Subscribe to RSS
DOI: 10.1055/s-0036-1597297
Laboratory Monitoring of Parenteral Direct Thrombin Inhibitors
Publication History
Publication Date:
04 January 2017 (online)
![](https://www.thieme-connect.de/media/sth/201703/lookinside/thumbnails/10-1055-s-0036-1597297_02398-1.jpg)
Abstract
Argatroban and bivalirudin are parenteral direct inhibitors of the activity of thrombin, but, unlike heparin, can inhibit both soluble as well as clot-bound thrombin. These agents do not require antithrombin as a cofactor for activity. The parenteral direct thrombin inhibitors (DTIs) can be used in a variety of settings, including heparin-induced thrombocytopenia (HIT) or an allergy to heparin, and patients requiring anticoagulation for an invasive cardiovascular intervention. Both agents have a relatively short half-life in patients without organ system failure and are typically administered by continuous infusion. Argatroban is primarily eliminated by the liver, while bivalirudin is removed by a combination of proteolytic cleavage by thrombin and renal clearance mechanisms. Several laboratory tests are available for monitoring the anticoagulant effects of the DTIs: the activated partial thromboplastin time (aPTT) and the activated clotting time (ACT) are the most commonly used assays, but on occasion, the thrombin time may be useful. Other coagulation assays such as the dilute thrombin time (dTT), chromogenic anti-IIa assays, and the ecarin clotting time (ECT) can be used. The intensity of anticoagulation with DTIs depends on the indication for use. For patients with HIT, the target aPTT is 1.5 to 3.0 and 1.5 to 2.5 times the patient's baseline value for argatroban and bivalirudin, respectively. DTI anticoagulation used during percutaneous coronary intervention can be measured using ACT. Both DTIs may cause an elevation in the international normalized ratio depending on their plasma concentration. This article will review the use of parenteral DTIs and related laboratory assays for assessing the anticoagulant effect of these drugs.
-
References
- 1 Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schünemann HJ. for the American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. Executive summary. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl): 7S-47S
- 2 https://www.gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Argatroban/pdf/ARGATROBAN.PDF . Accessed October 13, 2015
- 3 Angiomax. Package Insert. The Medicines Company Parsippany. NJ 07054. 2013
- 4 Linkins LA, Dans AL, Moores LK , et al; American College of Chest Physicians. Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e495S-e530S
- 5 Anticoagulation Guideline ELSO. The Extracorporeal Life Support Organization (ELSO), Ann Arbor, MI, USA. 2014 . ELSO.org. Accessed December 25, 2015
- 6 Dyke CM, Smedira NG, Koster A , et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg 2006; 131 (3) 533-539
- 7 Smedira NG, Dyke CM, Koster A , et al. Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study. J Thorac Cardiovasc Surg 2006; 131 (3) 686-692
- 8 Koster A, Dyke CM, Aldea G , et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg 2007; 83 (2) 572-577
- 9 Dager WE, Dougherty JA, Nguyen PH, Militello MA, Smythe MA. Heparin-induced thrombocytopenia: treatment options and special considerations. Pharmacotherapy 2007; 27 (4) 564-587
- 10 Walenga JM, Ahmad S, Hoppensteadt D, Iqbal O, Hursting MJ, Lewis BE. Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia. Thromb Res 2002; 105 (5) 401-405
- 11 Arpino PA, Hallisey RK. Effect of renal function on the pharmacodynamics of argatroban. Ann Pharmacother 2004; 38 (1) 25-29
- 12 Fox I, Dawson A, Loynds P , et al. Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans. Thromb Haemost 1993; 69 (2) 157-163
- 13 Garcia DA, Baglin TP, Weitz JI, Samama MM. Parenteral anticoagulants: antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e24S-e43S
- 14 Warkentin TE, Koster A. Bivalirudin: a review. Expert Opin Pharmacother 2005; 6 (8) 1349-1371
- 15 Dager WE, Tsu LV, Pon TK. Considerations for systemic anticoagulation in ESRD. Semin Dial 2015; 28 (4) 354-362
- 16 Tsu LV, Dager WE. Bivalirudin dosing adjustments for reduced renal function with or without hemodialysis in the management of heparin-induced thrombocytopenia. Ann Pharmacother 2011; 45 (10) 1185-1192
