Skip to main content
Erschienen in: Die Anaesthesiologie 6/2008

01.06.2008 | Klinische Pharmakologie

Direkte Thrombininhibitoren

Pharmakologie und Anwendung in der kardiovaskulären Anästhesie

verfasst von: Prof. Dr. S.A. Kozek-Langenecker

Erschienen in: Die Anaesthesiologie | Ausgabe 6/2008

Einloggen, um Zugang zu erhalten

Zusammenfassung

Die Möglichkeiten der medikamentösen Antikoagulation werden zusehends vielfältiger. Im anästhesiologisch-intensivmedizinischen Bereich gilt es darüber hinaus spezielle Krankheitsbilder wie die Heparin-induzierte Thrombozytopenie (HIT) zu kennen, zu diagnostizieren und zu behandeln. Diese Arbeit liefert eine Übersicht über die Substanzgruppe der direkten Thrombininhibitoren (DTI) als alternative Antikoagulanzien bei HIT in Verbindung mit kardiovaskulären Erkrankungen. Beim Einsatz von DTI sind die Erfahrung und die richtige Dosis der Schlüssel zum Erfolg und entscheiden über die zwei Gesichter der Hämostase: Thrombose und Blutung.
Literatur
1.
Zurück zum Zitat Bates S, Weitz J (2000) The mechanisms of action of thrombin inhibitors. J Invasive Cardiol 12: 27F–32FPubMed Bates S, Weitz J (2000) The mechanisms of action of thrombin inhibitors. J Invasive Cardiol 12: 27F–32FPubMed
2.
Zurück zum Zitat Kozek-Langenecker S, Mohammad S, Masaki T et al. (2000) Effects of heparin, protamine, and heparinase 1 on platelets in vitro using whole blood flow cytometry. Anesth Analg 90: 808–812PubMedCrossRef Kozek-Langenecker S, Mohammad S, Masaki T et al. (2000) Effects of heparin, protamine, and heparinase 1 on platelets in vitro using whole blood flow cytometry. Anesth Analg 90: 808–812PubMedCrossRef
3.
Zurück zum Zitat 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: 251–256PubMed 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: 251–256PubMed
4.
Zurück zum Zitat 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: 557–564PubMedCrossRef 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: 557–564PubMedCrossRef
5.
Zurück zum Zitat Weitz J (2007) Factor Xa or thrombin: is thrombin a better target? J Thromb Haemost 5: S65–S67CrossRef Weitz J (2007) Factor Xa or thrombin: is thrombin a better target? J Thromb Haemost 5: S65–S67CrossRef
6.
Zurück zum Zitat Eriksson BI, Dahl O, Buller HR et al. (2005) A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 3: 103–111PubMedCrossRef Eriksson BI, Dahl O, Buller HR et al. (2005) A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 3: 103–111PubMedCrossRef
7.
Zurück zum Zitat Rydel T, Ravichandran K, Tulinsky A (1990) The structure of a complex of recombinant hirudin and human α-thrombin. Science 249: 277–280PubMedCrossRef Rydel T, Ravichandran K, Tulinsky A (1990) The structure of a complex of recombinant hirudin and human α-thrombin. Science 249: 277–280PubMedCrossRef
8.
Zurück zum Zitat Eichler P, Friesen H, Lubenow N et al. (2000) Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 96: 2373–2378PubMed Eichler P, Friesen H, Lubenow N et al. (2000) Antihirudin antibodies in patients with heparin-induced thrombocytopenia treated with lepirudin: incidence, effects on aPTT, and clinical relevance. Blood 96: 2373–2378PubMed
9.
Zurück zum Zitat Greinacher A, Lubenow N, Eichler P (2003) Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 108: 2062–2065PubMedCrossRef Greinacher A, Lubenow N, Eichler P (2003) Anaphylactic and anaphylactoid reactions associated with lepirudin in patients with heparin-induced thrombocytopenia. Circulation 108: 2062–2065PubMedCrossRef
10.
Zurück zum Zitat Veach S, Franks A, Allan M (2007) Severe anaphylactic reaction after repeated intermittent exposure to lepirudin. Pharmacotherapy 27: 760–765PubMedCrossRef Veach S, Franks A, Allan M (2007) Severe anaphylactic reaction after repeated intermittent exposure to lepirudin. Pharmacotherapy 27: 760–765PubMedCrossRef
11.
Zurück zum Zitat Maraganore JM, Bourdon P, Jablonski J et al. (1990) Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 29: 7095–7101PubMedCrossRef Maraganore JM, Bourdon P, Jablonski J et al. (1990) Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 29: 7095–7101PubMedCrossRef
12.
Zurück zum Zitat Parry M, Maraganore J, Stone S (1994) Kinetic mechanism for the interaction of hirulog with thrombin. Biochemistry 33: 14807–14814PubMedCrossRef Parry M, Maraganore J, Stone S (1994) Kinetic mechanism for the interaction of hirulog with thrombin. Biochemistry 33: 14807–14814PubMedCrossRef
13.
Zurück zum Zitat Robson R, White H, Aylward P, Frampton C (2002) Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose and gender. Clin Pharmacol Ther 71: 433–439PubMedCrossRef Robson R, White H, Aylward P, Frampton C (2002) Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose and gender. Clin Pharmacol Ther 71: 433–439PubMedCrossRef
14.
Zurück zum Zitat 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: 919–923PubMedCrossRef 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: 919–923PubMedCrossRef
