Delicate balance of bleeding and thrombosis in end-stage liver disease and liver transplantation

Digestion

Volumn 88, Issue 3, 2013, Pages 135-144

  Saner, Fuat Hakan ^a   Gieseler, Robert K ^a,b   Akz, Hikmet ^d   Canbay, Ali ^a   Görlinger, Klaus ^a,c  

^a UNIVERSITY HOSPITAL ESSEN   (Germany)

^b Rodos BioTarget GmbH   (Germany)

^c Lahmeyer International GmbH   (Germany)

^d CUKUROVA UNIVERSITY   (Turkey)

Author keywords

Bleeding risk; End stage liver disease; Hepatic coagulopathy; Hepatitis C treatment; Liver transplantation; Thromboprophylaxis; Thrombosis; Whole blood coagulation

Indexed keywords

ALPHA 2 ANTIPLASMIN; BLOOD CLOTTING FACTOR 10; BLOOD CLOTTING FACTOR 13; BLOOD CLOTTING FACTOR 5; BLOOD CLOTTING FACTOR 7; BLOOD CLOTTING FACTOR 9; ENOXAPARIN; FIBRINOGEN; FRESH FROZEN PLASMA; LOW MOLECULAR WEIGHT HEPARIN; PLASMINOGEN; PLASMINOGEN ACTIVATOR INHIBITOR 1; PROTEIN S; PROTHROMBIN; PROTHROMBIN COMPLEX; RECOMBINANT BLOOD CLOTTING FACTOR 7A; THROMBIN ACTIVATABLE FIBRINOLYSIS INHIBITOR; THROMBOMODULIN; TISSUE PLASMINOGEN ACTIVATOR; VON WILLEBRAND FACTOR; ANTICOAGULANT AGENT; FIBRINOLYTIC AGENT;

ACUTE LIVER FAILURE; BLEEDING; BLEEDING TENDENCY; BLOOD CLOTTING; BLOOD CLOTTING DISORDER; BLOOD CLOTTING TEST; END STAGE LIVER DISEASE; ERYTHROCYTE TRANSFUSION; FIBRINOGEN BLOOD LEVEL; HEMOSTASIS; HUMAN; IMPEDANCE AGGREGOMETRY; INTERNATIONAL NORMALIZED RATIO; LIVER CIRRHOSIS; LIVER CLEARANCE; LIVER TRANSPLANTATION; LUNG EMBOLISM; PARTIAL THROMBOPLASTIN TIME; PATHOPHYSIOLOGY; PLASMA TRANSFUSION; PLASMAPHERESIS; POINT OF CARE TESTING; PORTAL VEIN THROMBOSIS; PREOPERATIVE EVALUATION; PRIORITY JOURNAL; REVIEW; RISK ASSESSMENT; THROMBOCYTE DYSFUNCTION; THROMBOCYTE FUNCTION; THROMBOCYTOPENIA; THROMBOEMBOLISM; THROMBOSIS; THROMBOSIS PREVENTION; UPREGULATION; VASCULAR ENDOTHELIUM; VENOUS THROMBOEMBOLISM; HEPATITIS C; LABORATORY TEST;

BLOOD COAGULATION DISORDERS; END STAGE LIVER DISEASE; HEMORRHAGE; HUMANS; LIVER CIRRHOSIS; LIVER TRANSPLANTATION; THROMBOSIS;

EID: 84889673270     PISSN: 00122823     EISSN: 14219867     Source Type: Journal    
DOI: 10.1159/000354400     Document Type: Review

References (90)

