Comparative Antithrombotic and Antihemostatic Effects of the Direct Factor Xa Inhibitors, Apixaban and Rivaroxaban, and the Direct Thrombin Inhibitors, Dabigatran and Lepirudin, in Rabbit Models of Venous Thrombosis and Bleeding Time

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3025-3025
Author(s):  
Pancras C. Wong ◽  
Earl Crain ◽  
Carol Watson
Keyword(s):  
Venous Thrombosis ◽  
Bleeding Time ◽  
Vena Cava ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Direct Thrombin Inhibitors ◽  
Coronary Syndrome ◽  
Prevention And Treatment ◽  
Fxa Inhibitor ◽  
Stable Plasma

Abstract Background: Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor in late-stage clinical development for the prevention and treatment of venous thromboembolism, stroke prevention in patients with atrial fibrillation, and secondary prevention in patients with acute coronary syndrome. The objective of this study was to assess the antithrombotic and antihemostatic effects of apixaban in rabbits, compared to the direct FXa inhibitor, rivaroxaban, and thrombin inhibitors, dabigatran and lepirudin. Methods: We induced the formation of non-occlusive thrombus in venous thrombosis (VT) models by placing threads in the vena cava, and induced bleeding by the incision of cuticles in anesthetized rabbits. Apixaban, rivaroxaban, dabigatran and lepirudin were given as a bolus injection and supplemented with a constant IV infusion to achieve a stable plasma level. Results: Control thrombus weight in the prevention VT model ranged from 65±3 to 88±5 mg, and in the VT treatment model ranged from 76±5 to 90±5 mg. Control bleeding time (BT) ranged from 163±5 s to 173±8 s (n=6 per group). In the prevention VT model, apixaban, rivaroxaban, dabigatran and lepirudin (infusion started at 30 min before VT initiation) exhibited dose-related efficacy in preventing VT with ED50s (doses for 50% reduction of control thrombus weight; mg/kg) of 0.17±0.003, 0.15±0.03, 0.37±0.04 and 0.24±0.07 mg/kg, respectively. Apixaban, rivaroxaban and dabigatran, at doses for 80% reduction of control thrombus weight, prolonged BT by 13±2, 91±9*, 343±38* and 505±12%*, respectively (*P<0.05, vs. apixaban, n=6 per group). In the treatment VT model, these inhibitors (infusion started at 30 min after VT initiation) were equally effective in preventing growth of a preformed thrombus. Clot regression was observed following administration of apixaban, rivaroxaban and dabigatran at 2.7 mg/kg, and lepirudin at 3.5 mg/kg. The preformed thrombus decreased from an initial weight of 38±2 mg to 26±4*, 17±2*, 20±3* and 25±1* mg, respectively (*P<0.05, vs. control, n=6 per group). Conclusion: In summary, apixaban was as efficacious as rivaroxaban, dabigatran and lepirudin in the prevention and treatment VT models in rabbits. At equivalent antithrombotic doses, apixaban preserved hemostasis better than the other three agents in the rabbit cuticle BT model. Clinical studies will be required to assess the therapeutic windows in humans.

The Oral, Direct Factor Xa Inhibitor BAY 59-7939 Does Not Cross-React with Anti-Heparin/PF4 (Heparin-Induced Thrombocytopenia) Antibodies.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1883-1883 ◽  
Author(s):  
Jeanine M. Walenga ◽  
Debra Hoppensteadt ◽  
Omer Iqbal ◽  
Brian Neville ◽  
Walter P. Jeske ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Positive Response ◽  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Standards Of Care ◽  
Direct Thrombin Inhibitors ◽  
Direct Factor ◽  
Heparin Induced Thrombocytopenia ◽  
Prevention And Treatment ◽  
Fxa Inhibitor

