Parenteral Anticoagulants: Direct Thrombin Inhibitors and Pentasaccharides

  • Meghan L. Fletcher
  • Allison E. Burnett


Unfractionated heparin (UFH), while very effective in preventing or treating arterial and venous thromboembolic events, possesses numerous disadvantages. These include a non-specific mechanism of action, high degree of non-specific binding to plasma components, unpredictable pharmacokinetics and pharmacodynamics, considerable inter- and intra-patient variability, a narrow therapeutic index, need for routine monitoring, and the potential for adverse effects. Additionally, some clinical situations preclude the use of UFH, such as immune-mediated heparin-induced thrombocytopenia (HIT). To address many of the drawbacks of heparin, alternative parenteral anticoagulants have been developed. In this chapter, we will discuss two groups of these alternative anticoagulants: pentasaccharides and parenteral direct thrombin inhibitors. Optimized safety and efficacy of these drugs require familiarity with their pharmacology, clinical utility, and practical management.


Acute coronary syndrome Argatroban Bivalirudin Direct thrombin inhibitor Fondaparinux Heparin-induced thrombocytopenia Parenteral Pentasaccharide Percutaneous coronary intervention Superficial thrombophlebitis Venous thromboembolism 


  1. 1.
    Kaplan KL. Direct thrombin inhibitors. Expert Opin Pharmacother. 2003;4(5):653–66.CrossRefGoogle Scholar
  2. 2.
    Di Nisio M, Middeldorp S, Büller HR. Direct thrombin inhibitors. N Engl J Med. 2005;353(10):1028–40.CrossRefGoogle Scholar
  3. 3.
    Reed MD, Bell D. Clinical pharmacology of bivalirudin. Pharmacotherapy. 2002;22(6 Pt 2):105S–11S.CrossRefGoogle Scholar
  4. 4.
    Lee CJ, Ansell JE. Direct thrombin inhibitors. Br J Clin Pharmacol. 2011;72(4):581–92.CrossRefGoogle Scholar
  5. 5.
    Bivalirudin (Angiomax) package insert [Internet]. Available from: Accessed 18 Dec 2016.
  6. 6.
    Swan SK, Hursting MJ. The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction. Pharmacotherrapy. 2000;20(3):318–29.CrossRefGoogle Scholar
  7. 7.
  8. 8.
    Robson R, White H, Aylward P, Frampton C. Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender. Clin Pharmacol Ther. 2002;71(6):433–9.CrossRefGoogle Scholar
  9. 9.
    Garcia DA, Baglin TP, Weitz JI, Samama MM. American College of Chest Physicians. Parenteral anticoagulants: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e24S–43S.CrossRefGoogle Scholar
  10. 10.
    Donat F, Duret JP, Santoni A, Cariou R, Necciari J, Magnani H, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet. 2002;41(Suppl 2):1–9.CrossRefGoogle Scholar
  11. 11.
    Fondaparinux package insert [Internet]. Available from: Accessed 27 Nov 2016.
  12. 12.
    Hohlfelder B, DeiCicchi D, Sylvester KW, Connors JM. Development of a predictive nomogram for the change in PT/INR upon discontinuation of bivalirudin as a bridge to warfarin. Clin Appl Thromb Hemost. 2016;23(5):487–93.CrossRefGoogle Scholar
  13. 13.
    Walenga JM, Drenth AF, Mayuga M, Hoppensteadt DA, Prechel M, Harder S, et al. Transition from argatroban to oral anticoagulation with phenprocoumon or acenocoumarol: effect on coagulation factor testing. Clin Appl Thromb Hemost. 2008;14(3):325–31.CrossRefGoogle Scholar
  14. 14.
    Warkentin TE, Greinacher A, Koster A. Bivalirudin. Thromb Haemost. 2008;99(5):830–9.PubMedGoogle Scholar
  15. 15.
    Linkins L-A, Dans AL, Moores LK, Bona R, Davidson BL, Schulman S, et al. Treatment and prevention of heparin-induced thrombocytopenia. Chest. 2012;141(2 Suppl):e495S–530S.CrossRefGoogle Scholar
  16. 16.
    Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012;120(20):4160–7.CrossRefGoogle Scholar
  17. 17.
