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John T. Owings - One of the best experts on this subject based on the ideXlab platform.
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Comparing Direct Thrombin Inhibitors Using aPTT, Ecarin Clotting Times, and Thrombin Inhibitor Management Testing
2016Co-Authors: Robert C. Gosselin, William E Dager, Kim A Janatpour, Jeffrey H. King, Edward C. Larkin, John T. OwingsAbstract:Patients with documented heparin-induced thrombocy-topenia and thrombosis (HITT) or high suspicion for HITT, may be acutely anticoagulated with Direct Thrombin Inhibitors (DTIs) until long-term anticoagulation with war-farin is achieved. The most common means of monitoring DTI treatment is using the activated partial thromboplastin time (aPTT), with a target aPTT ratio from 1.5 to 2.5 or 3.0.1,2 However, the aPTT is of limited use in patients with HITT requiring higher DTI dosing in cardiopulmonary by-pass or cardiac intervention procedures. Other methods that have been employed for monitoring the anticoagulant effects of DTIs have included the ecarin clotting time (ECT) and the activated clotting time.3,4 The ECT method is based on the principle that the snake venom ecarin cleaves proThrombin to form meizoThrombin, which will, in turn, cleave fibrinogen to form fibrin. In the ECT method, the DTIs present in plasma will bind meizoThrombin, there-by prolonging clot formation. A newer method, the throm-bin inhibitor management (TIM), not yet approved for clinical use, is based on a modified ecarin clotting time.4 In this study, we sought to compare aPTTs and aPTT ra-tios obtained from samples containing 0.1–1.2 µg/mL of one of the following DTIs: argatroban, bivalirudin, or lep-irudin. We also compared the ECT and TIM methods from plasma containing 0.1–8.0 µg/mL of these DTIs
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effects of pentasaccharide fondaparinux and Direct Thrombin Inhibitors on coagulation testing
Archives of Pathology & Laboratory Medicine, 2004Co-Authors: Robert C. Gosselin, William E Dager, Jeffrey H. King, Edward C. Larkin, Kim A Janatpur, John T. OwingsAbstract:Abstract Context.—Direct Thrombin Inhibitors (DTIs) and fondaparinux represent a new class of anticoagulants. The effects of DTIs on activated partial thromboplastin time and proThrombin time measurements have been reported previously, but there are limited data on the impact of these anticoagulants on other coagulation tests. Objective.—To determine the effects of fondaparinux and 3 DTIs (argatroban, bivalirudin, and lepirudin) on miscellaneous coagulation tests. Design.—Bivalirudin, lepirudin, argatroban, and fondaparinux were added to pooled normal plasma and tested for fibrinogen, antiThrombin (Thrombin and Xa substrate methods), plasminogen, protein C (clot and chromogenic methods), protein S, von Willebrand factor, D-dimer, lupus anticoagulant testing (dilute Russell viper venom test [DRVVT] with ratio), and factors II, IX, and X activities. Results.—We found no drug interference on antiThrombin, plasminogen, chromogenic protein C, von Willebrand factor, or D-dimer results. All DTIs falsely decrease...
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comparing Direct Thrombin Inhibitors using aptt ecarin clotting times and Thrombin inhibitor management testing
Annals of Pharmacotherapy, 2004Co-Authors: Robert C. Gosselin, William E Dager, Kim A Janatpour, Jeffrey H. King, Edward C. Larkin, John T. OwingsAbstract:BACKGROUND:Patients with heparin-induced thrombocytopenia and thrombosis may be acutely anticoagulated with Direct Thrombin Inhibitors (DTIs). The anticoagulation is typically monitored using the activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT).OBJECTIVE:To compare 14 methods for measuring aPTT, as well as ECT and Thrombin inhibitor management test (TIM), in samples containing DTIs.METHODS:DTIs were added to pooled normal plasma to achieve low (0.1–1.2 μg/mL) and high (1.5–8.0 μg/mL) drug concentrations. Each low-concentration DTI sample was tested using all aPTT reagents, while each low- and high-concentration DTI was tested using the ECT and TIM.RESULTS:All aPTT reagents had a significant dose-dependent correlation with drug concentration. Only Actin FSL and APTT-S demonstrated equivalent aPTT ratios obtained from any DTI. The TAS-aPTT was the most sensitive aPTT reagent to argatroban, with the aPTT ranging from 52.7 to 121.2 seconds corresponding to 0.1 to 1.2 μg/mL of drug co...
