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High mortality associated with intracardiac and intrapulmonary thromboses after cardiopulmonary bypass

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Abstract

Purpose

Intrapulmonary or intracardiac thrombosis is a rare but catastrophic event following complex cardiothoracic surgery. Although there have been multiple cases reported in the literature, the causes of these events are largely unknown. In this retrospective review, we attempt to identify risk factors and propose possible mechanisms of thromboses after cardiopulmonary bypass (CPB).

Methods

A literature search was conducted using the MEDLINE and EMBASE with these keywords: (intra)pulmonary thrombosis, pulmonary embolism, pulmonary infarction, lung embolism, (intra)cardiac thrombosis, cardiac thrombi, in combination with CPB, extracorporeal membrane oxygenation, deep hypothermic circulatory arrest, or cardiac surgery. Putative risk factors were compiled from reported cases.

Results

We identified 34 cases of massive intrapulmonary and/or intracardiac thromboses. All but 2 cases (94.1%) were fatal. Clinical presentations were systemic hypotension and/or pulmonary hypertension, right ventricular failure, and cardiogenic shock in 32 (94.1%) cases. The timing was immediate (<10 min) following hemostatic intervention in 16 cases (47.1%), within 45 min in 8 cases (23.5%), and not reported in the rest. Putative risk factors included antifibrinolytic use (88.2%), congestive heart failure (55.9%), prolonged CPB use (>2 h) (41.1%), and low activated clotting time (<400 s) after initial heparinization (20.6%). The administration of tissue plasminogen activator in 5 cases was ineffective.

Conclusions

Massive thrombosis following cardiac surgery is a highly lethal event with limited treatment options. Particular attention should be paid to the status of thrombin regulatory proteins before protamine and other hemostatic interventions in patients undergoing complex cardiac surgery with antifibrinolytic agents.

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References

  1. Rauch U, Osende JI, Fuster V, Badimon JJ, Fayad Z, Chesebro JH. Thrombus formation on atherosclerotic plaques: pathogenesis and clinical consequences. Ann Intern Med. 2001;134:224–38.

    Article  CAS  PubMed  Google Scholar 

  2. Despotis GJ, Gravlee G, Filos K, Levy J. Anticoagulation monitoring during cardiac surgery: a review of current and emerging techniques. Anesthesiology. 1999;91:1122–51.

    Article  CAS  PubMed  Google Scholar 

  3. Blome M, Isgro F, Kiessling AH, Skuras J, Haubelt H, Hellstern P, Saggau W. Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery. Thromb Haemost. 2005;93:1101–7.

    CAS  PubMed  Google Scholar 

  4. Ide M, Bolliger D, Taketomi T, Tanaka KA. Lessons from the aprotinin saga: current perspective on antifibrinolytic therapy in cardiac surgery. J Anesth. 2010;24:96–106.

    Article  PubMed  Google Scholar 

  5. Green JA, Spiess BD. Current status of antifibrinolytics in cardiopulmonary bypass and elective deep hypothermic circulatory arrest. Anesthesiol Clin N Am. 2003;21:527–51.

    Article  CAS  Google Scholar 

  6. Nuttall GA, Oliver WC, Santrach PJ, Bryant S, Dearani JA, Schaff HV, Ereth MH. Efficacy of a simple intraoperative transfusion algorithm for nonerythrocyte component utilization after cardiopulmonary bypass. Anesthesiology. 2001;94:773–81.

    Article  CAS  PubMed  Google Scholar 

  7. Sniecinski RM, Chen EP, Levy JH, Szlam F, Tanaka KA. Coagulopathy after cardiopulmonary bypass in Jehovah’s Witness patients: management of two cases using fractionated components and factor VIIa. Anesth Analg. 2007;104:763–5.

    Article  PubMed  Google Scholar 

  8. Kohler M, Hellstern P, Lechler E, Uberfuhr P, Muller-Berghaus G. Thromboembolic complications associated with the use of prothrombin complex and factor IX concentrates. Thromb Haemost. 1998;80:399–402.

    CAS  PubMed  Google Scholar 

  9. Heindl B, Delorenzo C, Spannagl M. High dose fibrinogen administration for acute therapy of coagulopathy during massive perioperative transfusion. Anaesthesist. 2005;54:787–90.

    Article  CAS  PubMed  Google Scholar 

  10. Warnaar N, Molenaar IQ, Colquhoun SD, Slooff MJH, Sherwani S, de Wolf AM, Porte RJ. Intraoperative pulmonary embolism and intracardiac thrombosis complicating liver transplantation: a systematic review. J Thromb Haemost. 2008;6:297–302.

