New anticoagulants for secondary haemostasis

2009 ◽  
Vol 29 (03) ◽  
pp. 256-259 ◽  
Author(s):  
G. Nowak
Keyword(s):  
Blood Coagulation ◽  
Oral Anticoagulants ◽  
Individual Case ◽  
The Body ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
New Anticoagulants ◽  
Narrow Therapeutic Range ◽  
The Individual

SummaryIn contrast to heparins and oral anticoagulants, anti IIa inhibitors (thrombin inhibitors) are able to directly inhibit the protease activity of thrombin and can thereby precisely control the blood coagulation process.Direct thrombin inhibitors are either biosimilars (r-hirudin) or synthetically produced substances (bivalirudin, argatroban, dabigatran). In 1997 r-hirudin was introduced into clinical practice, however due to its narrow therapeutic range and the necessity of drug monitoring it has not gained widespread clinical use by now. Since 2004 and 2005 the synthetic thrombin inhibitors bivalirudin and argatroban, respectively, are available. With dabigatran the first oral synthetic thrombin inhibitor followed in 2008. These four drugs can inhibit even clot bound thrombin and show low plasma protein binding. They differ in respect to route and duration of application as well as elimination from the body, thereby offering a precise inhibition of blood coagulation adjusted to the individual case and without danger of HIT II. These advantages shall be used and advanced by the development of further direct thrombin inhibitors.

Old and new anticoagulants

2011 ◽  
Vol 31 (01) ◽  
pp. 21-27 ◽  
Author(s):  
U. Harbrecht
Keyword(s):  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
New Oral Anticoagulants ◽  
Thrombin Inhibitors ◽  
Clotting Factor ◽  
Direct Thrombin Inhibitors ◽  
Self Monitoring ◽  
New Anticoagulants ◽  
Gastrointestinal Side Effects

SummaryVitamin-K-antagonists (VKA) and heparins have been complementary anticoagulants for prevention and treatment of thrombosis for almost 70 years. In contrast to heparins, VKA have not been modified pharmacologically, however treatment surveillance has improved by introducing INR and self-monitoring/management. Disclosure of the molecular basis of interaction with VKORC1, the target enzyme of VKA, has helped to better understand coumarin sensitivity and resistance. New oral anticoagulants have now been approved and stimulated expectations in patients and physicians to get rid of the burdening frequent controls of VKA without loss of efficacy and safety.This review will summarize the development and profile of the new substances. Main difference compared to VKA is their direct mode of action against one clotting factor which is factor IIa in dabigatran and factor Xa in rivaroxaban and other “xabanes” currently under intensive investigation. Half lifes of the new anticoagulants are much shorter than that of the mainly used coumarins (phenprocoumon, warfarin), making “anticoagulation bridging” unnecessary before surgery. Therapeutic width of direct thrombin inhibitors and factor Xa inhibitors is broader and they are given at fixed doses. Clinical studies in thromboprophylaxis, thromboembolism and atrial fibrillation indicate at least non-inferiority or even superior efficacy compared with enoxaparin and VKA at comparable safety outcomes. Limitations of the new substances may arise from gastrointestinal side effects, mode of metabolism and route of elimination. Specific antidots are not available for none of them.Undoubtedly, the new oral anticoagulants are very promising. But, although thousands of study patients already have been treated, there are questions to be answered such as treatment adherence in absence of monitoring, safety and efficacy in risk patients, dosage adjustment and interactions with other drugs, before conclusions can be drawn towards their potential to replace VKA.

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.

scholarly journals A systematic review on the use of new anticoagulants in pregnancy

2013 ◽  
Vol 6 (2) ◽  
pp. 64-71 ◽  
Author(s):  
Ai-Wei Tang ◽  
Ian Greer
Keyword(s):  
Oral Anticoagulants ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Cochrane Library ◽  
Direct Thrombin Inhibitors ◽  
New Anticoagulants ◽  
Adverse Pregnancy ◽  
Newer Anticoagulants ◽  
The Cochrane Library ◽  
In Pregnancy

New anticoagulants such as direct factor Xa inhibitors and direct thrombin inhibitors have been recently developed, but their experience in pregnancy is limited. This review therefore aims to systematically search for studies on the use of these newer anticoagulants in pregnancy and the puerperal period. Searches were performed on electronic databases MEDLINE (from 1966), EMBASE (from 1974) and the Cochrane Library, until October 2011 using terms of ‘pregnancy’, ‘puerperium’, ‘breastfeeding’ and names of specific anticoagulants. The search yielded 561 citations and 11 studies (10 on fondaparinux, 1 on ximelagatran) were included. Newer anticoagulants (fondaparinux, hirudin and argatroban) on the limited evidence appear not to have adverse pregnancy outcomes, but there is currently no experience of new oral anticoagulants (rivaroxaban, apixaban, betrixaban or dabigatran) use in pregnancy. There is a need for reporting on new oral anticoagulation use in pregnancy to provide more information about the safety and risks to the fetus in utero.

