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Joseph H. Gorman - One of the best experts on this subject based on the ideXlab platform.
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Enoxaparin suppresses Thrombin Formation and activity during cardiopulmonary bypass in baboons
The Journal of thoracic and cardiovascular surgery, 1998Co-Authors: Nicolas Gikakis, Shinji Miyamoto, A. Koneti Rao, Joseph H. Gorman, Mohammed M.h. Khan, Harry L. Anderson, C.eric Hack, Ling Sun, Stefan Niewiarowski, Robert W. ColmanAbstract:Abstract Objective: This study tests the hypotheses that enoxaparin, a low molecular weight heparin and potent inhibitor of factor Xa, alone or in combination with standard heparin, inhibits Thrombin Formation and activity and modulates complement activation and neutrophil elastase release during cardiopulmonary bypass in baboons. Methods : After preliminary studies to determine doses and possible species differences to anticoagulants and protamine, 27 anesthesized baboons had normothermic cardiopulmonary bypass with standard, unfractionated, porcine intestinal heparin, enoxaparin, or a combination of heparin and enoxaparin. Protamine in appropriate doses was used to reverse anticoagulation. Blood samples were obtained at 6 time points. Activated clotting times were monitored; template bleeding times were measured before and up to 24 hours after cardiopulmonary bypass. Results : Hemodynamic measurements were not affected by the anticoagulant. Activated clotting times remained above 400 seconds throughout bypass, and no clots were observed. The anticoagulant did not alter platelet count, aggregation to adenosine diphosphate, release of β-thromboglobulin, release of neutrophil elastase, or complement C3b/c and C4b/c. Enoxaparin alone, but not in combination, significantly reduced plasma levels of proThrombin fragment F1.2, fibrinopeptide A, and Thrombin-antiThrombin complexes but prolonged template bleeding times for more than 24 hours. Conclusion : Enoxaparin significantly reduces Thrombin Formation and activity during cardiopulmonary bypass but does not suppress complement activation and neutrophil elastase release and is not adequately reversed by protamine after bypass. (J Thorac Cardiovasc Surg 1998;116:1043-51)
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Effect of factor Xa inhibitors on Thrombin Formation and complement and neutrophil activation during in vitro extracorporeal circulation.
Circulation, 1996Co-Authors: N Gikakis, Joseph H. Gorman, Mohammed M.h. Khan, C.eric Hack, Ling Sun, Stefan Niewiarowski, Y Hiramatsu, A K Rao, R W Colman, L H EdmundsAbstract:Even when large doses of heparin are administered during cardiopulmonary bypass, Thrombin is produced. Thrombin is a powerful protease that is associated with the thrombotic and bleeding complications of open heart surgery and is produced by cleavage of proThrombin by factor Xa. This study assessed the ability of a specific inhibitor of factor Xa, recombinant tick anticoagulant peptide (rTAP), alone or in combination with standard heparin and a low-molecular-weight heparin, enoxaparin, to suppress Thrombin Formation and activity during in vitro extracorporeal circulation. Fresh, anticoagulated human blood was recirculated for 2 hours in an extracorporeal membrane oxygenator perfusion circuit at 37 degrees C. Four anticoagulant protocols were evaluated; porcine heparin (3.75 U/mL); enoxaparin (17.5 U/mL); rTAP (4 mumol/L); and porcine heparin plus rTAP (2 mumol/L). Blood samples were obtained for analysis from the donor, after anticoagulation, and after 5, 30, 60, and 120 minutes of recirculation. There were no significant differences between groups in platelet count, response to adenosine diphosphate, or proThrombin fragment (F1.2) production. rTAP plus heparin reduced beta-thromboglobulin release; fibrinopeptide A concentrations were significantly higher with rTAP alone. Enoxaparin strongly and significantly inhibited complement C5b9 production and neutrophil elastase release and was associated with significantly increased concentrations of C1-C1 inhibitor and kallikrein-C1 inhibitor complexes. rTAP does not reduce Thrombin Formation or activity during in vitro extracorporeal circulation. Enoxaparin markedly inhibits Formation of the complement membrane attack complex and neutrophil elastase release, possibly by accelerating C1 inhibitor activity.