    Article  CAS  PubMed  Google Scholar 

  11. Augoustides JG. Fatal intraoperative thrombosis in contemporary adult thoracic aortic surgery requiring deep hypothermic circulatory arrest: observations from the literature, 1993–2006. J Thorac Cardiovasc Surg. 2007;134:1069–70.

    Article  PubMed  Google Scholar 

  12. Augoustides JG. Fatal thrombosis in complex cardiac surgery without deep hypothermic circulatory arrest in the setting of standard-of-care heparinization: status quo and directions for further research. J Thorac Cardiovasc Surg. 2007;134:1053–4.

    Article  PubMed  Google Scholar 

  13. Levi M, Levy JH, Andersen HF, Truloff D. Safety of recombinant activated factor VII in randomized clinical trials. N Engl J Med. 2010;363:1791–800.

    Article  CAS  PubMed  Google Scholar 

  14. Umbrain V, Christiaens F, Camu F. Intraoperative coronary thrombosis: can aprotinin and protamine be incriminated? J Cardiothorac Vasc Anesth. 1994;8:198–201.

    Article  CAS  PubMed  Google Scholar 

  15. Alderman EL, Levy JH, Rich JB, Nili M, Vidne B, Schaff H, Uretzky G, Pettersson G, Thiis JJ, Hantler CB, Chaitman B, Nadel A. Analyses of coronary graft patency after aprotinin use: results from the International Multicenter Aprotinin Graft Patency Experience (IMAGE) trial. J Thorac Cardiovasc Surg. 1998;116:716–30.

    Article  CAS  PubMed  Google Scholar 

  16. Chun R, Poon M-C, Haigh J, Seal D, Donahue B, Royston D. Case 1–2005: cardiac surgery in congenital afibrinogenemia with thrombo-occlusive disease. J Cardiothorac Vasc Anesth. 2005;19:109–17.

    Article  PubMed  Google Scholar 

  17. Sundt TM 3rd, Kouchoukos NT, Saffitz JE, Murphy SF, Wareing TH, Stahl DJ. Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg. 1993;55:1418–24.

    Article  PubMed  Google Scholar 

  18. Saffitz JE, Stahl DJ, Sundt TM, Wareing TH, Kouchoukos NT. Disseminated intravascular coagulation after administration of aprotinin in combination with deep hypothermic circulatory arrest. Am J Cardiol. 1993;72:1080–2.

    Article  CAS  PubMed  Google Scholar 

  19. Bui JD, Despotis GD, Trulock EP, Alexander Patterson G, Goodnough LT. Fatal thrombosis after administration of activated prothrombin complex concentrates in a patient supported by extracorporeal membrane oxygenation who had received activated recombinant factor VII. J Thorac Cardiovasc Surg. 2002;124:852–4.

    Article  PubMed  Google Scholar 

  20. Swaminathan M, Shaw AD, Greenfield RA, Grichnik KP. Fatal thrombosis after factor seven administration during extracorporeal membrane oxygenation. J Cardiothorac Vasc Anesth. 2008;22:259–60.

    Article  PubMed  Google Scholar 

  21. Lukauskis K, Banks D. Factor IX complex: help or harm? (abstract). In: 33rd Annual Meeting of Society of Cardiovascular Anesthesiologists in Savannah, GA, USA. 2011.

  22. Apostolidou I, Sweeney MF, Missov E, Joyce LD, John R, Prielipp RC. Acute left atrial thrombus after recombinant factor VIIa administration during left ventricular assist device implantation in a patient with heparin-induced thrombocytopenia. Anesth Analg. 2008;106:404–8.

    Article  CAS  PubMed  Google Scholar 

  23. Lichtman AD, Carullo V, Minhaj M, Karkouti K. Case 6–2007: massive intraoperative thrombosis and death after recombinant activated factor VII administration. J Cardiothorac Vasc Anesth. 2007;21:897–902.

    Article  PubMed  Google Scholar 

  24. Gitter R, Alivizators P, Capehart J, Ramsay M, Jett GK. Aprotinin and aortic cannula thrombosis. J Thorac Cardiovasc Surg. 1996;112:537–8.

    Article  CAS  PubMed  Google Scholar 

  25. Alvarez JM, Goldstein J, Mezzatesta J, Flanagan B, Dodd M. Fatal intraoperative pulmonary thrombosis after graft replacement of an aneurysm of the arch and descending aorta in association with deep hypothermic circulatory arrest and aprotinin therapy. J Thorac Cardiovasc Surg. 1998;115:723–4.