1. Starzl TE, Iwatsuki S, Van Thiel DH, Gartner JC, Zitelli BJ, Malatack JJ, Schade RR, Shaw BW Jr, Hakala TR, Rosenthal JT, Porter KA: Evolution of liver transplantation. Hepatology 1982; 2: 614-636. (Pubitemid 13173945)
2. Dara SI, Rana R, Afessa B, Moore SB, Gajic O: Fresh frozen plasma transfusion in critically ill medical patients with coagulopathy. Crit Care Med 2005; 33: 2667-2671. (Pubitemid 41682123)
3. Khan H, Belsher J, Yilmaz M, Afessa B, Winters JL, Moore SB, Hubmayr RD, Gajic O: Fresh frozen plasma and platelet transfusions are associated with development of acute lung injury in critically ill medical patients. Chest 2007; 131: 1308-1314. (Pubitemid 46762333)
4. Pereboom IT, de Boer MT, Haagsma EB, Hendriks HG, Lisman T, Porte RJ: Platelet transfusion during liver transplantation is associated with increased postoperative mortality due to acute lung injury. Anesth Analg 2009; 108: 1083-1091.
5. Sarani B, Dunkman WJ, Dean L, Sonnad S, Rohrbach JI, Gracias VH: Transfusion of fresh frozen plasma in critically ill surgical patients is associated with an increased risk of infection. Crit Care Med 2008; 36: 1114-1118. (Pubitemid 351482658)
6. Groenland TH, Porte RJ, Bakker CM, Stibbe J: Hemostasis in heterotopic liver transplantation. Semin Thromb Hemost 1993; 19: 213-217. (Pubitemid 23214833)
7. Porte RJ: Coagulation and fibrinolysis in orthotopic liver transplantation: current views and insights. Semin Thromb Hemost 1993; 19: 191-196. (Pubitemid 23214830)
8. Gorlinger K, Dirkmann D, Hanke AA, Kamler M, Kottenberg E, Thielmann M, Jakob H, Peters J: First-line therapy with coagulation factor concentrates combined with point-ofcare coagulation testing is associated with decreased allogeneic blood transfusion in cardiovascular surgery: a retrospective, singlecenter cohort study. Anesthesiology 2011; 115: 1179-1191.
9. Gorlinger K, Dirkmann D, Muller-Beissenhirtz H, Paul A, Hartmann M, Saner F: Thromboelastometry-based perioperative coagulation management in visceral surgery and liver transplantation: experience of 10 years and 1105 LTX. Liver Transpl 2010; 16:S86.
10. Northup PG, Sundaram V, Fallon MB, Reddy KR, Balogun RA, Sanyal AJ, Anstee QM, Hoffman MR, Ikura Y, Caldwell SH: Hypercoagulation and thrombophilia in liver disease. J Thromb Haemost 2008; 6: 2-9.
11. Hugenholtz GC, Adelmeijer J, Meijers JC, Porte RJ, Stravitz RT, Lisman T: An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: implications for hemostasis and clinical outcome. Hepatology 2013; 58: 752-761.
12. Lisman T, Porte RJ: Rebalanced hemostasis in patients with liver disease: evidence and clinical consequences. Blood 2010; 116: 878-885.
13. Lisman T, Bongers TN, Adelmeijer J, Janssen HL, de Maat MP, de Groot PG, Leebeek FW: Elevated levels of von Willebrand factor in cirrhosis support platelet adhesion despite reduced functional capacity. Hepatology 2006; 44: 53-61. (Pubitemid 44049138)
14. Hollestelle MJ, Geertzen HG, Straatsburg IH, van Gulik TM, van Mourik JA: Factor VIII expression in liver disease. Thromb Haemost 2004; 91: 267-275. (Pubitemid 38240171)
15. Francis JL, Armstrong DJ: Fibrinogenbound sialic acid levels in the dysfibrinogenaemia of liver disease. Haemostasis 1982; 11: 215-222. (Pubitemid 12060540)
16. Oksuzoglu G, Simsek H, Haznedaroglu IC, Kirazli S: Tissue factor pathway inhibitor concentrations in cirrhotic patients with and without portal vein thrombosis. Am J Gastroenterol 1997; 92: 303-306. (Pubitemid 27076481)
17. Leebeek FW, Kluft C, Knot EA, de Maat MP, Wilson JH: A shift in balance between profibrinolytic and antifibrinolytic factors causes enhanced fibrinolysis in cirrhosis. Gastroenterology 1991; 101: 1382-1390.