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Effect of factor Xa inhibitors on Thrombin Formation and complement and neutrophil activation during in vitro extracorporeal circulation
Circulation, 1996Co-Authors: Nicolas Gikakis, Mohammad M.h Khan, Robert W. Colman, Joseph H. Gorman, C.eric Hack, Ling Sun, Stefan Niewiarowski, Y Hiramatsu, A K Rao, L H EdmundsAbstract:Background Even when large doses of heparin are administered during cardiopulmonary bypass, Thrombin is produced. Thrombin is a powerful protease that is associated with the thrombotic and bleeding complications of open heart surgery and is produced by cleavage of proThrombin by factor Xa. This study assessed the ability of a specific inhibitor of factor Xa, recombinant tick anticoagulant peptide (rTAP), alone or in combination with standard heparin and a low-molecular-weight heparin, enoxaparin, to suppress Thrombin Formation and activity during in vitro extracorporeal circulation. Methods and Results Fresh, anticoagulated human blood was recirculated for 2 hours in an extracorporeal membrane oxygenator perfusion circuit at 37°C. Four anticoagulant protocols were evaluated : porcine heparin (3.75 U/mL) ; enoxaparin (17.5 U/mL) ; rTAP (4 μmol/L) ; and porcine heparin plus rTAP (2 μmol/L). Blood samples were obtained for analysis from the donor, after anticoagulation, and after 5, 30, 60, and 120 minutes of recirculation. There were no significant differences between groups in platelet count, response to adenosine diphosphate, or proThrombin fragment (Fl.2) production. rTAP plus heparin reduced β-thromboglobulin release ; fibrinopeptide A concentrations were significantly higher with rTAP alone. Enoxaparin strongly and significantly inhibited complement C5b9 production and neutrophil elastase release and was associated with significantly increased concentrations of C1-C1 inhibitor and kallikrein-C1 inhibitor complexes. Conclusions rTAP does not reduce Thrombin Formation or activity during in vitro extracorporeal circulation. Enoxaparin markedly inhibits Formation of the complement membrane attack complex and neutrophil elastase release, possibly by accelerating Cl inhibitor activity.
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Surface-bound heparin fails to reduce Thrombin Formation during clinical cardiopulmonary bypass.
The Journal of thoracic and cardiovascular surgery, 1996Co-Authors: Robert C. Gorman, Nicolas Gikakis, A. Koneti Rao, Mohammed M.h. Khan, Ling Sun, Nicholas P. Ziats, Nina Stenach, Suneeti Sapatnekar, Vibhuti D. Chouhan, Joseph H. GormanAbstract:Abstract The hypothesis that heparin-coated perfusion circuits reduce Thrombin Formation and activity; fibrinolysis; and platelet, complement, and neutrophil activation was tested in 20 consecutive, randomized adults who had cardiopulmonary bypass. Twenty identical perfusion systems were used; in 10, all blood-contacting surfaces were coated with partially degraded heparin (Carmeda process; Medtronic Cardiopulmonary, Anaheim, Calif.). All patients received a 300 U/kg dose of heparin. Activated clotting times were maintained longer than 400 seconds. Cardiopulmonary bypass lasted 36 to 244 minutes. Blood samples for platelet count, platelet response to adenosine diphosphate, plasma β-thromboglobulin, inactivated complement 3b, neutrophil elastase, fibrinopeptide A, proThrombin fragment F1.2, Thrombin-antiThrombin complex, tissue plasminogen activator, plasminogen activator inhibitor-1, plasmin α 2 -antiplasmin complex, and D-dimer were obtained at these times: after heparin was given, 5 and 30 minutes after cardiopulmonary bypass was started, within 5 minutes after bypass was stopped, and 15 minutes after protamine was given. After cardiopulmonary bypass, tubing segments were analyzed for surface-adsorbed antiThrombin, fibrinogen, factor XII, and von Willebrand factor by radioimmunoassay. Heparin-coated circuits significantly (p (p = 0.015), but did not reduce release of β-thromboglobulin. There were no significant differences between groups at any time for fibrinopeptide A, proThrombin fragment F1.2, or Thrombin-antiThrombin complex or in the markers for fibrinolysis: D-dimer, tissue plasminogen activator, plasminogen activator inhibitor-1, and α 2 -antiplasmin complex. In both groups, concentrations of proThrombin fragment F1.2 and Thrombin-antiThrombin complex increased progressively and significantly during cardiopulmonary bypass and after protamine was given. Concentrations of D-dimer, α 2 -antiplasmin complex, and plasminogen activator inhibitor-1 also increased significantly during bypass in both groups. Fibrinopeptide A levels did not increase during bypass but in both groups increased significantly after protamine was given. No significant differences were observed between groups for levels of inactivated complement 3b or neutrophil elastase. Radioimmunoassay showed a significant increase in surface-adsorbed antiThrombin on coated circuits but no significant differences between groups for other proteins. We conclude that heparin-coated circuits used with standard doses of systemic heparin reduce platelet adhesion and improve platelet function but do not produce a meaningful anticoagulant effect during clinical cardiopulmonary bypass. The data do not support the practice of reducing systemic heparin doses during cardiac operations with heparin-coated extracorporeal perfusion circuitry. (J THORAC CARDIOVASC SURG 1996;111:1-12)
Anetta Undas - One of the best experts on this subject based on the ideXlab platform.