15.
Zurück zum Zitat Lewis B, Hursting M (2004) Argatroban therapy in heparin-induced thrombocytopenia. In: Warkentin T, Greinacher A (eds) Heparin-induced thrombocytopenia. Dekker, New York, pp 437–474 Lewis B, Hursting M (2004) Argatroban therapy in heparin-induced thrombocytopenia. In: Warkentin T, Greinacher A (eds) Heparin-induced thrombocytopenia. Dekker, New York, pp 437–474
16.
Zurück zum Zitat Hauptmann J, Sturzebecher J (1999) Synthetic inhibitors of thrombin and factor Xa: from bench to bedside. Thromb Res 93: 203–241PubMedCrossRef Hauptmann J, Sturzebecher J (1999) Synthetic inhibitors of thrombin and factor Xa: from bench to bedside. Thromb Res 93: 203–241PubMedCrossRef
17.
Zurück zum Zitat 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: 381–386PubMed 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: 381–386PubMed
18.
Zurück zum Zitat Swan S, Hursting M (2000) The pharmacokinetics and pharmacodynamics of argatroban: effect of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 20: 318–329PubMedCrossRef Swan S, Hursting M (2000) The pharmacokinetics and pharmacodynamics of argatroban: effect of age, gender, and hepatic or renal dysfunction. Pharmacotherapy 20: 318–329PubMedCrossRef
19.
Zurück zum Zitat Walenga J, Ahmad S, Hoppensteadt D et al. (2002) Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia. Thromb Res 105: 401–405PubMedCrossRef Walenga J, Ahmad S, Hoppensteadt D et al. (2002) Argatroban therapy does not generate antibodies that alter its anticoagulant activity in patients with heparin-induced thrombocytopenia. Thromb Res 105: 401–405PubMedCrossRef
20.
Zurück zum Zitat Chong B, Magnani H (2004) Danaparoid for the treatment of the heparin-induced thrombocytopenia. In: Warkentin T, Greinacher A (eds) Heparin-induced thrombocytopenia. Dekker, New York, pp 371–398 Chong B, Magnani H (2004) Danaparoid for the treatment of the heparin-induced thrombocytopenia. In: Warkentin T, Greinacher A (eds) Heparin-induced thrombocytopenia. Dekker, New York, pp 371–398
21.
Zurück zum Zitat Magnani HN, Gallus AS (2006) Heparin-induced thrombocytopenia (HIT). A report of 1478 clinical outcomes of patients treated with danaparoid (Orgaran) from 1982 to mid-2004. Thromb Haemost 95: 967–981PubMed Magnani HN, Gallus AS (2006) Heparin-induced thrombocytopenia (HIT). A report of 1478 clinical outcomes of patients treated with danaparoid (Orgaran) from 1982 to mid-2004. Thromb Haemost 95: 967–981PubMed
22.
Zurück zum Zitat Fenyvesi T, Jorg I, Harenberg J (2002) Monitoring of anticoagulant effects of direct thrombin inhibitors. Semin Thromb Hemost 28: 361–368PubMedCrossRef Fenyvesi T, Jorg I, Harenberg J (2002) Monitoring of anticoagulant effects of direct thrombin inhibitors. Semin Thromb Hemost 28: 361–368PubMedCrossRef
23.
Zurück zum Zitat Clarke R, Mayo G, Fitzgerald G, Fitzgerald D (1991) Combined administration of aspirin and a specific thrombin inhibitor in man. Circulation 83: 1510–1518PubMed Clarke R, Mayo G, Fitzgerald G, Fitzgerald D (1991) Combined administration of aspirin and a specific thrombin inhibitor in man. Circulation 83: 1510–1518PubMed
24.
Zurück zum Zitat Moser M, Ruef J, Peter K (2001) Ecarin clotting time but not aPTT correlates with PEG-hirudin plasma activity. J Thromb Thrombolysis 12: 165–169PubMedCrossRef Moser M, Ruef J, Peter K (2001) Ecarin clotting time but not aPTT correlates with PEG-hirudin plasma activity. J Thromb Thrombolysis 12: 165–169PubMedCrossRef
25.
Zurück zum Zitat 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(abstract). Ann Haematol 1: A58 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(abstract). Ann Haematol 1: A58
26.
Zurück zum Zitat Callas D, Fareed J (1996) Comparative anticoagulant effects of various thrombin inhibitors, as determined in the ecarin clotting time method. Thromb Res 83: 463–468PubMedCrossRef Callas D, Fareed J (1996) Comparative anticoagulant effects of various thrombin inhibitors, as determined in the ecarin clotting time method. Thromb Res 83: 463–468PubMedCrossRef
27.
Zurück zum Zitat 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. Dekker, New York, pp 531–532 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. Dekker, New York, pp 531–532
28.
Zurück zum Zitat 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: 55–60PubMedCrossRef 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: 55–60PubMedCrossRef
29.
Zurück zum Zitat Kieta D, McCammon A, Holman W, Nielson V (2003) Hemostatic analysis of a patient undergoing off-pump coronary artery bypass surgery with argatroban anticoagulation. Anesth Analg 96: 956–958PubMedCrossRef Kieta D, McCammon A, Holman W, Nielson V (2003) Hemostatic analysis of a patient undergoing off-pump coronary artery bypass surgery with argatroban anticoagulation. Anesth Analg 96: 956–958PubMedCrossRef
30.
