Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects

Sarich, Troy C.; Wolzt, Michael; Eriksson, Ulf G.; Mattsson, Christer; Schmidt, Alice; Elg, Susanne; Andersson, Magnus; Wollbratt, Maria; Fager, Gunnar; Gustafsson, David

doi:10.1016/s0735-1097(02)02868-1

Cited by 64 publications

(58 citation statements)

References 17 publications

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“…It also increased the template bleeding time consistent with several reports on the antihemostatic effects of LMWH. [29][30][31][32][33][34] The bleeding time test, which remains the most reliable global marker of treatment-induced hemostasis impairment, [22][23][24][35][36][37] was therefore used for the safety assessment of PCA treatment infusion in the equiefficacious dose range. While the absence of significant increase in the bleeding time during PCA infusion does not exclude the possibility of bleeding side effects, 38 the direct comparison between LMWH and PCA strongly suggested that the latter was considerably safer.…”

Section: Discussionmentioning

confidence: 99%

Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

Gruber

Marzec

Bush

et al. 2007

Blood

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The anticoagulant and anti-inflammatory enzyme, activated protein C (APC), naturally controls thrombosis without affecting hemostasis. We therefore evaluated whether the integrity of primary hemostasis was preserved during limited pharmacological antithrombotic protein C activator (PCA) treatment in baboons. The double-mutant thrombin (Trp215Ala/ Glu217Ala) with less than 1% procoagulant activity was used as a relatively selective PCA and compared with systemic anticoagulation by APC and low-molecular-weight heparin (LMWH) at doses that inhibited fibrin deposition on thrombogenic segments of arteriovenous shunts. As expected, both systemic anticoagulants, APC (0.028 or 0.222 mg/kg for 70 minutes) and LMWH (0.325 to 2.6 mg/kg for 70 minutes), were antithrombotic and prolonged the template bleeding time. In contrast, PCA at doses (0.0021 to 0.0083 mg/kg for 70 minutes) that had antithrombotic effects comparable with LMWH did not demonstrably impair primary hemostasis. PCA bound to platelets and leukocytes, and accumulated in thrombi. APC infusion at higher circulating APC levels was less antithrombotic than PCA infusion at lower circulating APC levels. The observed dissociation of antithrombotic and antihemostatic effects during PCA infusion thus appeared to emulate the physiological regulation of intravascular blood coagulation (thrombosis) by the endogenous protein C system. Our data suggest that limited pharmacological protein C activation might exhibit considerable thrombosis specificity. IntroductionSystemic anticoagulants can completely interrupt thrombus formation, but their usefulness is limited because their antithrombotic and antihemostatic activities are mechanistically tied. Highly effective plasma concentrations of systemic anticoagulants, such as those used for temporary thrombo-prophylaxis in interventional cardiology, prevent thrombin generation in both the blood vessel and the wound and can paralyze hemostasis with potentially fatal consequences. Due to safety considerations, the vast majority of patients who receive antithrombotic treatment are not anticoagulated to full efficacy. Thrombotic blood vessel occlusions causing myocardial infarction and ischemic stroke thus continue to contribute to mortality statistics. 1 Until more thrombosis-specific intravascular anticoagulants become available, balancing the potential benefits and risks of systemic anticoagulation remains a critical hurdle for the clinician.Occlusive thrombus formation is naturally down-regulated without bleeding complications most of the time following thrombogenic stimuli, such as blood vessel injuries or infections. It thus seems possible that selective pharmacological enhancement of the natural antithrombotic systems could achieve thrombosis specificity. Enhancement of the endogenous protein C pathway in the vicinity of thrombus formation might offer this wider therapeutic window. Thrombin is the natural protein C activator enzyme that activates protein C on such anatomic surfaces as the endothelial lining of blood vessels. ...

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Section: Discussionmentioning

confidence: 99%

Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

Gruber

Marzec

Bush

et al. 2007

Blood

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“…44 In addition, unlike heparin, DTIs have an antiplatelet effect. 45,46 Their pharmacokinetic profile precludes the need to measure activated clotting times during the procedure or before sheath removal. Additionally, it has been reported that the most commonly used DTI, bivali rudin, is associated with lower frequency of bleeding at the access site (4%) than are UFH or LMWH (plus glycoprotein IIb/IIIa inhibitors; 7%) in patients undergoing PCI (P<.001).…”

Section: Medicationsmentioning

confidence: 99%

Managing Risk of Complications at Femoral Vascular Access Sites in Percutaneous Coronary Intervention

Merriweather

Sulzbach-Hoke

2012

Critical Care Nurse

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Percutaneous coronary intervention for acute coronary syndrome or non–ST-elevation myocardial infarction requires the use of potent oral and intravenous anti-platelet and antithrombin medications. Although these potent antithrombotic agents and regimens may increase the effectiveness of percutaneous coronary intervention, they are also generally associated with an increased risk of vascular access complications such as hematoma, retroperitoneal hematoma, pseudoaneurysm, arterial occlusion, and arteriovenous fistula, which in turn are associated with increased morbidity, mortality, and costs. Risk factors predisposing patients to these complications are both modifiable (procedure technique, medications, hemostasis method) and nonmodifiable (sex, age, body mass index, blood pressure, renal function). Patients’ risks can be reduced by nurses who are knowledgeable about these risk factors and identify complications before they become problematic.