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Asthma is associated with enhanced Thrombin Formation and impaired fibrinolysis
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 2016Co-Authors: Stanisława Bazan-socha, Lucyna Mastalerz, Agnieszka Cybulska, Lech Zareba, Romy Kremers, Michal Zabczyk, Grazyna Pulka, Teresa Iwaniec, Coenraad Hemker, Anetta UndasAbstract:BACKGROUND There is evidence that altered blood coagulation and fibrinolysis are involved in the pathogenesis of asthma. Increased thromboembolic risk has been reported in asthmatics. OBJECTIVE To investigate whether enhanced Thrombin generation and impaired fibrinolysis occur in asthmatics. METHODS Plasma Thrombin generation profile together with a computational assessment of Thrombin dynamics and fibrinolytic capacity expressed as clot lysis time (CLT) were determined in 164 consecutive patients with stable asthma and 72 controls matched for age, gender, weight and smoking. RESULTS Asthma patients had 20.2% increased endogenous Thrombin potential (ETP), 41.4% higher peak Thrombin concentration, 61% higher maximal proThrombin conversion rate, 15.5% faster rate of Thrombin Formation (all, P < 0.0001) and 10% lower Thrombin decay capacity (P = 0.0004) compared with controls. Asthmatics had also 14.4% longer CLT (P = 0.001) associated with 21.3% higher plasminogen activator inhibitor-1 (PAI-1) (P < 0.0001), and 13% higher plasma α2 -macroglobulin (P = 0.0002). Using ETP and CLT above 75th percentile of the control values as the cut-off levels, we found increased risks of enhanced Thrombin generation and hypofibrinolysis in asthmatics, also after correction for potential confounders. ETP and CLT were associated inversely with forced expiratory volume in 1 s/vital capacity (FEV1 /VC) index, after adjustment for age and body mass index. Non-allergic asthma (n = 70, 42.6%) was characterized by 17.5% longer CLT (P = 0.02), which positively associated with PAI-1. Thrombin generation profile was not affected by allergy. CONCLUSION AND CLINICAL RELEVANCE Asthma is associated with enhanced Thrombin generation and impaired fibrinolysis, which might contribute to thromboembolic events in this disease.
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reduced Thrombin Formation and altered fibrin clot properties induced by polyunsaturated omega 3 fatty acids on top of dual antiplatelet therapy in patients undergoing percutaneous coronary intervention omega pci clot
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Grzegorz Gajos, Jaroslaw Zalewski, Pawel Rostoff, Jadwiga Nessler, Wieslawa Piwowarska, Anetta UndasAbstract:Objective— The goal of this study was to investigate whether omega-3 polyunsaturated fatty acids (n-3 PUFA) are able to alter plasma fibrin clot properties and reduce Thrombin Formation in stable coronary artery disease patients undergoing percutaneous coronary intervention (PCI). Methods and Results— In an investigator-initiated, prospective, double-blind, placebo-controlled, randomized study, patients undergoing PCI who received standard pharmacotherapy were assigned to the treatment with 1 g/day n-3 PUFA (n=30) or placebo (n=24) for 1 month. Plasma fibrin clot permeability ( K s); lysis time ( t 50%); proThrombin fragment 1.2; and peak Thrombin generation from automated thrombogram, 8-isoprostaglandin F2α (8-iso-PGF2α, an oxidative stress marker), and C-reactive protein were determined at baseline, 3 to 5 days after randomization, and 30 days after randomization. At baseline, both treatment groups did not differ significantly. A 1-month treatment with n-3 PUFA compared with placebo was associated with 15.3% higher K s, indicating larger pores in the fibrin network ( P =0.0005); 14.3% shorter t 50%, indicating increased susceptibility to fibrinolysis ( P <0.0001); 33.8% lower proThrombin fragment 1.2 ( P =0.0013); 13.4% lower peak Thrombin generation ( P =0.04); and 13.1% lower 8-iso-PGF2α ( P =0.009). Treatment with n-3 PUFA had no effect on fibrinogen and C-reactive protein. After 1 month of treatment, fibrinogen ( r =−0.53, P <0.0001), treatment assignment ( r =0.29, P =0.006) and 8-iso-PGF2α ( r =−0.27, P =0.015) were independently associated with clot permeability ( P <0.0001, R 2=0.66). Conclusion— Adding n-3 PUFA to standard therapy in stable patients undergoing PCI significantly decreases Thrombin Formation and oxidative stress and favorably alters fibrin clot properties. These findings indicate novel antithrombotic effects induced by n-3 PUFA in humans.
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Reduced Thrombin Formation and Altered Fibrin Clot Properties Induced by Polyunsaturated Omega-3 Fatty Acids on Top of Dual Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention (OMEGA-PCI Clot)
Arteriosclerosis thrombosis and vascular biology, 2011Co-Authors: Grzegorz Gajos, Pawel Rostoff, Jadwiga Nessler, Wieslawa Piwowarska, Jarosław Zalewski, Anetta UndasAbstract:Objective— The goal of this study was to investigate whether omega-3 polyunsaturated fatty acids (n-3 PUFA) are able to alter plasma fibrin clot properties and reduce Thrombin Formation in stable coronary artery disease patients undergoing percutaneous coronary intervention (PCI). Methods and Results— In an investigator-initiated, prospective, double-blind, placebo-controlled, randomized study, patients undergoing PCI who received standard pharmacotherapy were assigned to the treatment with 1 g/day n-3 PUFA (n=30) or placebo (n=24) for 1 month. Plasma fibrin clot permeability ( K s); lysis time ( t 50%); proThrombin fragment 1.2; and peak Thrombin generation from automated thrombogram, 8-isoprostaglandin F2α (8-iso-PGF2α, an oxidative stress marker), and C-reactive protein were determined at baseline, 3 to 5 days after randomization, and 30 days after randomization. At baseline, both treatment groups did not differ significantly. A 1-month treatment with n-3 PUFA compared with placebo was associated with 15.3% higher K s, indicating larger pores in the fibrin network ( P =0.0005); 14.3% shorter t 50%, indicating increased susceptibility to fibrinolysis ( P
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Tissue factor +5466A>G polymorphism determines Thrombin Formation following vascular injury and Thrombin-lowering effects of simvastatin in patients with ischemic heart disease.