Zurück zum Zitat Pivalizza E (2002) Monitoring of hirudin therapy with the thromboelastograph. J Clin Anesth 14: 456–458PubMedCrossRef Pivalizza E (2002) Monitoring of hirudin therapy with the thromboelastograph. J Clin Anesth 14: 456–458PubMedCrossRef
31.
Zurück zum Zitat Taketomi T, Szlam F, Vinten-Johansen J et al. (2007) Thrombin-activated thrombelastography for evaluation of thrombin interaction with thrombin inhibitors. Blood Coagul Fibrinolysis 18: 761–767PubMedCrossRef Taketomi T, Szlam F, Vinten-Johansen J et al. (2007) Thrombin-activated thrombelastography for evaluation of thrombin interaction with thrombin inhibitors. Blood Coagul Fibrinolysis 18: 761–767PubMedCrossRef
32.
Zurück zum Zitat 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: 115–121PubMedCrossRef 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: 115–121PubMedCrossRef
33.
Zurück zum Zitat 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: 1110–1112PubMedCrossRef 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: 1110–1112PubMedCrossRef
34.
Zurück zum Zitat Welsby I, Stafford-Smith M (2004) Monitoring direct thrombin inhibitors: time for standardization (comment). Anesthesiology 101: 1048–1049PubMedCrossRef Welsby I, Stafford-Smith M (2004) Monitoring direct thrombin inhibitors: time for standardization (comment). Anesthesiology 101: 1048–1049PubMedCrossRef
35.
Zurück zum Zitat Harder S, Graff J, Klinkhardt U et al. (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: 1137–1145PubMed Harder S, Graff J, Klinkhardt U et al. (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: 1137–1145PubMed
36.
Zurück zum Zitat Selleng K, Greinacher A (2005) Heparin-induzierte Thrombozytepenie in der Intensivmedizin. Intensivmedizin Update 1: 1–16CrossRef Selleng K, Greinacher A (2005) Heparin-induzierte Thrombozytepenie in der Intensivmedizin. Intensivmedizin Update 1: 1–16CrossRef
37.
Zurück zum Zitat Warkentin T, Greinacher A (2004) Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 311S–337SPubMedCrossRef Warkentin T, Greinacher A (2004) Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 311S–337SPubMedCrossRef
38.
Zurück zum Zitat Muslimani A, Ricaurte B, Daw H (2007) Immune heparin-induced thrombocytopenia resulting from preceding exposure to heparin catheter flushes. Am J Haematol 82: 652–655CrossRef Muslimani A, Ricaurte B, Daw H (2007) Immune heparin-induced thrombocytopenia resulting from preceding exposure to heparin catheter flushes. Am J Haematol 82: 652–655CrossRef
39.
Zurück zum Zitat 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: 3691–3693PubMed 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: 3691–3693PubMed
40.
Zurück zum Zitat Greinacher A, Vögel H, Janssen U (1999) Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Circulation 100: 587–590PubMed Greinacher A, Vögel H, Janssen U (1999) Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Circulation 100: 587–590PubMed
41.
Zurück zum Zitat Lubenow N, Eichler P, Lietz T et al. (2004) Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3 prospective studies. Blood 104: 3072–3077PubMedCrossRef Lubenow N, Eichler P, Lietz T et al. (2004) Lepirudin for prophylaxis of thrombosis in patients with acute isolated heparin-induced thrombocytopenia: an analysis of 3 prospective studies. Blood 104: 3072–3077PubMedCrossRef
42.
Zurück zum Zitat Warkentin TE, Greinacher A (2004) Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 311S-337SPubMedCrossRef Warkentin TE, Greinacher A (2004) Heparin-induced thrombocytopenia: recognition, treatment, and prevention: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 126: 311S-337SPubMedCrossRef
43.
Zurück zum Zitat Stribling W, Slaughter TF, Houly T, Sane D (2007) Beyond the platelet count: heparin antibodies as independent risk predictors. Am Heart J 153: 900–906PubMedCrossRef Stribling W, Slaughter TF, Houly T, Sane D (2007) Beyond the platelet count: heparin antibodies as independent risk predictors. Am Heart J 153: 900–906PubMedCrossRef
44.
Zurück zum Zitat Wan C, Warner M, Varennes B de et al. (2006) Clinical presentation, temporal relationship, and outcome in thirty-three patients with type 2 heparin-induced thrombocytopenia after cardiotomy. Ann Thorac Surg 82: 21–27PubMedCrossRef Wan C, Warner M, Varennes B de et al. (2006) Clinical presentation, temporal relationship, and outcome in thirty-three patients with type 2 heparin-induced thrombocytopenia after cardiotomy. Ann Thorac Surg 82: 21–27PubMedCrossRef
45.
Zurück zum Zitat Pappalardo F, Crescnzi G, Franco A, Zangrillo A (2006) Early heparin-induced thrombocytopaenia (HIT) after cardiac surgery. Eur J Anaesthesiol 23: 806–814PubMedCrossRef Pappalardo F, Crescnzi G, Franco A, Zangrillo A (2006) Early heparin-induced thrombocytopaenia (HIT) after cardiac surgery. Eur J Anaesthesiol 23: 806–814PubMedCrossRef
46.
Zurück zum Zitat Everett B, Yeh R, Foo S et al. (2007) Prevalence of heparin/platelet factor 4 antibodies before and after cardiac surgery. Ann Thorac Surg 83: 592–597PubMedCrossRef Everett B, Yeh R, Foo S et al. (2007) Prevalence of heparin/platelet factor 4 antibodies before and after cardiac surgery. Ann Thorac Surg 83: 592–597PubMedCrossRef
