Hamostaseologie 2006; 26(S 02): S76-S86
DOI: 10.1055/s-0037-1617085
Original Article
Schattauer GmbH

Bleeding after cardiac surgery

The role of recombinant factor VIIa
C. von Heymann
1   Department of Anaesthestics and Surgical Intensive Care, Charité – University Hospital Berlin, Campus Charité Mitte and Campus Virchow Klinikum
,
C. Spies
1   Department of Anaesthestics and Surgical Intensive Care, Charité – University Hospital Berlin, Campus Charité Mitte and Campus Virchow Klinikum
,
H. Grubitzsch
2   Department of Cardiovascular Surgery, Campus Charité Mitte, Germany
,
H. Schönfeld
1   Department of Anaesthestics and Surgical Intensive Care, Charité – University Hospital Berlin, Campus Charité Mitte and Campus Virchow Klinikum
,
M. Sander
1   Department of Anaesthestics and Surgical Intensive Care, Charité – University Hospital Berlin, Campus Charité Mitte and Campus Virchow Klinikum
,
Th. Volk
1   Department of Anaesthestics and Surgical Intensive Care, Charité – University Hospital Berlin, Campus Charité Mitte and Campus Virchow Klinikum
› Author Affiliations
Further Information

Publication History

Publication Date:
23 December 2017 (online)

Summary

Cardiac surgery carries the risk of significant blood loss requiring the transfusion of blood products. In addition to such blood loss, international studies have shown that severe bleeding necessitating re-operation occurs in 3–5% of patients. Morbidity and mortality are significantly increased, so effective and safe haemostatic measures will decisively improve outcome of patients.

Recombinant activated factor VII (rFVIIa) has been approved for the treatment of patients with inhibitor haemophilia, as well as with Glanzmann’s thrombasthenia and factor VII deficiency. Many publications have appeared in the last few years which report the successful and reliable use of rFVIIa for the treatment of refractory bleeding after cardiac surgery. This review presents the pathophysiological changes in the coagulation system which occur when a heart-lung machine is used and which have been blamed for an increased risk of bleeding in patients who have undergone cardiac surgery. Published experience with rFVIIa in paediatric and adult cardiac surgery is presented and discussed critically with regard to the efficacy and safety of its use.

 
  • References

  • 1 Al Douri M, Shafi T, Al Khudairi D. et al. Effect of the administration of recombinant activated factor VII (rFVIIa; NovoSeven) in the management of severe uncontrolled bleeding in patients undergoing heart valve replacement surgery. Blood Coag Fibrinol 2000; 11 (Suppl. 01) 121-127.
  • 2 Aldea GS, Soltow LO, Chandler WL. et al. Limitation of thrombin generation, platelet activation, and inflammation by elimination of cardiotomy suction in patients undergoing coronary artery bypass grafting treated with heparin-bonded circuits. J Thorac Cardiovasc Surg 2002; 123: 742-755.
  • 3 Antiplatelet Trialists’ Collaboration.. Collaborative overview of randomised trials of antiplatelet therapy. I. Prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 1994; 308: 81-106.
  • 4 Antithrombotic Trialist’s Collaboration.. Collaborative metaanalysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. Br Med J 2002; 324: 71-86.
  • 5 Antovic JP, Antovic A. Does recombinant factor VIIa, apart from overall hemostasis, regulate TAFI dependent fibrinolysis? In vitro analysis using overall hemostasis potential (OHP) assay. Thromb Haemost 2003; 90: 620-627.
  • 6 Asimakopoulos G, Thompson R, Nourshargh S. et al. An anti-inflammatory property of aprotinin detected at level of leukocyte extravasation. J Thorac Cardiovasc Surg 2000; 120: 361-369.
  • 7 Brastad RM, Stephens RW, Hamers MJ. et al. Protamine sulphate inhibits platelet membrane glycoprotein Ib-von Willebrand factor activity. Thromb Haemost 2000; 83: 334-337.