Atherosclerosis, 2008Co-Authors: Anetta Undas, Ewa Stępień, Daniel P. Potaczek, Wiesława TraczAbstract:Summary Objective We examined the hypothesis that the +5466A>G variant (rs3917643) of the tissue factor (TF) gene is associated with Thrombin Formation following simvastatin in patients with ischemic heart disease (IHD). Methods and results ProThrombin 1.2 fragments (F1.2) and Thrombin–antiThrombin complexes (TAT) were assessed in 95 men with stable IHD, aged 54.4 ± 6.8 years, in blood collected every 60 s from the bleeding-time wounds before and after a 3-month simvastatin administration (40 mg/day). We identified 16 patients with the TF +5466AG genotype and 79 subjects with the +5466AA genotype. Baseline maximum rates of F1.2 and TAT Formation and their maximum levels at the site of vascular injury, but not in venous blood, were higher in +5466G allele carriers than in those with +5466AA genotype ( P P P Conclusions Thrombin Formation following vascular injury and Thrombin-lowering effect of statins in patients with IHD are at least in part genetically determined by the TF +5466A>G polymorphism.
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Thrombin Formation in platelet-rich plasma after oral methionine loading: preliminary report.
Thrombosis research, 2002Co-Authors: Teresa B. Domagala, Anetta Undas, Wojciech Sydor, Andrzej SzczeklikAbstract:Homocysteine, an intermediate of methionine metabolism, has been found to be an independent risk factor for thromboembolism [1]. Various mechanisms have been proposed to explain possible homocysteine-induced thrombogenicity, including endothelial damage, enhanced lipid peroxidation, impaired activity of the anticoagulant protein C system and increased expression of tissue factor [1–5]. Relevance of these findings in vivo remains controversial. Much less is known on the effects of homocysteine on platelet function [6]. In patients with homocystinuria, homocysteine might increase thromboxane A2 production [7] and stimulate platelet aggregation [8], though the effect of homocysteine on platelet survival is less evident [6]. Oxidative stress might lead to homocysteine oxidation, enhanced platelet activation and increased prothrombotic potential in hyperhomocysteinemia [9]. Methionine loading test is recognized as a method to induce a transient acute hyperhomocysteinemia and helps to identify individuals with abnormal methionine metabolism [10,11]. It remains to be determined whether in mild hyperhomocysteinemia platelet-mediated prothrombotic effects might be of importance. The aim of the study was to evaluate potential alterations in Thrombin Formation in platelet-rich plasma after oral methionine loading in healthy subjects. 2. Materials and methods
Nicolas Gikakis - One of the best experts on this subject based on the ideXlab platform.
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Aprotinin inhibits Thrombin Formation and monocyte tissue factor in simulated cardiopulmonary bypass.
The Annals of thoracic surgery, 1999Co-Authors: Mohammad M.h Khan, Nicolas Gikakis, Shinji Miyamoto, A. Koneti Rao, Stuart L. Cooper, L. Henry Edmunds, Robert W. ColmanAbstract:Abstract Background . Aprotinin reduces perioperative bleeding after open heart surgery, primarily by inhibiting fibrinolysis. In addition, the drug has both procoagulant and anticoagulant effects that involve complex reactions of coagulation proteins and cells that are incompletely understood. This study tests the hypothesis that aprotinin has an anticoagulant effect on the extrinsic coagulation pathway. Methods . Human heparinized blood was recirculated through a membrane oxygenator with and without high concentrations of aprotinin (18.4 μM). Serial plasma samples were obtained at intervals up to 240 minutes. Results . Aprotinin significantly reduced the progressive increase in proThrombin fragments (F1.2) and Thrombin-antiThrombin complex beginning immediately. Aprotinin also significantly reduced monocyte expression of tissue factor and Mac-1. Aprotinin did not significantly reduce factor VII or factor VIIa. Conclusions . During simulated cardiopulmonary bypass, aprotinin immediately inhibits kallikrein and Thrombin Formation via the intrinsic coagulation pathway. Later, aprotinin inhibits monocyte expression of tissue factor and the extrinsic coagulation pathway. The ability of aprotinin to inhibit monocyte tissue factor provides a means to reduce Thrombin Formation in blood aspirated from the wound during open heart surgery.