Abstract BAY 59-7939 is an orally bioavailable, small-molecule, direct Factor Xa (FXa) inhibitor in advanced clinical trials for the prevention and treatment of thromboembolic disorders. Unfractionated heparin and the low molecular weight heparins (LMWHs) are the current standards of care for patients requiring anticoagulation. However, their use can be restricted by heparin-induced thrombocytopenia (HIT), which may be associated with severe thrombotic complications. It has been reported previously that fondaparinux, a heparin-derived pentasaccharide that indirectly inhibits FXa, does not cross-react with anti-heparin/PF4 (HIT) antibodies. However, we have shown that increased sulfation of fondaparinux does result in strong cross-reactivity with HIT antibodies, leading to platelet activation/aggregation. Previous studies have shown that direct thrombin inhibitors (DTIs), such as argatroban and lepirudin, do not cross-react with HIT antibodies. Current guidelines for patients who have HIT recommend use of a DTI to prevent or treat associated thrombosis. This study was performed to evaluate whether BAY 59-7939 cross-reacts with HIT antibodies, in order to examine its potential as an alternative anticoagulant for the management of patients with HIT. The effect of BAY 59-7939 on platelet activation mediated by HIT antibodies was examined in sera collected from 63 patients diagnosed with HIT (HIT sera), using platelet aggregation assays, the [14C]serotonin release assay, and flow cytometry for the detection of platelet P-selectin expression and platelet microparticle formation. Heparin, the LMWH enoxaparin, fondaparinux, and the DTI melagatran were included for comparison. BAY 59-7939 did not activate platelets or cause aggregation with any of the HIT sera tested, establishing that there is no interaction between BAY 59-7939 and HIT antibodies. As expected, heparin strongly activated platelets and caused their aggregation, and gave a positive response with 100% of the HIT sera tested. Enoxaparin showed positive responses with 73% of the sera. Of all the HIT sera tested, one exhibited a weak positive response with fondaparinux. As has been observed with other DTIs, melagatran did not cause any platelet activation or aggregation responses with the HIT sera. This study clearly demonstrates that BAY 59-7939, a novel, orally active, direct FXa inhibitor, does not interact with preformed HIT antibodies. Therefore, BAY 59-7939 has potential as a new option for the prevention and treatment of thrombosis in patients with HIT.

Dose-Dependent Antithrombotic Effects of Apixaban, an Oral Direct Factor Xa Inhibitor, in Prevention and Treatment of Thrombosis in Rabbit Models of Arteriovenous-Shunt and Venous Thrombosis at Doses That Preserve Hemostasis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 933-933 ◽  
Author(s):  
Pancras C. Wong ◽  
Earl J. Crain ◽  
Donald J. Pinto ◽  
Carol A. Watson
Keyword(s):  
Venous Thrombosis ◽  
Thrombus Formation ◽  
Vena Cava ◽  
Factor Xa ◽  
Arteriovenous Shunt ◽  
Thrombin Inhibitor ◽  
Phase Ii Trials ◽  
Prevention And Treatment ◽  
Fxa Inhibitor ◽  
Dose Dependent