    Lewis BE, Wallis DE, Berkowitz SD, Matthai WH, Fareed J, Walenga JM, et al. Argatroban anticoagulant therapy in patients with heparin-induced thrombocytopenia. Circulation. 2001;103(14):1838–43.CrossRefGoogle Scholar
  18. 18.
    Lewis BE, Wallis DE, Leya F, Hursting MJ, Kelton JG, Argatroban-915 Investigators. Argatroban anticoagulation in patients with heparin-induced thrombocytopenia. Arch Intern Med. 2003;163(15):1849–56.CrossRefGoogle Scholar
  19. 19.
    Cuker A, Cines DB. How I treat heparin-induced thrombocytopenia. Blood. 2012;119(10):2209–18.CrossRefGoogle Scholar
  20. 20.
    Bain J, Meyer A. Comparison of bivalirudin to lepirudin and argatroban in patients with heparin-induced thrombocytopenia. Am J Health Syst Pharm. 2015;72(17 Suppl. 2):S104–9.CrossRefGoogle Scholar
  21. 21.
    Vo QA, Lin JK, Tong LM. Efficacy and safety of argatroban and bivalirudin in patients with suspected heparin-induced thrombocytopenia. Ann Pharmacother. 2015;49(2):178–84.CrossRefGoogle Scholar
  22. 22.
    Zeymer U, Rao SV, Montalescot G. Anticoagulation in coronary intervention. Eur Heart J. 2016;37(45):3376–85.CrossRefGoogle Scholar
  23. 23.
    Jang I-K, Lewis BE, Matthai WH, Kleiman NS. Argatroban anticoagulation in conjunction with glycoprotein IIb/IIIa inhibition in patients undergoing percutaneous coronary intervention: an open-label, nonrandomized pilot study. J Thromb Thrombolysis. 2004;18(1):31–7.CrossRefGoogle Scholar
  24. 24.
    Lee MS, Liao H, Yang T, Dhoot J, Tobis J, Fonarow G, et al. Comparison of bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitors in patients undergoing an invasive strategy: a meta-analysis of randomized clinical trials. Int J Cardiol. 2011;152(3):369–74.CrossRefGoogle Scholar
  25. 25.
    Amsterdam EA, Wenger NK, Brindis RG, Casey DE, Ganiats TG, Holmes DR, et al. 2014 AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes. J Am Coll Cardiol. 2014;64(24):e139–228.CrossRefGoogle Scholar
  26. 26.
    O’Gara PT, Kushner FG, Ascheim DD, Casey DE, Chung MK, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction. Circulation. 2013;127(4):e362–425.CrossRefGoogle Scholar
  27. 27.
    Roffi M, Patrono C, Collet J-P, Mueller C, Valgimigli M, Andreotti F, 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.CrossRefGoogle Scholar
  28. 28.
    Steg PG, James SK, Atar D, Badano LP, Lundqvist CB, et al. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33(20):2569–619.CrossRefGoogle Scholar
  29. 29.
    Cavender MA, Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials. Lancet. 2014;384(9943):599–606.CrossRefGoogle Scholar
  30. 30.
    Bavry AA, Elgendy IY, Mahmoud A, Jadhav MP, Huo T. Critical appraisal of bivalirudin versus heparin for percutaneous coronary intervention: a meta-analysis of randomized trials. PLoS One. 2015;10(5):e0127832.CrossRefGoogle Scholar
  31. 31.
    Windecker S, Kolh P, Alfonso F, Collet J-P, Cremer J, et al. ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J. 2014;35(37):2541–619.CrossRefGoogle Scholar
  32. 32.
    Lewis BE, Matthai WH, Cohen M, Moses JW, Hursting MJ, Leya F, et al. Argatroban anticoagulation during percutaneous coronary intervention in patients with heparin-induced thrombocytopenia. Catheter Cardiovasc Interv. 2002;57(2):177–84.CrossRefGoogle Scholar
  33. 33.
    Cruz-Gonzalez I, Sanchez-Ledesma M, Baron SJ, Healy JL, Watanabe H, Osakabe M, et al. Efficacy and safety of argatroban with or without glycoprotein IIb/IIIa inhibitor in patients with heparin induced thrombocytopenia undergoing percutaneous coronary intervention for acute coronary syndrome. J Thromb Thrombolysis. 2008;25(2):214–8.CrossRefGoogle Scholar
  34. 34.