47.
Zurück zum Zitat Kress D, Aronson S, McDonald M et al. (2007) Positive heparin-platelet factor 4 antibody complex and cardiac surgical outcomes. Ann Thorac Surg 83: 1737–1743PubMedCrossRef Kress D, Aronson S, McDonald M et al. (2007) Positive heparin-platelet factor 4 antibody complex and cardiac surgical outcomes. Ann Thorac Surg 83: 1737–1743PubMedCrossRef
48.
Zurück zum Zitat Kuitunen A, Suojaranta-Ylinen R, Raivio P et al. (2007) Heparin-induced thrombocytopenia following cardiac surgery is associated with poor outcome. J Thorac Cardiovasc Surg 21: 18–22 Kuitunen A, Suojaranta-Ylinen R, Raivio P et al. (2007) Heparin-induced thrombocytopenia following cardiac surgery is associated with poor outcome. J Thorac Cardiovasc Surg 21: 18–22
49.
Zurück zum Zitat Warkentin T, Kelton J (2001) Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 344: 1286–1292PubMedCrossRef Warkentin T, Kelton J (2001) Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 344: 1286–1292PubMedCrossRef
50.
Zurück zum Zitat Pötsch B, Klovekorn W, Madlener K (2000) Use of heparin during cardiopulmonary bypass in patients with history of heparin-induced thrombocytopenia. N Engl J Med 343: 515–519CrossRef Pötsch B, Klovekorn W, Madlener K (2000) Use of heparin during cardiopulmonary bypass in patients with history of heparin-induced thrombocytopenia. N Engl J Med 343: 515–519CrossRef
51.
Zurück zum Zitat Edwards J, Hamby J, Worrall N (2003) Successful use of argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient. Ann Thorac Surg 75: 1622–1624PubMedCrossRef Edwards J, Hamby J, Worrall N (2003) Successful use of argatroban as a heparin substitute during cardiopulmonary bypass: heparin-induced thrombocytopenia in a high-risk cardiac surgical patient. Ann Thorac Surg 75: 1622–1624PubMedCrossRef
52.
Zurück zum Zitat Furukawa K, Ohteki H, Hirahara K et al. (2001) The use of argatroban as an anticoagulant for cardiopulmonary bypass in cardiac operations. J Thorac Cardiovasc Surg 122: 1255–1256PubMedCrossRef Furukawa K, Ohteki H, Hirahara K et al. (2001) The use of argatroban as an anticoagulant for cardiopulmonary bypass in cardiac operations. J Thorac Cardiovasc Surg 122: 1255–1256PubMedCrossRef
53.
Zurück zum Zitat Gasparovic H, Nathan N, Fitzgerald D, Aranki S (2004) Severe argatroban-induced coagulopathy in a patient with a history of heparin-induced thrombocytopenia. Ann Thorac Surg 78: 89–91CrossRef Gasparovic H, Nathan N, Fitzgerald D, Aranki S (2004) Severe argatroban-induced coagulopathy in a patient with a history of heparin-induced thrombocytopenia. Ann Thorac Surg 78: 89–91CrossRef
54.
Zurück zum Zitat Reichert M, MacGregor D, Kincaid E, Dolinski S (2003) Excessive argatroban anticoagulation for heparin-induced thrombocytopenia. Ann Pharmacother 37: 652–654PubMedCrossRef Reichert M, MacGregor D, Kincaid E, Dolinski S (2003) Excessive argatroban anticoagulation for heparin-induced thrombocytopenia. Ann Pharmacother 37: 652–654PubMedCrossRef
55.
Zurück zum Zitat Kurup V, Transue S, Wu Y et al. (2006) Cardiac surgery in a patient with heparin-induced thrombocytopenia – cautions with use of the direct thrombin inhibitor argatroban. Conn Med 70: 245–250PubMed Kurup V, Transue S, Wu Y et al. (2006) Cardiac surgery in a patient with heparin-induced thrombocytopenia – cautions with use of the direct thrombin inhibitor argatroban. Conn Med 70: 245–250PubMed
56.
Zurück zum Zitat Nuttall G, Oliver W, Santarach P (2003) Patients with a history of type II heparin-induced thrombocytopenia with thrombosis requiring cardiac surgery with cardiopulmonary bypass: a prospective observational case series. Anesth Analg 96: 344–350PubMedCrossRef Nuttall G, Oliver W, Santarach P (2003) Patients with a history of type II heparin-induced thrombocytopenia with thrombosis requiring cardiac surgery with cardiopulmonary bypass: a prospective observational case series. Anesth Analg 96: 344–350PubMedCrossRef
57.
Zurück zum Zitat Koster A, Hansen R, Kuppe H et al. (2000) Recombinant hirudin as an alternative for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: a 1-year experience in 57 patients. J Cardiothorac Vasc Anesth 14: 243–248PubMedCrossRef Koster A, Hansen R, Kuppe H et al. (2000) Recombinant hirudin as an alternative for anticoagulation during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II: a 1-year experience in 57 patients. J Cardiothorac Vasc Anesth 14: 243–248PubMedCrossRef
58.
Zurück zum Zitat Koster A, Spiess B, Chew DP (2004) Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. Am J Cardiol 93: 356–359PubMedCrossRef Koster A, Spiess B, Chew DP (2004) Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. Am J Cardiol 93: 356–359PubMedCrossRef
59.
