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Hypercoagulable State in Trauma Patients
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Hirudin, which can be prepared by genetic engineering, inhibits thrombin directly, without the necessity of a plasma cofactor and with a bioavailability after subcutaneous injection of over 80%. It has a favorable antithrombotic activity/bleeding risk ratio in animal models in comparison with heparin.43 The use of hirudin may offer a more immediate improvement in the treatment of trauma patients.
Acquired Bleeding Disorders Associated with Disease and Medications
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
William A. Rock, Sue D. Walker
Hirudin, a thrombin inhibitor developed from leeches, is a 65-amino acid polypeptide and is the most potent and selective inhibitor of thrombin known. Through DNA recombinant technology, hirudin is now available in sufficient quantity for testing. Hirudin has high affinity for thrombin and effectively blocks all proteolytic functions of the enzyme. So, hirudin prevents not only fibrin formation but the thrombin-catalyzed hemostatic reactions, such as activation of factors V, VIII, XIII, and the thrombin-induced platelet reactions. Whereas platelet factor 4 is the naturally occurring inhibitor of heparin, there is no natural inhibitor of hirudin, so the only limiting factor for thrombin blockade is the dose of hirudin. Preclinical studies of hirudin in humans are well under way (149).
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.
Hirudin versus citrate as an anticoagulant for ROTEM platelet whole blood impedance aggregometry in thrombocytopenic patients
Published in Platelets, 2023
Wasanthi Wickramasinghe, Bhawani Yasassri Alvitigala, Thisarika Perera, Panduka Karunanayake, Saroj Jayasinghe, Senaka Rajapakse, Praveen Weeratunga, Ananda Wijewickrama, Roopen Arya, Klaus Goerlinger, Lallindra Viranjan Gooneratne
Platelets play a crucial role in hemostasis.1 The rotational thromboelastometry (ROTEM) platelet module used together with the ROTEM delta device (TEM Innovations GmbH, Munich, Germany) assesses platelet aggregation by whole blood impedance aggregometry and displays platelet aggregation graphically and numerically.2 3.2% sodium citrate is the most widely used and conveniently available anticoagulant for platelet function tests (PFTs), although its chelation of ionized calcium in blood affects platelet function by the inhibition of platelet aggregation since intra-platelet calcium concentration is an important modulator of platelet function.3 Moreover, as a result of reduction in calcium levels, citrated samples have resulted in low reproducibility and sensitivity to tests associated with thrombin activation of platelets.4 The non-calcium chelating anticoagulant hirudin which was introduced subsequently, is a polypeptide present in the leech (Hirudo medicinalis) having a strong and direct antithrombin activity by inhibiting the conversion of fibrinogen to fibrin. Hence, hirudin maintains the physiological milieu of the sample.5 Thrombin-receptor activating peptide-6 is used in platelet function testing in order to provide a standardized activation.6–8
Bivalirudin during percutaneous coronary intervention in acute coronary syndromes
Published in Expert Opinion on Pharmacotherapy, 2019
Marc Laine, Gilles Lemesle, Thibaut Dabry, Vassili Panagides, Michael Peyrol, Franck Paganelli, Laurent Bonello
Bivalirudin is a direct thrombin inhibitor approved for PCI in ACS patients in 2000 [5]. This synthetic anhydrous free base 20 amino-acid peptide comprised of the amino and carboxyl termini of hirudin, a natural anticoagulant derived from the saliva of the European medicinal leech Hirudo Medicinalis. This molecule weights 2180 Daltons (Table 1). The seminal publications on the pharmacological properties of bivalirudin were published in 1989 [6,7]. This drug reversibly binds to circulating and fibrin-bound thrombin. Bivalirudin targets thrombin catalytic site and anion-binding exosite I. Unlike UFH, bivalirudin does not require cofactor to develop its anticoagulant properties. Unlike UFH that increases platelet reactivity, bivalirudin targets and inhibits thrombin (a platelet agonist) and thus decreases platelet reactivity, a biological property that can be beneficial in patients undergoing PCI [8].
Evaluation of platelet function in thrombocytopenia
Published in Platelets, 2018
Mette Tiedemann Skipper, Peter Rubak, Jesper Stentoft, Anne-Mette Hvas, Ole Halfdan Larsen
Platelet function analysis was performed employing the Multiplate® Analyzer (Roche, Basel, Switzerland). Hirudin anticoagulated whole blood rested for 30 to 120 minutes before analysis. Whole blood was diluted with 37°Celsius (C) isotonic saline 1:1 followed by three minutes of incubation at 37°C. The following agonists (final concentrations) were used: collagen 3.2 µg/mL (COLtest), adenosine diphosphate (ADP) 6.5 µM (ADPtest), thrombin receptor activating peptide-6 (TRAP) 32 µM (TRAPtest), and ristocetin 0.77 mg/mL (RISTOhigh) (all from Roche, Basel, Switzerland). Platelet aggregation was expressed as area under the aggregation curve (AUC, aggregation units (AU) × minutes), which integrates platelet aggregation and aggregation velocity [19]. Reproducibility of the aggregation response in thrombocytopenia was determined based on five repeated measurements in thrombocytopenic samples from five healthy volunteers (platelet count range: 37–57 × 109/l) using TRAPtest. The coefficient of variation (CV) of the aggregation response was <7.0%.