Skip to main content

Advertisement

SpringerLink
Log in

Direct thrombin inhibitors: pharmacology and application in intensive care medicine

  • Review
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Purpose

Anticoagulation is part of the daily routine of intensive care physicians. As the possibilities of pharmacological anticoagulation are becoming more numerous and diverse, intensive care physicians have to be familiar with indications, contraindications, dosing, and reversal of many different substances. This paper presents an overview of the substance group of direct thrombin inhibitors (DTI) indicated for alternative anticoagulation in intensive care medicine.

Methods

The review is a synopsis of scientific evidence, expert opinion, open forum commentary, and clinical feasibility data.

Results and conclusions

Due to their antithrombotic potential without direct activation of platelets, DTI could offer potential advantages over heparins and vitamin K antagonists in critically ill patients, especially regarding heparin-induced thrombocytopenia. Because of multiple organ dysfunction, organ failure, and comedications, simple extrapolation of results of medical to critically ill patients is not permissible. The fine line between thrombosis and bleeding in intensive care patients requires cautious dosing and close drug monitoring. Studies dealing with DTI in the intensive care setting are of utmost clinical interest.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Oliveira GB, Crespo EM, Becker RC, Honeycutt EF, Abrams CS, Anstrom KJ, Berger PB, Davidson-Ray LD, Eisenstein EL, Kleiman NS, Moliterno DJ, Moll S, Rice L, Rodgers JE, Steinhubl SR, Tapson VF, Ohman EM, Granger CB, Complications After Thrombocytopenia Caused by Heparin (CATCH) Registry Investigators (2008) Incidence and prognostic significance of thrombocytopenia in patients treated with prolonged heparin therapy. Arch Intern Med 168:94–102

    Article  PubMed  Google Scholar 

  2. Bates S, Weitz J (2000) The mechanisms of action of thrombin inhibitors. J Invasive Cardiol 12:27F–32F

    PubMed  Google Scholar 

  3. Weitz JI (2003) A novel approach to thrombin inhibition. Thromb Res 109(Suppl 1):S17–S22

    Article  PubMed  CAS  Google Scholar 

  4. Kozek-Langenecker S, Mohammad S, Masaki T (2000) Effects of heparin, protamine, and heparinase 1 on platelets in vitro using whole blood flow cytometry. Anesth Analg 90:808–812

    Article  PubMed  CAS  Google Scholar 

  5. Xiao Z, Theroux P (1998) Platelet activation with unfractionated heparin at therapeutic concentrations and comparisons with a low-molecular-weight heparin and with a direct thrombin inhibitor. Circulation 97:251–256

    PubMed  CAS  Google Scholar 

  6. Sarich T, Woltz M, Eriksson U (2003) Effects of ximelagatran, an oral direct thrombin inhibitor, r-hirudin and enoxaparin on thrombin generation and platelet activation in healthy male subjects. J Am Coll Cardiol 41:557–564

    Article  PubMed  CAS  Google Scholar 

  7. Hoppensteadt D, Jeske W, Walenga JM, Bick RL, Fareed J (2008) The anti-inflammatory effects of argatroban can be differentiated from other direct thrombin inhibitors: experimental and clinical observations. Semin Thromb Haemost 34:97–102

    Article  Google Scholar 

  8. Selleng K, Greinacher A (2005) Heparin-induzierte Thrombozytopenie in der Intensivmedizin. Intensivmedizin Update 1:1–16

    Article  Google Scholar 

  9. Selleng K, Selleng S, Greinacher A (2008) Heparin-induced thrombocytopenia in intensive care patients. Semin Thromb Hemost 34:425–438

    Article  PubMed  CAS  Google Scholar 

  10. Warkentin T, Greinacher A, Koster A, Lincoff AM (2008) Treatment and prevention of heparin-induced thrombocytopenia: American College of Chest Physicians evidence-based clinical practice guidelines (8th edn). Chest 133:340S–380S

    Article  PubMed  CAS  Google Scholar 

  11. Verma AK, Levine M, Shalansky SJ, Carter CJ, Kelton JG (2003) Frequency of heparin-induced thrombocytopenia in critical care patients. Pharmacotherapy 23:745–753

    Article  PubMed  Google Scholar 

  12. Muslimani A, Ricaurte B, Daw H (2007) Immune heparin-induced thrombocytopenia resulting from preceding exposure to heparin catheter flushes. Am J Haematol 82:652–655

