Heparin and its derivatives in the treatment of arterial thrombosis: a review
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Arterial occlusion due to thrombosis caused by ruptured atherosclerotic plaques (Baba et al., 1975) has been recognized as a major cause of morbidity and mortality in western populations. Thrombosis may occur in various sections of arterial circulation, peripheral arteries of the limbs, coronary arteries, brain arteries, or both major and minor vessels within the abdominal cavity. The ultimate consequence is varying degrees of organ failure, mostly of ischemic origin. Arterial thrombosis represents a continuous problem, debilitating patients and decreasing their quality of life. Moreover, along with chronic heart failure, it can significantly decrease patient life expectancy. Arterial thrombosis results in ischemia, with serious systemic consequences, such as metabolic breakdown. The major goal of treatment remains fast and efficient recanalization - surgical, interventional or thrombolytic. To be able to prevent acute reocclusion with severe consequences (rhabdomyolysis, compartment syndrome, excessive tissue necrosis leading to limb amputation, etc.), several adjunctive treatment regimens have been advocated. Among others, thrombin inhibitors and platelet inhibitors have been widely used for both prophylaxis and adjunctive treatment. Direct thrombin inhibitors and antithrombin stimulators have been recognized as typical antithrombotic drugs. Direct (antithrombin-independent) thrombin inhibitors can be divided into two main categories: monovalent, active site inhibitors (argatroban, efegatran, inovastan, melagatran) and bivalent (hirudin, hirugen, hirulog, bivalirudin), while antithrombin stimulators represent standard (unfractionated) heparin (UFH) and its depolymerizing products - low molecular weight heparins (LMWH's). Recently, a clear change in the main use of heparin, as well as low-molecular weight heparins has been advocated representing a shift from treatment and prophylaxis of deep vein thrombosis to prophylaxis of thromboembolic disease following vascular, cardiovascular or orthopedic surgery, treatment of unstable angina and prevention of acute myocardial infarction. The main effect of heparins lies in their anticoagulant activity. Heparins are involved in different pathways of the coagulation cascade with anticoagulant, antithrombotic, profibrinolytic, anti-aggregative, as well as anti-inflammatory effects. Moreover, there is a little doubt about their anti-proliferative and anti-ischemic activity (Penka and Bulikova, 2006). Unlike standard heparin, low-molecular weight heparins do not affect the patient's general coagulation profile. Obviously, the difference in molecular weight results in different pharmacokinetic and pharmacodynamic properties of the agents.Keywords:
Bivalirudin
Hirudin
Direct thrombin inhibitor
Patients with or at risk of heparin-induced thrombocytopenia (HIT) who are undergoing percutaneous coronary intervention (PCI) are at particular risk of thrombosis due to the prothrombotic nature of HIT and the endovascular disruption from PCI. Patients require aggressive anticoagulation during PCI, and alternative, nonheparin anticoagulation is recommended over heparin in patients with acute or previous HIT. Argatroban, bivalirudin, and lepirudin are nonheparin, fast-acting, parenteral direct thrombin inhibitors (DTIs). Multicenter, prospective studies have demonstrated that argatroban and lepirudin each reduce thrombosis in HIT and that argatroban and bivalirudin each provide adequate anticoagulation during PCI in patients with or at risk of HIT. We review current therapeutic practices with direct thrombin inhibitors in patients with or at risk of HIT during PCI, including individuals requiring periprocedural anticoagulation, and the factors influencing the choice of DTI in this setting.
Bivalirudin
Lepirudin
Heparin-Induced Thrombocytopenia
Direct thrombin inhibitor
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Hirudin
Direct thrombin inhibitor
Coagulation cascade
Bivalirudin
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Direct thrombin inhibitors inactivate thrombin without the need for antithrombin and some inactivate not only thrombin but also fibrin-bound thrombin. Hirudin has been shown to be more effective than low-dose unfractionated heparin and low molecular weight heparin for the prevention of deep vein thrombosis in high-risk orthopaedic patients. Major studies are assessing the value of direct thrombin inhibitors in patients with acute coronary syndromes. Currently, argatroban is the drug of choice in patients with heparin-induced thrombocytopenia.