Zurück zum Zitat Vasquez J, Vichiendilokkul A, Mahmood S, Baciewicz F (2002) Anticoagulation with bivalirudin during cardiopulmonary bypass in cardiac surgery. Ann Thorac Surg 74: 2177–2179PubMedCrossRef Vasquez J, Vichiendilokkul A, Mahmood S, Baciewicz F (2002) Anticoagulation with bivalirudin during cardiopulmonary bypass in cardiac surgery. Ann Thorac Surg 74: 2177–2179PubMedCrossRef
60.
Zurück zum Zitat Dyke CK, Smedira N, Koster A et al. (2006) 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 131: 533–539PubMedCrossRef Dyke CK, Smedira N, Koster A et al. (2006) 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 131: 533–539PubMedCrossRef
61.
Zurück zum Zitat Smedira N, Dyke CK, Koster A et al. (2006) Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study. J Thorac Cardiovasc Surg 131: 686–692PubMedCrossRef Smedira N, Dyke CK, Koster A et al. (2006) Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: the results of the EVOLUTION-OFF study. J Thorac Cardiovasc Surg 131: 686–692PubMedCrossRef
62.
Zurück zum Zitat Davis Z, Anderson R, Short D (2003) Favorable outcome with bivalirudin anticoagulation during cardiopulmonary bypass. Ann Thorac Surg 74: 2177–2179 Davis Z, Anderson R, Short D (2003) Favorable outcome with bivalirudin anticoagulation during cardiopulmonary bypass. Ann Thorac Surg 74: 2177–2179
63.
Zurück zum Zitat Bott J, Reddy B, Krick S (2003) Bivalirudin in off-pump myocardial revascularization in patients with heparin-induced thrombocytopenia. Ann Thorac Surg 76: 273–275PubMedCrossRef Bott J, Reddy B, Krick S (2003) Bivalirudin in off-pump myocardial revascularization in patients with heparin-induced thrombocytopenia. Ann Thorac Surg 76: 273–275PubMedCrossRef
64.
Zurück zum Zitat Aouifi A, Blanc P, Piriou V (2001) Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia. Ann Thorac Surg 71: 678–683PubMedCrossRef Aouifi A, Blanc P, Piriou V (2001) Cardiac surgery with cardiopulmonary bypass in patients with type II heparin-induced thrombocytopenia. Ann Thorac Surg 71: 678–683PubMedCrossRef
65.
Zurück zum Zitat Warkentin TE, Greinacher A (2003) Heparin-induced thrombopenia and cardiac surgery. Ann Thorac Surg 76: 2121–2131PubMedCrossRef Warkentin TE, Greinacher A (2003) Heparin-induced thrombopenia and cardiac surgery. Ann Thorac Surg 76: 2121–2131PubMedCrossRef
66.
Zurück zum Zitat Merry AF, Raudkivi PJ, Middleton NG et al. (2004) Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery. Ann Thorac Surg 77: 925–931; discussion 931PubMedCrossRef Merry AF, Raudkivi PJ, Middleton NG et al. (2004) Bivalirudin versus heparin and protamine in off-pump coronary artery bypass surgery. Ann Thorac Surg 77: 925–931; discussion 931PubMedCrossRef
67.
Zurück zum Zitat Riess F, Poetszsch B, Madlener K et al. (2007) Recombinant hirudin for cardiopulmonary bypass anticoagulation: a randomized, prospective, and heparin-controlled pilot study. Throrac Cardiovasc Surg 55: 233–238CrossRef Riess F, Poetszsch B, Madlener K et al. (2007) Recombinant hirudin for cardiopulmonary bypass anticoagulation: a randomized, prospective, and heparin-controlled pilot study. Throrac Cardiovasc Surg 55: 233–238CrossRef
68.
Zurück zum Zitat Saravanan P, Rege K, Falter F (2007) Use of continuous venovenous hemofiltration for reversal of anticoagulation with lepirudin post-cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia after heart transplantation. J Thorac Cardiovasc Surg 21: 269–272 Saravanan P, Rege K, Falter F (2007) Use of continuous venovenous hemofiltration for reversal of anticoagulation with lepirudin post-cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia after heart transplantation. J Thorac Cardiovasc Surg 21: 269–272
69.
Zurück zum Zitat Koster A, Merkle F, Hansen R (2000) Elimination of recombinant hirudin by modified ultrafiltration during simulated cardiopulmonary bypass: assessment of different filter systems. Anesth Analg 91: 265–269PubMedCrossRef Koster A, Merkle F, Hansen R (2000) Elimination of recombinant hirudin by modified ultrafiltration during simulated cardiopulmonary bypass: assessment of different filter systems. Anesth Analg 91: 265–269PubMedCrossRef
70.
Zurück zum Zitat Lubenow N, Selleng K, Wollert H (2003) Heparin-induced thrombocytopenia and cardiopulmonary bypass: perioperative argatroban use. Ann Thorac Surg 75: 577–579PubMedCrossRef Lubenow N, Selleng K, Wollert H (2003) Heparin-induced thrombocytopenia and cardiopulmonary bypass: perioperative argatroban use. Ann Thorac Surg 75: 577–579PubMedCrossRef
71.
Zurück zum Zitat Martin M, Kloecker G, Laber D (2006) Argatroban for anticoagulation during cardiac surgery. Eur J Haematol 78: 161–166 Martin M, Kloecker G, Laber D (2006) Argatroban for anticoagulation during cardiac surgery. Eur J Haematol 78: 161–166
72.
Zurück zum Zitat Cormack G, Kaufman L (2007) Severe heparin-induced thrombocytopenia: when the obvious is not obvious, a case report. J Med Case Rep 1: 1–13CrossRef Cormack G, Kaufman L (2007) Severe heparin-induced thrombocytopenia: when the obvious is not obvious, a case report. J Med Case Rep 1: 1–13CrossRef