    Article  CAS  Google Scholar 

  13. Warkentin T, Hayward C, Boshkowv L (1994) Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood 84:3691–3693

    PubMed  CAS  Google Scholar 

  14. Greinacher A, Vögel H, Janssen U (1999) Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Circulation 100:587–590

    PubMed  CAS  Google Scholar 

  15. Lewis B, Hursting M (2004) Argatroban therapy in heparin-induced thrombocytopenia. In: Warkentin T, Greinacher A (eds) Heparin-induced thrombocytopenia. Marcel Dekker, New York, pp 437–474

    Google Scholar 

  16. Lubenow N, Eichler P, Lietz T (2004) Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3 prospective studies. Blood 104:3072–3077

    Article  PubMed  CAS  Google Scholar 

  17. Metnitz PG, Krenn CG, Steltzer H, Lang T, Ploder J, Lenz K, Le Gall JR, Druml W (2002) Effect of acute renal failure requiring renal replacement therapy on outcome in critically ill patients. Crit Care Med 30:2051–2058

    Article  PubMed  Google Scholar 

  18. Kozek-Langenecker S (2002) Hämofiltration und Blutgerinnung. Anaesthesist 51:210–217

    Article  PubMed  CAS  Google Scholar 

  19. Salmon J, Cardigan R, Mackie I, Cohen SL, Machin S, Singer M (1997) Continuous venovenous hemofiltration using polyacrylonitrile filters does not activate contact system and intrinsic coagulation pathways. Intensive Care Med 23:38–43

    Article  PubMed  CAS  Google Scholar 

  20. Cardigan R, McGloin H, Mackie I, Machin SJ, Singer M (1999) Activation of the tissue factor pathway occurs during continuous venovenous hemofiltration. Kidney Int 55:1568–1574

    Article  PubMed  CAS  Google Scholar 

  21. LaMonte M, Brown P, Hursting M (2005) Alternative parenteral anticoagulation with argatroban, a direct thrombin inhibitor. Expert Rev Cardiovasc Ther 3:31–41

    Article  PubMed  CAS  Google Scholar 

  22. Davenport A (2007) Anticoagulation options for patients with heparin-induced thrombocytopenia requiring renal support in the intensive care unit. In: Ronco C, Bellomo R, Kellum J (eds) Acute kidney injury, vol 156. Karger, Basel, pp 259–266

    Chapter  Google Scholar 

  23. Rydel T, Ravichandran K, Tulinsky A (1990) The structure of a complex of recombinant hirudin and human a-thrombin. Science 249:277–280

    Article  PubMed  CAS  Google Scholar 

  24. Vanholder R, Camez A, Veys N (1997) Pharmacokinetics of recombinant hirudin in hemodialyzed end-stage renal failure patients. Thromb Haemost 77:650–655

    PubMed  CAS  Google Scholar 

  25. Eichler P, Friesen H, Lubenow N (2000) Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 96:2373–2378

    PubMed  CAS  Google Scholar 

  26. Greinacher A, Lubenow N, Eichler P (2003) Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 108:2062–2065

    Article  PubMed  CAS  Google Scholar 

  27. Veach S, Franks A, Allan M (2007) Severe anaphylactic reaction after repeated intermittent exposure to lepirudin. Pharmacotherapy 27:760–765

    Article  PubMed  CAS  Google Scholar 

  28. Fenyvesi T, Jorg I, Harenberg J (2002) Monitoring of anticoagulant effects of direct thrombin inhibitors. Semin Thromb Hemost 28:361–368

    Article  PubMed  CAS  Google Scholar 

  29. Wenzel C, Stoiser B, Locker G, Laczika K, Quehenberger P, Kapiotis S, Frass M, Pabinger I, Knöbl P (2002) Frequent development of lupus anticoagulants in critically ill patients treated under intensive care conditions. Crit Care Med 30:763–770

    Article  PubMed  CAS  Google Scholar 

  30. Clarke R, Mayo G, Fitzgerald G, Fitzgerald D (1991) Combined administration of aspirin and a specific thrombin inhibitor in man. Circulation 83:1510–1518

    PubMed  CAS  Google Scholar 

  31. Francis JL, Hursting MJ (2005) Effect of argatroban on the activated partial thromboplastin time: a comparison of 21 commercial reagents. Blood Coagul Fibrinolysis 16:251–257

