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Alte und neue Gerinnungshemmer

Antidota und Maßnahmen bei akuter Blutung sowie dringenden Eingriffen

Old and new anticoagulants

Antidotes and measures for acute hemorrhaging and urgent interventions

  • Klinische Pharmakologie
  • Published:
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Zusammenfassung

Gerinnungshemmende Medikamente werden häufig zur primären sowie sekundären Prävention und zur Therapie bei diversen thrombembolischen Krankheitsbildern eingesetzt. Eine wesentliche Nebenwirkung aller Gerinnungshemmer ist die hämorrhagische Diathese. Diese erfordert eine akute Behandlung. Idealerweise ist hier die medikamentöse Therapie mit einem Antidot möglich. Mit traditionellen Gerinnungshemmern wie z. B. Heparin und Vitamin-K-Antagonisten liegen ausreichende Erfahrungen vor. Für beide existieren anerkannte Behandlungsstrategien; hierbei kommen u. a. auch Antagonisten zum Einsatz. Aktuell steht eine Vielzahl faktorenspezifischer Antikoagulanzien kurz vor der Zulassung oder ist in der jüngeren Vergangenheit auf den Markt gekommen. Für diese Antikoagulanzien der neuen Generation gibt es zurzeit weder valide Laborparameter noch effektive Antagonisten. In Ermangelung ausreichender Studien kann eine Behandlung hier momentan lediglich symptomatisch erfolgen.

Abstract

Anticoagulation medications are frequently used for primary and secondary treatment of several thrombo-embolic disorders. An important side effect of all anticoagulants is hemorrhagic diathesis which necessitates acute treatment, ideally using medicinal therapy with an antidote. Much experience has been gained in treating bleeding while on traditional anticoagulants, such as heparins and vitamin K antagonists by the use of antagonists. A multitude of factor-specific anticoagulants have recently been introduced or will soon receive approval. With this new generation of anticoagulants no valid laboratory parameters or effective antagonists are presently available. Due to a lack of adequate studies regarding acute treatment this can at present only be carried out on a symptomatic basis.

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Literatur

  1. Hirsh J, Guyatt G, Albers GW et al (2008) Antithrombotic and thrombolytic therapy. In: American College of Chest Physicians (eds) Evidence-based clinical practice guidelines, 8th edn. Chest 133 [Suppl 6]:110–112

  2. Serebruany VL, Makarov LM (2009) Future of oral antiplatelet therapy: four challenged hypotheses. Thromb Haemost 101(6):1041–1043

    CAS  PubMed  Google Scholar 

  3. Fang MC, Go AS, Chang Y et al (2007) Death and disability from warfarin-associated intracranial and extracranial hemorrhages. Am J Med 120(8):700–705

    Article  PubMed  Google Scholar 

  4. Schulman S, Beyth RJ, Kearon C, Levine MN (2008) Hemorrhagic complications of anticoagulant and thrombolytic treatment. In: American College of Chest Physicians (eds) Evidence-based clinical practice guidelines, 8th edn. Chest 133 [Suppl 6]:257–298

  5. Palareti G, Cosmi B (2009) Bleeding with anticoagulation therapy – Who is at risk, and how best to identify such patients. Thromb Haemost 102(2):268–278

    CAS  PubMed  Google Scholar 

  6. Crowther MA (2009) Managing bleeding in anticoagulated patients with focus on novel therapeutic agents. J Thromb Haemost 7 [Suppl 1]:107–110

    Google Scholar 

  7. Stanworth SJ, Hyde CJ, Murphy MF (2007) Evidence for indications of fresh frozen plasma. Transfus Clin Biol 14(6):551–556

    Article  CAS  PubMed  Google Scholar 

  8. Henry DA, Carless PA, Moxey AJ et al (2007) Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev (4):CD001886

    Google Scholar 

  9. Carless PA, Henry DA, Moxey AJ et al (2004) Desmopressin for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev (1):CD001884

    Google Scholar 

  10. Benz K, Nauck MA, Bohler J, Fischer KG (2007) Hemofiltration of recombinant hirudin by different hemodialyzer membranes: implications for clinical use. Clin J Am Soc Nephrol 2(3):470–476