Abstract Apixaban is an oral, direct and highly selective factor Xa (FXa) inhibitor, which is currently in late stage clinical development for the prevention and treatment of thromboembolic diseases. The dose-dependent antithrombotic and antihemostatic profile of apixaban was determined in the rabbit models of arteriovenous-shunt thrombosis (AVST), venous thrombosis (VT), and cuticle bleeding time (BT), and compared to those of the direct thrombin inhibitor lepirudin, the indirect FXa inhibitor fondaparinux and the oral anticoagulant warfarin. We induced the formation of thrombus in the AVST and VT models by placing threads in the extracorporeal shunt and vena cava, respectively, and bleeding by the incision of cuticles in anesthetized rabbits. In the AVST and VT prevention models, apixaban (0.03 to 3 mg/kg/h), lepirudin (0.006 to 0.75 mg/kg/h) and fondaparinux (0.01 to 1 mg/kg/h) were infused IV 30–60 min before the initiation of thrombosis. Warfarin (0.1 to 3 mg/kg/day) was administered orally for 4 days before the study. Control thrombus weight averaged 290±11 mg and 64±2 mg in AVST and VT, respectively, and control BT averaged 179±5 s (n=6 per group). Apixaban exhibited similar dose-related efficacy as lepirudin, fondaparinux, and warfarin in preventing AVST and VT. At doses that prevented 80 to 90% of thrombus formation in AVST and VT, apixaban, fondaparinux, lepirudin and warfarin increased BT by 20±2, 30±5, 500±10, 502±20%, respectively (n=6 per group). Doses for 50% reduction of control thrombus weight in AVST, VT were 0.27±0.03, 0.11±0.02 mg/kg/h IV for apixaban, 0.04±0.01, 0.05±0.01 mg/kg/h IV for lepirudin, 0.05±0.01, 0.05±0.005 mg/kg/h IV for fondaparinux and 0.53±0.04, 0.27±0.02 mg/kg PO for warfarin, respectively. To increase BT by 3-fold required higher doses of apixaban and fondaparinux (>3 mg/kg/h IV), lepirudin (0.24±0.05 mg/kg/h IV) and warfarin (0.70±0.07 mg/kg PO). In a VT treatment model, apixaban, lepirudin and fondaparinux, administered IV as a bolus injection supplemented with a continuous infusion after thrombus formation, were all able to arrest thrombus growth. However clot regression was only observed following administration of apixaban (0.6 mg/kg+0.87 mg/kg/h IV) where the preformed thrombus decreased from an initial weight of 38±2 mg (n=6) to 26±4 mg (n=6; P<0.05). In summary, apixaban and fondaparinux were effective in the prevention and treatment of experimental thrombosis at doses that preserve hemostasis in rabbits. Warfarin and lepirudin also prevented thrombus formation but with greater increases in BT. Furthermore, these standard anticoagulant agents have well-known limitations including narrow therapeutic index, frequent laboratory monitoring, or the requirement of parenteral administration. The favorable preclinical antithrombotic and antihemostatic profile of apixaban demonstrated here is consistent with clinical efficacy and safety results in recent Phase II trials, and indicates that direct inhibition of FXa with apixaban is a promising approach for the prevention and treatment of venous thromboembolism.

Animal Models of Thrombosis Help Predict the Human Therapeutic Concentration of PRT54021, a Potent Oral Factor Xa Inhibitor.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 901-901 ◽  
Author(s):  
Keith Abe ◽  
Gail Siu ◽  
Susan Edwards ◽  
Pei Hua Lin ◽  
Bing Yan Zhu ◽  
...  
Keyword(s):  
Animal Models ◽  
Venous Thrombosis ◽  
Thrombin Generation ◽  
Ex Vivo ◽  
Vena Cava ◽  
Factor Xa ◽  
Fold Change ◽  
In Vivo Models ◽  
Antithrombotic Activity ◽  
Fxa Inhibitor

Abstract Factor Xa (fXa) inhibition has resulted in the emergence of a new class of antithrombotics. Pharmacodynamic monitoring of these agents has proven problematic. The present study was designed to determine the target concentration of an oral fXa inhibitor required for clinical trials using both thrombin generation assays and three in vivo models and determine whether clotting assays such as activated partial thromboplastin time (aPTT) and prothrombin time (PT) would be suitable for monitoring human dosing. PRT54021 (PRT021) is a potent inhibitor of human fXa (Ki=117pM). PRT021 and fondaparinux, an indirect fXa inhibitor, both significantly inhibited TAT and F1.2 generation in human whole blood. Compared to a therapeutic level of fondaparinux (200nM), PRT021 (200nM) was more potent in suppressing both markers. Multiple doses of PRT021 were evaluated in three animal models. The first model, which measured clot accretion on cotton threads placed in rabbit abdominal vena cava, compared inhibition of thrombus mass by PRT021 to that of supratherapeutic doses of enoxaparin (a LMW heparin). The second model compared the ability of PRT021 to maintain vessel patency under arterial flow conditions in FeCl3 induced thrombosis in rat carotid artery to that achieved by enoxaparin or clopidogrel (an antiplatelet agent). The third model investigated inhibition of 111In labeled platelet deposition on dacron grafts and expansion chambers placed in femoral arteriovenous shunts in baboons. PRT021 and enoxaparin were administered as IV infusions and clopidogrel was dosed orally for three days. Ex vivo PT and aPTT were measured in all models. The models encompass stringent criteria of arterial and venous thrombosis and PRT021 produced dose-responsive antithrombotic activity in each of the three models. The efficacy of PRT021 compared favorably to supratherapeutic levels of enoxaparin and clopidogrel. Unlike in the rodent models, efficacy in primates was attained at a much lower dose with minimal prolongation of PT. Species specificity was also demonstrated by in vitro extensions of PT and aPTT in rat, rabbit, baboon and human plasma. A 2X change of PT was attained at concentrations of 8.9, 1.6, 1 and 0.4μM respectively. The data indicate that doses of PRT021 that inhibit thrombin generation in human blood and that provide anticoagulation similar to baboon dosed at 0.49mg/kg may be sufficient to prevent venous thrombosis in humans. Comparative modeling of extents of change in PT to levels of antithrombotic efficacy also leads us to predict that human therapeutic activity for PRT021 may be attained without concurrent changes in ex vivo clotting parameters. The targeted concentration is currently being tested in Phase II trials for its ability to prevent venous thromboembolism in orthopedic surgery patients. Model of Thrombosis Agent, Dose Antithrombotic Activity aPTT fold change PT fold change Rabbit vena cava PRT021,3mg/kg 76% inhibition 2.22 2.34 Rabbit vena cava Enoxaparin, 1.6mg/kg 96% inhibition 2.06 2.01 Rat carotid PRT021,19.1mg/kg 90% patency 1.69 2.20 Rat carotid Enoxaparin, 7.6mg/kg 70% patency 3.49 1.19 Rat carotid Clopidogrel, 3mg/kg/day 80% patency 1.03 1.01 Baboon arteriovenous PRT021,0.49mg/kg 90% inhibition (venous), 32% inhibition (arterial) 1.29 1.17

Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 597939) – an oral, direct factor Xa inhibitor

2007 ◽  
Vol 97 (03) ◽  
pp. 471-477 ◽  
Author(s):  
Elisabeth Perzborn ◽  
Philip Friederich ◽  
Marcel Levi ◽  
Ulf Buetehorn ◽  
Harry Büller ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Factor Xa ◽  
Vehicle Control ◽  
Venous Stasis ◽  
Treatment Model ◽  
Direct Factor ◽  
Experimental Thrombosis ◽  
Prevention And Treatment ◽  
Prevention Model ◽  
Fxa Inhibitor

SummaryCurrent anticoagulant therapies for the prevention and treatment of thromboembolic disorders have many drawbacks: vitamin K antagonists interact with food and drugs and require frequent laboratory monitoring, and heparins require parenteral administration. Oral rivaroxaban (BAY 597939) is a new, highly selective and potent direct factor-Xa (FXa) inhibitor with a predictable pharmacodynamic and pharmacokinetic profile and could therefore be an attractive antithrombotic drug. It was the objective of this study to investigate the antithrombotic efficacy of oral rivaroxaban in two rabbit models of experimental venous thrombosis. In the venous stasis (prevention) model, animals were randomized to receive oral rivaroxaban 0.3, 1.0, 3.0 or 10.0 mg/kg or vehicle control. Thrombosis was induced by jugular vein stasis and injection of thromboplastin into the ear vein. In the venous thrombosis (treatment) model, intravenous (1.0 and 3.0 mg/kg) and oral (3.0 mg/kg) rivaroxaban was compared with intravenous nadroparin (40 U bolus and 20 U/h), fon-daparinux (42 Mg/kg) and vehicle control. Thrombus growth was assessed by measuring the accretion of radiolabeled fibrinogen into preformed clots in the jugular veins. Bleeding was assessed using an ear bleeding model. In the prevention model, rivaroxaban reduced thrombus formation dose-dependently (calculated ED50 1.3 mg/kg). In the treatment model, oral rivaroxaban (3.0 mg/kg) reduced thrombus growth to a similar extent to intravenous rivaroxaban (1.0 mg/kg), nadroparin and fondapari-nux. Oral rivaroxaban did not prolong bleeding time. In conclusion, the orally available selective, direct FXa inhibitor rivaroxaban is effective in the prevention and treatment of venous thrombosis in two well-established models of experimental thrombosis.

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.