    Article  PubMed  CAS  Google Scholar 

  32. Pötsch B, Madlener K (2004) Management of cardiopulmonary bypass anticoagulation in patients with heparin-induced thrombocytopenia. In: Warkentin T, Greinacher A (eds) Heparin-induced thrombocytopenia. Marcel Dekker, New York, pp 531–532

    Google Scholar 

  33. Moser M, Ruef J, Peter K (2001) Ecarin clotting time but not aPTT correlates with PEG-hirudin plasma activity. J Thromb Thrombolysis 12:165–169

    Article  PubMed  CAS  Google Scholar 

  34. Callas D, Hoppensteadt D, Iqbal O, Fareed J (1996) Ecarin clotting time (ECT) is a reliable method for the monitoring of hirudins, argatroban, efegatran and related drugs in therapeutic and cardiovascular indications. Ann Haematol 1:A58 (abstract)

    Google Scholar 

  35. Callas D, Fareed J (1996) Comparative anticoagulant effects of various thrombin inhibitors, as determined in the ecarin clotting time method. Thromb Res 83:463–468

    Article  PubMed  CAS  Google Scholar 

  36. Lange U, Nowak G, Bucha E (2003) Ecarin chromogenic assay—a new method for quantitative determination of direct thrombin inhibitors like hirudin. Pathophysiol Haemost Thromb 33:184–191

    Article  PubMed  CAS  Google Scholar 

  37. Lindhoff-Last E, Piechotta G, Rabe F, Bauersachs R (2000) Hirudin determination in plasma can be strongly influenced by the prothrombin level. Thromb Res 100:55–60

    Article  PubMed  CAS  Google Scholar 

  38. Lubenow N, Eichler P, Lietz T, Greinacher A, Hit Investigators Group (2005) Lepirudin in patients with heparin-induced thrombocytopenia—results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and HAT-3. J Thromb Haemost 3:2428–2436

    Article  PubMed  CAS  Google Scholar 

  39. Hacquard M, de Maistre E, Lecompte T (2005) Lepirudin: is the approved dosing schedule too high? J Thromb Haemost 3:2593–2596

    Article  PubMed  CAS  Google Scholar 

  40. Greinacher A (2004) Lepirudin: a bivalent direct thrombin inhibitor for anticoagulation therapy. Expert Rev Cardiovasc Ther 2:339–357

    Article  PubMed  CAS  Google Scholar 

  41. Greinacher A, Eichler P, Lubenow N (2000) Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood 96:846–851

    PubMed  CAS  Google Scholar 

  42. Kassimatis T, Apostolou T, Theodoridis T (2006) The use of lepirudin in haemodialysis complicated with heparin-induced thrombocytopenia type II (HIT II)—dosage monitoring. Nephrol Dial Transplant 21:3341–3342

    Article  PubMed  CAS  Google Scholar 

  43. Dager W, White R (2001) Use of lepirudin in patients with heparin-induced thrombocytopenia and renal failure requiring hemodialysis. Ann Pharmacother 35:885–890

    Article  PubMed  CAS  Google Scholar 

  44. Fischer K, van de Loo A, Bohler J (1999) Recombinant hirudin (lepirudin) as anticoagulant in intensive care patients treated with continuous hemodialysis. Kidney Int Suppl 72:S46–S50

    Article  PubMed  CAS  Google Scholar 

  45. Chuang P, Parikh C, Reilly R (2001) A case review: anticoagulation in hemodialysis patients with heparin-induced thrombocytopenia. Am J Nephrol 21:226–231

    Article  PubMed  CAS  Google Scholar 

  46. Kozek-Langenecker S, Fries D, Gütl M (2005) Locoregional anesthesia and coagulation inhibitors. Recommendations of the Task Force on Perioperative Coagulation of the Austrian Society for Anesthesiology and Intensive Care Medicine. Anaesthesist 54:476–484

    Article  PubMed  CAS  Google Scholar 

  47. http://www.oegari.at/dateiarchiv/116/Regionalanaesthesia%20engl.pdf. Accessed 24 Feb 2010

  48. Ibbotson SH, Grant PJ, Kerry R (1991) The influence of infusions of 1-desamino-8-d-arginine vasopressin (DDAVP) in vivo on the anticoagulant effect of recombinant hirudin (CGP39393) in vitro. Thromb Haemost 65:64–66