  • 8 Birdi I, Regragui I, Izzat MB. et al. Influence of normothermic systemic perfusion during coronary artery bypass operations: a randomized prospective study. J Thorac Cardiovasc Surg 1997; 114: 475-481.
  • 9 Bizzarri F, Scolletta S, Tucci E. et al. Perioperative use of tirofiban hydrochloride (Aggrastat) does not increase surgical bleeding after emergency or urgent coronary artery bypass grafting. J Thorac Cardiovasc Surg 2001; 122: 1181-1185.
  • 10 Boisclair MD, Lane DA, Philippou H. et al. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993; 82: 3350-3357.
  • 11 Boldt J, Knothe C, Welters I. et al. Normothermic versus hypothermic cardiopulmonary bypass: do changes in coagulation differ?. Ann Thorac Surg 1996; 62: 130-135.
  • 12 Bruckenberger E. Herzbericht 2004 mit Transplantationschirurgie, Eigenverlag. ISBN 3–00–017046-4.
  • 13 Bull MH, Huse WM, Bull BS. Evaluation of tests used to monitor heparin therapy during extracorporeal circulation. Anesthesiology 1975; 43: 346-353.
  • 14 Butterworth J, Lin YA, Prielipp RC. et al. Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass. Ann Thorac Surg 2002; 74: 1589-1595.
  • 15 Campbell DJ, Dixon B, Kladis A. et al. Activation of the kallikrein-kinin system by cardiopulmonary bypass in humans. Am J Physiol Regul Integr Comp Physiol 2001; 281: R1059-R1070.
  • 16 Carless PA, Moxey AJ, Stokes BJ. et al. Are antifibrinolytic drugs equivalent in reducing blood loss and transfusion in cardiac surgery? A meta-analysis of randomized head-to-head trials. BMC Cardiovasc Disord 2005; 5: 19.
  • 17 Charalambous CP, Zipitis CS, Keenan DJ. Chest reexploration in the intensive care unit after cardiac surgery: a safe alternative to returning to the operating theater. Ann Thorac Surg 2006; 8: 191-194.
  • 18 Chung A, Wildhirt SM, Wang S. et al. Combined administration of nitric oxide gas and iloprost during cardiopulmonary bypass reduces platelet dysfunction: a pilot clinical study. J Thorac Cardiovasc Surg 2005; 129: 782-790.
  • 19 Cicala C, Cirino G. Linkage between inflammation and coagulation: an update on the molecular basis of the crosstalk. Life Sci 1998; 62: 1817-1824.
  • 20 Dacey LJ, Munoz JJ, Baribeau YR. et al. Reexploration for hemorrhage following coronary artery bypass grafting: incidence and risk factors. Northern New England Cardiovascular Disease Study Group. Arch Surg 1998; 133: 442-447.
  • 21 Davidson SJ, Burman JF, Rutherford LC. et al. High molecular weight kininogen deficiency: a patient who underwent cardiac surgery. Thromb Haemost 2001; 85: 195-197.
  • 22 De Haan J, Boonstra PW, Monnink SH. et al. Retransfusion of suctioned blood during cardiopulmonary bypass impairs hemostasis. Ann Thorac Surg 1995; 59: 901-907.
  • 23 Despotis GJ, Joist JH, Hogue Jr CW. et al. The impact of heparin concentration and activated clotting time monitoring on blood conservation. A prospective, randomized evaluation in patients undergoing cardiac operation. J Thorac Cardiovasc Surg 1995; 110: 46-54.
  • 24 Dietrich W. Cardiac surgery and the coagulation system. Curr OpinAnaesthesiol 2000; 13: 27-34.
  • 25 Diprose P, Herbertson MJ, O’Shaughnessy D. et al. Reducing allogeneic transfusion in cardiac surgery: a randomized double-blind placebo-controlled trial of antifibrinolytic therapies used in addition to intra-operative cell salvage. Br J Anaesth 2005; 94: 271-278.