    Mahaffey KW, Lewis BE, Wildermann NM, Berkowitz SD, Oliverio RM, Turco MA, et al. The anticoagulant therapy with bivalirudin to assist in the performance of percutaneous coronary intervention in patients with heparin-induced thrombocytopenia (ATBAT) study: main results. J Invasive Cardiol. 2003;15(11):611–6.PubMedGoogle Scholar
  35. 35.
    Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58(24):e44–122.CrossRefGoogle Scholar
  36. 36.
    Jang I-K, Brown DFM, Giugliano RP, Anderson HV, Losordo D, Nicolau JC, et al. A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with Novastan and TPA (MINT) study. J Am Coll Cardiol. 1999;33(7):1879–85.CrossRefGoogle Scholar
  37. 37.
    Vermeer F, Vahanian A, Fels PW, Besse P, Müller E, Van de Werf F, et al. Argatroban and alteplase in patients with acute myocardial infarction: the ARGAMI Study. J Thromb Thrombolysis. 2000;10(3):233–40.CrossRefGoogle Scholar
  38. 38.
    Dyke CM, Smedira NG, Koster A, Aronson S, McCarthy HL, Kirshner R, 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):533–9.CrossRefGoogle Scholar
  39. 39.
    Smedira NG, Dyke CM, Koster A, Jurmann M, Bhatia DS, Hu T, 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):686–92.CrossRefGoogle Scholar
  40. 40.
    Koster A, Dyke CM, Aldea G, Smedira NG, McCarthy HL, Aronson S, 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):572–7.CrossRefGoogle Scholar
  41. 41.
    Beiderlinden M, Treschan T, Görlinger K, Peters J. Argatroban in extracorporeal membrane oxygenation. Artif Organs. 2007;31(6):461–5.CrossRefGoogle Scholar
  42. 42.
    Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S, et al. Prevention of vte in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb 1;141(2 suppl):e278S–325S.CrossRefGoogle Scholar
  43. 43.
    Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e227S–77S.CrossRefGoogle Scholar
  44. 44.
    Kahn SR, Lim W, Dunn AS, Cushman M, Dentali F, Akl EA, et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e195S–226S.CrossRefGoogle Scholar
  45. 45.
    Smythe MA, Priziola J, Dobesh PP, Wirth D, Cuker A, Wittkowsky AK. Guidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism. J Thromb Thrombolysis. 2016;41(1):165–86.CrossRefGoogle Scholar
  46. 46.
    Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, et al. Antithrombotic therapy for vte disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb 1;141(2 Suppl):e419S–94S.CrossRefGoogle Scholar
  47. 47.
    Warkentin TE. HIT paradigms and paradoxes. J Thromb Haemost. 2011;9(Suppl 1):105–17.CrossRefGoogle Scholar
  48. 48.
    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):260–5.CrossRefGoogle Scholar
  49. 49.
    Hursting MJ, Lewis BE, Macfarlane DE. Transitioning from argatroban to warfarin therapy in patients with heparin-induced thrombocytopenia. Clin Appl Thromb Hemost. 2005;11(3):279–87.CrossRefGoogle Scholar
  50. 50.
    Bartholomew JR, Hursting MJ. Transitioning from argatroban to warfarin in heparin-induced thrombocytopenia: an analysis of outcomes in patients with elevated international normalized ratio (INR). J Thromb Thrombolysis. 2005;19(3):183–8.CrossRefGoogle Scholar
  51. 51.
    Tolwani AJ, Wille KM. Anticoagulation for continuous renal replacement therapy. Semin Dial. 2009;22(2):141–5.CrossRefGoogle Scholar
  52. 52.
    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):1185–92.CrossRefGoogle Scholar
  53. 53.
    Pieri M, Agracheva N, Bonaveglio E, Greco T, Bonis MD, Covello RD, et al. Bivalirudin versus heparin as an anticoagulant during extracorporeal membrane oxygenation: a case-control study. J Cardiothorac Vasc Anesth. 2013;27(1):30–4.CrossRefGoogle Scholar
  54. 54.
