Entries Tagged as 'Arterioscler Thromb Vasc Biol'
Coagulation factor IXa as a target for treatment and prophylaxis of venous thromboembolism.
Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):382-7
Authors: Eikelboom JW, Zelenkofske SL, Rusconi CP
Venous thromboembolism remains a frequent cause of vascular death. Despite advances in anticoagulant drug development, unmet needs remain, including limited treatment options for patients with severe renal impairment and the inability to fully reverse the effects of anticoagulants approved or in late-stage development. Because coagulation factor IXa plays a pivotal role in tissue factor-mediated thrombin generation, it represents an attractive target for anticoagulant development. This article discusses the rationale for factor IXa as an anticoagulant target and the potential role in venous thromboembolism prevention or management of the 2 factor IXa inhibitors that have undergone testing in phase 1 or 2 trials: TTP889, an oral, small-molecule compound, and RB006, an aptamer-based compound, the intravenous and subcutaneous formulations of which are the anticoagulant components of the REG1 and REG2 anticoagulation systems, respectively.
PMID: 20139356 [PubMed - indexed for MEDLINE]
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Rivaroxaban: a new oral factor Xa inhibitor.
Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):376-81
Authors: Perzborn E, Roehrig S, Straub A, Kubitza D, Mueck W, Laux V
Rivaroxaban is a direct inhibitor of factor Xa, a coagulation factor at a critical juncture in the blood coagulation pathway leading to thrombin generation and clot formation. It is selective for human factor Xa, for which it has >10 000-fold greater selectivity than for other biologically relevant serine proteases (half-maximal inhibitory concentration [IC(50)], >20 micromol/L). Rivaroxaban inhibits factor Xa in a concentration-dependent manner (inhibitory constant [K(i)], 0.4 nmol/L) and binds rapidly (kinetic association rate constant [k(on)], 1.7×10(7) mol/L(-1) s(-1)) and reversibly (kinetic dissociation rate constant [k(off)], 5×10(-3) s(-1)). By inhibiting prothrombinase complex-bound (IC(50), 2.1 nmol/L) and clot-associated factor Xa (IC(50), 75 nmol/L), rivaroxaban reduces the thrombin burst during the propagation phase. In animal models of venous and arterial thrombosis, rivaroxaban showed dose-dependent antithrombotic activity. In healthy individuals, rivaroxaban was found to have predictable pharmacokinetics and pharmacodynamics across a 5- to 80-mg total daily dose range, inhibiting factor Xa activity and prolonging plasma clotting time. In phase III clinical trials, rivaroxaban regimens reduced rates of venous thromboembolism in patients after total hip or knee arthroplasty compared with enoxaparin regimens, without significant differences in rates of major bleeding, showing that rivaroxaban has a favorable benefit-to-risk profile.
PMID: 20139357 [PubMed - indexed for MEDLINE]
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Inhibition of factor XIa as a new approach to anticoagulation.
Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):388-92
Authors: Schumacher WA, Luettgen JM, Quan ML, Seiffert DA
The dose-limiting issue with available anticoagulant therapies is bleeding. Is there an approach that could provide antithrombotic protection with reduced bleeding? One hypothesis is that targeting proteases upstream from the common pathway provides a reduction in thrombin sufficient to impede occlusive thrombosis yet allows enough thrombin generation to support hemostasis. The impairment of intrinsic coagulation by selective inhibition of factor XI (FXI) leaves the extrinsic and common pathways of coagulation intact, making FXI a drug target. This concept is supported by the observation that human deficiency in FXI results in a mild bleeding disorder compared with other coagulation factor deficiencies, and that elevated levels of FXI are a risk factor for thromboembolic disease. Moreover, FXI knockout mice have reduced thrombosis with little effect on hemostasis. The results from genetic models have been supported by studies using neutralizing antibodies, peptide inhibitors, and small-molecule inhibitors. These agents impede thrombosis without affecting bleeding time in a variety of experimental animals, including primates. Together, these data strongly support FXIa inhibition as a viable method to increase the ratio of benefit to risk in an antithrombotic drug.
PMID: 20139363 [PubMed - indexed for MEDLINE]
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Current treatment of venous thromboembolism.