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effect of Direct Thrombin Inhibitors bivalirudin lepirudin and argatroban on proThrombin time and inr values
American Journal of Clinical Pathology, 2004Co-Authors: Robert C. Gosselin, William E Dager, Kim A Janatpour, Jeffrey H. King, Edward C. Larkin, Kathleen Mahackian, John T. OwingsAbstract:Direct Thrombin Inhibitors (DTIs) represent a new class of promising anticoagulation agents. The DTIs frequently are used to provide initial anticoagulation, with long-term therapy requiring eventual transition to coumarins. Unfortunately, DTIs not only prolong the activated partial thromboplastin time but also can affect international normalized ratio (INR) values. We approximated the DTI effect on INRs by each drug to pooled plasma at concentrations between 0.1 and 1.2 microg/mL. We then concurrently tested these samples using 14 proThrombin time (PT) reagents. By using repeated measures analysis of variance, we found significant differences (P < .05) between the median INRs for lepirudin and argatroban for all PT reagents, between lepirudin and bivalirudin for all reagents except PT-Fibrinogen HS Plus (P = .07), and between bivalirudin and argatroban for all reagents except Thromborel S (P = .05). The DTI effect on INRs was dependent on drug, drug concentration, and reagent. Argatroban had the most effect on INRs, while lepirudin had the least effect. Reagents with a lower international sensitivity index were less affected by DTI; ThromboMax HS was the least sensitive PT reagent to any DTI.
Christina T Moramangano - One of the best experts on this subject based on the ideXlab platform.
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a thrombus in the venous reservoir while using bivalirudin in a patient with heparin induced thrombocytopenia undergoing heart transplantation
Anesthesia & Analgesia, 2010Co-Authors: Jim K Wong, Ying Tian, Paul Shuttleworth, Anthony D Caffarelli, Bruce A Reitz, Christina T MoramanganoAbstract:Direct Thrombin Inhibitors are heparin alternatives for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia. We report a case of a large thrombus forming in the venous reservoir while using bivalirudin. We suggest that blood stasis associated with the full
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a thrombus in the venous reservoir while using bivalirudin in a patient with heparin induced thrombocytopenia undergoing heart transplantation
Anesthesia & Analgesia, 2010Co-Authors: Jim K Wong, Ying Tian, Paul Shuttleworth, Anthony D Caffarelli, Bruce A Reitz, Christina T MoramanganoAbstract:Direct Thrombin Inhibitors are heparin alternatives for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia. We report a case of a large thrombus forming in the venous reservoir while using bivalirudin. We suggest that blood stasis associated with the full venous reservoir maintained in this case led to formation of a large thrombus at the top of the venous canister. Furthermore, activated clotting times may not accurately reflect the magnitude of anticoagulation when using Direct Thrombin Inhibitors.
Gregory Y H Lip - One of the best experts on this subject based on the ideXlab platform.
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Direct Thrombin Inhibitors
2016Co-Authors: Eduard Shantsila, Gregory Y H LipAbstract:Anticoagulation can be achieved by inhibition of the various coagulation factors. Non-VKA oral anticoagulant (NOAC) development has focused on the synthesis of selective Inhibitors of coagulation factors, preferably acting independently of cofactors. The NOACs act on a number of targets in the coagulation cascade, but two of its key factors, Xa and IIa (Thrombin), are the major therapeutic targets. As they are involved in the final steps of the coagulation cascade, their inhibition allows blocking of both intrinsic and extrinsic coagulation pathways.
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review Direct Thrombin Inhibitors are similar to lmwh and vitamin k antagonists for preventing vte after hip or knee replacement
Annals of Internal Medicine, 2010Co-Authors: Alena Shantsila, Gregory Y H LipAbstract:Source Citation Salazar CA, Malaga G, Malasquez G. Direct Thrombin Inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total ...
William E Dager - One of the best experts on this subject based on the ideXlab platform.
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laboratory monitoring of parenteral Direct Thrombin Inhibitors
Seminars in Thrombosis and Hemostasis, 2017Co-Authors: Elizabeth M Van Cott, Joshua A Roberts, William E DagerAbstract:Argatroban and bivalirudin are parenteral Direct Inhibitors of the activity of Thrombin, but, unlike heparin, can inhibit both soluble as well as clot-bound Thrombin. These agents do not require antiThrombin as a cofactor for activity. The parenteral Direct Thrombin Inhibitors (DTIs) can be used in a variety of settings, including heparin-induced thrombocytopenia (HIT) or an allergy to heparin, and patients requiring anticoagulation for an invasive cardiovascular intervention. Both agents have a relatively short half-life in patients without organ system failure and are typically administered by continuous infusion. Argatroban is primarily eliminated by the liver, while bivalirudin is removed by a combination of proteolytic cleavage by Thrombin and renal clearance mechanisms. Several laboratory tests are available for monitoring the anticoagulant effects of the DTIs: the activated partial thromboplastin time (aPTT) and the activated clotting time (ACT) are the most commonly used assays, but on occasion, the Thrombin time may be useful. Other coagulation assays such as the dilute Thrombin time (dTT), chromogenic anti-IIa assays, and the ecarin clotting time (ECT) can be used. The intensity of anticoagulation with DTIs depends on the indication for use. For patients with HIT, the target aPTT is 1.5 to 3.0 and 1.5 to 2.5 times the patient's baseline value for argatroban and bivalirudin, respectively. DTI anticoagulation used during percutaneous coronary intervention can be measured using ACT. Both DTIs may cause an elevation in the international normalized ratio depending on their plasma concentration. This article will review the use of parenteral DTIs and related laboratory assays for assessing the anticoagulant effect of these drugs.