    Ranucci M, Ballotta A, Kandil H, Isgrò G, Carlucci C, Baryshnikova E, et al. Bivalirudin-based versus conventional heparin anticoagulation for postcardiotomy extracorporeal membrane oxygenation. Crit Care. 2011;15:R275.CrossRefGoogle Scholar
  55. 55.
    Angiox. European medicines agency summary of product characteristics [Internet]. Available from: Accessed 1 Jan 2017.
  56. 56.
    Young SK, Al-Mondhiry HA, Vaida SJ, Ambrose A, Botti JJ. Successful use of argatroban during the third trimester of pregnancy: case report and review of the literature. Pharmacotherapy. 2008;28(12):1531–6.CrossRefGoogle Scholar
  57. 57.
    Buck ML. Bivalirudin as an alternative to heparin for anticoagulation in infants and children. J Pediatr Pharmacol Ther. 2015;20(6):408–17.PubMedPubMedCentralGoogle Scholar
  58. 58.
    Chan VHT, Monagle P, Massicotte P, Chan AK. Novel paediatric anticoagulants: a review of the current literature. Blood Coagul Fibrinolysis. 2010;21(2):144–51.CrossRefGoogle Scholar
  59. 59.
    Young G. Anticoagulants in children and adolescents. Hematology Am Soc Hematol Educ Program. 2015;2015:111–6.PubMedGoogle Scholar
  60. 60.
    Weitz JI. Factor Xa or thrombin: is thrombin a better target? J Thromb Haemost. 2007;5:65–7.CrossRefGoogle Scholar
  61. 61.
    Olson ST, Björk I, Sheffer R, Craig PA, Shore JD, Choay J. Role of the antithrombin-binding pentasaccharide in heparin acceleration of antithrombin-proteinase reactions. Resolution of the antithrombin conformational change contribution to heparin rate enhancement. J Biol Chem. 1992;267(18):12528–38.PubMedGoogle Scholar
  62. 62.
    Choay J, Petitou M, Lormeau JC, Sinaÿ P, Casu B, Gatti G. Structure-activity relationship in heparin: a synthetic pentasaccharide with high affinity for antithrombin III and eliciting high anti-factor Xa activity. Biochem Biophys Res Commun. 1983;116(2):492–9.CrossRefGoogle Scholar
  63. 63.
    Paolucci F, Claviés M-C, Donat F, Necciari J. Fondaparinux sodium mechanism of action: identification of specific binding to purified and human plasma-derived proteins. Clin Pharmacokinet. 2002;41(12):11–8.CrossRefGoogle Scholar
  64. 64.
    Arixtra. European medicines agency summary of product characteristics [Internet]. Available from: Accessed 27 Nov 2016.
  65. 65.
    Bergqvist D. Review of fondaparinux sodium injection for the prevention of venous thromboembolism in patients undergoing surgery. Vasc Health Risk Manag. 2006;2(4):365–70.CrossRefGoogle Scholar
  66. 66.
    Koshida S, Suda Y, Sobel M, Ormsby J, Kusumoto S. Synthesis of heparin partial structures and their binding activities to platelets. Bioorg Med Chem Lett. 1999;9(21):3127–32.CrossRefGoogle Scholar
  67. 67.
    Smogorzewska A, Brandt JT, Chandler WL, Cunningham MT, Hayes TE, Olson JD, et al. Effect of fondaparinux on coagulation assays: results of College of American Pathologists proficiency testing. Arch Pathol Lab Med. 2006;130(11):1605–11.PubMedGoogle Scholar
  68. 68.
    Turpie AGG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies. Arch Intern Med. 2002;162(16):1833–40.CrossRefGoogle Scholar
  69. 69.
    Colwell CW, Kwong LM, Turpie AGG, Davidson BL. Flexibility in administration of fondaparinux for prevention of symptomatic venous thromboembolism in orthopaedic surgery. J Arthroplast. 2006;21(1):36–45.CrossRefGoogle Scholar
  70. 70.
    Turpie AGG, Bauer KA, Eriksson BI, Lassen MR. Superiority of fondaparinux over enoxaparin in preventing venous thromboembolism in major orthopedic surgery using different efficacy end points. Chest. 2004;126(2):501–8.CrossRefGoogle Scholar
  71. 71.
    Eriksson BI, Lassen MR. PENTasaccharide in HIp-FRActure Surgery Plus Investigators. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery: a multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med. 2003;163(11):1337–42.CrossRefGoogle Scholar
  72. 72.