- 17 Runyan CL, Cabral KP, Riker RR , et al. Correlation of bivalirudin dose with creatinine clearance during treatment of heparin-induced thrombocytopenia. Pharmacotherapy 2011; 31 (9) 850-856
- 18 Gosselin RC, Dager WE, King JH , et al. Effect of direct thrombin inhibitors, bivalirudin, lepirudin, and argatroban, on prothrombin time and INR values. Am J Clin Pathol 2004; 121 (4) 593-599
- 19 Love JE, Ferrell C, Chandler WL. Monitoring direct thrombin inhibitors with a plasma diluted thrombin time. Thromb Haemost 2007; 98 (1) 234-242
- 20 Shaikh S, Van Cott EM. The effect of argatroban on activated protein C resistance. Am J Clin Pathol 2009; 131 (6) 828-833
- 21 Kim YA, Gosselin R, Van Cott EM. The effects of dabigatran on lupus anticoagulant, diluted plasma thrombin time, and other specialized coagulation assays. Int J Lab Hematol 2015; 37 (4) e81-e84
- 22 Adcock DM, Gosselin R, Kitchen S, Dwyre DM. The effect of dabigatran on select specialty coagulation assays. Am J Clin Pathol 2013; 139 (1) 102-109
- 23 Walenga JM, Fasanella AR, Iqbal O , et al. Coagulation laboratory testing in patients treated with argatroban. Semin Thromb Hemost 1999; 25 (Suppl. 01) 61-66
- 24 Moll S, Ortel TL. Monitoring warfarin therapy in patients with lupus anticoagulants. Ann Intern Med 1997; 127 (3) 177-185
- 25 Gosselin RC. Heparin induced thrombocytopenia in a post-operative cardiopulmonary bypass patient requiring extracorporeal and intra-aortic balloon support: diagnosis and management. American Society for Clinical Pathology, Check Sample April 2007.
- 26 Laposata M, Green D, Van Cott EM, Barrowcliffe TW, Goodnight SH, Sosolik RC. College of American Pathologists Conference XXXI on laboratory monitoring of anticoagulant therapy: the clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med 1998; 122 (9) 799-807
- 27 Dager W. Parenteral Direct Thrombin Inhibitors. . In: Dager W, Gulseth M, Nutescu E, , eds. Anticoagulation Therapy: A Point-of-Care Guide. Bethesda, MD: American Society of Health-System Pharmacists; 2011
- 28 Arpino PA, Goeller AJ, Fatalo A, Van Cott EM. Evaluation of 2 nomogram-based strategies for dosing argatroban in patients with known or suspected heparin-induced thrombocytopenia. Clin Appl Thromb Hemost 2015; 21 (3) 260-265
- 29 Kiser TH, Mann AM, Trujillo TC, Hassell KL. Evaluation of empiric versus nomogram-based direct thrombin inhibitor management in patients with suspected heparin-induced thrombocytopenia. Am J Hematol 2011; 86 (3) 267-272
- 30 Gilmore JF, Adams CD, Blum RM, Fanikos J, Anne Hirning B, Matta L. Evaluation of a multi-target direct thrombin inhibitor dosing and titration guideline for patients with suspected heparin-induced thrombocytopenia. Am J Hematol 2015; 90 (8) E143-E145
- 31 Lincoff AM, Bittl JA, Harrington RA , et al; REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003; 289 (7) 853-863
- 32 Shahzad A, Kemp I, Mars C , et al; HEAT-PPCI trial investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 2014; 384 (9957): 1849-1858
- 33 Stone GW, Witzenbichler B, Guagliumi G , et al; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358 (21) 2218-2230
- 34 Roffi M, Patrono C, Collet JP , et al; 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37 (3) 267-315
- 35 Kastrati A, Neumann FJ, Mehilli J , et al; ISAR-REACT 3 Trial Investigators. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 2008; 359 (7) 688-696
- 36 Chia S, Van Cott EM, Raffel OC, Jang IK. Comparison of activated clotting times obtained using Hemochron and Medtronic analysers in patients receiving anti-thrombin therapy during cardiac catheterisation. Thromb Haemost 2009; 101 (3) 535-540
- 37 Castellone DD, Van Cott EM. Laboratory monitoring of new anticoagulants. Am J Hematol 2010; 85 (3) 185-187
- 38 Arpino PA, Demirjian Z, Van Cott EM. Use of the chromogenic factor X assay to predict the international normalized ratio in patients transitioning from argatroban to warfarin. Pharmacotherapy 2005; 25 (2) 157-164
- 39 Gosselin RC, King JH, Janatpur KA, Dager WH, Larkin EC, Owings JT. Effects of pentasaccharide (fondaparinux) and direct thrombin inhibitors on coagulation testing. Arch Pathol Lab Med 2004; 128 (10) 1142-1145