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Enoxaparin suppresses Thrombin Formation and activity during cardiopulmonary bypass in baboons
The Journal of thoracic and cardiovascular surgery, 1998Co-Authors: Nicolas Gikakis, Shinji Miyamoto, A. Koneti Rao, Joseph H. Gorman, Mohammed M.h. Khan, Harry L. Anderson, C.eric Hack, Ling Sun, Stefan Niewiarowski, Robert W. ColmanAbstract:Abstract Objective: This study tests the hypotheses that enoxaparin, a low molecular weight heparin and potent inhibitor of factor Xa, alone or in combination with standard heparin, inhibits Thrombin Formation and activity and modulates complement activation and neutrophil elastase release during cardiopulmonary bypass in baboons. Methods : After preliminary studies to determine doses and possible species differences to anticoagulants and protamine, 27 anesthesized baboons had normothermic cardiopulmonary bypass with standard, unfractionated, porcine intestinal heparin, enoxaparin, or a combination of heparin and enoxaparin. Protamine in appropriate doses was used to reverse anticoagulation. Blood samples were obtained at 6 time points. Activated clotting times were monitored; template bleeding times were measured before and up to 24 hours after cardiopulmonary bypass. Results : Hemodynamic measurements were not affected by the anticoagulant. Activated clotting times remained above 400 seconds throughout bypass, and no clots were observed. The anticoagulant did not alter platelet count, aggregation to adenosine diphosphate, release of β-thromboglobulin, release of neutrophil elastase, or complement C3b/c and C4b/c. Enoxaparin alone, but not in combination, significantly reduced plasma levels of proThrombin fragment F1.2, fibrinopeptide A, and Thrombin-antiThrombin complexes but prolonged template bleeding times for more than 24 hours. Conclusion : Enoxaparin significantly reduces Thrombin Formation and activity during cardiopulmonary bypass but does not suppress complement activation and neutrophil elastase release and is not adequately reversed by protamine after bypass. (J Thorac Cardiovasc Surg 1998;116:1043-51)
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Effect of factor Xa inhibitors on Thrombin Formation and complement and neutrophil activation during in vitro extracorporeal circulation
Circulation, 1996Co-Authors: Nicolas Gikakis, Mohammad M.h Khan, Robert W. Colman, Joseph H. Gorman, C.eric Hack, Ling Sun, Stefan Niewiarowski, Y Hiramatsu, A K Rao, L H EdmundsAbstract:Background Even when large doses of heparin are administered during cardiopulmonary bypass, Thrombin is produced. Thrombin is a powerful protease that is associated with the thrombotic and bleeding complications of open heart surgery and is produced by cleavage of proThrombin by factor Xa. This study assessed the ability of a specific inhibitor of factor Xa, recombinant tick anticoagulant peptide (rTAP), alone or in combination with standard heparin and a low-molecular-weight heparin, enoxaparin, to suppress Thrombin Formation and activity during in vitro extracorporeal circulation. Methods and Results Fresh, anticoagulated human blood was recirculated for 2 hours in an extracorporeal membrane oxygenator perfusion circuit at 37°C. Four anticoagulant protocols were evaluated : porcine heparin (3.75 U/mL) ; enoxaparin (17.5 U/mL) ; rTAP (4 μmol/L) ; and porcine heparin plus rTAP (2 μmol/L). Blood samples were obtained for analysis from the donor, after anticoagulation, and after 5, 30, 60, and 120 minutes of recirculation. There were no significant differences between groups in platelet count, response to adenosine diphosphate, or proThrombin fragment (Fl.2) production. rTAP plus heparin reduced β-thromboglobulin release ; fibrinopeptide A concentrations were significantly higher with rTAP alone. Enoxaparin strongly and significantly inhibited complement C5b9 production and neutrophil elastase release and was associated with significantly increased concentrations of C1-C1 inhibitor and kallikrein-C1 inhibitor complexes. Conclusions rTAP does not reduce Thrombin Formation or activity during in vitro extracorporeal circulation. Enoxaparin markedly inhibits Formation of the complement membrane attack complex and neutrophil elastase release, possibly by accelerating Cl inhibitor activity.
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Surface-bound heparin fails to reduce Thrombin Formation during clinical cardiopulmonary bypass.