18. Violi F, Leo R, Basili S, Ferro D, Cordova C, Balsano F: Association between prolonged bleeding time and gastrointestinal hemorrhage in 102 patients with liver cirrhosis: results of a retrospective study. Haematologica 1994; 79: 61-65.
19. Ferro D, Celestini A, Violi F: Hyperfibrinolysis in liver disease. Clin Liver Dis 2009; 13: 21-31.
20. Gorlinger K: Coagulation management during liver transplantation (in German). Hamostaseologie 2006; 26:S64-S76.
21. Tripodi A, Mannucci PM: The coagulopathy of chronic liver disease. N Engl J Med 2011; 365: 147-156.
22. Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M, Primignani M, Mannuccio Mannucci P: Evidence of normal thrombin generation in cirrhosis despite abnormal conventional coagulation tests. Hepatology 2005; 41: 553-558. (Pubitemid 40289502)
23. Tripodi A, Primignani M, Chantarangkul V, DellEra A, Clerici M, de Franchis R, Colombo M, Mannucci PM: An imbalance of provs. anti-coagulation factors in plasma from patients with cirrhosis. Gastroenterology 2009; 137: 2105-2111.
24. Ben-Ari Z, Panagou M, Patch D, Bates S, Osman E, Pasi J, Burroughs A: Hypercoagulability in patients with primary biliary cirrhosis and primary sclerosing cholangitis evaluated by thrombelastography. J Hepatol 1997; 26: 554-559. (Pubitemid 27112720)
25. Lang T, Johanning K, Metzler H, Piepenbrock S, Solomon C, Rahe-Meyer N, Tanaka KA: The effects of fibrinogen levels on thromboelastometric variables in the presence of thrombocytopenia. Anesth Analg 2009; 108: 751-758.
26. Lisman T, Porte RJ, Leebeek FW, Caldwell SH: Methodological issues with coagulation testing in patients with liver disease. J Thromb Haemost 2006; 4: 2061-2062. (Pubitemid 44226790)
27. Tripodi A: Tests of coagulation in liver disease. Clin Liver Dis 2009; 13: 55-61.
28. Lang T, von Depka M: Possibilities and limitations of thrombelastometry/-graphy (in German). Hamostaseologie 2006; 26:S20-S29.
29. Kashuk JL, Moore EE, Sabel A, Barnett C, Haenel J, Le T, Pezold M, Lawrence J, Biffl WL, Cothren CC, Johnson JL: Rapid thrombelastography (r-TEG) identifies hypercoagulability and predicts thromboembolic events in surgical patients. Surgery 2009; 146: 764- 772; discussion 772-764.
30. McCrath DJ, Cerboni E, Frumento RJ, Hirsh AL, Bennett-Guerrero E: Thromboelastography maximum amplitude predicts postoperative thrombotic complications including myocardial infarction. Anesth Analg 2005; 100: 1576-1583. (Pubitemid 40712703)
31. Rahe-Meyer N, Winterhalter M, Boden A, Froemke C, Piepenbrock S, Calatzis A, Solomon C: Platelet concentrates transfusion in cardiac surgery and platelet function assessment by multiple electrode aggregometry. Acta Anaesthesiol Scand 2009; 53: 168-175.
32. Toth O, Calatzis A, Penz S, Losonczy H, Siess W: Multiple electrode aggregometry: a new device to measure platelet aggregation in whole blood. Thromb Haemost 2006; 96: 781-788. (Pubitemid 44883819)
33. Hanke AA, Roberg K, Monaca E, Sellmann T, Weber CF, Rahe-Meyer N, Gorlinger K: Impact of platelet count on results obtained from multiple electrode platelet aggregometry (Multiplate). Eur J Med Res 2010; 15: 214-219.
34. Blonski W, Siropaides T, Reddy KR: Coagulopathy in liver disease. Curr Treat Options Gastroenterol 2007; 10: 464-473. (Pubitemid 350284929)
35. De Gasperi A, Corti A, Mazza E, Prosperi M, Amici O, Bettinelli L: Acute liver failure: managing coagulopathy and the bleeding diathesis. Transplant Proc 2009; 41: 1256-1259.
36. Lisman T, Bakhtiari K, Pereboom IT, Hendriks HG, Meijers JC, Porte RJ: Normal to increased thrombin generation in patients undergoing liver transplantation despite prolonged conventional coagulation tests. J Hepatol 2010; 52: 355-361.
37. Hellstern P: Solvent/detergent-treated plasma: composition, efficacy, and safety. Curr Opin Hematol 2004; 11: 346-350. (Pubitemid 40221052)