    Article  CAS  PubMed  Google Scholar 

  11. Alban S (2008) Pharmacology of heparins and direct anticoagulants. Hamostaseologie 28(5):400–420

    CAS  PubMed  Google Scholar 

  12. Tripodi A, van den Besselaar A (2009) Laboratory monitoring of anticoagulation: where do we stand? Semin Thromb Hemost 35(1):34–41

    Article  CAS  PubMed  Google Scholar 

  13. Brummel-Ziedins KE, Whelihan MF, Gissel M et al (2009) Thrombin generation and bleeding in haemophilia A. Haemophilia (in press)

  14. Gatt A, van Veen JJ, Woolley AM et al (2008) Thrombin generation assays are superior to traditional tests in assessing anticoagulation reversal in vitro. Thromb Haemost 100(2):350–355

    CAS  PubMed  Google Scholar 

  15. Crowther MA, Berry LR, Monagle PT, Chan AK (2002) Mechanisms responsible for the failure of protamine to inactivate low-molecular-weight heparin. Br J Haematol 116(1):178–186

    Article  CAS  PubMed  Google Scholar 

  16. Hirsh J, Bauer KA, Donati MB et al (2008) Parenteral anticoagulants. In: American College of Chest Physicians (eds) Evidence-based clinical practice guidelines, 8th edn. Chest 133 [Suppl 6]:141–159

  17. Nielsen VG (2006) Protamine enhances fibrinolysis by decreasing clot strength: role of tissue factor-initiated thrombin generation. Ann Thorac Surg 81(5):1720–1727

    Article  PubMed  Google Scholar 

  18. Nybo M, Madsen JS (2008) Serious anaphylactic reactions due to protamine sulfate: a systematic literature review. Basic Clin Pharmacol Toxicol 103(2):192–196

    Article  CAS  PubMed  Google Scholar 

  19. Kimmel SE, Sekeres MA, Berlin JA et al (1998) Risk factors for clinically important adverse events after protamine administration following cardiopulmonary bypass. J Am Coll Cardiol 32(7):1916–1922

    Article  CAS  PubMed  Google Scholar 

  20. Welsby IJ, Stafford-Smith M (2005) Protamine contributes to myocardial ischemia. Anesthesiology 103(3):669; author reply 669–670

    Article  PubMed  Google Scholar 

  21. Levi M (2009) Emergency reversal of antithrombotic treatment. Intern Emerg Med 4(2):137–145

    Article  PubMed  Google Scholar 

  22. Fiore LD, Scola MA, Cantillon CE, Brophy MT (2001) Anaphylactoid reactions to vitamin K. J Thromb Thrombolysis 11(2):175–183

    Article  CAS  PubMed  Google Scholar 

  23. Dietrich GV (2009) Coagulation therapy made to measure. Anaesthesiol Intensivmed 50(03):142–156

    Google Scholar 

  24. Leissinger CA, Blatt PM, Hoots WK, Ewenstein B (2008) Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 83(2):137–143

    Article  CAS  PubMed  Google Scholar 

  25. Crowther MA, Warkentin TE (2008) Bleeding risk and the management of bleeding complications in patients undergoing anticoagulant therapy: focus on new anticoagulant agents. Blood 111(10):4871–4879

    Article  CAS  PubMed  Google Scholar 

  26. Schneider SO, Rensing H, Graber S et al (2009) Impact of platelets and fresh frozen plasma in contrast to red cell concentrate on unstimulated and stimulated cytokine release in an in vitro model of transfusion. Scand J Immunol 70(2):101–105

    Article  CAS  PubMed  Google Scholar 

  27. Erhardtsen E, Nony P, Dechavanne M et al (1998) The effect of recombinant factor VIIa (NovoSeven) in healthy volunteers receiving acenocoumarol to an International Normalized Ratio above 2.0. Blood Coagul Fibrinolysis 9(8):741–748

    Article  CAS  PubMed  Google Scholar 

  28. Dager WE, King JH, Regalia RC et al (2006) Reversal of elevated international normalized ratios and bleeding with low-dose recombinant activated factor VII in patients receiving warfarin. Pharmacotherapy 26(8):1091–1098

    Article  CAS  PubMed  Google Scholar 

  29. Yu G, LeBrun L, Gunay NS et al (2000) Heparinase I acts on a synthetic heparin pentasaccharide corresponding to the antithrombin III binding site. Thromb Res 100(6):549–556

