Seminars in vascular medicine最新文献

Nowadays D-dimer testing is frequently applied in the diagnosis of venous thromboembolism. However, the test results of different quantitative D-dimer tests can differ significantly. The background of this variability, which is mainly caused by the variety of fibrin degradation products in plasma, the specificity of D-dimer assays, and the calibrators used in the test, is summarized here. Because D-dimer is not a single entity in plasma but a mixture of heterogeneous fibrin degradation products, method standardization is in principle impossible. Efforts undertaken in the past to standardize D-dimer methods are summarized. All these projects failed and it was concluded that only harmonization of D-dimer test results seems to be feasible. The results of a large field study on which a new approach to the harmonization of quantitative D-dimer methods will be based is summarized in this article. This approach seems to be an adequate solution for overcoming the practical problem of variation of test outcome in different D-dimer assays.

D-dimer measurement is commonly included in the diagnostic workup of patients with suspected acute symptomatic deep venous thrombosis and pulmonary embolism. As a haemostatic marker, it could be theoretically useful in other thromboembolic disorders, such as acute cerebrovascular events. In this review we summarize published literature on D-dimer testing in acute ischemic stroke and cerebral sinus and venous thrombosis (CSVT), discussing possible clinical diagnostic and therapeutical applications. In ischemic stroke, mounting evidence suggests a possible role of D-dimer in the acute diagnosis of ischemic stroke subtypes, especially in identifying tromboembolic and lacunar stroke. Its prognostic role still remains unclear, due to conflicting data. D-dimer could be also an useful screening test for excluding CSVT in patients presenting with acute headache, making the presence of cerebral thrombosis unlikely with low plasma levels. In this clinical setting sensitivity and negative predictive value are comparable to that reported in the diagnosis of acute thromboembolic disease. However, more studies are needed to confirm these recent findings as well as management studies to correctly introduce D-dimer measurement in clinical daily practice of ischemic stroke and CSVT.

Assays for D-dimer antigen are based on monoclonal antibodies reactive with epitopes found on fibrin fragment D-dimer but not on fibrinogen fragment D, other fibrinogen degradation products, or native fibrinogen. The antibodies react with conformational epitopes generated by factor XIII-induced linkage of the C-terminal appendages of the fibrin gamma-chains of adjacent D-domains within a fibrin polymer. For some monoclonal antibodies, degradation of the cross-linked fibrin compound by plasmin is an additional requirement for the generation of the epitope. In clinical plasma samples, D-dimer antigen assays detect an array of fibrin compounds of different molecular weights, including fibrin fragment D-dimer as well as higher-molecular-weight fibrin degradation products and fibrin X-oligomers. Most D-dimer antigen represents cross-linked soluble fibrin present in circulation rather than degradation products from particulate clots. Due to differences in epitope reactivity, harmonization of D-dimer antigen assays can only be achieved with standard preparations containing a similar variety of cross-linked fibrin compounds. Assay technologies include manual latex agglutination assays, automated latex-enhanced light-scattering immunoassays, enzyme-linked immunoassays, and others.

The clinical development of ximelagatran for the treatment and prevention of various arterial and venous thromboembolic disorders has used fixed-dose regimens without coagulation monitoring in all indications. Although monitoring is not required, effects on the various coagulation assays that are available are seen with its active form melagatran, and there are situations where an assessment of anticoagulant effect may help to inform clinical decisions. However, the sensitivity of different coagulation assays varies considerably. The thrombin clotting time (TT) and ecarin clotting time (ECT) are highly sensitive to plasma melagatran concentrations (IC 50 approximately 0.01 micromol/L and approximately 0.15 micromol/L, respectively), with an approximate linear relationship between plasma melagatran concentration and prolongation of clotting time. In comparison, the activated partial thromboplastin time (APTT) (IC 50 approximately 0.3 to 0.8 micromol/L) and prothrombin time (PT) (IC 50 approximately 0.9 to 2.9 micromol/L) are relatively insensitive, and the concentration-response relationship shows a flattening with increasing plasma melagatran concentration. Commercially available APTT and PT reagents varied considerably in their sensitivity to melagatran. Comparing the various coagulation assays, the APTT, ECT, and TT are suitable choices when an indicator of the anticoagulant effect of ximelagatran is required, although the absence of international standards requires calibration of each test in individual laboratories and the ECT is not widely available.