    PubMed  CAS  Google Scholar 

  49. Amin DM, Mant TG, Walker SM (1997) Effect of a 15-minute infusion of DDAVP on the pharmacokinetics and pharmacodynamics of REVASC during a four-hour intravenous infusion in healthy male volunteers. Thromb Haemost 77:127–132

    PubMed  CAS  Google Scholar 

  50. Bove CM, Casey B, Marder VJ (1996) DDAVP reduces bleeding during continued hirudin administration in the rabbit. Thromb Haemost 75:471–475

    PubMed  CAS  Google Scholar 

  51. Butler KD, Dolan SL, Talbot MD, Wallis RB (1993) Factor VIII and DDAVP reverse the effect of recombinant desulphatohirudin (CGP 39393) on bleeding in the rat. Blood Coagul Fibrinolysis 4:459–464

    Article  PubMed  CAS  Google Scholar 

  52. Irani MS, White HJ Jr, Sexon RG (1995) Reversal of hirudin-induced bleeding diathesis by prothrombin complex concentrate. Am J Cardiol 75:422–423

    Article  PubMed  CAS  Google Scholar 

  53. Fareed J, Walenga JM, Pifarre R (1991) Some objective considerations for the neutralization of the anticoagulant actions of recombinant hirudin. Haemostasis 21(Suppl 1):64–72

    PubMed  CAS  Google Scholar 

  54. Irani M, White H, Sexon G (1995) Reversal of hirudin-induced bleeding diathesis by prothrombin complex concentrate. Am J Cardiol 75:422–423

    Article  PubMed  CAS  Google Scholar 

  55. Diehl K, Romisch J, Hein B (1995) Investigation of activated prothrombin complex concentrate as potential hirudin antidote in animal models. Haemostasis 25:182–192

    PubMed  CAS  Google Scholar 

  56. Novak G, Bucha E (1995) Prothrombin conversion intermediate effectively neutralizes toxic levels of hirudin. Thromb Res 80:317–325

    Article  Google Scholar 

  57. Maraganore J, MBourdon P, Jablonski J (1990) Design and characterization of Hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 29:7095–7101

    Article  PubMed  CAS  Google Scholar 

  58. Parry M, Maraganore J, Stone S (1994) Kinetic mechanism for the interaction of Hirulog with thrombin. Biochemistry 33:14807–14814

    Article  PubMed  CAS  Google Scholar 

  59. Robson R, White H, Aylward P, Frampton C (2002) Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose and gender. Clin Pharmacol Ther 71:433–439

    Article  PubMed  CAS  Google Scholar 

  60. Chew D, Bhatt D, Kimball W (2003) Bivalirudin provides increasing benefit with decreasing renal function: a meta-analysis of randomized trials. Am J Cardiol 92:919–923

    Article  PubMed  CAS  Google Scholar 

  61. Welsby I, Stafford-Smith M (2004) Monitoring direct thrombin inhibitors: time for standardization (comment). Anesthesiology 101:1048–1049

    Article  PubMed  Google Scholar 

  62. Casserly I, Kereiakes D, Gray W (2004) Point-of-care ecarin clotting time versus activated clotting time in correlation with bivalirudin concentration. Thromb Res 113:115–121

    Article  PubMed  CAS  Google Scholar 

  63. Cho L, Kottke-Marchant K, Lincoff A (2003) Correlation of point-of-care ecarin clotting time versus activated clotting time with bivalirudin concentration. Am J Cardiol 91:1110–1112

    Article  PubMed  Google Scholar 

  64. Chamberlin J, Lewis B, Leya F (1995) Successful treatment of heparin-associated thrombocytopenia and thrombosis using Hirulog. Can J Cardiol 11:511–514

    PubMed  CAS  Google Scholar 

  65. Francis JL, Drexler A, Gwyn G (2003) Bivalirudin, a direct thrombin inhibitor, is a safe and effective treatment for heparin-induced thrombocytopenia (abstract). Blood (Suppl) 102:164a

    Google Scholar 

  66. Kiser T, Fish D (2006) Evaluation of bivalirudin treatment for heparin-induced thrombocytopenia in critically ill patients with hepatic and/or renal dysfunction. Pharmacotherapy 26:452–460