    Article  CAS  PubMed  Google Scholar 

  26. Heindel SW, Mill MR, Freid EB, Valley RD, White GC, Norfleet EA. Fatal thrombosis associated with a hemi-Fontan procedure, heparin–protamine reversal, and aprotinin. Anesthesiology. 2001;94:369–71.

    Article  CAS  PubMed  Google Scholar 

  27. Fanashawe MP, Shore-Lesserson L, Reich DL. Two cases of fatal thrombosis after aminocaproic acid therapy and deep hypothermic circulatory arrest. Anesthesiology. 2001;95:1525–7.

    Article  CAS  PubMed  Google Scholar 

  28. Ramsey MAE, Marcel RJ, Capehart J, Cheung EH, Ring WS. Massive intravascular thrombosis and thromboembolism after cardiopulmonary bypass. Internet J Thorac Cardiovasc Surg. 2003;5. http://www.ispub.com.

  29. Lagare JF, Arora R, Wood JW. Massive intracavitary clot formation during cardiopulmonary bypass. Can J Cardiol. 2004;20:825–6.

    Google Scholar 

  30. Augoustides JGT, Lin J, Gambone AJ, Cheung AT. Fatal thrombosis in an adult after thoracoabdominal aneurysm repair with aprotinin and deep hypothermic circulatory arrest. Anesthesiology. 2005;103:215–6.

    Article  PubMed  Google Scholar 

  31. Augoustides JG, Kilbaugh T, Harris H, Glick JH, Acker M, Savino JS. Fatal thrombosis after mitral valve replacement for endocarditis: aprotinin and disseminated intravascular coagulation. Anesthesiology. 2006;104:213.

    Article  PubMed  Google Scholar 

  32. Shore-Lesserson L, Reich DL. A case of severe diffuse venous thromboembolism associated with aprotinin and hypothermic circulatory arrest in a cardiac surgical patient with factor V Leiden. Anesthesiology. 2006;105:219–21.

    Article  PubMed  Google Scholar 

  33. Kottenberg-Assenmacher E, Volbracht L, Jakob H, Greinacher A, Peters J. Disseminated intravascular clotting associated with Fc-receptor IIa-mediated platelet activation in a patient with endocarditis after aortic valve replacement. Br J Anaesth. 2006;97:630–3.

    Article  CAS  PubMed  Google Scholar 

  34. Schmitz A, Hartmann M. Acute intracardiac thrombus formation during thoracoabdominal aortic surgery. Anesth Analg. 2006;102:1658–9.

    Article  PubMed  Google Scholar 

  35. Neira VM, Sawchuk C, Bonneville KS, Chu V, Warkentin TE. Case report: management of immediate post-cardiopulmonary bypass massive intra-cardiac thrombosis. Can J Anaesth. 2007;54:461–6.

    Article  PubMed  Google Scholar 

  36. Trigo P, Stone M, Fisher G. A patient presenting for concurrent thoracoabdominal aortic aneurysm repair and left ventricular assist device placement (abstract). In: 33rd Annual Meeting of Society of Cardiovascular Anesthesiologists in Savannah, GA, USA. 2011.

  37. Stone ME, Silverman SH, Nomoto K. Intracardiac thrombosis and acute right ventricular failure following complex reoperative cardiac surgery with aprotinin and deep hypothermic circulatory arrest. Semin Cardiothorac Vasc Anesth. 2007;11:177–84.

    Article  PubMed  Google Scholar 

  38. Cooper JR Jr, Abrams J, Frazier OH, Radovancevic R, Radovancevic B, Bracey AW, Kindo MJ, Gregoric ID. Fatal pulmonary microthrombi during surgical therapy for end-stage heart failure: possible association with antifibrinolytic therapy. J Thorac Cardiovasc Surg. 2006;131:963–8.

    Article  CAS  PubMed  Google Scholar 

  39. Donahue BS, Gailani D, Mast AE. Disposition of tissue factor pathway inhibitor during cardiopulmonary bypass. J Thromb Haemost. 2006;4:1011–6.

    Article  CAS  PubMed  Google Scholar 

  40. Journois D, Mauriat P, Pouard P, Marchot P, Amiral J, Safran D. Assessment of coagulation factor activation during cardiopulmonary bypass with a new monoclonal antibody. J Cardiothorac Vasc Anesth. 1994;8:157–61.

    Article  CAS  PubMed  Google Scholar 

  41. Boyle EM Jr, Verrier ED, Spiess BD. Endothelial cell injury in cardiovascular surgery: the procoagulant response. Ann Thorac Surg. 1996;62:1549–57.