  • 26 Diprose P, Herbertson MJ, O’Shaughnessy D. et al. Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study. Br J Anaesth 2005; 95: 596-602.
  • 27 Ekert H, Brizard C, Eyers R, Cochrane A. et al. Elective administration of low dose recombinant activated factor VII (rFVIIa) in cardiopulmonary bypasssurgery for congenital heart disease does not shorten time to chest closure or reduce blood loss or need for transfusions:a randomized, double-blind, parallel group, plcebo controlled studyof rFVIIa and standardhaemostatic replacement therapy versus standard haemostatic therapy. Blood Coagul Fibrinol 2006; 17: 389-395.
  • 28 Egan JR, Lammi A, Schell DN. et al. Recombinant activated factor VII in paediatric cardiac surgery. Intensive Care Med 2004; 30: 682-685.
  • 29 Engoren MC, Habib RH, Zacharias A. et al. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg 2002; 74: 1180-1186.
  • 30 Gallistl S, Cvirn G, Muntean W. Recombinant factor VIIa does not induce hypercoagulability in vitro. Thromb Haemost 1999; 81: 245-249.
  • 31 Gori AM, Pepe G, Attanasio M. et al. Tissue factor reduction and tissue factor pathway inhibitor release after heparin administration. Thromb Haemost 1999; 81: 589-593.
  • 32 Gram J, Janetzko T, Jespersen J. et al. Enhanced effective fibrinolysis following the neutralization of heparin in open heart surgery increases the risk of post-surgical bleeding. Thromb Haemost 1990; 63: 241-245.
  • 33 Gravlee GP, Haddon S, Rothberger HK. et al. Heparin dosing and monitoring for cardiopulmonary bypass. A comparison of techniques with measurement of subclinical plasma coagulation. J Thorac Cardiovasc Surg 1990; 99: 518-527.
  • 34 Hattori T, Khan MM, Colman RW. et al. Plasma tissue factor plus activated peripheral mononuclear cells activate factors VII and X in cardiac surgical wounds. J Am Coll Cardiol 2005; 46: 707-713.
  • 35 Hedner S, Glazer S, Mingel K. et al. Successful use of recombinant factor VIIa in patient with severe haemophilia A during synovectomy. Lancet 1988; 2: 1193.
  • 36 Hoffman M, Monroe DM. A cell based model of hemostasis. Thromb Haemost 2001; 88: 958-965.
  • 37 Hongo RH, Ley J, Dick SE. et al. The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002; 40: 231-237.
  • 38 Hunt BJ, Parratt RN, Segal HC. et al. Activation of coagulation and fibrinolysis during cardiothoracic operations. Ann Thorac Surg 1998; 65: 712-718.
  • 39 Jones HU, Muhlestein JB, Jones KW. et al. Preoperative use of enoxaparin compared with unfractionated heparin increases the incidence of reexploration for postoperative bleeding after openheart surgery in patients who present with an acute coronary syndrome: clinical investigation and reports. Circulation 2002; 106: I19-22.
  • 40 Karkouti K, Beattie WS, Wijeysundera DN. et al. Recombinant factor VIIa for intractable blood loss after cardiac surgery: a propensity score-matched case-control analysis. Transfusion 2005; 45: 26-34.
  • 41 Karkouti K, Wijeysundera DN, Yau TM. et al. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion 2004; 44: 1453-1462.
  • 42 Karthik S, Grayson AD, McCarron EE. et al. Reexploration for bleeding after coronary artery bypass surgery: risk factors, outcomes, and the effect of time delay. Ann Thorac Surg 2004; 78: 527-534.
  • 43 Khuri SF, Valeri CR, Loscalzo J. et al. Heparin causes platelet dysfunction and induces fibrinolysis before cardiopulmonary bypass. Ann Thorac Surg 1995; 60: 1008-1014.