The Journal of thoracic and cardiovascular surgery, 1996Co-Authors: Robert C. Gorman, Nicolas Gikakis, A. Koneti Rao, Mohammed M.h. Khan, Ling Sun, Nicholas P. Ziats, Nina Stenach, Suneeti Sapatnekar, Vibhuti D. Chouhan, Joseph H. GormanAbstract:Abstract The hypothesis that heparin-coated perfusion circuits reduce Thrombin Formation and activity; fibrinolysis; and platelet, complement, and neutrophil activation was tested in 20 consecutive, randomized adults who had cardiopulmonary bypass. Twenty identical perfusion systems were used; in 10, all blood-contacting surfaces were coated with partially degraded heparin (Carmeda process; Medtronic Cardiopulmonary, Anaheim, Calif.). All patients received a 300 U/kg dose of heparin. Activated clotting times were maintained longer than 400 seconds. Cardiopulmonary bypass lasted 36 to 244 minutes. Blood samples for platelet count, platelet response to adenosine diphosphate, plasma β-thromboglobulin, inactivated complement 3b, neutrophil elastase, fibrinopeptide A, proThrombin fragment F1.2, Thrombin-antiThrombin complex, tissue plasminogen activator, plasminogen activator inhibitor-1, plasmin α 2 -antiplasmin complex, and D-dimer were obtained at these times: after heparin was given, 5 and 30 minutes after cardiopulmonary bypass was started, within 5 minutes after bypass was stopped, and 15 minutes after protamine was given. After cardiopulmonary bypass, tubing segments were analyzed for surface-adsorbed antiThrombin, fibrinogen, factor XII, and von Willebrand factor by radioimmunoassay. Heparin-coated circuits significantly (p (p = 0.015), but did not reduce release of β-thromboglobulin. There were no significant differences between groups at any time for fibrinopeptide A, proThrombin fragment F1.2, or Thrombin-antiThrombin complex or in the markers for fibrinolysis: D-dimer, tissue plasminogen activator, plasminogen activator inhibitor-1, and α 2 -antiplasmin complex. In both groups, concentrations of proThrombin fragment F1.2 and Thrombin-antiThrombin complex increased progressively and significantly during cardiopulmonary bypass and after protamine was given. Concentrations of D-dimer, α 2 -antiplasmin complex, and plasminogen activator inhibitor-1 also increased significantly during bypass in both groups. Fibrinopeptide A levels did not increase during bypass but in both groups increased significantly after protamine was given. No significant differences were observed between groups for levels of inactivated complement 3b or neutrophil elastase. Radioimmunoassay showed a significant increase in surface-adsorbed antiThrombin on coated circuits but no significant differences between groups for other proteins. We conclude that heparin-coated circuits used with standard doses of systemic heparin reduce platelet adhesion and improve platelet function but do not produce a meaningful anticoagulant effect during clinical cardiopulmonary bypass. The data do not support the practice of reducing systemic heparin doses during cardiac operations with heparin-coated extracorporeal perfusion circuitry. (J THORAC CARDIOVASC SURG 1996;111:1-12)
L H Edmunds - One of the best experts on this subject based on the ideXlab platform.
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Effect of factor Xa inhibitors on Thrombin Formation and complement and neutrophil activation during in vitro extracorporeal circulation.
Circulation, 1996Co-Authors: N Gikakis, Joseph H. Gorman, Mohammed M.h. Khan, C.eric Hack, Ling Sun, Stefan Niewiarowski, Y Hiramatsu, A K Rao, R W Colman, L H EdmundsAbstract:Even when large doses of heparin are administered during cardiopulmonary bypass, Thrombin is produced. Thrombin is a powerful protease that is associated with the thrombotic and bleeding complications of open heart surgery and is produced by cleavage of proThrombin by factor Xa. This study assessed the ability of a specific inhibitor of factor Xa, recombinant tick anticoagulant peptide (rTAP), alone or in combination with standard heparin and a low-molecular-weight heparin, enoxaparin, to suppress Thrombin Formation and activity during in vitro extracorporeal circulation. Fresh, anticoagulated human blood was recirculated for 2 hours in an extracorporeal membrane oxygenator perfusion circuit at 37 degrees C. Four anticoagulant protocols were evaluated; porcine heparin (3.75 U/mL); enoxaparin (17.5 U/mL); rTAP (4 mumol/L); and porcine heparin plus rTAP (2 mumol/L). Blood samples were obtained for analysis from the donor, after anticoagulation, and after 5, 30, 60, and 120 minutes of recirculation. There were no significant differences between groups in platelet count, response to adenosine diphosphate, or proThrombin fragment (F1.2) production. rTAP plus heparin reduced beta-thromboglobulin release; fibrinopeptide A concentrations were significantly higher with rTAP alone. Enoxaparin strongly and significantly inhibited complement C5b9 production and neutrophil elastase release and was associated with significantly increased concentrations of C1-C1 inhibitor and kallikrein-C1 inhibitor complexes. rTAP does not reduce Thrombin Formation or activity during in vitro extracorporeal circulation. Enoxaparin markedly inhibits Formation of the complement membrane attack complex and neutrophil elastase release, possibly by accelerating C1 inhibitor activity.
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Effect of factor Xa inhibitors on Thrombin Formation and complement and neutrophil activation during in vitro extracorporeal circulation
Circulation, 1996Co-Authors: Nicolas Gikakis, Mohammad M.h Khan, Robert W. Colman, Joseph H. Gorman, C.eric Hack, Ling Sun, Stefan Niewiarowski, Y Hiramatsu, A K Rao, L H EdmundsAbstract:Background Even when large doses of heparin are administered during cardiopulmonary bypass, Thrombin is produced. Thrombin is a powerful protease that is associated with the thrombotic and bleeding complications of open heart surgery and is produced by cleavage of proThrombin by factor Xa. This study assessed the ability of a specific inhibitor of factor Xa, recombinant tick anticoagulant peptide (rTAP), alone or in combination with standard heparin and a low-molecular-weight heparin, enoxaparin, to suppress Thrombin Formation and activity during in vitro extracorporeal circulation. Methods and Results Fresh, anticoagulated human blood was recirculated for 2 hours in an extracorporeal membrane oxygenator perfusion circuit at 37°C. Four anticoagulant protocols were evaluated : porcine heparin (3.75 U/mL) ; enoxaparin (17.5 U/mL) ; rTAP (4 μmol/L) ; and porcine heparin plus rTAP (2 μmol/L). Blood samples were obtained for analysis from the donor, after anticoagulation, and after 5, 30, 60, and 120 minutes of recirculation. There were no significant differences between groups in platelet count, response to adenosine diphosphate, or proThrombin fragment (Fl.2) production. rTAP plus heparin reduced β-thromboglobulin release ; fibrinopeptide A concentrations were significantly higher with rTAP alone. Enoxaparin strongly and significantly inhibited complement C5b9 production and neutrophil elastase release and was associated with significantly increased concentrations of C1-C1 inhibitor and kallikrein-C1 inhibitor complexes. Conclusions rTAP does not reduce Thrombin Formation or activity during in vitro extracorporeal circulation. Enoxaparin markedly inhibits Formation of the complement membrane attack complex and neutrophil elastase release, possibly by accelerating Cl inhibitor activity.