73.
Zurück zum Zitat Magnani HN, Beijering R, Cate H ten (1997) Orgaran anticoagulation for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia. In: Pifarre R (ed) New anticoagulants for the cardiovascular patient. Hanley & Belfus, Philadelphia, pp 487–500 Magnani HN, Beijering R, Cate H ten (1997) Orgaran anticoagulation for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia. In: Pifarre R (ed) New anticoagulants for the cardiovascular patient. Hanley & Belfus, Philadelphia, pp 487–500
74.
Zurück zum Zitat Walls J, Curtis J, Silver D et al. (1992) Heparin-induced thrombocytopenia in open heart surgical patients: sequelae of late recognition. Ann Thorac Surg 53: 787–791PubMedCrossRef Walls J, Curtis J, Silver D et al. (1992) Heparin-induced thrombocytopenia in open heart surgical patients: sequelae of late recognition. Ann Thorac Surg 53: 787–791PubMedCrossRef
75.
Zurück zum Zitat Koster A, Meyer O, Fischer T (2001) One-year experience with the platelet glycoprotein IIb/IIIa antagonist tirofiban and heparin during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II. J Thorac Cardiovasc Surg 122: 1254–1255PubMedCrossRef Koster A, Meyer O, Fischer T (2001) One-year experience with the platelet glycoprotein IIb/IIIa antagonist tirofiban and heparin during cardiopulmonary bypass in patients with heparin-induced thrombocytopenia type II. J Thorac Cardiovasc Surg 122: 1254–1255PubMedCrossRef
76.
Zurück zum Zitat Schreiber C, Dietrich W, Braun S et al. (2006) Use of heparin upon reoperation in a pediatric patient with heparin-induced thrombocytopenia after disappearance of antibodies. Clin Res Cardiol 95: 379–382PubMedCrossRef Schreiber C, Dietrich W, Braun S et al. (2006) Use of heparin upon reoperation in a pediatric patient with heparin-induced thrombocytopenia after disappearance of antibodies. Clin Res Cardiol 95: 379–382PubMedCrossRef
77.
Zurück zum Zitat Klenner A, Lubenow N, Ratschke R, Greinacher A (2004) Heparin-induced thrombocytopenia in children: 12 new cases and review of the literature. Thromb Haemost 91: 719–724PubMed Klenner A, Lubenow N, Ratschke R, Greinacher A (2004) Heparin-induced thrombocytopenia in children: 12 new cases and review of the literature. Thromb Haemost 91: 719–724PubMed
78.
Zurück zum Zitat Dyke P, Russo P, Mureebe L (2005) Argatroban for anticoagulation during cardiopulmonary bypass in an infant. Pediatr Anesthesia 15: 328–333CrossRef Dyke P, Russo P, Mureebe L (2005) Argatroban for anticoagulation during cardiopulmonary bypass in an infant. Pediatr Anesthesia 15: 328–333CrossRef
79.
Zurück zum Zitat Malherbe S, Tsui B, Stobart K, Koller J (2004) Argatroban as anticoagulant in cardiopulmonary bypass in an infant and attempted reversal with recombinant activated factor VII. Anesthesiology 100: 443–445PubMedCrossRef Malherbe S, Tsui B, Stobart K, Koller J (2004) Argatroban as anticoagulant in cardiopulmonary bypass in an infant and attempted reversal with recombinant activated factor VII. Anesthesiology 100: 443–445PubMedCrossRef
80.
Zurück zum Zitat Dyke P, Russo P, Mureebe L et al. (2005) Argatroban for anticoagulation during cardiopulmonary bypass in an infant. Pediatric Anesthesia 15: 328–333PubMedCrossRef Dyke P, Russo P, Mureebe L et al. (2005) Argatroban for anticoagulation during cardiopulmonary bypass in an infant. Pediatric Anesthesia 15: 328–333PubMedCrossRef
81.
Zurück zum Zitat Hursting M, Dubb J, Verme-Gibboney C (2006) Argatroban anticoagulation in pediatric patients. J Pediatr Hematol Oncol 28: 4-10PubMedCrossRef Hursting M, Dubb J, Verme-Gibboney C (2006) Argatroban anticoagulation in pediatric patients. J Pediatr Hematol Oncol 28: 4-10PubMedCrossRef
82.
Zurück zum Zitat Powner DJ, Hartwell EA, Hoots WK (2005) Counteracting the effects of anticoagulants and antiplatelet agents during neurosurgical emergencies. Neurosurgery 57: 823–831; discussion 823–831PubMedCrossRef Powner DJ, Hartwell EA, Hoots WK (2005) Counteracting the effects of anticoagulants and antiplatelet agents during neurosurgical emergencies. Neurosurgery 57: 823–831; discussion 823–831PubMedCrossRef
83.
Zurück zum Zitat Ibbotson SH, Grant PJ, Kerry R et al. (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: 64–66PubMed Ibbotson SH, Grant PJ, Kerry R et al. (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: 64–66PubMed
84.
Zurück zum Zitat Amin DM, Mant TG, Walker SM et al. (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: 127–132PubMed Amin DM, Mant TG, Walker SM et al. (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: 127–132PubMed
85.
Zurück zum Zitat Bove CM, Casey B, Marder VJ (1996) DDAVP reduces bleeding during continued hirudin administration in the rabbit. Thromb Haemost 75: 471–475PubMed Bove CM, Casey B, Marder VJ (1996) DDAVP reduces bleeding during continued hirudin administration in the rabbit. Thromb Haemost 75: 471–475PubMed
86.