Vitamin K antagonists including warfarin are associated with numerous interactions with other drugs and foods. In clinical practice, this complicates the task of maintaining plasma levels of warfarin within a narrow therapeutic window and so maximizing protection against thromboembolic events while minimizing the risk of complications, particularly bleeding. In contrast, ximelagatran has a low potential for pharmacokinetic drug:drug and food interactions. There is no significant metabolism of melagatran, and the main route of elimination of melagatran is renal excretion that appears to occur via glomerular filtration. Most importantly, cytochrome P450 isoenzymes that mediate many drug:drug interactions are not involved in the biotransformation of ximelagatran to melagatran. No significant pharmacokinetic interactions have been observed when oral ximelagatran is administered with a range of agents, including diclofenac, diazepam, nifedipine, digoxin, atorvastatin, or amiodarone. The low potential for drug:drug interactions with ximelagatran is also supported by an analysis of the pharmacokinetic data from clinical studies in patients with atrial fibrillation receiving long-term treatment with oral ximelagatran. Increases of mean melagatran area under the curve and maximum plasma concentration ( Cmax) of up to approximately 80% have been observed when ximelagatran is co-administered with the macrolide antibiotics erythromycin or azithromycin, and the mechanism for this interaction is currently under investigation. The bioavailability of melagatran is not altered by co-administration with food or alcohol. The melagatran-induced prolongation of activated partial thromboplastin time (APTT), an ex vivo coagulation time assay used as a measure of thrombin inhibition, is not altered by other drugs [including digoxin, atorvastatin, acetylsalicylic acid (ASA), and amiodarone], food, or alcohol. The effect of melagatran on capillary bleeding time, which is prolonged as a result of the inhibition of thrombin-induced platelet aggregation, is relatively low and additive to the platelet-inhibitory effect of ASA.

Therapy for venous thromboembolism (VTE) currently involves a minimum of 3 months of anticoagulation. After cessation of therapy, however, recurrent venous thrombosis occurs at rates of 6 to 9% per year. Clinical trials have demonstrated the benefits of extending anticoagulation beyond 3 months for the prevention of recurrent VTE events. Despite this, many eligible patients do not receive the required thromboprophylaxis and the incidence of recurrent VTE remains too high for a preventable condition. A reason for failure to use prophylaxis is the fear of bleeding complications with current oral anticoagulants such as warfarin. Warfarin has an unpredictable pharmacokinetic profile and a variable dose-response relationship that requires frequent coagulation monitoring and dose adjustments to maintain a target intensity that is both safe and effective. Alternative strategies for long-term prophylaxis, which may potentially provide more consistent anticoagulant responses and reduce coagulation monitoring requirements, include the use of low-molecular-weight heparin (LMWH), treatment with warfarin at a lower intensity, and the introduction of novel anticoagulants. The long-term use of LMWH has been found to be a particularly favorable treatment option for cancer patients in whom it is difficult to control the intensity of anticoagulation. In clinical trials, LMWH significantly reduced the risk of recurrent VTE without increasing bleeding risk. The parenteral administration of the LMWHs, however, is a drawback for long-term use in the outpatient setting. A clinical trial assessing the efficacy and safety of long-term low-intensity warfarin treatment found this therapy to be better than placebo, but another study showed that conventional intensity warfarin was significantly more efficacious than low-intensity warfarin. New therapies in development that may offer improved safety-efficacy profiles are the synthetic pentasaccharides fondaparinux and idraparinux and the oral direct thrombin inhibitor ximelagatran. Parenterally administered fondaparinux has been shown to be as effective as LMWH for the acute treatment (5 to 7 days) of symptomatic deep vein thrombosis. Idraparinux, with once-weekly parenteral dosing, is currently being assessed in phase III clinical trials for the long-term secondary prevention of VTE. Ximelagatran is the first oral agent in the new class direct thrombin inhibitors. With a fast onset of action and oral administration, ximelagatran is a candidate for both acute and chronic therapy. The Thrombin Inhibitor in Venous Thromboembolism (THRIVE) clinical trial program has demonstrated that this agent has a favorable benefit-risk profile compared with standard therapy for the initial treatment (6 months) and secondary prevention (up to 18 months) of VTE. However, in a substantial proportion (6 to 13%) of patients given extended ximelagatran therapy, elevated serum transaminase enzymes developed, typically in the first 2 to 4 mont