    Article  PubMed  Google Scholar 

  42. Ernofsson M, Thelin S, Siegbahn A. Monocyte tissue factor expression, cell activation, and thrombin formation during cardiopulmonary bypass: a clinical study. J Thorac Cardiovasc Surg. 1997;113:576–84.

    Article  CAS  PubMed  Google Scholar 

  43. Sniecinski RM, Chen EP, Tanaka KA. Reduced levels of fibrin (antithrombin I) and antithrombin III underlie coagulopathy following complex cardiac surgery. Blood Coagul Fibrinolysis. 2008;19:178–9.

    Article  PubMed  Google Scholar 

  44. Ogawa S, Szlam F, Chen EP, Nishimura T, Kim H, Roback JD, Levy JH, Tanaka KA. A comparative evaluation of rotation thromboelastometry and standard coagulation tests in hemodilution-induced coagulation changes after cardiac surgery. Transfusion. 2011. doi:10.1111/j.1537-2995.2011.03241.x

  45. Ruggeri ZM, Dent JA, Saldivar E. Contribution of distinct adhesive interactions to platelet aggregation in flowing blood. Blood. 1999;94:172–8.

    CAS  PubMed  Google Scholar 

  46. Ni H, Denis CV, Subbarao S, Degen JL, Sato TN, Hynes RO, Wagner DD. Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogen. J Clin Invest. 2000;106:385–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Mosesson MW. Update on antithrombin I (fibrin). Thromb Haemost. 2007;98:105–8.

    CAS  PubMed  Google Scholar 

  48. Hathcock JJ, Nemerson Y. Platelet deposition inhibits tissue factor activity: in vitro clots are impermeable to factor Xa. Blood. 2004;104:123–7.

    Article  CAS  PubMed  Google Scholar 

  49. Elliott MA, Chen MG, Silverstein MN, Tefferi A. Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia. Br J Haematol. 1998;103:505–11.

    Article  CAS  PubMed  Google Scholar 

  50. Lentz SR, Tsiang M, Sadler JE. Regulation of thrombomodulin by tumor necrosis factor-alpha: comparison of transcriptional and posttranscriptional mechanisms. Blood. 1991;77:542–50.

    CAS  PubMed  Google Scholar 

  51. Raivio P, Fernandez JA, Kuitunen A, Griffin JH, Lassila R, Petaja J. Activation of protein C and hemodynamic recovery after coronary artery bypass surgery. J Thorac Cardiovasc Surg. 2007;133:44–51.

    Article  PubMed  Google Scholar 

  52. Sniecinski R, Szlam F, Chen EP, Bader SO, Levy JH, Tanaka KA. Antithrombin deficiency increases thrombin activity after prolonged cardiopulmonary bypass. Anesth Analg. 2008;106:713–8.

    Article  CAS  PubMed  Google Scholar 

  53. Maslow A, Lowenstein E, Steriti J, Leckie R, Cohn W, Haering M. Left ventricular thrombi: intraoperative detection by transesophageal echocardiography and recognition of a source of post CABG embolic stroke: a case series. Anesthesiology. 1998;89:1257–62.

    Article  CAS  PubMed  Google Scholar 

  54. Planinsic RM, Nicolau-Raducu R, Eghtesad B, Marcos A. Diagnosis and treatment of intracardiac thrombosis during orthotopic liver transplantation. Anesth Analg. 2004;99:353–6.

    Article  PubMed  Google Scholar 

  55. Jackson D, Botea A, Gubenko Y, Delphin E, Bennett H. Successful intraoperative use of recombinant tissue plasminogen activator during liver transplantation complicated by massive intracardiac/pulmonary thrombosis. Anesth Analg. 2006;102:724–8.

    Article  CAS  PubMed  Google Scholar 

  56. Krishnamurti C, Vukelja SJ, Alving BM. Inhibitory effects of lysine analogues on t-PA induced whole blood clot lysis. Thromb Res. 1994;73:419–30.

    Article  CAS  PubMed  Google Scholar 

  57. Stassen JM, Lambeir AM, Matthyssens G, Ripka WC, Nystrom A, Sixma JJ, Vermylen J. Characterisation of a novel series of aprotinin-derived anticoagulants. I. In vitro and pharmacological properties. Thromb Haemost. 1995;74:646–54.

    CAS  PubMed  Google Scholar 

  58. Diamond SL, Anand S. Inner clot diffusion and permeation during fibrinolysis. Biophys J. 1993;65:2622–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Despotis GJ, Joist JH, Hogue CW, Alsoufiev A, Joiner-Maier D, Santoro SA, Spitznagel E, Weitz JI, Goodnough LT. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemost. 1996;76:902–8.