38. De Jonge J, Groenland TH, Metselaar HJ, IJzermans JN, van Vliet HH, Visser L, Tilanus HW: Fibrinolysis during liver transplantation is enhanced by using solvent/detergent virusinactivated plasma (ESDEP). Anesth Analg 2002; 94: 1127-1131. (Pubitemid 34441819)
39. Depasse F, Sensebe L, Seghatchian J, Andreu G, Samama MM: The influence of methylene blue light treatment and methylene blue removal filter on fibrinogen activity states and fibrin polymerisation indices. Transfus Apher Sci 2005; 33: 63-69. (Pubitemid 40982152)
40. Dara SI, Rana R, Afessa B, Moore SB, Gajic O: Fresh frozen plasma transfusion in critically ill medical patients with coagulopathy. Crit Care Med 2005; 33: 2667-2671. (Pubitemid 41682123)
41. Hatano E, Terajima H, Yabe S, Asonuma K, Egawa H, Kiuchi T, Uemoto S, Inomata Y, Tanaka K, Yamaoka Y: Hepatic artery thrombosis in living related liver transplantation. Transplantation 1997; 64: 1443-1446. (Pubitemid 27513624)
42. Sarani B, Dunkman WJ, Dean L, Sonnad S, Rohrbach JI, Gracias VH: Transfusion of fresh frozen plasma in critically ill surgical patients is associated with an increased risk of infection. Crit Care Med 2008; 36: 1114-1118. (Pubitemid 351482658)
43. Keller-Stanislawski B, Reil A, Gunay S, Funk MB: Frequency and severity of transfusionrelated acute lung injury - German haemovigilance data (2006-2007). Vox Sang 2010; 98: 70-77.
44. Stanworth SJ: The evidence-based use of FFP and cryoprecipitate for abnormalities of coagulation tests and clinical coagulopathy. Hematology Am Soc Hematol Educ Prog 2007: 179-186.
45. Lorenz R, Kienast J, Otto U, Egger K, Kiehl M, Schreiter D, Kwasny H, Haertel S, Barthels M: Efficacy and safety of a prothrombin complex concentrate with two virus-inactivation steps in patients with severe liver damage. Eur J Gastroenterol Hepatol 2003; 15: 15-20. (Pubitemid 36135657)
46. Scherer R, Gille A, Erhard J, Paar D, Kox WJ: The effect of substitution with AT III- and PPSB concentrates in patients with terminal liver insufficiency (in German). Anaesthesist 1994; 43: 178-182. (Pubitemid 24103777)
47. Sakai T, Matsusaki T, Dai F, Tanaka KA, Donaldson JB, Hilmi IA, Wallis Marsh J, Planinsic RM, Humar A: Pulmonary thromboembolism during adult liver transplantation: incidence, clinical presentation, outcome, risk factors, and diagnostic predictors. Br J Anaesth 2012; 108: 469-477.
48. Kirchner C, Goerlinger K, Dirkmann D, Schumann R, Treckmann J, Paul A, Saner FH: Safety and efficacy of prothrombin complex and fibrinogen concentrates in liver transplantation. Liver Transplant 2012; 18:S189.
49. Levy JH, Fingerhut A, Brott T, Langbakke IH, Erhardtsen E, Porte RJ: Recombinant factor VIIa in patients with coagulopathy secondary to anticoagulant therapy, cirrhosis, or severe traumatic injury: review of safety profile. Transfusion 2006; 46: 919-933. (Pubitemid 43800910)
50. Lodge JP, Jonas S, Jones RM, Olausson M, Mir-Pallardo J, Soefelt S, Garcia-Valdecasas JC, McAlister V, Mirza DF: Efficacy and safety of repeated perioperative doses of recombinant factor VIIa in liver transplantation. Liver Transpl 2005; 11: 973-979. (Pubitemid 41122456)
51. Planinsic RM, van der Meer J, Testa G, Grande L, Candela A, Porte RJ, Ghobrial RM, Isoniemi H, Schelde PB, Erhardtsen E, Klintmalm G, Emre S: Safety and efficacy of a single bolus administration of recombinant factor VIIa in liver transplantation due to chronic liver disease. Liver Transpl 2005; 11: 895-900. (Pubitemid 41122446)
52. Porte RJ, Knot EA, Bontempo FA: Hemostasis in liver transplantation. Gastroenterology 1989; 97: 488-501. (Pubitemid 19192190)
53. Findlay JY, Rettke SR, Ereth MH, Plevak DJ, Krom RA, Kufner RP: Aprotinin reduces red blood cell transfusion in orthotopic liver transplantation: a prospective, randomized, double-blind study. Liver Transpl 2001; 7: 802-807. (Pubitemid 32851302)