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Comparing Direct Thrombin Inhibitors Using aPTT, Ecarin Clotting Times, and Thrombin Inhibitor Management Testing
2016Co-Authors: Robert C. Gosselin, William E Dager, Kim A Janatpour, Jeffrey H. King, Edward C. Larkin, John T. OwingsAbstract:Patients with documented heparin-induced thrombocy-topenia and thrombosis (HITT) or high suspicion for HITT, may be acutely anticoagulated with Direct Thrombin Inhibitors (DTIs) until long-term anticoagulation with war-farin is achieved. The most common means of monitoring DTI treatment is using the activated partial thromboplastin time (aPTT), with a target aPTT ratio from 1.5 to 2.5 or 3.0.1,2 However, the aPTT is of limited use in patients with HITT requiring higher DTI dosing in cardiopulmonary by-pass or cardiac intervention procedures. Other methods that have been employed for monitoring the anticoagulant effects of DTIs have included the ecarin clotting time (ECT) and the activated clotting time.3,4 The ECT method is based on the principle that the snake venom ecarin cleaves proThrombin to form meizoThrombin, which will, in turn, cleave fibrinogen to form fibrin. In the ECT method, the DTIs present in plasma will bind meizoThrombin, there-by prolonging clot formation. A newer method, the throm-bin inhibitor management (TIM), not yet approved for clinical use, is based on a modified ecarin clotting time.4 In this study, we sought to compare aPTTs and aPTT ra-tios obtained from samples containing 0.1–1.2 µg/mL of one of the following DTIs: argatroban, bivalirudin, or lep-irudin. We also compared the ECT and TIM methods from plasma containing 0.1–8.0 µg/mL of these DTIs
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effects of pentasaccharide fondaparinux and Direct Thrombin Inhibitors on coagulation testing
Archives of Pathology & Laboratory Medicine, 2004Co-Authors: Robert C. Gosselin, William E Dager, Jeffrey H. King, Edward C. Larkin, Kim A Janatpur, John T. OwingsAbstract:Abstract Context.—Direct Thrombin Inhibitors (DTIs) and fondaparinux represent a new class of anticoagulants. The effects of DTIs on activated partial thromboplastin time and proThrombin time measurements have been reported previously, but there are limited data on the impact of these anticoagulants on other coagulation tests. Objective.—To determine the effects of fondaparinux and 3 DTIs (argatroban, bivalirudin, and lepirudin) on miscellaneous coagulation tests. Design.—Bivalirudin, lepirudin, argatroban, and fondaparinux were added to pooled normal plasma and tested for fibrinogen, antiThrombin (Thrombin and Xa substrate methods), plasminogen, protein C (clot and chromogenic methods), protein S, von Willebrand factor, D-dimer, lupus anticoagulant testing (dilute Russell viper venom test [DRVVT] with ratio), and factors II, IX, and X activities. Results.—We found no drug interference on antiThrombin, plasminogen, chromogenic protein C, von Willebrand factor, or D-dimer results. All DTIs falsely decrease...
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comparing Direct Thrombin Inhibitors using aptt ecarin clotting times and Thrombin inhibitor management testing
Annals of Pharmacotherapy, 2004Co-Authors: Robert C. Gosselin, William E Dager, Kim A Janatpour, Jeffrey H. King, Edward C. Larkin, John T. OwingsAbstract:BACKGROUND:Patients with heparin-induced thrombocytopenia and thrombosis may be acutely anticoagulated with Direct Thrombin Inhibitors (DTIs). The anticoagulation is typically monitored using the activated partial thromboplastin time (aPTT) or ecarin clotting time (ECT).OBJECTIVE:To compare 14 methods for measuring aPTT, as well as ECT and Thrombin inhibitor management test (TIM), in samples containing DTIs.METHODS:DTIs were added to pooled normal plasma to achieve low (0.1–1.2 μg/mL) and high (1.5–8.0 μg/mL) drug concentrations. Each low-concentration DTI sample was tested using all aPTT reagents, while each low- and high-concentration DTI was tested using the ECT and TIM.RESULTS:All aPTT reagents had a significant dose-dependent correlation with drug concentration. Only Actin FSL and APTT-S demonstrated equivalent aPTT ratios obtained from any DTI. The TAS-aPTT was the most sensitive aPTT reagent to argatroban, with the aPTT ranging from 52.7 to 121.2 seconds corresponding to 0.1 to 1.2 μg/mL of drug co...
