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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.
Briefing Therapeutic Approaches in Anticoagulant, Thrombolytic, and Antiplatelet Therapy
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Hirudin, the first parenteral DTI, was isolated in the late 1800s. It is a peptide originally isolated from the salivary glands of the medicinal leech, Hirudo medicinalis. However, issues related to unsuccessful purification and availability led to its abandonment following the introduction of heparin. Lepirudin and desirudin are derivatives of hirudin that were developed by recombinant technology in Saccharomyces cerevisiae. Both are 65-amino acid protein. Compared with hirudin, their affinity is 10 times weaker for thrombin. They are still considered the most potent of all the thrombin inhibitors. Both recombinant hirudins (r-hirudins) are bivalent direct thrombin inhibitors that bind simultaneously to the active site and exosite 1 domain on thrombin, an interaction that increases their specificity for thrombin as presented in Figure 7.8. They also have the highest affinity for thrombin as they rapidly form essentially irreversible, 1:1 stoichiometric complexes. Lepirudin was approved for anticoagulation in patients with HIT by the Food and Drug Administration (FDA) in 1998. It can inhibit free and clot-bound thrombin. It is not activated by platelet factor 4, making it more effective in the presence of platelet-rich thrombi [62–65].
Classifications
Published in Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani, Pharmacology in 7 Days for Medical Students, 2018
Fazal-I-Akbar Danish, Ahmed Ehsan Rabbani
MiscellaneousHuman antithrombin-IIILepirudin
Inflammatory state does not affect the antiplatelet efficacy of potent P2Y12 inhibitors in ACS
Published in Platelets, 2021
Benedikt S. Biesinger, Aleksandra Gasecka, Thomas Perkmann, Johann Wojta, Maciej Lesiak, Marek Grygier, Ceren Eyileten, Marek Postuła, Krzysztof J. Filipiak, Aurel Toma, Christian Hengstenberg, Jolanta M. Siller-Matula
Blood collection was performed during the hospital stay after primary PCI (days 1–3). Venous blood was collected in evacuated container tubes (Vacuette tubes; Greiner Bio-One, Kremsmuenster, Austria) containing (i) silica particles to prepare serum, (ii) lithium heparin to prepare plasma, and (iii) lepirudin to analyze platelet function. The latter two were cautiously filled to the right capacity and inverted 3 to 5 times for gentle mixing. To prepare serum, blood was left to clot for 30 minutes and the clot was removed by 20 min centrifugation at 1,300 g. To prepare plasma, heparin blood was centrifuged within 30 min after blood collection at 2,5000 g for 15 minutes. Serum and plasma were aliquoted into 1.5 ml test tubes which were labeled with unique codes and stored at −80°C until analysis.
NHDL, a recombinant VL/VH hybrid antibody control for IgG2/4 antibodies
Published in mAbs, 2020
Corinna Lau, Martin Berner McAdam, Grethe Bergseth, Algirdas Grevys, Jack Ansgar Bruun, Judith Krey Ludviksen, Hilde Fure, Terje Espevik, Anders Moen, Jan Terje Andersen, Tom Eirik Mollnes
Fresh human or porcine whole blood from three independent individuals was anti-coagulated with 50 µg/mL lepirudin (Refludan®, Pharmion, Copenhagen, Denmark) and incubated in 1.8 mL Cryo Tube vials (Nunc, 377267) for 120 min at 37⁰C on a rock’n’roller with either sterile PBS with MgCl2 and CaCl2 (Sigma-Aldrich, D8662) or an inflammation-inducing agent. Here, we used 100 ng/mL ultrapure LPS from E. coli O111:B4 (InvivoGen, tlrl-3pelps) for human blood and 1x105/mL heat-inactivated E. coli strain LE392 (ATCC 33572) for porcine blood. The incubation was further done in the presence or absence of increasing or fixed amounts of the IgG2/4 control antibody NHDL, raNIP, anti-human CD14 (r18D11), and anti-porcine CD14 (rMil2). To stop the response, 10 mM (human blood) or 20 mM (porcine blood) EDTA was added, and plasma was gained by 15 min centrifugation at 3220 xg and 4°C.
Evaluation of platelet function in essential thrombocythemia under different analytical conditions
Published in Platelets, 2020
Federico Lussana, Eti Alessandra Femia, Mariateresa Pugliano, Gianmarco Podda, Cristina Razzari, Norma Maugeri, Anna Lecchi, Sabrina Caberlon, Giancarla Gerli, Marco Cattaneo
Adenosine diphosphate (ADP), 14-residue thrombin receptor activator peptide (TRAP-14, SFLLRNPNDKYEPF), the TxA2 mimetic U46619, adrenaline, Na2EDTA, N-ethylmaleimide, o-phthaldialdehyde and aprotinin were from Sigma Aldrich (Milano, IT). Horm collagen was from Mascia Brunelli (Milano, IT). Thrombofix was from Beckman Coulter (Milano, IT). EIA kit for TxB2 measurements was from Cayman Chemical Company (Ann Arbor, MI, USA). Lepirudin (a hirudin analogue)-containing tubes for blood collection were from (Verum Diagnostica, Munich, DE), K-EDTA tubes were from Sarsted (Verona, IT). All reagent concentrations reported in the text are expressed as final concentrations.