54. Molenaar IQ, Warnaar N, Groen H, Tenvergert EM, Slooff MJ, Porte RJ: Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review and metaanalysis. Am J Transplant 2007; 7: 185-194. (Pubitemid 44952872)
55. Ramsay MA: Con: Antifibrinolytics are not safe and effective in patients undergoing liver transplantation. J Cardiothorac Vasc Anesth 2006; 20: 891-893. (Pubitemid 44809985)
56. Mangano DT, Rieves RD, Weiss KD: Judging the safety of aprotinin. N Engl J Med 2006; 355: 2261-2262.
57. Mangano DT, Tudor IC, Dietzel C: The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353-365. (Pubitemid 43145060)
58. Warnaar N, Mallett SV, de Boer MT, Rolando N, Burroughs AK, Nijsten MW, Slooff MJ, Rolles K, Porte RJ: The impact of aprotinin on renal function after liver transplantation: an analysis of 1,043 patients. Am J Transplant 2007; 7: 2378-2387. (Pubitemid 47347862)
59. European Medicines Agency recommends lifting suspension of aprotinin. 2012.
60. Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, Teoh K, Duke PC, Arellano R, Blajchman MA, Bussieres JS, Cote D, Karski J, Martineau R, Robblee JA, Rodger M, Wells G, Clinch J, Pretorius R: A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358: 2319-2331. (Pubitemid 351749156)
61. Porte RJ, Leebeek FW: Pharmacological strategies to decrease transfusion requirements in patients undergoing surgery. Drugs 2002; 62: 2193-2211. (Pubitemid 35252830)
62. Giovannini I, Chiarla C, Giuliante F, Vellone M, Nuzzo G: Modulation of plasma fibrinogen levels in acute-phase response after hepatectomy. Clin Chem Lab Med 2004; 42: 261-265. (Pubitemid 38477519)
63. Caldwell SH, Sanyal AJ: Coagulation disorders and bleeding in liver disease: future directions. Clin Liver Dis 2009; 13: 155-157.
64. Fenger-Eriksen C, Tonnesen E, Ingerslev J, Sorensen B: Mechanisms of hydroxyethyl starch-induced dilutional coagulopathy. J Thromb Haemost 2009; 7: 1099-1105.
65. Fries D: Dilutional coagulopathy: development, diagnostic options and management (in German). Hamostaseologie 2006; 26:S15-S19.
66. Hiippala ST: Dextran and hydroxyethyl starch interfere with fibrinogen assays. Blood Coagul Fibrinolysis 1995; 6: 743-746. (Pubitemid 26047204)
67. Danes AF, Cuenca LG, Bueno SR, Mendarte Barrenechea L, Ronsano JB: Efficacy and tolerability of human fibrinogen concentrate administration to patients with acquired fibrinogen deficiency and active or in high-risk severe bleeding. Vox Sang 2008; 94: 221-226. (Pubitemid 351379659)
68. Fenger-Eriksen C, Ingerslev J, Sorensen B: Fibrinogen concentrate - a potential universal hemostatic agent. Expert Opin Biol Ther 2009; 9: 1325-1333.
69. Weinkove R, Rangarajan S: Fibrinogen concentrate for acquired hypofibrinogenaemic states. Transfus Med 2008; 18: 151-157. (Pubitemid 351847329)
70. Gorlinger K: Differenzierte Therapie komplexer Gerinnungsstorungen. J Anaesth Intensivbeh 2005; 12: 120-124.
71. Rahe-Meyer N, Solomon C, Winterhalter M, Piepenbrock S, Tanaka K, Haverich A, Pichlmaier M: Thromboelastometry-guided administration of fibrinogen concentrate for the treatment of excessive intraoperative bleeding in thoracoabdominal aortic aneurysm surgery. J Thorac Cardiovasc Surg 2009; 138: 694-702.
72. De Boer MT, Christensen MC, Asmussen M, van der Hilst CS, Hendriks HG, Slooff MJ, Porte RJ: The impact of intraoperative transfusion of platelets and red blood cells on survival after liver transplantation. Anesth Analg 2008; 106: 32-44.
73. Burger R, Offergeld R: Festlegung der Haltbarkeitsfrist von Thrombozytenkonzentraten mit dem Ziel der Reduktion lebensbedrohlicher septischer Transfusionsreaktionen durch bakterielle Kontamination. Bundesgesundheitsblatt Gesundheitsforsch Gesundheitsschutz 2008; 51: 1484.
74. Hsieh L, Nugent D: Factor XIII deficiency. Haemophilia 2008; 14: 1190-1200.