  • 44 Kojima T, Gando S, Kenmotsu O. et al. Another point of view on the mechanism of thrombin generation during cardiopulmonary bypass: role of tissue factor pathway inhibitor. J Cardiothorac Vasc Anesth 2001; 15: 60-64.
  • 45 Koster A, Chew DP, Kübler W. et al. Effects of tirofiban on hemostatic activation and inflammatory response during cardiopulmonary bypass. Am J Cardiol 2003; 91: 346-347.
  • 46 Koster A, Fischer T, Praus M. et al. Hemostatic activation and inflammatory response during cardiopulmonary bypass: impact of heparin management. Anesthesiology 2002; 97: 837-841.
  • 47 Koster A, Hübler S, Merkle F. et al. Heparin-levelbased anticoagulation management during cardiopulmonary bypass: a pilot investigation on the effects of a half-dose aprotinin protocol on postoperative blood loss and hemostatic activation and inflammatory response. Anesth Analg 2004; 98: 285-290.
  • 48 Kuitunen A, Hiippala S, Vahtera E. et al. The effects of aprotinin and tranexamic acid on thrombin generation and fibrinolytic response after cardiac surgery. Acta Anaesthesiol Scand 2005; 49: 1272-1279.
  • 49 Laga S, Bollen H, Arnout J. et al. Heparin influences human platelet behavior in cardiac surgery with or without cardiopulmonary bypass. Artif Organs 2005; 29: 541-546.
  • 50 Leibovitch L, Kenet G, Mazor K. et al. recombinant activated factor VII for life-threatening pulmonary hemorrhage after pediatric cardiac surgery. Pediatr Crit Care Med 2003; 4: 444-446.
  • 51 Leitlinien zur Therapie mit Blutkomponenten und Plasmaderivaten 3.. Aufl. Wissenschaftlicher Beirat der Bundesärztekammer, Köln: Deutscher Ärzte-Verlag; 2003
  • 52 Levi M, Cromheecke ME, de Jonge E. et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999; 354: 1940-1947.
  • 53 Levy JH, Pifarre R, Schaff HV. et al. A multicenter, double-blind trial, placebo-controlled trial of aprotinin for reducing blood loss and the requirements for donor-blood transfusion in patients undergoing repeat coronary artery bypass grafting. Circulation 1995; 92: 2236-2244.
  • 54 Lindblad B, Wakefield TW, Whitehouse Jr WM. et al. The effect of protamine sulfate on platelet function. Scand J Thorac Cardiovasc Surg 1988; 22: 55-59.
  • 55 Lindblad B. Protamine sulphate: a review of its effects: hypersensitivity and toxicity. Eur J Vasc Surg 1989; 3: 195-201.
  • 56 Lo B, Fijnheer R, Nierich AP. et al. Activation of hemostasis is associated with early cognitive decline after off-pump coronary artery bypass surgery. J Thromb Haemost 2005; 3: 2114-2117.
  • 57 Mangano DT, Tudor IC, Dietzel C. Multicenter Study of Perioperative Ischemia Research group; Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353-365.
  • 58 Mangano DT. Multicenter Study of Perioperative Ischemia Research Group. Aspirin and mortality from coronary bypass surgery. N Engl J Med 2002; 347: 1309-17.
  • 59 Mazer CD, Hornstein A, Freedman J. Platelet activation in warm and cold heart surgery. Ann Thorac Surg 1995; 59: 1481-1486.
  • 60 McDonald SB, Renna M, Spitznagel EL. et al. Preoperative use of enoxaparin increases the risk of postoperative bleeding and re-exploration in cardiac surgery patients. J Cardiothorac Vasc Anesth 2005; 19: 4-10.
  • 61 Michelson AD, MacGregor H, Barnard MR. et al. Reversible inhibition of human platelet activation by hypothermia in vivo and in vitro. Thromb Haemost 1994; 71: 633-640.