    Agnelli G, Bergqvist D, Cohen AT, Gallus AS, Gent M, PEGASUS investigators. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg. 2005;92(10):1212–20.CrossRefGoogle Scholar
  73. 73.
    Turpie AGG, Bauer KA, Caprini JA, Comp PC, Gent M, Muntz JE, et al. Fondaparinux combined with intermittent pneumatic compression vs. intermittent pneumatic compression alone for prevention of venous thromboembolism after abdominal surgery: a randomized, double-blind comparison. J Thromb Haemost. 2007;5(9):1854–61.CrossRefGoogle Scholar
  74. 74.
    Cohen AT, Davidson BL, Gallus AS, Lassen MR, Prins MH, Tomkowski W, et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. BMJ. 2006;332(7537):325–9.CrossRefGoogle Scholar
  75. 75.
    Büller HR, Davidson BL, Decousus H, Gallus A, Gent M, Piovella F, et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis: a randomized trial. Ann Intern Med. 2004;140(11):867–73.CrossRefGoogle Scholar
  76. 76.
    Büller HR, Davidson BL, Decousus H, Gallus A, Gent M, Piovella F, et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N Engl J Med. 2003;349(18):1695–702.CrossRefGoogle Scholar
  77. 77.
    Davidson BL, Büller HR, Decousus H, Gallus A, Gent M, Piovella F, et al. Effect of obesity on outcomes after fondaparinux, enoxaparin, or heparin treatment for acute venous thromboembolism in the Matisse trials. J Thromb Haemost. 2007;5(6):1191–4.CrossRefGoogle Scholar
  78. 78.
    Di Nisio M, Middeldorp S. Treatment of lower extremity superficial thrombophlebitis. JAMA. 2014;311(7):729–30.CrossRefGoogle Scholar
  79. 79.
    Decousus H, Prandoni P, Mismetti P, Bauersachs RM, Boda Z, Brenner B, et al. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med. 2010;363(13):1222–32.CrossRefGoogle Scholar
  80. 80.
    Blondon M, Righini M, Bounameaux H, Veenstra DL. Fondaparinux for isolated superficial vein thrombosis of the legs: a cost-effectiveness analysis. Chest. 2012;141(2):321–9.CrossRefGoogle Scholar
  81. 81.
    Kang M, Alahmadi M, Sawh S, Kovacs MJ, Lazo-Langner A. Fondaparinux for the treatment of suspected heparin-induced thrombocytopenia: a propensity score-matched study. Blood. 2015;125(6):924–9.CrossRefGoogle Scholar
  82. 82.
    Warkentin TE, Pai M, Sheppard JI, Schulman S, Spyropoulos AC, Eikelboom JW. Fondaparinux treatment of acute heparin-induced thrombocytopenia confirmed by the serotonin-release assay: a 30-month, 16-patient case series. J Thromb Haemost. 2011;9(12):2389–96.CrossRefGoogle Scholar
  83. 83.
    Schindewolf M, Steindl J, Beyer-Westendorf J, Schellong S, Dohmen PM, Brachmann J, et al. Frequent off-label use of fondaparinux in patients with suspected acute heparin-induced thrombocytopenia (HIT)--findings from the GerHIT multi-centre registry study. Thromb Res. 2014;134(1):29–35.CrossRefGoogle Scholar
  84. 84.
    Warkentin TE, Maurer BT, Aster RH. Heparin-induced thrombocytopenia associated with fondaparinux. N Engl J Med. 2007;356(25):2653–5.CrossRefGoogle Scholar
  85. 85.
    Rota E, Bazzan M, Fantino G. Fondaparinux-related thrombocytopenia in a previous low-molecular-weight heparin (LMWH)-induced heparin-induced thrombocytopenia (HIT). Thromb Haemost. 2008;99(4):779–81.CrossRefGoogle Scholar
  86. 86.
    Alsaleh KA, Al-Nasser SMA, Bates SM, Patel A, Warkentin TE, Arnold DM. Delayed-onset HIT caused by low-molecular-weight heparin manifesting during fondaparinux prophylaxis. Am J Hematol. 2008;83(11):876–8.CrossRefGoogle Scholar
  87. 87.