75. Peyvandi F, Palla R, Menegatti M, Mannucci PM: Rare bleeding disorders: general aspects of clinical features, diagnosis, and management. Semin Thromb Hemost 2009; 35: 349-355.
76. Wettstein P, Haeberli A, Stutz M, Rohner M, Corbetta C, Gabi K, Schnider T, Korte W: Decreased factor XIII availability for thrombin and early loss of clot firmness in patients with unexplained intraoperative bleeding. Anesth Analg 2004; 99: 1564-1569. (Pubitemid 39407316)
77. Gerlach R, Tolle F, Raabe A, Zimmermann M, Siegemund A, Seifert V: Increased risk for postoperative hemorrhage after intracranial surgery in patients with decreased factor XIII activity: implications of a prospective study. Stroke 2002; 33: 1618-1623. (Pubitemid 34619968)
78. Tacke F, Fiedler K, von Depka M, Luedde T, Hecker H, Manns MP, Ganser A, Trautwein C: Clinical and prognostic role of plasma coagulation factor XIII activity for bleeding disorders and 6-year survival in patients with chronic liver disease. Liver Int 2006; 26: 173-181.
79. Koliscak L, Maynor L: Pharmacologic prophylaxis against venous thromboembolism in hospitalized patients with cirrhosis and associated coagulopathies. Am J Health Syst Pharm 2012; 69: 658-663.
80. Renne T, Schmaier AH, Nickel KF, Blomback M, Maas C: In vivo roles of factor XII. Blood 2012; 120: 4296-4303.
81. Villa E, Camma C, Marietta M, Luongo M, Critelli R, Colopi S, Tata C, Zecchini R, Gitto S, Petta S, Lei B, Bernabucci V, Vukotic R, De Maria N, Schepis F, Karampatou A, Caporali C, Simoni L, Del Buono M, Zambotto B, Turola E, Fornaciari G, Schianchi S, Ferrari A, Valla D: Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143: 1253-1260, e1251-e1254.
82. Bechmann LP, Sichau M, Wichert M, Gerken G, Kroger K, Hilgard P: Low-molecularweight heparin in patients with advanced cirrhosis. Liver Int 2011; 31: 75-82.
83. Mira JA, Lopez-Cortes LF, Merino D, Arizcorreta-Yarza A, Rivero A, Collado A, Rios-Villegas MJ, Gonzalez-Serrano M, Torres-Tortoso M, Macias J, Valera-Bestard B, Fernandez-Fuertes E, Giron-Gonzalez JA, Lozano F, Pineda JA: Predictors of severe haematological toxicity secondary to pegylated interferon plus ribavirin treatment in HIV-HCV-coinfected patients. Antivir Ther 2007; 12: 1225-1235.
84. McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, Dienstag J, Lee WM, Mak C, Garaud JJ, Albrecht JK: Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology 2002; 123: 1061-1069.
85. Saleh MN, Bussel JB, Cheng G, Meyer O, Bailey CK, Arning M, Brainsky A: Safety and efficacy of eltrombopag for treatment of chronic immune thrombocytopenia: results of the long-term, open-label extend study. Blood 2013; 121: 537-545.
86. Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrere F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL: Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a doubleblind randomised controlled trial. Lancet 2008; 371: 395-403. (Pubitemid 351181334)
87. Heathcote EJ, Shiffman ML, Cooksley WG, Dusheiko GM, Lee SS, Balart L, Reindollar R, Reddy RK, Wright TL, Lin A, Hoffman J, De Pamphilis J: Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000; 343: 1673-1680.
88. McHutchison JG, Dusheiko G, Shiffman ML, Rodriguez-Torres M, Sigal S, Bourliere M, Berg T, Gordon SC, Campbell FM, Theodore D, Blackman N, Jenkins J, Afdhal NH: Eltrombopag for thrombocytopenia in patients with cirrhosis associated with hepatitis C. N Engl J Med 2007; 357: 2227-2236. (Pubitemid 350190753)
89. Tripodi A, Primignani M: Non-transfusional approach to increase platelet count in patients with cirrhosis and thrombocytopenia. Hepatology 2013, E-pub ahead of print.
90. Lier H, Vorweg M, Hanke A, Gorlinger K: Thromboelastometry guided therapy of severe bleeding. Essener Runde algorithm. Hamostaseologie 2013; 33: 51-61.