Direct oral anticoagulants – new challenge for laboratory medicine

2015 ◽  
Vol 51 (3) ◽  
pp. 221-228
Author(s):  
Anna Raszeja-Specht ◽  
Anna Michno
Keyword(s):  
Vitamin K Antagonists ◽  
Oral Anticoagulants ◽  
Direct Oral Anticoagulants ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Factor X ◽  
Clotting Time ◽  
Coagulation Tests ◽  
New Generation

A new generation of oral anticoagulants, direct thrombin or activated factor X inhibitors gradually replaces the existing antithrombotic agents, administered parenterally (heparin) or orally (vitamin K antagonists). Currently, the most widely used class of direct oral anticoagulants (DOACs) are the direct thrombin inhibitor dabigatran and rivaroxaban, apixaban and edoxaban – Xa inhibitors. Although previous reports suggested that DOACs therapy does not require laboratory screening, recently the new indications for monitoring and the types of laboratory tests used in the evaluation of the effectiveness of treatment have been updated. To quantify the activity of direct thrombin inhibitors a dilute thrombin clotting time (dTT) or ecarin clotting time (ECT) is recommended. The effect of rivaroxaban and apixaban can be determined by anti-Xa activity assay when calibrated with a rivaroxaban and apixaban standard. Observed changes in routine coagulation tests such as activated partial thromboplastin time (APTT), and prothrombin time (PT), with varying degrees of severity, can only be an indicator of an additional screening, which is the emergency clinical interventions.

New anticoagulants

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 453-463 ◽  
Author(s):  
Jack Hirsh ◽  
Martin O'Donnell ◽  
Jeffrey I. Weitz
Keyword(s):  
Atrial Fibrillation ◽  
Factor Viia ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Prosthetic Heart Valves ◽  
Soluble Thrombomodulin ◽  
New Anticoagulants ◽  
Prevention And Treatment

AbstractAnticoagulants are pivotal agents for prevention and treatment of thromboembolic disorders. Limitations of existing anticoagulants, vitamin K antagonist and heparins, have led to the development of newer anticoagulant therapies. These anticoagulants have been designed to target specific coagulation enzymes or steps in the coagulation pathway. New anticoagulants that are under evaluation in clinical trials include: (1) inhibitors of the factor VIIa/tissue factor pathway; (2) factor Xa inhibitors, both indirect and direct; (3) activated protein C and soluble thrombomodulin; and (4) direct thrombin inhibitors. Although most of these are parenteral agents, several of the direct inhibitors of factor Xa and thrombin are orally active. Clinical development of these therapies often starts with studies in the prevention of venous thrombosis before evaluation for other indications, such as prevention of cardioembolism in patients with atrial fibrillation or prosthetic heart valves. At present, the greatest clinical need is for an oral anticoagulant to replace warfarin for long-term prevention and treatment of patients with venous and arterial thrombosis. Ximelagatran, an oral direct thrombin inhibitor, is the first of a series of promising new agents that might fulfill this need. Large phase 3 trials evaluating ximelagatran for the secondary prevention of venous thromboembolism and prevention of cardioembolic events in patients with atrial fibrillation have been completed.

scholarly journals Calibrated automated thrombogram II: removing barriers for thrombin generation measurements

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
P. L. A. Giesen ◽  
A. J. W. Gulpen ◽  
R. van Oerle ◽  
H. ten Cate ◽  
M. Nagy ◽  
...  
Keyword(s):  
Thrombin Generation ◽  
Oral Anticoagulants ◽  
Calibration Method ◽  
Direct Thrombin Inhibitor ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
Calibration Methods ◽  
Dependent Inhibition ◽  
Almost All