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“…Авторы мета-анализа подтвердили данные предыдущего ис-следования [8] о том, что применение дабигатрана ас-социируется с увеличением риска сердечно-сосуди-стых осложнений и делают предположение о том, что па-циентам с увеличенным коронарным риском предпоч-тительнее рекомендовать прямые ингибиторы Xа фак-тора свёртывания, чем прямые ингибиторы тромбина. Анализируя механизмы влияния прямых ингибиторов тромбина и прямых ингибиторов Xа фактора свёртывания в отношении развития сердечно-сосудистых осложне-ний по результатам различных исследований, следует учи-тывать, что, несмотря на одинаковое снижение актива-ции тромбоцитов, генерации тромбина [11], эндогенного потенциала тромбина [12] ксимелагатраном и низко-молекулярными гепаринами, время снижения эндо-генного потенциала тромбина было больше для даль-тепарина в сравнении с ксимелагатраном [12]. Напро-тив, в ряде исследований ривароксабан превосходил дальтепарин в отношении генерации тромбина [13] и сни-жал уровень тканевого фактора, вызывающего агрега-цию тромбоцитов [14].…”

Section: прямые ингибиторы тромбинаunclassified

Era of New Anticoagulants in the Treatment of Non-Valvular Atrial Fibrillation: Prospects and Challenges

Safiullina

Шалаев

2013

Racionalʹnaâ farmakoterapiâ v kardiologii

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ВведениеФибрилляция предсердий (ФП) является одной из ведущих причин развития тромбоэмболических осложнений, значительно ухудшая прогноз пациентов. Лица с ФП в пять раз более подвержены риску разви-тия ишемического инсульта по сравнению с общей по-пуляцией [1]. Данное нарушение ритма является при-чиной развития инсультов у 15% пациентов всех воз-растов и у 30% пациентов старше 80 лет [2].На протяжении более 50 лет антагонист витамина К варфарин оставался основным препаратом, исполь-зующимся для снижения риска тромбоэмболических осложнений у пациентов с ФП. Несмотря на доказан-ную клиническую эффективность, варфарин имеет множество хорошо известных ограничений, включая ле-карственные взаимодействия и необходимость регу-лярного контроля показателей свёртывания крови, коррекцию дозы. Это диктовало необходимость и по-требность в новых пероральных антикоагулянтах для профилактики тромбоэмболических осложнений у пациентов с ФП. Прямые ингибиторы тромбинаДабигатран -прямой пероральный ингибитор тромбина. Он выгодно отличается от варфарина тем, что его метаболизм не связан с системой цитохрома P-450, его эффективность менее подвержена влиянию принимаемой пищи и не зависит от генотипа больно-го, его применение не требует мониторирования коа-гулограммы и титрования доз.В исследовании RE-LY (Randomized Evaluation of Longterm anticoagulant therapY with dabigatran etexilate) [3][4][5] было включено 18113 пациентов с мерцатель-ной аритмией и риском инсульта, которым в случайном порядке вслепую назначали дабигатран в фиксиро-ванных дозах (по 110 или 150 мг 2 р/д) или открыто подбирали дозу варфарина (МНО поддерживался на уровне 2-3). Медиана длительности наблюдения со-ставила 2,0 года, первичными конечными точками были инсульт и системная эмболия. Частота первичной конечной точки составила 1,69% за год в группе вар-фарина, 1,53% -в группе пациентов, получавших да-бигатран 110 мг [относительный риск (ОР) 0,91; 95% доверительный интервал (ДИ) 0,74-1,11; p< 0,001 для гипотезы «не уступает») и 1,11% за год в группе да-бигатрана 150 мг (ОР=0,66; 95% ДИ 0,53-0,82; p<0,001 для гипотезы превосходства). Частота больших кровотечений за год составила 3,36% в группе вар-фарина, в сравнении с 2,71% на фоне 110 мг даби-гатрана (p=0,003) и 3,11% на фоне 150 мг дабигат- Studies data on new anticoagulants, direct oral thrombin inhibitor (dabigatran) and direct inhibitors of coagulation factor Xa (rivaroxaban, apixaban), in the treatment of nonvalvular atrial fibrillation are presented. Effects of these drugs on cardiovascular events in atrial fibrillation are analyzed based on the results of various studies. Prospects for further research are discussed.

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Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects

Cited by 64 publications

References 17 publications

Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

Relative antithrombotic and antihemostatic effects of protein C activator versus low-molecular-weight heparin in primates

Managing Risk of Complications at Femoral Vascular Access Sites in Percutaneous Coronary Intervention

Era of New Anticoagulants in the Treatment of Non-Valvular Atrial Fibrillation: Prospects and Challenges

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