Antithrombotic Properties of DU-176b, a Novel, Potent and Orally Active Direct Factor Xa Inhibitor in Rat Models of Arterial and Venous Thrombosis: Comparison with Fondaparinux, an Antithrombin Dependent Factor Xa Inhibitor.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1852-1852 ◽  
Author(s):  
Toshio Fukuda ◽  
Chikako Matsumoto ◽  
Yuko Honda ◽  
Nobutoshi Sugiyama ◽  
Yoshiyuki Morishima ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Arterial Thrombosis ◽  
Thrombus Formation ◽  
Dose Range ◽  
Vena Cava ◽  
Factor Xa ◽  
Coagulation Cascade ◽  
Factor Xa Inhibitor ◽  
Rat Models ◽  
Fxa Inhibitor

Abstract Factor Xa (FXa) is an attractive target for the treatment of thrombosis due to its crucial role in the blood coagulation cascade. Fondaparinux, a selective FXa inhibitor, has been approved for clinical use to prevent deep vein thrombosis after orthopedic surgery; however, it requires antithrombin (AT) to exert its antithrombotic effect. It is reported that AT dependent anticoagulants such as heparin are less effective to suppress platelet-rich arterial-type thrombus due to its inaccessibility to thrombus-bound FXa/thrombin. We have developed a potent direct (i.e. AT independent) FXa inhibitor, DU-176b. The objective of this study is to compare the antithrombotic properties of a direct selective FXa inhibitor, DU-176b, with an AT dependent selective FXa inhibitor, fondaparinux. We evaluated the antithrombotic effects of DU-176b and fondaparinux in rat models of arterial and venous thrombosis. The arterial and venous thrombosis was induced by topical application of ferric chloride to the carotid artery and by insertion of a platinum wire into the inferior vena cava, respectively. DU-176b (0.05 – 1.25 mg/kg/h) and fondaparinux (1 – 10 mg/kg/h for arterial thrombosis and 0.03 – 1 mg/kg/h for venous thrombosis) were intravenously administered as continuous infusions. DU-176b prevented both arterial and venous thrombosis in the same dose range. In contrast, the effective doses of fondaparinux markedly differed between these models. A higher dose of fondaparinux more than 100 times was required to inhibit arterial thrombosis compared with venous thrombosis. These results suggest that direct inhibition of FXa is a preferable strategy to AT dependent inhibition for the prevention of thrombus formation in the arteries.

Effects of the Factor Xa Inhibitor Apixaban on Venous Thrombosis and Hemostasis in Rabbits.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 917-917 ◽  
Author(s):  
Pancras C. Wong ◽  
Carol A. Watson ◽  
Earl J. Crain ◽  
Joseph M. Luettgen ◽  
Martin L. Ogletree ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Prothrombin Time ◽  
Bleeding Time ◽  
Ex Vivo ◽  
Vena Cava ◽  
Factor Xa ◽  
Coagulation Factor ◽  
Vehicle Group ◽  
Dependent Manner ◽  
Venous Thrombus

Abstract Apixaban is a small-molecule, potent, reversible and direct inhibitor of human coagulation factor Xa (FXa) (Ki = 0.08 nM) with greater than 30000-fold selectivity over other coagulation proteases. It is orally bioavailable in rats, dogs, chimpanzees and humans, and is currently in clinical development for prevention and treatment of thromboembolic diseases. The objective of this study was to compare antithrombotic and bleeding time effects of apixaban and warfarin in rabbits. We selected rabbits as the animal model because apixaban has similar potency in inhibiting human and rabbit FXa, but is less potent in inhibiting rat and dog FXa (Ki (nM): 0.16, rabbit; 1.3, rat; 1.8, dog). We induced the formation of venous thrombus by placing threads in the vena cava, and bleeding by the incision of cuticles in anesthetized rabbits. Apixaban was infused IV 60 min before the initiation of thrombosis. Warfarin was administered orally for 4 days before the study. Thrombus weight averaged 73±5 mg and bleeding time averaged 183±7 s in the vehicle group (n=6 per group). Apixaban and warfarin inhibited the formation of venous thrombus in a dose-dependent manner. The estimated IC50 for apixaban was 0.16±0.04 μM. At antithrombotic doses studied, apixaban did not alter blood pressure and heart rate, suggesting hemodynamic effects are not likely to be involved in its antithrombotic activity. At the antithrombotic ID80, apixaban and warfarin increased bleeding time by 9±4% and 516±24%, respectively (n=6 per group). At this dose, apixaban increased ex vivo activated partial thromboplastin time and prothrombin time to 1.4±0.1 and 1.7±0.1 times control, respectively, and warfarin increased prothrombin time to 4.5±0.1 times control. Apixaban at antithrombotic doses selectively inhibited ex vivo FXa but not thrombin activity. In summary, these findings demonstrate potent activity of apixaban as a selective FXa inhibitor exhibiting potential strong efficacy in prevention of venous thrombosis at doses that preserve hemostasis and produce less increases in systemic anticoagulation than warfarin.