Abstract Background Thrombin generation (TG) assessed by Calibrated Automated Thrombogram (CAT-I) reflects the overall capacity of plasma to generate thrombin, thus evaluating the balance between the anti- and procoagulant processes. However, with this method the calibrator curve is usually not measured until completion which has a severe impact on the calculation of the TG parameters, especially under conditions where almost all substrate is consumed. In addition, direct thrombin inhibitor (DTI) cannot be present in the calibration sample due to inhibition of the calibrator. We have developed a modified TG assay (CAT-II) and performed head-to-head comparison with the CAT-I method using the same fluorometer. Furthermore, we have compared our CAT-II method to a new automated TG instrument (ST®-Genesia) using the same calibration method. Methods TG was assessed with CAT-I and CAT-II using the same fulorometer and with ST®-Genesia in control plasma and plasma containing different anticoagulants (dabigatran, rivaroxaban, apixaban) and plasmas to which common interfering substances, bilirubin, hemoglobin and lipids were added. In CAT-I, calibration was against the same plasma containing calibrator in the presence of fluorogenic substrate (Z-GGR-AMC). In contrast, CAT-II method and ST®-Genesia used a standard concentration of thrombin in buffer and 7-amino-4-methylcoumarin (AMC) in a separate plasma sample for calibration. Results TG obtained from CAT-I using anticoagulant-free plasmas was lower compared with TG from CAT-II but both methods demonstrated an intra-assay variation less than 5% on all measured parameters. When comparing the two different calibration methods in the presence of different anticoagulants, a high correlation was seen in the presence of rivaroxaban and apixaban (R2 > 0.97), but not with dabigatran, a direct thrombin inhibitor. CAT-II method showed dose-dependent inhibition of TG in the presence of dabigatran, while CAT-I was not able to detect it. Both methods were able to correct for the interfering substances. Conclusions Our results showed high similarity between the results of CAT-I and CAT-II method when it is applied in control plasmas and plasmas not inhibited with a direct thrombin inhibitor. Furthermore, both the CAT-II method and ST-Genesia using the same calibration method were able to detect the effect of all oral anticoagulants. Taken together, applying a new calibration method is a significant improvement for monitoring patients on direct thrombin inhibitors while not introducing any bias to results obtained on other types of samples.

scholarly journals Bivalirudin Use in an Infant With Persistent Clotting on Unfractionated Heparin

2011 ◽  
Vol 16 (2) ◽  
pp. 108-112
Author(s):  
Katherine M. Malloy ◽  
Tara A. McCabe ◽  
Robert J. Kuhn
Keyword(s):  
Unfractionated Heparin ◽  
Pediatric Population ◽  
Coronary Intervention ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Direct Thrombin Inhibitors ◽  
First Year ◽  
Heparin Infusion ◽  
Percutaneous Coronary ◽  
First Year Of Life

ABSTRACT Bivalirudin is a direct thrombin inhibitor approved for use in adult patients with heparin-induced thrombocytopenia (HIT) undergoing percutaneous coronary intervention. Recently, its use in the pediatric population has increased due to its anti-thrombin-independent mechanism of action. As heparin products produce great inter- and intraindividual variability in pediatric patients, often due to decreased anti-thrombin concentrations in the first year of life, some practitioners have turned to direct thrombin inhibitors, such as bivalirudin, for more predictable pharmacokinetics and effects on bound and circulating thrombin. We report our experience using bivalirudin in a 2-month-old female with recurrent systemic thrombi despite continuous unfractionated heparin infusion. Due to the patient's inability to maintain therapeutic activated partial thromboplastin time (aPTT) values during heparin infusion, bivalirudin was initiated at 0.1 mg/kg/h and increased due to subtherapeutic aPTTs to a maximum of 0.58 mg/kg/h. Therapeutic aPTTs were achieved at the increased dose; however, the patient's worsening renal impairment with resultant drug accumulation and overwhelming sepsis on day 5 of therapy led to discontinuation of the infusion and the initiation of comfort measures.

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.

Spotlight on real-world evidence for the treatment of DVT: XALIA

2016 ◽  
Vol 116 (S 02) ◽  
pp. S41-S49 ◽  
Author(s):  
Alexander Turpie ◽  
Walter Ageno
Keyword(s):  
Venous Thromboembolism ◽  
Real World ◽  
Oral Anticoagulants ◽  
Factor Xa ◽  
Standard Of Care ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Vein Thrombosis ◽  
Real World Evidence ◽  
Recurrent Vte