  • 62 Morgan EN, Pohlman TH, Vocelka C. et al. Nuclear factor kappaB mediates a procoagulant response in monocytes during extracorporeal circulation. J Thorac Cardiovasc Surg 2003; 125: 165-171.
  • 63 Moulton MJ, Creswell LL, Mackey ME. et al. Reexploration for bleeding is a risk factor for adverse outcomes after cardiac operations. J Thorac Cardiovasc Surg 1996; 111: 1037-1046.
  • 64 Muriithi EW, Belcher PR, Day SP. et al. Heparininduced platelet dysfunction and cardiopulmonary bypass. Ann Thorac Surg 2000; 69: 1827-1832.
  • 65 Muriithi EW, Belcher PR, Rao JN. et al. The effects of heparin and extracorporeal circulation on platelet counts and platelet microaggregation during cardiopulmonary bypass. J Thorac Cardiovasc Surg 2000; 120: 538-543.
  • 66 Murkin JM, Lux J, Shannon RA. et al. Aprotinin significantly decreases bleeding and transfusion requirements in patients receiving aspirin and undergoing cardiac operations. J Thorac Cardiovasc Surg 1994; 107: 554-561.
  • 67 O’Connell KA, Wood JJ, Wise RP. et al. Thromboembolic adverse events after use of recombinant human coagulation factor VIIa. JAMA 2006; 295: 293-298.
  • 68 Paparella D, Brister SJ, Buchanan MR. Coagulation disorders of cardiopulmonary bypass: a review. Intensive Care Med 2004; 30: 1873-1881.
  • 69 Paparella D, Yau TM, Young E. Cardiopulmonary bypass induced inflammation: pathophysiology and treatment. An update. Eur J Cardiothorac Surg 2002; 21: 232-244.
  • 70 Poullis M, Manning R, Laffan M. et al. The antithrombotic effect of aprotinin actions mediated via the protease activated receptor 1. J Thorac Cardiovasc Surg 2000; 120: 370-378.
  • 71 Pychynska-Pokorska M, Moll JJ, Krajewski W. et al. The use of recombinant coagulation factor VIIa in uncontrolled postoperative bleeding in children undergoing cardiac surgery with cardiopulmonary bypass. Pediatr Crit Care Med 2004; 5: 246-250.
  • 72 Raivio P, Suojaranta-Ylinen R, Kuitunen AH. Recombinant factor VIIa in the treatment of postoperative hemorrhage after cardiac surgery. Ann Thorac Surg 2005; 80: 66-71.
  • 73 Royston D, Bidstrup BP, Taylor KM. et al. Effect of aprotinin on need for blood transfusion after repeat open heart surgery. Lancet 1987; 2: 1289-1291.
  • 74 Saw J, Topol EJ, Steinhubl SR. et al. CREDO Investigators. Comparison of long-term usefulness of clopidogrel therapy after the first percutaneous coronary intervention or coronary artery bypass grafting versus that after the second or repeat intervention. Am J Cardiol 2004; 94: 623-625.
  • 75 Sedrakyan A, Treasure T, Eletheriades JA. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004; 128: 442-448.
  • 76 Shander A, Moskowitz D, Rijhwani TS. The safety and efficacy of bloodless“ cardiac surgery. Semin Cardiothorac VascAnesth 2005; 9: 53-63.
  • 77 Shuhaibar MN, Hargrove M, Millat MH. et al. How much heparin do we really need to go on pump? A rethink of current practices. Eur J Cardiothorac Surg 2004; 26: 947-950.
  • 78 Siegel LJ, Gerigk L, Tüttenberg J. et al. Cerebral Sinus Thrombosis in a Trauma Patient after recombinant Activated Factor VII Infusion. Anesthesiology 2004; 100: 441-443.
  • 79 Taggart DP, Djapardy V, Naik M. et al. A randomized trial of aprotinin (Trasylol) on blood loss, blood product requirement, and myocardial injury in total arterial grafting. J Thorac Cardiovasc Surg 2003; 126: 1087-1094.