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 New anticoagulants in the prevention and treatment of venous thromboembolism

2011 ◽  
Vol 152 (25) ◽  
pp. 983-992 ◽  
Author(s):  
Mátyás Keltai ◽  
Katalin Keltai
Keyword(s):  
Venous Thromboembolism ◽  
Treatment Options ◽  
Factor Xa ◽  
Bleeding Risk ◽  
Current Treatment ◽  
Thrombin Inhibitors ◽  
Major Surgery ◽  
Direct Thrombin Inhibitors ◽  
New Anticoagulants ◽  
Prevention And Treatment

Clinical data on the risk factors, incidence, consequences and current treatment options of venous thromboembolism are reviewed. Current guidelines advise anticoagulant treatment for a few weeks or months in immobilized patients treated in hospital, and after major surgery. The initial treatment is based on heparin, followed by vitamin K antagonist treatment. Recently a number of new, partially orally administered medications have undergone clinical investigations and based on the results three of them were also registered for the prevention and treatment of venous thromboembolism. Direct thrombin inhibitors, direct and indirect Factor Xa inhibitors exhibited proven non-inferiority or superiority compared with traditional treatment options. The superior efficacy or non-inferiority was not accompanied with an increase in the bleeding risk. Results of the most important clinical trials are reviewed. Based on these results, prevention and treatment of venous thromboembolism will change substantially in the next future. Orv. Hetil., 2011, 152, 983–992.

The uncalibrated prothrombinase-induced clotting time test

2010 ◽  
Vol 30 (04) ◽  
pp. 212-216 ◽  
Author(s):  
R. Jovic ◽  
M. Hollenstein ◽  
P. Degiacomi ◽  
M. Gautschi ◽  
A. Ferrández ◽  
...  
Keyword(s):  
Factor Xa ◽  
Heparin Therapy ◽  
Thrombin Inhibitors ◽  
Coagulation Cascade ◽  
Diagnostic Tools ◽  
Direct Thrombin Inhibitors ◽  
Functional Assay ◽  
Clotting Time ◽  
Coagulation Time ◽  
Time Test

SummaryThe activated partial thromboplastin time test (aPTT) represents one of the most commonly used diagnostic tools in order to monitor patients undergoing heparin therapy. Expression of aPTT coagulation time in seconds represents common practice in order to evaluate the integrity of the coagulation cascade. The prolongation of the aPTT thus can indicate whether or not the heparin level is likely to be within therapeutic range. Unfortunately aPTT results are highly variable depending on patient properties, manufacturer, different reagents and instruments among others but most importantly aPTT’s dose response curve to heparin often lacks linearity. Furthermore, aPTT assays are insensitive to drugs such as, for example, low molecular weight heparin (LMWH) and direct factor Xa (FXa) inhibitors among others. On the other hand, the protrombinase-induced clotting time assay (PiCT®) has been show to be a reliable functional assay sensitive to all heparinoids as well as direct thrombin inhibitors (DTIs). So far, the commercially available PiCT assay (Pefakit®-PiCT®, DSM Nutritional Products Ltd. Branch Pentapharm, Basel, Switzerland) is designed to express results in terms of units with the help of specific calibrators, while aPTT results are most commonly expressed as coagulation time in seconds. In this report, we describe the results of a pilot study indicating that the Pefakit PiCT UC assay is superior to the aPTT for the efficient monitoring of patients undergoing UFH therapy; it is also suitable to determine and quantitate the effect of LMWH therapy. This indicates a distinct benefit when using this new approach over the use of aPPT for heparin monitoring.

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