    Article  CAS  PubMed  Google Scholar 

  30. Bijsterveld NR, Moons AH, Boekholdt SM et al (2002) Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 106(20):2550–2554

    Article  CAS  PubMed  Google Scholar 

  31. Bijsterveld NR, Vink R, van Aken BE et al (2004) Recombinant factor VIIa reverses the anticoagulant effect of the long-acting pentasaccharide idraparinux in healthy volunteers. Br J Haematol 124(5):653–658

    Article  CAS  PubMed  Google Scholar 

  32. Buller HR, Cohen AT, Davidson B et al (2007) Extended prophylaxis of venous thromboembolism with idraparinux. N Engl J Med 357(11):1105–1112

    Article  CAS  PubMed  Google Scholar 

  33. Savi P, Herault JP, Duchaussoy P et al (2008) Reversible biotinylated oligosaccharides: a new approach for a better management of anticoagulant therapy. J Thromb Haemost 6(10):1697–1706

    Article  CAS  PubMed  Google Scholar 

  34. Bianchini EP (2009) Design of a recombinant antithrombin variant as a potent antidote for fondaparinux and other heparin derivates. J Thromb Haemost 7 [Suppl 2] (in press)

  35. Lassen MR, Raskob GE, Gallus A et al (2009) Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 361(6):594–604

    Article  CAS  PubMed  Google Scholar 

  36. Olesen JB (2009) Haemostatic response to in vitro addition of recombinant factor VIIa, prothrombin complex concentrate, or factor IX/X in blood spiked with a direct Xa inhibitor. J Thromb Haemost 7 [Suppl 2] (in press)

  37. Perzeborn E (2009) Prothrombin complex concentrate reverses the effects of high dose rivaroxaban in rats. J Thromb Haemost 7 [Suppl 2] (in press)

  38. Lu G (2009) Reconstructed recombinant factor Xa as an antidote to reverse anticoagulation by factor Xa inhibitors. J Thromb Haemost 7 [Suppl 2] (in press)

  39. Hursting MJ, Soffer J (2009) Reducing harm associated with anticoagulation: practical considerations of argatroban therapy in heparin-induced thrombocytopenia. Drug Saf 32(3):203–218

    Article  CAS  PubMed  Google Scholar 

  40. 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(4):184–191

    Article  CAS  PubMed  Google Scholar 

  41. Amiral JJ (2009) New assays for measuring direct thrombin inhibitors on plasma. J Thromb Haemost 7 [Suppl 2] (in press)

  42. Ammollo CT (2009) Enhancement of clot lysis by anticoagulants: dabigatran is more equal than heparin. J Thromb Haemost 7 [Suppl 2] (in press)

  43. Semeraro F (2009) The novel direct thrombin inhibitor dabigatran accelerates plasma fibrinolysis through TAFI-independent mechanism. J Thromb Haemost 7 [Suppl 2] (in press)

  44. Warkentin TE, Crowther MA (2002) Reversing anticoagulants both old and new. Can J Anaesth 49(6):S11–S25

    PubMed  Google Scholar 

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Danksagung

Die Autoren danken Dr. J. Schreiber für das kritische Durchlesen des Beitrags und die hieraus folgende Diskussion.

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Authors and Affiliations

  1. Klinik für Anästhesiologie und Schmerztherapie, Universitätsklinikum MUMC+, P.Debyelaan 25, P.O. Box 5800, 6202, AZ Maastricht, Niederlande

    M. Lancé, B. Stessel & M.A. Marcus

  2. Abteilung Hämatologie und Laboratorium, Medizinische Klinik, Universitätsklinikum MUMC+, Maastricht, Niederlande

    K. Hamulyák

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  1. M. Lancé
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  2. B. Stessel
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  3. K. Hamulyák
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  4. M.A. Marcus
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Correspondence to M. Lancé.

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Lancé, M., Stessel, B., Hamulyák, K. et al. Alte und neue Gerinnungshemmer. Anaesthesist 59, 62–68 (2010). https://doi.org/10.1007/s00101-009-1645-6

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  • DOI: https://doi.org/10.1007/s00101-009-1645-6

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