Zurück zum Zitat 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: 459–464PubMedCrossRef 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: 459–464PubMedCrossRef
87.
Zurück zum Zitat Irani MS, White HJ Jr, Sexon RG (1995) Reversal of hirudin-induced bleeding diathesis by prothrombin complex concentrate. Am J Cardiol 75: 422–423PubMedCrossRef Irani MS, White HJ Jr, Sexon RG (1995) Reversal of hirudin-induced bleeding diathesis by prothrombin complex concentrate. Am J Cardiol 75: 422–423PubMedCrossRef
88.
Zurück zum Zitat Fareed J, Walenga JM, Pifarre R et al. (1991) Some objective considerations for the neutralization of the anticoagulant actions of recombinant hirudin. Haemostasis 21 [Suppl 1]: 64–72 Fareed J, Walenga JM, Pifarre R et al. (1991) Some objective considerations for the neutralization of the anticoagulant actions of recombinant hirudin. Haemostasis 21 [Suppl 1]: 64–72
89.
Zurück zum Zitat Oh K, Akers W, Lewis D et al. (2006) Recombinant factor VIIa for refractory bleeding after cardiac surgery secondary to anticoagulation with the direct thrombin inhibitor lepirudin. Pharmacotherapy 26: 569–577PubMedCrossRef Oh K, Akers W, Lewis D et al. (2006) Recombinant factor VIIa for refractory bleeding after cardiac surgery secondary to anticoagulation with the direct thrombin inhibitor lepirudin. Pharmacotherapy 26: 569–577PubMedCrossRef
90.
Zurück zum Zitat Stratmann G, Silva A di, Tseng E et al. (2004) Reversal of direct thrombin inhibition after cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia. Anesth Analg 98: 1635–1639PubMedCrossRef Stratmann G, Silva A di, Tseng E et al. (2004) Reversal of direct thrombin inhibition after cardiopulmonary bypass in a patient with heparin-induced thrombocytopenia. Anesth Analg 98: 1635–1639PubMedCrossRef
91.
Zurück zum Zitat Irani M, White H, Sexon G (1995) Reversal of hirudin-induced bleeding diathesis by prothrombin complex concentrate. Am J Cardiol 75: 422–423PubMedCrossRef Irani M, White H, Sexon G (1995) Reversal of hirudin-induced bleeding diathesis by prothrombin complex concentrate. Am J Cardiol 75: 422–423PubMedCrossRef
92.
Zurück zum Zitat Diehl K, Romisch J, Hein B et al. (1995) Investigation of activated prothrombin complex concentrate as potential hirudin antidote in animal models. Haemostasis 25: 182–192PubMed Diehl K, Romisch J, Hein B et al. (1995) Investigation of activated prothrombin complex concentrate as potential hirudin antidote in animal models. Haemostasis 25: 182–192PubMed
93.
Zurück zum Zitat Novak G, Bucha E (1995) Prothrombin conversion intermediate effectively neutralizes toxic levels of hirudin. Thromb Res 80: 317–325CrossRef Novak G, Bucha E (1995) Prothrombin conversion intermediate effectively neutralizes toxic levels of hirudin. Thromb Res 80: 317–325CrossRef
94.
Zurück zum Zitat Yee AJ, Kuter DJ (2006) Successful recovery after an overdose of argatroban. Ann Pharmacother 40: 336–339PubMedCrossRef Yee AJ, Kuter DJ (2006) Successful recovery after an overdose of argatroban. Ann Pharmacother 40: 336–339PubMedCrossRef
95.
Zurück zum Zitat Murray PT, Reddy BV, Grossman EJ et al. (2004) A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease. Kidney Int 66: 2446–2453PubMedCrossRef Murray PT, Reddy BV, Grossman EJ et al. (2004) A prospective comparison of three argatroban treatment regimens during hemodialysis in end-stage renal disease. Kidney Int 66: 2446–2453PubMedCrossRef
96.
Zurück zum Zitat Young G, Yonekawa K, Nakagawa P et al. (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: 547–553PubMedCrossRef Young G, Yonekawa K, Nakagawa P et al. (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: 547–553PubMedCrossRef
97.
Zurück zum Zitat Koster A, Chew DP, Gründel M et al. (2003) An assessment of different filter systems for extracorporeal elimination of bivalirudin: an in vitro study. Anesth Analg 96: 1316–1319PubMedCrossRef Koster A, Chew DP, Gründel M et al. (2003) An assessment of different filter systems for extracorporeal elimination of bivalirudin: an in vitro study. Anesth Analg 96: 1316–1319PubMedCrossRef
98.
Zurück zum Zitat Mann M, Tseng EE, Ratcliff M et al. (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: 222–225PubMedCrossRef Mann M, Tseng EE, Ratcliff M et al. (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: 222–225PubMedCrossRef
99.
Zurück zum Zitat Kozek-Langenecker S, Fries D, Gütl M et al. (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: 476–484PubMedCrossRef Kozek-Langenecker S, Fries D, Gütl M et al. (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: 476–484PubMedCrossRef
Metadaten
Titel
Direkte Thrombininhibitoren
Pharmakologie und Anwendung in der kardiovaskulären Anästhesie
verfasst von
Prof. Dr. S.A. Kozek-Langenecker
Publikationsdatum
01.06.2008
Verlag
Springer-Verlag
Erschienen in
Die Anaesthesiologie / Ausgabe 6/2008
Print ISSN: 2731-6858
Elektronische ISSN: 2731-6866
DOI
https://doi.org/10.1007/s00101-008-1347-5