    Article  PubMed  CAS  Google Scholar 

  67. Bartholomew J (2004) Bivaliruding for the treatment of heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A (eds) Heparin-induced thrombocytopenia, vol 3. Marcel Dekker, New York, pp 475–507

    Google Scholar 

  68. Kiser TH, Burch JC, Klem PM, Hassell KL (2008) Safety, efficacy, and dosing requirements of bivalirudin in patients with heparin-induced thrombocytopenia. Pharmacotherapy 28:1115–1124

    Article  PubMed  CAS  Google Scholar 

  69. Young G, Yonekawa K, Nakagawa P (2007) Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux argatroban, and bivalirudin ex vivo as measured using thrombelastography. Blood Coagul Fibrinolysis 18:547–553

    Article  PubMed  CAS  Google Scholar 

  70. Koster A, Chew DP, Gründel M (2003) An assessment of different filter systems for extracorporeal elimination of bivalirudin: an in vitro study. Anesth Analg 96:1316–1319

    Article  PubMed  CAS  Google Scholar 

  71. Mann M, Tseng EE, Ratcliff M (2005) Use of bivalirudin, a direct thrombin inhibitor, and its reversal with modified ultrafiltration during heart transplantation in a patient with heparin-induced thrombocytopenia. J Heart Lung Transplant 24:222–225

    Article  PubMed  Google Scholar 

  72. Hauptmann J, Sturzebecher J (1999) Synthetic inhibitors of thrombin and factor Xa: from bench to bedside. Thromb Res 93:203–241

    Article  PubMed  CAS  Google Scholar 

  73. Berry C, Girardot C, Lecroffre C, Lunven C (1994) Effect of synthetic thrombin inhibitor argatroban on fibrin- and clot-incorporated thrombin: comparison with heparin and recombinant hirudin. Thromb Haemost 72:381–386

    PubMed  CAS  Google Scholar 

  74. Swan S, Hursting M (2000) The pharmacokinetics and pharmacodynamics of argatroban: effect of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 20:318–329

    Article  PubMed  CAS  Google Scholar 

  75. Walenga J, Ahmad S, Hoppensteadt D (2002) Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia. Thromb Res 105:401–405

    Article  PubMed  CAS  Google Scholar 

  76. Warkentin TE, Greinacher A, Craven S, Dewar L, Sheppard JA, Ofosu FA (2005) Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation. Thromb Haemost 94:958–964

    PubMed  CAS  Google Scholar 

  77. Molinaro RJ, Szlam F, Levy JH, Fantz CR, Tanaka KA (2008) Low plasma fibrinogen levels with the Clauss method during anticoagulation with bivalirudin. Anesthesiology 109:160–161

    Article  PubMed  Google Scholar 

  78. Engström M, Rundgren M, Schött U (2010) An evaluation of monitoring possibilities of argatroban using rotational thromboelastometry and activated partial thromboplastin time. Acta Anaesthesiol Scand 54:86–91

    Article  PubMed  CAS  Google Scholar 

  79. Harder S, Graff J, Klinkhardt U (2004) Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effects on prothrombin time, activated partial thromboplastin time, and ecarin clotting time. Thromb Haemost 91:1137–1145

    PubMed  CAS  Google Scholar 

  80. Lewis B, Wallis D, Berkowitz S (2001) Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation 103:1838–1843

    PubMed  CAS  Google Scholar 

  81. Lewis B, Wallis D, Leya F (2003) Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med 163:1849–1856

    Article  PubMed  CAS  Google Scholar 

  82. Williamson D, Boulanger I, Tardif M (2004) Argatroban dosing in intensive care patients with acute renal failure and liver dysfunction. Pharmacotherapy 24:409–414

    Article  PubMed  CAS  Google Scholar 

  83. Dyke P, Russo P, Mureebe L (2005) Argatroban for anticoagulation during cardiopulmonary bypass in an infant. Pediat Anesthesia 15:328–333

    Article  Google Scholar 

  84. Risch L, Huber AR, Schmugge M (2006) Diagnosis and treatment of heparin-induced thrombocytopenia in neonates and children. Thromb Res 118:123–135

    Article  PubMed  CAS  Google Scholar 

  85. Beiderlinden M, Treschan T, Görlinger K, Peters J (2007) Argatroban anticoagulation in critically ill patients. Ann Pharmacother 41:749–754