Arterioscler Thromb Vasc Biol. 2010 Mar;30(3):372-5
Authors: Key NS, Kasthuri RS
Venous thromboembolism, comprising deep vein thrombosis and pulmonary embolism, is a common disorder with at least 250 000 new events occurring each year in the United States alone. Treatment of venous thromboembolism includes anticoagulation, which is achieved initially with the use of a parenterally administered agent followed by a more prolonged course of treatment with an oral vitamin K antagonist. The duration of treatment depends on the clinical assessment of the benefit-to-risk ratio of prolonged anticoagulation versus the risk of recurrent events. In this review, we discuss some of the issues that we believe are among the most critical unanswered questions in the management of venous thromboembolism in the present era.
PMID: 20139364 [PubMed - indexed for MEDLINE]
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Venous thromboembolism: risk factors for recurrence.
Arterioscler Thromb Vasc Biol. 2009 Mar;29(3):298-310
Authors: Zhu T, Martinez I, Emmerich J
Patients who have a first episode of venous thromboembolism (VTE) have an elevated risk of a recurrent episode, and this necessitates secondary prophylaxis. Anticoagulant therapy is a double-edged sword, however, as it reduces the risk of recurrent VTE but increases the risk of hemorrhage. This balance must be taken into account when assessing the risk-benefit ratio of long-term anticoagulation. Some clinical characteristics of the index VTE event can help to categorize the individual risk of recurrence. Patients with persistent risk factors such as cancer have a significantly higher risk of recurrent thrombosis. In contrast, VTE provoked by transient risk factors is associated with a lower risk of recurrence. Intrinsic features of patients with VTE (gender, age, hereditary thrombophilia) have also been linked to the risk of recurrent VTE. There is increasing evidence that a normal D-dimer level and the absence of residual venous thrombosis after discontinuation of oral anticoagulation are associated with a lower risk of recurrent VTE events. Future studies are needed to refine the predictive value of known risk factors for VTE recurrence and to discover better markers.
PMID: 19228602 [PubMed - indexed for MEDLINE]
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Venous thrombosis in the antiphospholipid syndrome.
Arterioscler Thromb Vasc Biol. 2009 Mar;29(3):321-5
Authors: Farmer-Boatwright MK, Roubey RA
The antiphospholipid syndrome is a relatively common acquired cause of venous thrombosis. Up to 20% of cases of deep vein thrombosis, with and without pulmonary embolism, may be associated with antiphospholipid antibodies. These antibodies are typically detected in lupus anticoagulant assays and tests for anticardiolipin antibodies. Most antiphospholipid antibodies are directed against several phospholipid-binding plasma proteins. The most common antigens are beta2-glycoprotein I and prothrombin. Immunoassays using these purified antigens are now available. In addition to being markers for thrombotic risk, antiphospholipid antibodies have been shown to directly contribute to hypercoagulability in animal models and in various in vitro studies. Prevention of recurrent venous thrombosis in patients with the antiphospholipid syndrome requires long-term anticoagulation. The optimal intensity of warfarin therapy is an ongoing issue, but most clinicians currently favor a target INR in the 2.0 to 3.0 range. In certain patients, antiphospholipid antibodies may interfere with determination of the INR, requiring other approaches to monitor and adjust the warfarin dose. Low-dose aspirin is typically recommended for primary prevention of thrombosis in asymptomatic patients with moderate to high levels of antiphospholipid antibodies, although strong supporting data are lacking.
PMID: 19228605 [PubMed - indexed for MEDLINE]
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Biomarkers and venous thromboembolism.
Arterioscler Thromb Vasc Biol. 2009 Mar;29(3):332-6
Authors: Pabinger I, Ay C
Venous thromboembolism (VTE) represents a significant health concern because of its high morbidity and mortality and is moreover characterized by high rates of recurrence. It would be useful to know biomarkers that enable early identification of patients at high or low risk of primary and recurrent VTE. Various established and novel biomarkers associated with VTE have been investigated with regard to their potential for predicting primary or recurrent VTE, for facilitating the diagnosis and for optimizing the clinical management of VTE. In this review, data on selected biomarkers (D-Dimer, soluble P-selectin, coagulation factor VIII, inflammatory markers and thrombin generation) having procoagulant properties or reflecting a prothrombotic state are summarized, and their role in clinical application is discussed.
PMID: 19228607 [PubMed - indexed for MEDLINE]
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