Weitere Artikel der Ausgabe 6/2008

Die Anaesthesiologie 6/2008 Zur Ausgabe

Bei schweren Reaktionen auf Insektenstiche empfiehlt sich eine spezifische Immuntherapie

Insektenstiche sind bei Erwachsenen die häufigsten Auslöser einer Anaphylaxie. Einen wirksamen Schutz vor schweren anaphylaktischen Reaktionen bietet die allergenspezifische Immuntherapie. Jedoch kommt sie noch viel zu selten zum Einsatz.

Hinter dieser Appendizitis steckte ein Erreger

23.04.2024 Appendizitis Nachrichten

Schmerzen im Unterbauch, aber sonst nicht viel, was auf eine Appendizitis hindeutete: Ein junger Mann hatte Glück, dass trotzdem eine Laparoskopie mit Appendektomie durchgeführt und der Wurmfortsatz histologisch untersucht wurde.

Ärztliche Empathie hilft gegen Rückenschmerzen

23.04.2024 Leitsymptom Rückenschmerzen Nachrichten

Personen mit chronischen Rückenschmerzen, die von einfühlsamen Ärzten und Ärztinnen betreut werden, berichten über weniger Beschwerden und eine bessere Lebensqualität.

Mehr Schaden als Nutzen durch präoperatives Aussetzen von GLP-1-Agonisten?

23.04.2024 Operationsvorbereitung Nachrichten

Derzeit wird empfohlen, eine Therapie mit GLP-1-Rezeptoragonisten präoperativ zu unterbrechen. Eine neue Studie nährt jedoch Zweifel an der Notwendigkeit der Maßnahme.

Update AINS

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.