Thrombin inhibition

Anticoagulants. Figure 3 Relative effects of UFH, LMWH, and fondaparinux on AT-mediated inhibition of factor Xa and thrombin (lla). Whereas UFH catalyzes inhibition of Xa and thrombin equally well, only LMWH chains of 18 saccharide units or longer catalyze thrombin inhibition thus, the anti-Xa/anti-lla ratio of LMWH preparations ranges from 2 1 to 4 1. In contrast, fondaparinux exclusively inhibits Xa. (Modified from [3], with permission from Chest.)... 

Danaparoid (Orgaran mean MW, 6,000 Da) is a mixture of nonheparin glycosaminoglycans derived from pig gut (dermatan sulfate, heparan sulfate, chondroitin sulfate). Die anti-Xa/anti-IIa ratio (22 1) is even greater than seen with LMWH. Die anti-IIa effect may be mediated in part by dermatan sulfate, which catalyzes thrombin inhibition by heparin cofactor II. 

Eriksson B. I., Ekmann S. T Kalebo P., et al. Prevention of deep-vein thrombosis after total hip replacement Direct thrombin inhibition with recombinant hirudin, CCG 39393. Lancet 1996 347,635-9. 

A typical example of such parallelized measurements is given in Figure 20. For a variety of inhibitors, the binding inhibition assay is given for a thrombin inhibition Figure 20 shows the binding curves obtained in parallel from 96 wells37. 

Fitzgerald, G. (1996). The human pharmacology of thrombin inhibition. Coronary Artery Dis. 7(12), 911-918. Markwardt, F. (1991). Hirudin and its derivatives as anticoagulant agents. Thromb. Haemost. 66, 141-152. 

Heparin binds to antithrombin III and induces a conformational change that accelerates the interaction of antithrombin III with the coagulation factors. Heparin also catalyzes the inhibition of thrombin by heparin cofactor II, a circulating inhibitor. Smaller amounts of heparin are needed to prevent the formation of free thrombin than are needed to inhibit the protease activity of clot-bound thrombin. Inhibition of free thrombin is the basis of low-dose prophylactic therapy. 

Mechanism of Action An anticoagulant that binds specifically and directly to thrombin, inhibiting free circulating and clot-bound ihmmhinT herapeuticEffect Prolongs the clotting time of human plasma. 

Mechanism of Action A low-molecular-weight heparinthat inhibits factor Xa. Causes less inactivation of thrombin, inhibition of platelets, and bleedingthan standard heparin. Does not significantlyinfluence bleeding time, PT, aPTT. Therapeutic Effect Produces anticoagulation. 

The oleosin fusion procedure was used for the purification of the commercially valuable plant-based blood anticoagulant hirudin in transgenic Brassica carinata and Brassica napus. Hirudin, a natural protein from the medicinal leech Hirudo medicinalis, is superior to other anticoagulants such as heparin. Recombinant hirudin was cleaved from oil-bodies using endoproteinase Factor Xa. Released hirudin was biologically active, as determined by a colorimetric thrombin inhibition assay. 

Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction results from the GUSTO-lib Trial. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-lib) Investigators. J Am Coll Cardiol, 1998.31(7) 1493-8. 

Most drug discovery efforts focus on thrombin inhibition as a means to prevent the serious consequences of thrombus formation in myocardial infarction and stroke. Thrombin inhibitors may also prevent clot formation in patients prone to deep vein thrombosis or repeat heart attack. In combination with thrombus dissolution therapies, thrombin inhibitors may decrease the incidence of reocclusion due, in part, to the release of active clot-bound thrombin. 

UFH binds to exosite 2, located on antithrombin, forming a ternary complex. This ternary complex is necessary for the inhibition of thrombin by antithrombin (Fig. I A, left). Conversely to thrombin inhibition, inactivation of factor Xa does not require the formation of the ternary complex. UFH inhibits thrombin and factor Xa in the same proportion (the ratio of anti-Xa/lla activity equals I) (Fig, I A, right). The interaction of the heparins (UFH and LMWH) with antithrombin is mediated by a unique pentasaccharide sequence, which is present in approximately one-third of the UFH chains (2). 

Direct thrombin inhibition in percutaneous coronary intervention... 

DTI meta-analysis. Abbreviations DTI, direct thrombin inhibition MI, myocardial infarction OR, odds ratio PCI, percutaneous coronary intervention UFH, unfractionated heparin. 

Thrombin inhibition Irreversible Reversible Irreversible Reversible... 

Antman EM for the TIMI 9b Investigators, Hirudin in acute myocardial infarction thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9b trial, Circulation 1996 94 91 1-921. 

Antman E for the TIMI 9A Investigators. Hirudin in acute myocardial infarction safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial. Circulation 1994 90 1624-1630. 

Slow onset and offset of action Rapid onset of action, rapid reversal of thrombin inhibition after cessation of therapy (dependent on plasma concentration and elimination half-life)... 

EXPRESS, Expanded PRophylaxis Evaluation Surgery Study EXULT, EXanta Used to Lessen Thrombosis INR, international normalized ratio s.c., subcutaneous METHRO, MElagatran for THRombin inhibition in Orthopedic... 

Eriksson Bl, Arfwidsson AC, Frison L, et al. A dose-ranging study ofthe oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement METHRO I, MEIagatran for THRombin inhibition in Orthopaedic surgery. Thromb Haemost 2002 87 231-237. 

Halperin JL. Ximelagatran oral direct thrombin inhibition as anticoagulant therapy in atrial fibrillation. J Am Coll Cardiol 2005 45 1-9. 

K. Padmanabhan et al., The structure of alpha-thrombin inhibited by a 15-mer single-stranded DNA aptamer. J. Biol. Chem. 268, 17651-17654 (1993)... 

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