SummaryVenous thromboembolism (VTE), comprising both deep-vein thrombosis (DVT) and pulmonary embolism (PE), is a serious and common cardiovascular disease associated with the risk of chronic complications, recurrent VTE events and even death. The treatment landscape has, in recent years, seen a paradigm shift from the use of traditional anticoagulants (low-molecular-weight heparin [LMWH] overlapping with and followed by a vitamin K antagonist [VKA]) to non-VKA oral anticoagulants (NOACs). This class of agents, encompassing direct factor Xa inhibitors and direct thrombin inhibitors have shown non-inferior efficacy and better safety to standard of care in randomised controlled trials (RCTs). The direct, oral factor Xa inhibitor rivaroxaban was the first to be approved for treatment of acute DVT and PE and secondary prevention of recurrent VTE events based on data from EINSTEIN DVT and EINSTEIN PE, respectively. Real-world evidence now helps to further support data from RCTs, and also bridges the gap for physicians regarding any areas of clinical uncertainty that may not be addressed by RCTs. XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) was the first large, prospective, observational, real-world study that has investigated the safety and effectiveness profile of rivaroxaban in patients with DVT and PE associated with DVT in routine clinical practice. This article will present the key clinical outcomes from this important global non-interventional study, and will discuss remaining questions to be addressed in Phase IV studies.

Evaluation of Assay Performance Monitoring the New Oral Anticoagulants Rivaroxaban and Dabigatran

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3424-3424
Author(s):  
Lieselotte Wagner ◽  
Martina Leitner ◽  
Viktoria Kaufmann ◽  
Jutta Mager
Keyword(s):  
Calibration Curve ◽  
Oral Anticoagulants ◽  
New Oral Anticoagulants ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Good Precision ◽  
Thrombin Time ◽  
Target Value ◽  
Calibration Curves ◽  
High Range

Abstract Abstract 3424 Introduction: Dabigatran etexilate is a new orally direct thrombin inhibitor and rivaroxaban is a new oral direct Factor Xa (FXa) inhibitor. The increasing use of the new oral anticoagulants administered for prevention of VTE in patients after orthopedic surgery creates the need of their measurement in the clinical routine. A modified thrombin time based assay can be used for measurement of thrombin inhibitors like dabigatran and the direct Xa inhibitor rivaroxaban can be measured with a chromogenic anti-Xa assay. The aim of this study was to evaluate the performance of the two assays on coagulation analyzers using lyophilized calibrators and controls. Method: The assay for dabigatran measurement is a clotting assay based on the inhibition of a constant and defined concentration of thrombin. Clotting times measured are directly related to thrombin inhibitor concentrations. Calibration of the assay is performed using the lyophilized calibrators with assigned dabigatran values. Lyophilized controls in two ranges with assigned values for dabigatran are measured to calculate recovery and precision. A one stage chromogenic assay for the determination of Xa inhibitor activity in human citrated plasma is used for rivaroxaban measurement. The assay is based on the inhibition of activated factor × (FXa) by the direct Xa inhibitor rivaroxaban as measured by a chromogenic FXa substrate. Lyophilzed calibrators with assigned rivaroxaban values are used for assay calibration. Controls in 3 ranges are measured to calculate recovery and precision. Both assays are performed automated using the coagulation analyzers Ceveron alpha, Coasys Plus C and STA Compact with adapted pipetting schemes for the two anticoagulants on each analyzer. Results: For dabigatran measurement calibration curves in the range of 0–500ng/mL were made on each analyzer and curves with R2=1.0±0.1 were obtained on all analyzers. The recovery of control was ± 10% of target value for all controls on each analyzer. Precission data of the assay are summarized below: For rivaroxaban calibration curves in low range 0–150ng/mL and high range 0–500ng/mL were made using two adjusted analyzer settings. Calibration curves with R2=1.0±0.1 were obtained for rivaroxaban in the range of 0–150ng/mL, as well as for the range of 0–500ng/mL on all analyzers. The recovery of control was ± 10% of target value on all analyzers and precision was very good with intra-assay variations between 0.9%-4.2% and inter-assay variations between 1.8–4.9%. The detection limit for rivaroxaban was 10ng/mL using low range calibration curve and 25ng/mL using high range calibration curve. Conclusions: Our data demonstrate that the diluted thrombin time assay is suitable for mmeasurement of dabigatran and the chromogenic anti-Xa assay is suitable for measurement of rivaroxaban if lyophilized calibrators are used for assay calibration. Optimised pipetting schemes have to be validated for each of the analyzers used in order to obtain results with good precision. Disclosures: No relevant conflicts of interest to declare.

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