Ling Sun - One of the best experts on this subject based on the ideXlab platform.
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Enoxaparin suppresses Thrombin Formation and activity during cardiopulmonary bypass in baboons
The Journal of thoracic and cardiovascular surgery, 1998Co-Authors: Nicolas Gikakis, Shinji Miyamoto, A. Koneti Rao, Joseph H. Gorman, Mohammed M.h. Khan, Harry L. Anderson, C.eric Hack, Ling Sun, Stefan Niewiarowski, Robert W. ColmanAbstract:Abstract Objective: This study tests the hypotheses that enoxaparin, a low molecular weight heparin and potent inhibitor of factor Xa, alone or in combination with standard heparin, inhibits Thrombin Formation and activity and modulates complement activation and neutrophil elastase release during cardiopulmonary bypass in baboons. Methods : After preliminary studies to determine doses and possible species differences to anticoagulants and protamine, 27 anesthesized baboons had normothermic cardiopulmonary bypass with standard, unfractionated, porcine intestinal heparin, enoxaparin, or a combination of heparin and enoxaparin. Protamine in appropriate doses was used to reverse anticoagulation. Blood samples were obtained at 6 time points. Activated clotting times were monitored; template bleeding times were measured before and up to 24 hours after cardiopulmonary bypass. Results : Hemodynamic measurements were not affected by the anticoagulant. Activated clotting times remained above 400 seconds throughout bypass, and no clots were observed. The anticoagulant did not alter platelet count, aggregation to adenosine diphosphate, release of β-thromboglobulin, release of neutrophil elastase, or complement C3b/c and C4b/c. Enoxaparin alone, but not in combination, significantly reduced plasma levels of proThrombin fragment F1.2, fibrinopeptide A, and Thrombin-antiThrombin complexes but prolonged template bleeding times for more than 24 hours. Conclusion : Enoxaparin significantly reduces Thrombin Formation and activity during cardiopulmonary bypass but does not suppress complement activation and neutrophil elastase release and is not adequately reversed by protamine after bypass. (J Thorac Cardiovasc Surg 1998;116:1043-51)
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Effect of factor Xa inhibitors on Thrombin Formation and complement and neutrophil activation during in vitro extracorporeal circulation.
Circulation, 1996Co-Authors: N Gikakis, Joseph H. Gorman, Mohammed M.h. Khan, C.eric Hack, Ling Sun, Stefan Niewiarowski, Y Hiramatsu, A K Rao, R W Colman, L H EdmundsAbstract:Even when large doses of heparin are administered during cardiopulmonary bypass, Thrombin is produced. Thrombin is a powerful protease that is associated with the thrombotic and bleeding complications of open heart surgery and is produced by cleavage of proThrombin by factor Xa. This study assessed the ability of a specific inhibitor of factor Xa, recombinant tick anticoagulant peptide (rTAP), alone or in combination with standard heparin and a low-molecular-weight heparin, enoxaparin, to suppress Thrombin Formation and activity during in vitro extracorporeal circulation. Fresh, anticoagulated human blood was recirculated for 2 hours in an extracorporeal membrane oxygenator perfusion circuit at 37 degrees C. Four anticoagulant protocols were evaluated; porcine heparin (3.75 U/mL); enoxaparin (17.5 U/mL); rTAP (4 mumol/L); and porcine heparin plus rTAP (2 mumol/L). Blood samples were obtained for analysis from the donor, after anticoagulation, and after 5, 30, 60, and 120 minutes of recirculation. There were no significant differences between groups in platelet count, response to adenosine diphosphate, or proThrombin fragment (F1.2) production. rTAP plus heparin reduced beta-thromboglobulin release; fibrinopeptide A concentrations were significantly higher with rTAP alone. Enoxaparin strongly and significantly inhibited complement C5b9 production and neutrophil elastase release and was associated with significantly increased concentrations of C1-C1 inhibitor and kallikrein-C1 inhibitor complexes. rTAP does not reduce Thrombin Formation or activity during in vitro extracorporeal circulation. Enoxaparin markedly inhibits Formation of the complement membrane attack complex and neutrophil elastase release, possibly by accelerating C1 inhibitor activity.