    Article  PubMed  CAS  Google Scholar 

  86. Beiderlinden M, Treschan T, Görlinger K, Peters J (2007) Argatroban in extracorporeal membrane oxygenation. Artif Organs 31:461–465

    Article  PubMed  CAS  Google Scholar 

  87. Koster A, Hentschel T, Groman T (2007) Argatroban anticoagulation for renal replacement therapy in patients with heparin-induced thrombocytopenia after cardiovascular surgery. J Thorac Cardiovasc Surg 133:1376–1377

    Article  PubMed  Google Scholar 

  88. Reddy B, Grossman E, Trevino S (2005) Argatroban anticoagulation in patients with heparin-induced thrombocytopenia requiring renal replacement therapy. Ann Pharmacother 39:1601–1605

    Article  PubMed  CAS  Google Scholar 

  89. Ota K, Akizawa T, hirasawa Y (2003) Effects of argatroban as an anticoagulant for haemodialysis in patients with antithrombin III deficiency. Nephrol Dial Transplant 18:1623–1630

    Article  PubMed  CAS  Google Scholar 

  90. Tang I, Cox D, Patel K (2005) Argatroban and renal replacement therapy in patients with heparin-induced thrombocytopenia. Ann Pharmacother 39:231–236

    Article  PubMed  CAS  Google Scholar 

  91. Murray P, Hursting M (2006) Heparin-induced thrombocytopenia in patients administered heparin solely for hemodialysis. Ren Fail 28:537–539

    Article  PubMed  Google Scholar 

  92. Murray P, Reddy B, Grossman E (2004) A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease. Kidney Int 66:2446–2453

    Article  PubMed  CAS  Google Scholar 

  93. Krieger D, Geisen U, Is A, Fischer K (2007) Hemodialyser membranes allow for removal of argatroban. J Thromb Haemost 5(Suppl 1):P-S-669

    Google Scholar 

  94. Yee AJ, Kuter DJ (2006) Successful recovery after an overdose of argatroban. Ann Pharmacother 40:336–339

    Article  PubMed  Google Scholar 

  95. Murray PT, Reddy BV, Grossman EJ (2004) A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease. Kidney Int 66:2446–2453

    Article  PubMed  CAS  Google Scholar 

  96. Stangier J, Clemens A (2009) Pharmacology, pharmacokinetics, and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor. Clin Appl Thromb Hemost. Aug 19 [Epub ahead of print]

  97. Alban S (2008) Pharmacology of heparins and direct anticoagulants. Haemostaseologie 28:400–420

    CAS  Google Scholar 

  98. Direct Thrombin Inhibitor Trialists’ Collaborative Group (2002) Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet 359:294–302

    Article  Google Scholar 

  99. Sinnaeve PR, Simes J, Yusuf S, Garg J, Mehta S, Eikelboom J, Bittl JA, Serruys P, Topol EJ, Granger CB (2005) Direct thrombin inhibitors in acute coronary syndromes: effect in patients undergoing early percutaneous coronary intervention. Eur Heart J 26:2396–2403

    Article  PubMed  CAS  Google Scholar 

  100. Lewis BE, Hursting MJ (2007) Direct thrombin inhibition during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Expert Rev Cardiovasc Ther 5:57–68

    Article  PubMed  CAS  Google Scholar 

  101. Taketomi T, Szlam F, Vinten-Johansen J (2007) Thrombin-activated thrombelastography for evaluation of thrombin interaction with thrombin inhibitors. Blood Coagul Fibrinolysis 18:761–767

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology, General Intensive Care and Pain Management, Medical University of Vienna, Währinger Guertel 18-20, 1090, Vienna, Austria

    Eva Schaden & Sibylle A. Kozek-Langenecker

  2. Department of Anaesthetics and Intensive Care, Evangelisches Krankenhaus Vienna, Vienna, Austria

    Sibylle A. Kozek-Langenecker

Authors
  1. Eva Schaden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sibylle A. Kozek-Langenecker
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eva Schaden.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Schaden, E., Kozek-Langenecker, S.A. Direct thrombin inhibitors: pharmacology and application in intensive care medicine. Intensive Care Med 36, 1127–1137 (2010). https://doi.org/10.1007/s00134-010-1888-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-010-1888-3

Keywords

Search

Navigation