marlar and Griffin (1980) and then isolated from human plasma as a homogeneous form and characterized by the authors (1983). PCI is a single chain glycoprotein with M 57,000 and a plasma concentration of 5 ug/ml. Analysis of a cDNA nucleotide sequence has clarified that a precursor of human PCI consists of a mature protein of 387 amino acid residues (M 43,759) and a signal peptide of 19 amino acid residues. Only one cysteine residue is present in the entire protein as in α1antitrypsin (α1AT) and α1antichymotrypsin (α1ACT). Three Asn-X-Ser/Thr sequences and two Ser/Thr-X-X-Pro sequences are present as potential attachment sites of carbohydrate chains. Based on the amino acid sequence of the carboxyl-terminal peptide released from the inhibitor by APC digestion, the reactive site peptide bond of PCI was found to be Arg(354)-Ser(355). It is similar to the reactive sites of the other serine protease inhibitors which are located to their carboxyl-terminal Arg(393)-Ser (394), Met(358)-Ser(359) and Leu(358)-Ser(359) in antithrombin III, α1AT and α1ACT, respectively. The alignment of the amino acid sequence of PCI with heparin cofactor II, α1plasmin inhibitor, ovalbumin, angiotensinogen and the above noted plasma inhibitors showed that PCI is a member of serine protease inhibitor superfamily. PCI inhibits APC noncompetitively in a 1:1 stoichiometry and forms a covalent acyl-bond with a Ser residue in the active center of APC. The half life of APC in plasma approximately 30 min, which is rather slow compared with the other protease inhibitors. However, optimal concentrations of heparin, dextran sulfate and its derivatives potentiate the rate of inhibition 30-60 fold. PCI has Ki of 10-8m for APC, and can inhibit thrombin, Factor Xa, urokinase and tissue plasminogen activator as well in the presence of heparin or dextran sulfate, though the Ki for these enzymes is slightly higher. During the complex formation with APC, PCI is cleaved by the complexed APC to form a modified form with M 54,000. PCI is synthesized in several hepatoma cell lines and decreased in plasma of patients with liver cirrhosis. It is also decreased in patients with DIC or those during cardiopulmonary bypass in parallel with the decrease in protein C, suggesting that PCI participates in regulation of the protein C pathway in intravascular coagulation. Recently, we have obtained the recombinant PCI from COS-1 cells which were transfected with expression vector pSV2 containing the cDNA of PCI. The recombinant PCI had the same Mr and specific activity as the protein purified from plasma. It also had an affinity for heparin and dextran sulfate. Moreover, we have predicted a three dimentional structure of the proteolytically modified PCI with computer graphics based on its amino acid sequence homology with the modified α1AT whose structure had been elucidated with X-ray crystallography. All potential carbohydrate attachment sites were estimated to exist on the surface of the protein. Succesively we have constructed the interaction model between the intact PCI predicted from the modified form and the active center of APC which was simulated from that of trypsin. From the model, it was observed that the amino-group of Arg (354, PI site) of PCI could strongly interact with the carboxy1-group of Asp (88, SI site) of the heavy chain of APC at the base of the active center pocket of the enzyme.
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Qureshi, G. D., M. Sun, C. Gervin, and H. Evans. "RAT HEPAT0CYTES IN CULTURE INACTIVATE FACTOR Xa." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1643294.
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Plasma contains zymogens of clotting factors, which under various stimuli are activated to serine proteases. Whereas much knowledge has been gained about the activation of clotting factors, relatively little is known about inactivation of these proteases. Antithrombin III has been shown to inactivate some activated clotting factors in plasma. Studies in intact animals have suggested that activated clotting factors are mainly inactivated in the liver. To investigate more fully the role of liver in inactivating the activated factors, we studied the stability of activated factor X(Xa) in hepatocyte cultures. Monolayer cultures on non-proliferating rat hepatocytes were prepared according to the method of Bissell et al. The culture medium was chemically defined and was free from serum or serum products. After the 24 h stabilization period, 0.5 units/ml of 100% activated bovine factor Xa was co-cultured with hepatocytes for 8 h. Samples were collected at 0, ½, 1 2, 4 and 8 h and tested for Xa activity using chromogenic substrate S-2222. At the end of 8 h only 41.07% of the initial Xa activity remained. Xa inactivation was not affected by a commercially prepared unfractionated heparin (1 unit/ml) and estradiol at 12.5, 25, 125 nM, a potentiator and inhibitor of antithrombin III, respectively. Inactivation of Xa in hepatocyte cultures was inhibited by the addition of cycloheximide (10-4M). Our data suggests that factor Xa is inactivated in hepatocyte cultures by one or more hepatic derived factors which do not meet the functional characteristics of antithrombin III.
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Ofosu, F. A., G. J. Modi, M. R. Buchanan, J. Hirsh, and M. A. Blajchman. "HEPARIN IS NOT AN EFFICIENT INHIBITOR OF THE FACTOR Xa-DEPENDENT ACTIVATION OF FACTOR V AND FACTOR VIII." In XIth International Congress on Thrombosis and Haemostasis. Schattauer GmbH, 1987. http://dx.doi.org/10.1055/s-0038-1642931.
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We have previously proposed that the steps in coagulation most sensitive to inhibition by heparin are the thrombin-dependent activation of factor V and factor VIII. This observation was based on the demonstration that therapeutic concentrations of heparin or 1μM of the thrombin specific inhibitor, phe-pro-arg CH2Cl (PPACK) completely inhibited the activation of prothrombin when contact-activated plasma (CAP) was recalcified for up to 1 min. Under similar conditions, heparin and PPACK only partially inhibited the activation of factor X. Moreover, the addition of thrombin (lOnM) to CAP 1 min before that of heparin or PPACK reversed their inhibitory effects. We now provide further support for our hypothesis by showing that when the activity of thrombin is suppressed by heparin or PPACK, efficient activation of radiolabelled prothrombin occurs only when the factor Xa then present activates factor V and factor VIII. We compared the effects of HEP of PPACK on the following four systems for initiating the activation of prothrombin: (1) CAP; (2) CAP + lOnM thrombin; (3) CAP + InM Xa and (4) unactivated plasma + InM Xa + InM Va + coagulant phospholipids. In each system, the enzymes were added 1 min before the heparin or PPACK. In the absence of heparin or PPACK, all four systems generated the same amount of thrombin activity in 45s. Complete inhibition of prothrombin activation by heparin and PPACK was observed only in system 1 which did not contain exogenous thrombin or factor Xa. No inhibition by heparin or PPACK was observed when thrombin or factor Xa was added to CAP in systems (2) and (3). Only partial inhibition was observed in system (4) which contained exogenous prothrombi-nase complex. Factor Xa thus provides an effective by-pass mechanism for the activation of factor VIII and factor V in plasma containing therapeutic concentrations of heparin. Our data provide further evidence that the heparin-antithrombin III system is not effective in inactivating factor Xa. These results support the hypothesis that in unactivated normal plasma, the primary anticoagulant effect of heparin is the inhibition of the thrombin-dependent activation of factor V and factor VIII.