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Fibrinolytic Enzymes for Thrombolytic Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Swaroop S. Kumar, Sabu Abdulhameed
Several thrombin inhibitors have been developed during the past couple of decades and proved their efficacy as anticoagulants. Hirudin is one of the most important, naturally occurring thrombin inhibitor molecule isolated from leach. Administration of hirudin has been associated with increased risk of bleeding as well as formation of non-neutralizing antibodies in patients (Hoppensteadt et al., 2008). Later, many thrombin inhibitors with better efficacy and therapeutic potential have been developed such as argatroban, bivalirudin, lepirudin, and dabigatran etexilate. The first used thrombin inhibitor is argatroban and it is now widely used in Japan. It was recommended as an alternate anticoagulant for patients suffering from HIT and its clinical use significantly reduced bleeding complications in comparison to heparin (Lewis et al., 2001, 2003). Bivalirudin is a bivalent reversible inhibitor and when compared to heparin and LMWHs, they declined the bleeding complications by almost 50%, whereas the efficacy remained same for all of them (Carswell and Plosker, 2002; Ahrens et al., 2007). Another thrombin inhibitor lepirudin was found to be marginally superior to heparin and more suitable for patients with previously reported HIT though continuous monitoring is required here also (Lubenow et al., 2004). Dabigatran etexilate is an oral prodrug that would get converted into active dabigatran, a direct thrombin inhibitor, upon intestinal absorption (Lee and Ansell, 2011). All those thrombin inhibitors described here are FDA approved for preventing various cardiovascular diseases.
Direct Oral Anticoagulants: New Options
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
In contrast to FXa inhibition, there have been several parenteral anticoagulants providing clinical evidence of the efficacy of direct thrombin inhibition (Alban, 2008a). The first ones were lepirudin (Refludan®) and desirudin (Revasc®): These two recombinant forms of the highly potent DTI hirudin from salivary glands of the medicinal leech (Hirudo medicinalis) were approved in 1997 and clinically used until a couple of years ago. In 2000 (FDA) and 2004 (EC), respectively, bivalirudin (Angiox®), a synthetic 20 amino acid polypeptide related to hirudin, was approved and can be applied in patients undergoing percutaneous coronary intervention (PCI) and in patients with HIT.
Device profile of the Impella 5.0 and 5.5 system for mechanical circulatory support for patients with cardiogenic shock: overview of its safety and efficacy
Published in Expert Review of Medical Devices, 2022
Mohit Pahuja, Jaime Hernandez-Montfort, Evan H. Whitehead, Masashi Kawabori, Navin K. Kapur
Impella device involves blood to flow continuously into the catheter, hence, a purge solution flows runs retrograde to the blood flow that creates a pressure barrier and prevents blood entry into the motor. It also requires heparin which helps to maintain adequate purge pressure by preventing thrombotic complications. Currently the manufacturer recommends titrating heparin to maintain the goal activated clotting time (ACT) of 160–180. Many patients require non-purge systemic heparin to maintain this target but, in some patients, purge heparin solution may be sufficient to maintain the therapeutic targets. If the patients is running higher targets with only the purge solution, it is recommended to reducing the heparin to half concentration. In patients with heparin-induced thrombocytopenia, a direct thrombin inhibitor such as bivalirudin or argatroban can by given separately outside the purge solution [45].
Structural basis of different surface-modified fullerene derivatives as novel thrombin inhibitors: insight into the inhibitory mechanism through molecular modelling studies
Published in Molecular Physics, 2021
Zhijie Yang, Yongfeng Wan, Jingwen E, Zhijian Luo, Shanshan Guan, Song Wang, Hao Zhang
Thrombin inhibitors can block enzyme activity by binding to any of the three regions, including the active site, exosite I, or exosite II. For example, agatroban [19] acts as a competitive inhibitor by binding to the active site, hirudin [20] and bivalirudin [21] can interact with exosite I to inhibit thrombin, and exosite II is the region of action of heparin [22]. The inhibitors that act at the active site and the exosite I region are called direct thrombin inhibitors [23]. The anticoagulant response of direct inhibitors is predictable and unaffected by platelet factors and is the main direction of research and development [24].