scholarly journals Direct Thrombin Inhibitor Resistance and Possible Mechanisms

2016 ◽  
Vol 51 (11) ◽  
pp. 922-927 ◽  
Author(s):  
Maria Cardinale ◽  
Michael Ha ◽  
Michael H. Liu ◽  
David P. Reardon
Keyword(s):  
International Normalized Ratio ◽  
Resistance Mechanisms ◽  
Direct Thrombin Inhibitor ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Heparin Induced Thrombocytopenia ◽  
Vein Thrombosis ◽  
Inhibitor Resistance ◽  
Deep Vein

Objective To report 3 cases in which doses of bivalirudin higher than commonly used in clinical practice were required in order to achieve therapeutic anticoagulation as monitored by the activated partial thromboplastin time (aPTT). Case Summary The medical records of 3 patients who required large doses of bivalirudin to remain therapeutic were thoroughly reviewed. In all 3 patients, bivalirudin was initiated at a rate appropriate for the patients' renal function and titrated using a nurse-driven protocol with recommended dose adjustments based on aPTT. Indications for bivalirudin were anticoagulation in intra-aortic balloon pump, treatment of deep vein thrombosis, and heparin-induced thrombocytopenia with thrombosis. Target aPTT was achieved between 25.5 and 134 hours after initiation despite appropriate titration intervals per protocol. Discussion Bivalirudin is a direct thrombin inhibitor frequently used off-label for the medical management of heparin-induced thrombocytopenia. It typically exhibits predictable, dose-dependent anticoagulation. Heparin-induced thrombocytopenia was suspected in 2 of the 3 cases and confirmed in 1. In all 3 patients, target aPTT was initially achieved with doses between 0.456 and 1.0 mg/kg/h after a median of 30.7 hours; up to 1.8 mg/kg/h was required to maintain therapeutic aPTT. In 2 of the cases, the international normalized ratio also increased unexpectedly upon achievement of therapeutic aPTT values. Conclusion Direct thrombin inhibitors may be subject to resistance mechanisms similar to those previously described in patients receiving heparin. The anticoagulation status of these patients remains unknown.

Differential Inhibition of Thrombin Activity and Thrombin Generation by a Synthetic Direct Thrombin Inhibitor (Napsagatran, Ro 46-6240) and Unfractionated Heparin in Patients with Deep Vein Thrombosis

1999 ◽  
Vol 81 (04) ◽  
pp. 498-501 ◽  
Author(s):  
Henri Bounameaux ◽  
Herbert Ehringer ◽  
Alain Gast ◽  
Johan Hulting ◽  
Herbert Rasche ◽  
...  
Keyword(s):  
Deep Vein Thrombosis ◽  
Unfractionated Heparin ◽  
Thrombin Generation ◽  
Thrombin Inhibitors ◽  
Fixed Dose ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Vein Thrombosis ◽  
Thrombin Activity ◽  
Deep Vein

Summary Background: Direct thrombin inhibitors belong to a new class of antithrombotic drugs whose effects on blood coagulation in vivo in patients suffering from acute thrombotic conditions have not yet been fully explored. Methods and Results: One hundred and five patients with acute proximal deep-vein thrombosis were randomized to receive a continuous intravenous infusion of napsagatran, a novel synthetic thrombin inhibitor, at a fixed dose of 5 mg/h (n = 36) or 9 mg/h (n = 25) for five days, or APTT-adjusted unfractionated heparin (UFH, n = 44) for the same time. In these patients, thrombin activity and thrombin generation could be assessed by measuring thrombin-antithrombin III complexes (TAT) and prothrombin fragment 1+2 (F1+2), respectively, on three occasions. At baseline, TAT and F1+2 did not differ among the three groups. On Day 2 (steady state), TAT significantly decreased in all groups, and the decrease was significantly more pronounced in the patients given higher-dose napsagatran. F1+2 decreased significantly only in UFH-treated patients. Two hours after cessation of the infusion, the TAT levels increased in the two napsagatran groups but not in the UFH group, whilst F1+2 went back to the baseline levels in the napsagatran-treated patients but remained low in the UFH-treated patients. There was no rebound effect. Conclusions: The data presented suggest that direct thrombin inhibition with napsagatran at 9 mg/h is more potent than UFH in attenuating thrombin activity, but is less potent than UFH in inhibiting thrombin generation. The real significance of these findings will have to be substantiated in further trials with clinically relevant endpoints.

Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement

2003 ◽  
Vol 89 (02) ◽  
pp. 288-296 ◽  
Author(s):  
Giancarlo Agnelli ◽  
Alexander Cohen ◽  
Ola Dahl ◽  
Patrick Mouret ◽  
Nadia Rosencher ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Knee Replacement ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Double Blind Study ◽  
Double Blind ◽  
Total Hip ◽  
Vein Thrombosis ◽  
Major Orthopaedic Surgery

SummaryWe evaluated whether a postoperative regimen with melagatran followed by oral ximelagatran, two new direct thrombin inhibitors, was an optimal regimen for thromboprophylaxis in major orthopaedic surgery. In a double-blind study, 2788 patients undergoing total hip or knee replacement were randomly assigned to receive for 8 to 11 days either 3 mg of subcutaneous melagatran started 4-12 h postoperatively, followed by 24 mg of oral ximelagatran twice-daily or 40 mg of subcutaneous enoxaparin once-daily, started 12 h preoperatively. Ximelagatran was to be initiated within the first two postoperative days. The primary efficacy endpoint was venous thromboembolism (deep-vein thrombosis detected by mandatory venography, pulmonary embolism or unexplained death). The main safety endpoint was bleeding. Venous thromboembolism occurred in 355/1146 (31.0%) and 306/1122 (27.3%) patients in the ximelagatran and enoxaparin group, respectively, a difference in risk of 3.7% in favour of enoxaparin (p = 0.053). Bleeding was comparable between the two groups.

scholarly journals New anticoagulants for the treatment of venous thromboembolism

2016 ◽  
Vol 42 (2) ◽  
pp. 146-154 ◽  
Author(s):  
Caio Julio Cesar dos Santos Fernandes ◽  
José Leonidas Alves Júnior ◽  
Francisca Gavilanes ◽  
Luis Felipe Prada ◽  
Luciana Kato Morinaga ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Vitamin K Antagonists ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Vein Thrombosis ◽  
New Anticoagulants ◽  
Acute Pulmonary Thromboembolism ◽  
Deep Vein

Worldwide, venous thromboembolism (VTE) is among the leading causes of death from cardiovascular disease, surpassed only by acute myocardial infarction and stroke. The spectrum of VTE presentations ranges, by degree of severity, from deep vein thrombosis to acute pulmonary thromboembolism. Treatment is based on full anticoagulation of the patients. For many decades, it has been known that anticoagulation directly affects the mortality associated with VTE. Until the beginning of this century, anticoagulant therapy was based on the use of unfractionated or low-molecular-weight heparin and vitamin K antagonists, warfarin in particular. Over the past decades, new classes of anticoagulants have been developed, such as factor Xa inhibitors and direct thrombin inhibitors, which significantly changed the therapeutic arsenal against VTE, due to their efficacy and safety when compared with the conventional treatment. The focus of this review was on evaluating the role of these new anticoagulants in this clinical context.

State-of-the-Art Review: Anticoagulation: The Present and Future

2001 ◽  
Vol 7 (3) ◽  
pp. 195-204 ◽  
Author(s):  
Hugo Van Aken ◽  
Christoph Bode ◽  
Harald Darius ◽  
Curt Diehm ◽  
Albrecht Encke ◽  
...  
Keyword(s):  
Subcutaneous Administration ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Close Monitoring ◽  
Molecular Weights ◽  
Vein Thrombosis ◽  
Therapeutic Prevention ◽  
Arterial Damage ◽  
Deep Vein ◽  
Anticoagulant Response