Hirudin
Direct thrombin inhibitor
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Direct thrombin inhibitors (DTIs) are a new class of anticoagulants that bind directly to thrombin and block its interaction with its substrates. Four parenteral DTIs have been approved by the FDA — hirudin and argatroban for heparin-induced thrombocytopenia, bivalirudin as an alternative to heparin in percutaneous coronary intervention, and desirudin as prophylaxis against venous thromboembolism in hip replacement. This article discusses the clinical data on this important new class of medications.
Bivalirudin
Hirudin
Direct thrombin inhibitor
Lepirudin
Heparin-Induced Thrombocytopenia
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Bivalirudin
Hirudin
Lepirudin
Direct thrombin inhibitor
Antithrombins
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Bivalirudin
Direct thrombin inhibitor
Antithrombins
Hirudin
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Bivalirudin
Hirudin
Direct thrombin inhibitor
Ximelagatran
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Bivalirudin
Hirudin
Direct thrombin inhibitor
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Activated partial thromboplastin time (aPTT) is the primary test used to monitor intravenous (IV) direct thrombin inhibitors (DTIs) but has many limitations. The plasma diluted thrombin time (dTT) has shown better correlation with DTI levels than aPTT. This study compared dose-response curves for dTT and aPTT in pediatric patients receiving argatroban and bivalirudin.A retrospective review of pediatric patients treated with argatroban (n = 45) or bivalirudin (n = 14) monitored with dTT and aPTT.The dTT assay was calibrated to report DTI concentrations in µg/mL for argatroban and bivalirudin with good analytic sensitivity and specificity. The dTT was fivefold more likely to show a stable dose-response slope than the aPTT (P < .0002; odds ratio, 4.9). For patients in whom both dTT and aPTT showed a significant correlation between dose and assay results, dTT had a higher average correlation factor compared with aPTT (P = .007). Argatroban dose-response slopes showed more inter- and intrapatient variation than bivalirudin (dose-response slope coefficient of variation, 132% vs 52%).The dTT assay was more likely to show a stable dose response and have a stronger correlation with DTI dose than aPTT. Argatroban shows more variation in dose response than bivalirudin.
Bivalirudin
Direct thrombin inhibitor
Thrombin time
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Heparin-induced thrombocytopenia (HIT) is an immunologic response to heparin exposure that may lead to thrombosis. Argatroban and bivalirudin are two commonly used direct thrombin inhibitors (DTIs) for the prevention of thrombosis in patients with HIT. However, DTIs may lead to major bleeding events. Data on the use and consequences of DTIs is limited. Of note, patients with suspected HIT are of interest in the thesis, as current guidelines recommend the initiation of DTI treatment at the time of clinical suspicion of HIT. This thesis focused on the identification of suspected HIT, and the use and consequences of direct thrombin inhibitors (DTI) for the treatment of suspected HIT. First, algorithms based on diagnostic codes, medications and diagnostic tests were developed and validated to identify patients with suspected HIT. An algorithm based only on the timing of medication and diagnostic tests was recommended for the identification of suspected HIT from claims data, as it was observed to have the highest positive predictive value and sensitivity. Second, the rates of thrombosis, major bleeding, amputation and mortality were compared between argatroban-treated and bivalirudin-treated patients using administrative claims data obtained from the University HealthSystem Consortium. The difference in the likelihood of thrombosis, amputation and mortality between the two DTI groups was not statistically significant. However, bivalirudin-treated patients were more likely to experience major bleeding than argatroban-treated patients. Third, the use of bivalirudin for the treatment of suspected HIT (off-label use) increased from one-third to half of DTI-treated patients from 2010 to 2012. Patients treated by surgeons or specialists were more likely to receive off-label bivalirudin compared to patients treated by primary care. In addition, hepatic impairment and skin infection increased the odds of patients to receive bivalirudin over argatroban. In conclusion, the off-label use of bivalirudin should be scrutinized for medical necessity due to the higher risk of bleeding than argatroban, except in patients with hepatic impairment.
Bivalirudin
Heparin-Induced Thrombocytopenia
Direct thrombin inhibitor
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