Nonvalvular atrial fibrillation (AF) is an independent risk factor for stroke that becomes increasingly prevalent as populations age. More than half a dozen clinical trials have demonstrated that anticoagulation with the vitamin K antagonist warfarin is the most effective therapy for stroke prophylaxis in AF. The narrow therapeutic index of warfarin requires that the intensity of anticoagulation be maintained within the international normalized ratio (INR) range of 2.0 to 3.0 to optimize efficacy while minimizing bleeding risk. The pharmacokinetics of warfarin are subject to variability due to interactions with multiple drugs and foods, making maintenance of the INR within this range difficult to achieve in clinical practice without close coagulation monitoring and frequent dose adjustments. Current guidelines recommend oral anticoagulation for high-risk individuals with AF but these inherent limitations lead to substantial underprescribing, particularly in elderly patients at greatest risk. This has stimulated the development of new agents with improved benefit-risk profiles, such as ximelagatran, the first of the oral direct thrombin inhibitors, which has a wider therapeutic margin and low potential for drug interactions, allowing fixed dosing without anticoagulation monitoring. Ximelagatran has been evaluated for stroke prevention in AF in the Stroke Prevention using an Oral Direct Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) program, the largest clinical trials of antithrombotic therapy for stroke prevention in AF to date. The phase III trials of ximelagatran in AF, SPORTIF III and V, found a fixed oral dose of ximelagatran (36 mg twice daily) comparable to dose-adjusted warfarin (INR 2.0 to 3.0) in preventing stroke and systemic thromboembolic complications among high-risk patients with AF. Results from the population of over 7000 patients in SPORTIF III and V demonstrate noninferiority of ximelagatran compared with warfarin. Data from SPORTIF III show an absolute reduction in stroke and systemic embolic events with ximelagatran compared with warfarin of 1.6% per year versus 2.3% per year, respectively ( P = 0.10). SPORTIF V further supports noninferiority between the two agents with an absolute risk reduction of 0.45%, well within the predefined noninferiority margin (95% confidence interval -0.13, 1.03; P = 0.13). Although event rates for major bleeding did not differ significantly with ximelagatran versus warfarin in either study, combined rates for major and minor bleeding were significantly reduced with ximelagatran. The overall net clinical benefit, taking into account effects on stroke or systemic embolic events, major bleeding, and death, was also greater with ximelagatran compared with warfarin in both studies. Elevated serum transaminase enzymes were observed in approximately 6% of patients given ximelagatran in these trials. These typically occurred 1 to 6 months after initiating treatment and usually abated without c

Thrombin plays a central role in thrombus formation through its conversion of fibrinogen to fibrin and activation of platelets as well as amplifying its own generation by feedback activation via factors V, VIII, and XI. Consequently, thrombin represents a logical and promising target for therapeutic interventions against arterial and venous thromboembolic disorders. Ximelagatran is the first oral agent in the new class of direct thrombin inhibitors and is rapidly absorbed and bioconverted to the active moiety, melagatran, which inhibits fluid-phase and clot-bound thrombin with similar high potency. Binding to the active site of thrombin is direct and competitive and does not require the presence of co-factors. Inhibition of thrombin generation and platelet activation has been demonstrated in vitro with melagatran as well as ex vivo after oral administration of ximelagatran to healthy human volunteers. Oral ximelagatran dose dependently reduced the total thrombus area in an ex vivo flow chamber model of arterial thrombosis, reflecting the cumulative effect of inhibition of thrombin activity, thrombin generation, and platelet activation. Melagatran has also been shown to reduce thrombin-mediated inflammation in vitro. The combination of antithrombotic and anti-inflammatory activity with the practicality of oral dosing provided by ximelagatran represents an important new option for the treatment of arterial and venous thromboembolic disorders.

Oral anticoagulant therapy with vitamin K antagonists (VKAs) such as warfarin has proven benefits in the treatment and prevention of thromboembolic disorders but has important limitations that result in substantial underuse. In particular, the VKAs have variable and unpredictable pharmacokinetics and pharmacodynamics and a narrow separation between antithrombotic and hemorrhagic effects that necessitates careful dose adjustment based on frequent coagulation monitoring. In contrast, the oral direct thrombin inhibitor ximelagatran has a predictable and reproducible pharmacokinetic/pharmacodynamic profile that allows treatment using fixed-dose regimens without coagulation monitoring. The bioavailability of melagatran, the active form of ximelagatran, after oral administration of ximelagatran is approximately 20% with low inter- and intra-individual variability. Peak plasma melagatran concentrations are reached approximately 2 hours after oral dosing of ximelagatran to healthy volunteers, and melagatran is eliminated with a half-life of approximately 3 hours with clearance predominantly by renal excretion. Hence, a higher melagatran exposure is seen in patients with renal failure; ximelagatran is currently not recommended for patients with severe renal impairment (creatinine clearance of <30 mL/min) as these patients were not included in the clinical trial program. Exposure to melagatran increases linearly with the ximelagatran dose. The pharmacokinetic/pharmacodynamic profile is consistent across a broad range of different patient populations and is unaffected by gender, age, body weight, ethnic origin, obesity, and mild-to-moderate hepatic impairment. Any differences in melagatran pharmacokinetics associated with these factors are attributable to differences in renal function.