Thrombin is a central bioregulator of coagulation and is therefore a key target in the therapeutic prevention and treatment of thromboembolic disorders, including deep vein thrombosis and pulmonary embolism. The current mainstays of anticoagulation treatment are heparins, which are indirect hrombin inhibitors, and coumarins, such as warfarin, which modutate the synthesis of vitamin K-dependent proteins. Although efficacious and widely used, heparins and coumarins have limitations because their pharmacokinetics and anticoagulant effects are unpredictable, with the risk of bleeding and other complications resulting in the need for close monitoring with their use. Low-molecular-weight heparins (LMWHs) provide a more predictable anticoagulant response, but their use is limited by the need for subcutaneous administration. In addition, discontinuation of heparin treatment can result in a thrombotic rebound due to the inability of these compounds to inhibit clot-bound thrombin. Direct thrombin inhibitors (DTI) are able to target both free and clot-bound thrombin. The first to be used was hirudin, but DTIs with lower molecular weights, such as DuP 714, PPACK, and efegatran, have subsequently been developed, and these agents are better able to inhibit clot-bound thrombin and the thrombotic processes that take place at sites of arterial damage. Such compounds inhibit thrombin by covalently binding to it, but this can result in toxicity and nonspecific binding. The development of reversible noncovalent DTIs, such as inogatran and melagairan, has resulted in safer, more specific and predictable anticoagulant treatment. Oral DTIs, such as ximelagatran, are set to provide a further breakthrough in the prophylaxis and treatment of thrombosis.

scholarly journals Evaluation of Bivalirudin’s Effect on International Normalized Ratio to Determine an Appropriate Strategy for Transitioning to Warfarin

2018 ◽  
Vol 34 (3) ◽  
pp. 117-122
Author(s):  
Andrea Fetea ◽  
Brian E. Gulbis ◽  
Andrea C. Hall
Keyword(s):  
Primary Endpoint ◽  
Major Bleeding ◽  
Partial Thromboplastin Time ◽  
International Normalized Ratio ◽  
Activated Partial Thromboplastin Time ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Limited Data ◽  
Heparin Induced Thrombocytopenia ◽  
Secondary Endpoints

Background: Direct thrombin inhibitors are recommended in confirmed or suspected heparin-induced thrombocytopenia. False elevation of the international normalized ratio (INR) occurs with these agents making bridging to warfarin challenging. There is limited data regarding bivalirudin’s effect on INR. Objective: To evaluate bivalirudin’s effect on the INR and determine a strategy for transitioning to warfarin. Methods: This was a retrospective observational study. Included patients were >18 years old receiving primary bridging therapy with overlapping bivalirudin and warfarin for at least 72 hours. Patients with administration of alternate anticoagulants during the transition interval or active major bleeding within 48 hours prior to bivalirudin initiation were excluded. The primary endpoint was to determine the effect on INR at first therapeutic activated partial thromboplastin time after bivalirudin initiation and prior to warfarin initiation. Secondary endpoints included change in INR 12 and 24 hours after bivalirudin initiation, change in INR 4 hours after bivalirudin cessation, and incidence of major bleeding or new thrombotic events. Results: Thirty-four patients met study criteria. For the primary endpoint, the change in INR at first therapeutic activated partial thromboplastin time was 0.37 (range = 0.28-0.48), which occurred at 8.4 hours (range = 4.6-14.2; n = 14). INR increased at 12 and 24 hours by a median of 0.55 and 0.5 from baseline, respectively. Median change in INR 4 to 8 hours post-bivalirudin cessation was −0.48. Conclusion: Targeting an INR > 2.5 when bridging to warfarin will account for this false elevation and maintain an INR above 2.0 on bivalirudin discontinuation.