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Effect of factor Xa inhibitors on Thrombin Formation and complement and neutrophil activation during in vitro extracorporeal circulation
Circulation, 1996Co-Authors: Nicolas Gikakis, Mohammad M.h Khan, Robert W. Colman, Joseph H. Gorman, C.eric Hack, Ling Sun, Stefan Niewiarowski, Y Hiramatsu, A K Rao, L H EdmundsAbstract:Background Even when large doses of heparin are administered during cardiopulmonary bypass, Thrombin is produced. Thrombin is a powerful protease that is associated with the thrombotic and bleeding complications of open heart surgery and is produced by cleavage of proThrombin by factor Xa. This study assessed the ability of a specific inhibitor of factor Xa, recombinant tick anticoagulant peptide (rTAP), alone or in combination with standard heparin and a low-molecular-weight heparin, enoxaparin, to suppress Thrombin Formation and activity during in vitro extracorporeal circulation. Methods and Results Fresh, anticoagulated human blood was recirculated for 2 hours in an extracorporeal membrane oxygenator perfusion circuit at 37°C. Four anticoagulant protocols were evaluated : porcine heparin (3.75 U/mL) ; enoxaparin (17.5 U/mL) ; rTAP (4 μmol/L) ; and porcine heparin plus rTAP (2 μmol/L). Blood samples were obtained for analysis from the donor, after anticoagulation, and after 5, 30, 60, and 120 minutes of recirculation. There were no significant differences between groups in platelet count, response to adenosine diphosphate, or proThrombin fragment (Fl.2) production. rTAP plus heparin reduced β-thromboglobulin release ; fibrinopeptide A concentrations were significantly higher with rTAP alone. Enoxaparin strongly and significantly inhibited complement C5b9 production and neutrophil elastase release and was associated with significantly increased concentrations of C1-C1 inhibitor and kallikrein-C1 inhibitor complexes. Conclusions rTAP does not reduce Thrombin Formation or activity during in vitro extracorporeal circulation. Enoxaparin markedly inhibits Formation of the complement membrane attack complex and neutrophil elastase release, possibly by accelerating Cl inhibitor activity.
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Surface-bound heparin fails to reduce Thrombin Formation during clinical cardiopulmonary bypass.
The Journal of thoracic and cardiovascular surgery, 1996Co-Authors: Robert C. Gorman, Nicolas Gikakis, A. Koneti Rao, Mohammed M.h. Khan, Ling Sun, Nicholas P. Ziats, Nina Stenach, Suneeti Sapatnekar, Vibhuti D. Chouhan, Joseph H. GormanAbstract:Abstract The hypothesis that heparin-coated perfusion circuits reduce Thrombin Formation and activity; fibrinolysis; and platelet, complement, and neutrophil activation was tested in 20 consecutive, randomized adults who had cardiopulmonary bypass. Twenty identical perfusion systems were used; in 10, all blood-contacting surfaces were coated with partially degraded heparin (Carmeda process; Medtronic Cardiopulmonary, Anaheim, Calif.). All patients received a 300 U/kg dose of heparin. Activated clotting times were maintained longer than 400 seconds. Cardiopulmonary bypass lasted 36 to 244 minutes. Blood samples for platelet count, platelet response to adenosine diphosphate, plasma β-thromboglobulin, inactivated complement 3b, neutrophil elastase, fibrinopeptide A, proThrombin fragment F1.2, Thrombin-antiThrombin complex, tissue plasminogen activator, plasminogen activator inhibitor-1, plasmin α 2 -antiplasmin complex, and D-dimer were obtained at these times: after heparin was given, 5 and 30 minutes after cardiopulmonary bypass was started, within 5 minutes after bypass was stopped, and 15 minutes after protamine was given. After cardiopulmonary bypass, tubing segments were analyzed for surface-adsorbed antiThrombin, fibrinogen, factor XII, and von Willebrand factor by radioimmunoassay. Heparin-coated circuits significantly (p (p = 0.015), but did not reduce release of β-thromboglobulin. There were no significant differences between groups at any time for fibrinopeptide A, proThrombin fragment F1.2, or Thrombin-antiThrombin complex or in the markers for fibrinolysis: D-dimer, tissue plasminogen activator, plasminogen activator inhibitor-1, and α 2 -antiplasmin complex. In both groups, concentrations of proThrombin fragment F1.2 and Thrombin-antiThrombin complex increased progressively and significantly during cardiopulmonary bypass and after protamine was given. Concentrations of D-dimer, α 2 -antiplasmin complex, and plasminogen activator inhibitor-1 also increased significantly during bypass in both groups. Fibrinopeptide A levels did not increase during bypass but in both groups increased significantly after protamine was given. No significant differences were observed between groups for levels of inactivated complement 3b or neutrophil elastase. Radioimmunoassay showed a significant increase in surface-adsorbed antiThrombin on coated circuits but no significant differences between groups for other proteins. We conclude that heparin-coated circuits used with standard doses of systemic heparin reduce platelet adhesion and improve platelet function but do not produce a meaningful anticoagulant effect during clinical cardiopulmonary bypass. The data do not support the practice of reducing systemic heparin doses during cardiac operations with heparin-coated extracorporeal perfusion circuitry. (J THORAC CARDIOVASC SURG 1996;111:1-12)