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effect of Direct Thrombin Inhibitors bivalirudin lepirudin and argatroban on proThrombin time and inr values
American Journal of Clinical Pathology, 2004Co-Authors: Robert C. Gosselin, William E Dager, Kim A Janatpour, Jeffrey H. King, Edward C. Larkin, Kathleen Mahackian, John T. OwingsAbstract:Direct Thrombin Inhibitors (DTIs) represent a new class of promising anticoagulation agents. The DTIs frequently are used to provide initial anticoagulation, with long-term therapy requiring eventual transition to coumarins. Unfortunately, DTIs not only prolong the activated partial thromboplastin time but also can affect international normalized ratio (INR) values. We approximated the DTI effect on INRs by each drug to pooled plasma at concentrations between 0.1 and 1.2 microg/mL. We then concurrently tested these samples using 14 proThrombin time (PT) reagents. By using repeated measures analysis of variance, we found significant differences (P < .05) between the median INRs for lepirudin and argatroban for all PT reagents, between lepirudin and bivalirudin for all reagents except PT-Fibrinogen HS Plus (P = .07), and between bivalirudin and argatroban for all reagents except Thromborel S (P = .05). The DTI effect on INRs was dependent on drug, drug concentration, and reagent. Argatroban had the most effect on INRs, while lepirudin had the least effect. Reagents with a lower international sensitivity index were less affected by DTI; ThromboMax HS was the least sensitive PT reagent to any DTI.
Rocco Caliandro - One of the best experts on this subject based on the ideXlab platform.
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synthesis and biological evaluation of Direct Thrombin Inhibitors bearing 4 piperidin 1 yl pyridine at the p1 position with potent anticoagulant activity
Journal of Medicinal Chemistry, 2013Co-Authors: Modesto De Candia, Filomena Fiorella, Gianfranco Lopopolo, Andrea Carotti, Maria Rosaria Romano, M D Lograno, Sophie Martel, Pierrealain Carrupt, Benny Danilo Belviso, Rocco CaliandroAbstract:The design and synthesis of a new class of nonpeptide Direct Thrombin Inhibitors, built on the structure of 1-(pyridin-4-yl)piperidine-4-carboxamide, are described. Starting from a strongly basic 1-amidinopiperidine derivative (6) showing poor Thrombin (fIIa) and factor Xa (fXa) inhibition activities, anti-fIIa activity and artificial membrane permeability were considerably improved by optimizing the basic P1 and the X-substituted phenyl P4 binding moieties. Structure–activity relationship studies, usefully complemented with molecular modeling results, led us to identify compound 13b, which showed excellent fIIa inhibition (Ki = 6 nM), weak anti-Xa activity (Ki = 5.64 μM), and remarkable selectivity over other serine proteases (e.g., trypsin). Compound 13b showed in vitro anticoagulant activity in the low micromolar range and significant membrane permeability. In mice (ex vivo), 13b demonstrated anticoagulant effects at 2 h after oral dosing (100 mg·kg–1), with a significant 43% prolongation of the activa...
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Synthesis and Biological Evaluation of Direct Thrombin Inhibitors Bearing 4‑(Piperidin-1-yl)pyridine at the P1 Position with Potent Anticoagulant Activity
2013Co-Authors: Modesto De Candia, Filomena Fiorella, Gianfranco Lopopolo, Andrea Carotti, M D Lograno, Sophie Martel, Pierrealain Carrupt, Benny Danilo Belviso, Maria Rosaria Romano, Rocco CaliandroAbstract:The design and synthesis of a new class of nonpeptide Direct Thrombin Inhibitors, built on the structure of 1-(pyridin-4-yl)piperidine-4-carboxamide, are described. Starting from a strongly basic 1-amidinopiperidine derivative (6) showing poor Thrombin (fIIa) and factor Xa (fXa) inhibition activities, anti-fIIa activity and artificial membrane permeability were considerably improved by optimizing the basic P1 and the X-substituted phenyl P4 binding moieties. Structure–activity relationship studies, usefully complemented with molecular modeling results, led us to identify compound 13b, which showed excellent fIIa inhibition (Ki = 6 nM), weak anti-Xa activity (Ki = 5.64 μM), and remarkable selectivity over other serine proteases (e.g., trypsin). Compound 13b showed in vitro anticoagulant activity in the low micromolar range and significant membrane permeability. In mice (ex vivo), 13b demonstrated anticoagulant effects at 2 h after oral dosing (100 mg·kg–1), with a significant 43% prolongation of the activated partial thromboplastin time (aPTT), over controls (P < 0.05)