New Anticoagulants

Hematology ◽  
2006 ◽  
Vol 2006 (1) ◽  
pp. 450-456 ◽  
Author(s):  
Kenneth A. Bauer
Keyword(s):  
Factor Xa ◽  
Direct Thrombin Inhibitor ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Percutaneous Coronary Interventions ◽  
New Anticoagulants ◽  
Fda Approval ◽  
Percutaneous Coronary ◽  
Prevention And Treatment

Abstract Traditional anticoagulant drugs, including unfractionated heparin and warfarin, have several limitations. New anticoagulants have been developed that target a single coagulation factor and have predictable dose-response relationships. These include direct thrombin inhibitors and factor Xa inhibitors. Two parenteral direct thrombin inhibitors, lepirudin and argatroban, have FDA approval for the management of heparin-induced thrombocytopenia (HIT). Bivalirudin is a parenteral direct thrombin inhibitor that is licensed for patients undergoing percutaneous coronary interventions and for those with HIT who require percutaneous coronary interventions. Ximelagatran, an oral prodrug of the direct thrombin inhibitor melagatran, showed efficacy in the prevention and treatment of venous thromboembolism as well as stroke prevention in patients with atrial fibrillation. However, due to nonhematologic safety concerns, it did not receive FDA approval in the US. Fondaparinux is a synthetic pentasaccharide, which binds to antithrombin, thereby indirectly selectively inhibiting factor Xa. Fondaparinux demonstrated efficacy compared to low-molecular-weight heparin in randomized clinical trials and is FDA approved for the prevention and treatment of venous thromboembolism. The OASIS 5 trial in non-ST-segment elevation acute coronary syndromes recently demonstrated that the fondaparinux dose approved for prophylaxis of deep venous thrombosis is as efficacious with respect to ischemic outcomes as therapeutic doses of enoxaparin; fondaparinux, however, was associated with a substantial reduction in major bleeding at 9 days and mortality at 1 and 6 months. A number of oral direct factor Xa inhibitors as well as other oral direct thrombin inhibitors are in clinical development for the prevention and treatment of thrombosis; the current status of these anticoagulants is reviewed along with the challenges faced in designing pivotal clinical trials of these agents in comparison to existing anticoagulants.

Direct thrombin inhibitors built on the azaphenylalanine scaffold provoke degranulation of mast cells

2006 ◽  
Vol 95 (02) ◽  
pp. 294-300 ◽  
Author(s):  
Mateja Štempelj ◽  
Manica Cerne ◽  
Anamarija Zega ◽  
Aleš Obreza ◽  
Marko Oblak ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Mast Cell Degranulation ◽  
Direct Thrombin Inhibitor ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Basic Group ◽  
Arterial Blood ◽  
Sar Study

SummaryThe main structural feature of direct thrombin inhibitor LK-732 responsible for the appropriate interaction at the thrombin active site is a strong basic group. A possibility that a strong basic group of LK-732 might contribute to the mast cell degranulation effect and consequent reduction of tracheal air flow (TAF) and fall of mean arterial blood pressure (MAP) in rats was investigated in the present study. At doses up to5 mg/kg (i. v.), LK-732 did not cause significant changes of TAF and MAP. At 7 mg/kg (i. v.),a sudden reduction of TAF and a fall of MAP was observed within 5 min after LK-732 administration (75% mortality, p=0. 007). A less basic direct thrombin inhibitor LK-658 (21 mg/ kg, i. v.) did not significantly disturb TAF and MAP. A reduction of TAF and a fall of MAP caused by LK-732 (7 mg/kg, i. v.) was almost completely abolished in rats with degranulated mast cells (0% mortality, p=0. 008). LK-732 concentration-dependently degranulated rat peritoneal mast cells in vitro (pEC50=1. 92±0. 05 µM). A structure-activity relationship (SAR) study revealed that the terminal basic groups attached to the aromatic ring are responsible for the mast cell degranulation effect. A good correlation was observed between mast cell degranulation and pKb of analogues of LK-732 (R2=0. 49), but not between mast cell degranulation and thrombin Ki (R2=0. 23). LK-732-induced reduction of TAF, the fall of MAP and high mortality originate from LK732-induced mast cell degranulation. As judged by the SAR study, this effect could be overcome by reducing the basicity of LK-732.

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