    Warkentin TE. Fondaparinux: does it cause HIT? Can it treat HIT? Expert Rev Hematol. 2010;3(5):567–81.CrossRefGoogle Scholar
  88. 88.
    Cuker A. Management of the multiple phases of heparin-induced thrombocytopenia. Thromb Haemost. 2016;116(5):835–42.PubMedGoogle Scholar
  89. 89.
    Mehta SR, Granger CB, Eikelboom JW, Bassand J-P, Wallentin L, Faxon DP, et al. Efficacy and safety of fondaparinux versus enoxaparin in patients with acute coronary syndromes undergoing percutaneous coronary intervention: results from the OASIS-5 trial. J Am Coll Cardiol. 2007;50(18):1742–51.CrossRefGoogle Scholar
  90. 90.
    Simoons ML, Bobbink IWG, Boland J, Gardien M, Klootwijk P, Lensing AWA, et al. A dose-finding study of fondaparinux in patients with non-ST-segment elevation acute coronary syndromes: the Pentasaccharide in Unstable Angina (PENTUA) Study. J Am Coll Cardiol. 2004;43(12):2183–90.CrossRefGoogle Scholar
  91. 91.
    Steg PG, Mehta S, Jolly S, Xavier D, Rupprecht H-J, Lopez-Sendon JL, et al. Fondaparinux with UnfracTionated heparin dUring Revascularization in Acute coronary syndromes (FUTURA/OASIS 8): a randomized trial of intravenous unfractionated heparin during percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes initially treated with fondaparinux. Am Heart J. 2010;160(6):1029–34. 1034.e1.CrossRefGoogle Scholar
  92. 92.
    Yusuf S, Mehta SR, Chrolavicius S, Afzal R, Pogue J, Granger CB, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295(13):1519–30.CrossRefGoogle Scholar
  93. 93.
    Davidson B, Turpie AGG, Colwell C, Kwong LM. Early vs delayed initiation of fondaparinux prophylaxis to prevent postoperative pulmonary embolism: a clinical endpoint study. Chest. 2004;126(4 MeetingAbstracts):783S-b–783S.CrossRefGoogle Scholar
  94. 94.
    Crowther MA, Berry LR, Monagle PT, Chan AKC. Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol. 2002;116(1):178–86.CrossRefGoogle Scholar
  95. 95.
    Bijsterveld NR, Moons AH, Boekholdt SM, van Aken BE, Fennema H, Peters RJG, et al. Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation. 2002;106(20):2550–4.CrossRefGoogle Scholar
  96. 96.
    Dentali F, Marchesi C, Giorgi Pierfranceschi M, Crowther M, Garcia D, Hylek E, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost. 2011;106(3):429–38.PubMedGoogle Scholar
  97. 97.
    Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363(19):1791–800.CrossRefGoogle Scholar
  98. 98.
    Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos A-M, Vandvik PO, et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e691S–736S.CrossRefGoogle Scholar
  99. 99.
    Carolis SD, di Pasquo E, Rossi E, Sordo GD, Buonomo A, Schiavino D, et al. Fondaparinux in pregnancy: could it be a safe option? A review of the literature. Thromb Res. 2015;135(6):1049–51.CrossRefGoogle Scholar
  100. 100.
    Young G, Yee DL, O’Brien SH, Khanna R, Barbour A, Nugent DJ. FondaKIDS: a prospective pharmacokinetic and safety study of fondaparinux in children between 1 and 18 years of age. Pediatr Blood Cancer. 2011;57(6):1049–54.CrossRefGoogle Scholar
  101. 101.
    Ko RH, Michieli C, Lira JL, Young G. FondaKIDS II: long-term follow-up data of children receiving fondaparinux for treatment of venous thromboembolic events. Thromb Res. 2014;134(3):643–7.CrossRefGoogle Scholar
  102. 102.
    Monagle P, Chan AKC, Goldenberg NA, Ichord RN, Journeycake JM, Nowak-Göttl U, et al. Antithrombotic therapy in neonates and children: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 Suppl):e737S–801S.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Inpatient Pharmacy DepartmentUniversity of New Mexico HospitalAlbuquerqueUSA
  2. 2.University of New Mexico College of PharmacyAlbuquerqueUSA

Personalised recommendations