    CAS  PubMed  Google Scholar 

  60. Avidan MS, Levy JH, Van Aken H, Feneck RO, Latimer RD, Ott E, Martin E, Birnbaum DE, Bonfiglio LJ, Kajdasz DK, Despotis GJ. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass. J Thorac Cardiovasc Surg. 2005;130:107–13.

    Article  CAS  PubMed  Google Scholar 

  61. Huyzen RJ, van Oeveren W, Wei F, Stellingwerf P, Boonstra PW, Gu YJ. In vitro effect of hemodilution on activated clotting time and high-dose thrombin time during cardiopulmonary bypass. Ann Thorac Surg. 1996;62:533–7.

    Article  CAS  PubMed  Google Scholar 

  62. Casbard AC, Williamson LM, Murphy MF, Rege K, Johnson T. The role of prophylactic fresh frozen plasma in decreasing blood loss and correcting coagulopathy in cardiac surgery. A systematic review. Anaesthesia. 2004;59:550–8.

    Article  CAS  PubMed  Google Scholar 

  63. Demeyere R, Gillardin S, Arnout J, Strengers PF. Comparison of fresh frozen plasma and prothrombin complex concentrate for the reversal of oral anticoagulants in patients undergoing cardiopulmonary bypass surgery: a randomized study. Vox Sang. 2010;99:251–60.

    Article  CAS  PubMed  Google Scholar 

  64. Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, Song HK, Clough ER, Shore-Lesserson LJ, Goodnough LT, Mazer CD, Shander A, Stafford-Smith M, Waters J, Baker RA, Dickinson TA, FitzGerald DJ, Likosky DS, Shann KG. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg. 2011;91:944–82.

    Article  PubMed  Google Scholar 

  65. Ryan DH, Crowther MA, Ginsberg JS, Francis CW. Relation of factor V Leiden genotype to risk for acute deep venous thrombosis after joint replacement surgery. Ann Intern Med. 1998;128:270–6.

    Article  CAS  PubMed  Google Scholar 

  66. Wahlander K, Larson G, Lindahl TL, Andersson C, Frison L, Gustafsson D, Bylock A, Eriksson BI. Factor V Leiden (G1691A) and prothrombin gene G20210A mutations as potential risk factors for venous thromboembolism after total hip or total knee replacement surgery. Thromb Haemost. 2002;87:580–5.

    CAS  PubMed  Google Scholar 

  67. Donahue BS. Factor V Leiden and perioperative risk. Anesth Analg. 2004;98:1623–34.

    Article  CAS  PubMed  Google Scholar 

  68. Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158:585–93.

    Article  CAS  PubMed  Google Scholar 

  69. Ferrucci L, Corsi A, Lauretani F, Bandinelli S, Bartali B, Taub DD, Guralnik JM, Longo DL. The origins of age-related proinflammatory state. Blood. 2005;105:2294–9.

    Article  CAS  PubMed  Google Scholar 

  70. Tanaka K, Szlam F, Katori N, Sato N, Vega J, Levy J. The effects of argatroban on thrombin generation and hemostatic activation in vitro. Anesth Analg. 2004;99:1283–9.

    Article  CAS  PubMed  Google Scholar 

  71. Tanaka KA, Szlam F, Vinten-Johansen J, Cardin AD, Levy JH. Effects of antithrombin and heparin cofactor II levels on anticoagulation with Intimatan. Thromb Haemost. 2005;94:808–13.

    PubMed  Google Scholar 

  72. Mangano DT, Tudor IC, Dietzel C, Multicenter Study of Perioperative Ischemia Research G, Ischemia Research and Education F. The risk associated with aprotinin in cardiac surgery. N Engl J Med. 2006;354:353–65.

    Article  CAS  PubMed  Google Scholar 

  73. 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, Investigators B. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med. 2008;358:2319–31.

    Article  CAS  PubMed  Google Scholar 

  74. Stein PD, Kayali F, Olson RE, Milford CE. Pulmonary thromboembolism in Asians/Pacific Islanders in the United States: analysis of data from the National Hospital Discharge Survey and the United States Bureau of the Census. Am J Med. 2004;116:435–42.

    Article  PubMed  Google Scholar 

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Acknowledgments

The authors acknowledge helpful discussions with George J. Despotis (Washington University, St. Louis, Missouri).

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Authors have no conflict of interest to disclose.

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Correspondence to Kenichi A. Tanaka.

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Ogawa, S., Richardson, J.E., Sakai, T. et al. High mortality associated with intracardiac and intrapulmonary thromboses after cardiopulmonary bypass. J Anesth 26, 9–19 (2012). https://doi.org/10.1007/s00540-011-1253-x

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