  • 80 Teoh KH, Young E, Blackall MH. et al. Can extra protamine eliminate heparin rebound following cardiopulmonary bypass surgery?. J Thorac Cardiovasc Surg 2004; 128: 211-219.
  • 81 Teoh KH, Young E, Bradley CA. et al. Heparin binding proteins. Contribution to heparin rebound after cardiopulmonary bypass. Circulation 1993; 88: II420-425.
  • 82 Teufelsbaer H, Proidl S, Havel M. et al. Early activation of hemostasis during cardiopulmonary bypass: evidence for thrombin mediated hyperfibrinolysis. Thromb Haemost 1992; 68: 250-252.
  • 83 Tobias JD, Simsic JM, Weinstein S. et al. Recombinant factor VIIa to control excessive bleeding following surgery for congenital heart disease in pediatric patients. J Intensive Care Med 2004; 19: 270-273.
  • 84 Tofil NM, Winkler MK, Watts RG. et al. The use of recombinant factor VIIa in a patient with Noonan syndrome and life threatening bleeding. Pediatr Crit Care Med 2005; 6: 352-354.
  • 85 Tokunaga C, Hiramatsu Y, Horigome H. et al. Palliative openheart surgery in an infant with factor VII deficiency. Ann Thorac Surg 2003; 76: 2093-2094.
  • 86 Tuman KJ, McCarthy RJ, O’Connor CJ. et al. Aspirin does not increase allogeneic blood transfusion in reoperative coronary artery surgery. Anesth Analg 1996; 83: 1178-1184.
  • 87 Unsworth-White MJ, Herriot A, Valencia O. et al. Resternotomy for bleeding after cardiac operation: a marker for increased morbidity and mortality. Ann Thorac Surg 1995; 59: 664-667.
  • 88 Valen G, Eriksson E, Risberg B. et al. Fibrinolysis during cardiac surgery. Release of tissue plasminogen activator in arterial and coronary sinus blood. Eur J Cardiothorac Surg 1994; 8: 324-330.
  • 89 Verrier ED, Morgan EN. Endothelial response to cardiopulmonary bypass surgery. Ann Thorac Surg 1998; 66: S17-S19.
  • 90 Von Heymann C, Redlich U, Jain U. et al. Recombinant activated factor VII for refractory bleeding after cardiac surgery--a retrospective analysis of safety and efficacy. Crit Care Med 2005; 33: 2241-2246.
  • 91 Von Heymann C, Redlich U, Moritz M. et al. Aspirin and clopidogrel taken until 2 days prior to coronary artery bypass graft surgery is associated with increased postoperative drainage loss. Thorac Cardiovasc Surg 2005; 53: 341-345.
  • 92 Wahba A, Rothe G, Lodes H. et al. The influence of the duration of cardiopulmonary bypass on coagulation, fibrinolysis and platelet function. Thorac Cardiovasc Surg 2001; 49: 153-156.
  • 93 Wittenstein B, Ng C, Ravn H. et al. Recombi- -nant factor VII for severe bleeding during extracorporeal membrane oxygenation following open heart surgery. Pediatr Crit Care Med 2005; 6: 473-476.
  • 94 Yende S, Wunderink RG. Effect of clopidogrel on bleeding after coronary artery bypass surgery. Crit Care Med 2001; 29: 2271-2275.
  • 95 Yilmaz BT, Alioglu B, Ozyurek E. et al. Successful use of recombinant factor VIIa (NovoSeven) during cardiac surgery in a pediatric patient with Glanzmann thrombasthenia. Pediatr Cardiol 2005; 26: 843-845.
  • 96 Yusuf S, Zhao F, Mehta SR. et al. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494-502.
  • 97 Zilla P, Fasol R, Groscurth P. et al. Blood platelets in cardiopulmonary bypass operations. Recovery occurs after initial stimulation, rather than continual activation. J Thorac Cardiovasc Surg 1989; 97: 379-388.