Activation of fibrinolysis in the pericardial cavity after cardiopulmonary bypass

Philipe N. Khalil; Mohamed Ismail; Peter Kalmar; Georg von Knobelsdorff; Guy Marx

doi:10.1160/TH03-07-0455

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 92(03): 568-574
DOI: 10.1160/TH03-07-0455

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Activation of fibrinolysis in the pericardial cavity after cardiopulmonary bypass

Philipe N. Khalil

¹Department of Thoracic and Cardiovascular Surgery, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany

,

Mohamed Ismail

¹Department of Thoracic and Cardiovascular Surgery, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany

,

Peter Kalmar

¹Department of Thoracic and Cardiovascular Surgery, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany

,

Georg von Knobelsdorff

²Department of Anesthesiology, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany

,

Guy Marx

³Department of Blood Coagulation Disorder, University Hospital Eppendorf, University of Hamburg, Hamburg, Germany

› Author Affiliations

Abstract

Summary

Aprotinin is frequently administered systemically in patients undergoing cardiopulmonary bypass to preserve platelet function and ameliorate excessive activation of fibrinolysis. More recently, aprotinin topically applied in the pericardial cavity was also found to improve postoperative blood loss. However, platelet activation was not reduced locally during surgery. Hence, we investigated in the present prospective, in a randomized double-blind trial, the intra- and early postoperative state of systemic and local fibrinolytic activity, and whether topically administered aprotinin acts as an antifibrinolytic and therefore improves local hemostasis. Patients undergoing elective coronary artery bypass grafting were divided in two groups containing 22 patients each. Both, group I and II patients received highdose aprotinin (6.0 × 10⁶ kallikrein inhibitor units (KIU)) systemically. Before resuming extracorporeal circulation (ECC), either 1.0 × 10⁶ KIU aprotinin (group I) or vehicle solution (group II) was applied into the pericardial cavity. Plasminogen, α₂-antiplasmin, plasmin-α₂-antiplasmin complex, plasminogenactivator-inhibitor type-1 and D-dimers were measured in the pericardial cavity and systemic circulation immediately before resuming extracorporeal circulation (ECC), and at 1 h and 4 h postoperatively. The local fibrinolytic activity was found to significantly exceed that measured in the systemic circulation over time, whether ot not they received aprotinin into the thoracic wound surface. Furthermore, evidence was provided that topically applied aprotinin reduces not only the local fibrinolytic activity but also the postoperative blood loss significantly by 33% which demonstrates the clinical relevance. The local activation of fibrinolysis seems to play an important role in blood loss after cardiopulmonary bypass. Therefore in fibrinolysis and blood coagulation the surgeon should not only consider what happens in the systemic circulation but also on a local level.

Keywords

Fibrinolysis - haemostasis - kallikrein inhibitor - aprotinin - cardiopulmonary bypass

Full Text

References

References
1 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: 442-7.
2 Unsworth-White MJ, Herriot A, Valencia O. Resternotomy for bleeding after cardiac operation: a marker for increase morbidity and mortality. Ann Thorac Surg 1995; 59: 664-7.
3 Smith CR. Management of bleeding complications in redo cardiac operations. Ann Thorac Surg 1998; 65: 2-8.
4 Mammen EF, Koetes MH, Washington BC. et al. Hemostasis changes during cardiopulmonary bypass surgery. Semin Thromb Hemost 1985; 11: 281-92.
5 Teufelsbauer H, Proidl S, Havel M. et al. Early activation of hemostasis during cardiopulmonary bypass: evidence for thrombin mediated hyperfibrinolysis. Thromb Haemost 1992; 68: 250-2.
6 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: 241-5.
7 Harker LA, Malpass TW, Branson HE. et al. Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: acquired transident platelet dysfunktion associated with selective alpha-granule release. Blood 1980; 56: 824-34.
8 Harker LA. Bleeding after cardiopulmonary bypass. N Engl J Med 1986; 314: 446-8.
9 Bidstrup BP, Royston D, Sapstord RN. et al. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin (trasylol). J Thorac Cardiovasc Surg 1989; 97: 364-72.
10 Fremes SE, Wong BI, Lee E. et al. Metaanalysis of prophylactic drug treatment in the prevention of postoperative bleeding. Ann Thorac Surg 1994; 58: 1580-8.
11 Laupacis A, Fergusson D. for The International Study of Peri-operative Transfusion (ISPOT) Investigators. Drugs to minimize perioperative blood loss in cardiac surgery: meta-analyses using perioperative blood transfusion as the outcome. Anesth Analg 1997; 85: 1258-67.
12 Levi M, Cromheecke ME, de Jonge E. et al. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a metaanalysis of clinically relevant endpoints. Lancet 1999; 354: 1940-7.
13 Blauhaupt B, Gross C, Necek S. et al. Effects of high-dose aprotinin on blood loss, platelet function, fibrinolysis, complement and renal function after cardiopulmonary Bypass. J Thorac Cardiovasc Surg 1991; 101: 958-67.
14 Huang H, Ding W, Su W. et al. Mechanism of the preserving effect of aprotinin on platelet function and its use in cardic surgery. J Thorac Cardiovasc Surg 1993; 106: 11-8.
15 Kallis P, Tooze JA, Talbot S. et al. Aprotinin inhibits fibrinolysis, improves platelet adhesion and reduces blood loss: results of a double-blind randomized clinical trial. Eur J Cardiothorac Surg 1994; 08: 315-23.
16 Mannucci L, Gerometta PS, Mussoni L. et al. One month follow-up of haemostatic variables in patients undergoing aortocoronary bypass surgery- effect of Aprotinin. Thromb Haemost 1995; 73: 356-61.
17 Mastroroberto P, Chello M, Zofrea S. et al. Suppressed fibrinolysis after administration of low-dose aprotinin: reduced level of plasminalpha-2-plasmin inhibitor complexes and postoperative blood loss. Eur J Cardio-Thorac Surg 1995; 09: 143-5.
18 Marx G, Pokar H, Reuter H. et al. The effects of aprotinin on hemostatic function during cardiac surgery. J Cardiothorac Vasc Anesth 1991; 05: 467-74.
19 Alvarez JM, Jackson LR, Chatwin C. et al. Low-dose postoperative aprotinin reduces mediastional drainage and blood product use in patients undergoing primary coronary artery bypass grafting who are taking aspirin: a prospective randomized, double-blind, placebo-controlled trial. J Thorac Cardiovasc Surg 2001; 122: 457-63.
20 D’Ambra MN, Akins CW, Blackstone EH. et al. Aprotinin in primary valve replacement and reconstuction: a multicenter, double-blind, placebo-controlld trial. J Thorac Cardiovasc Surg 1996; 112: 1081-9.
21 Hardy JF, Desroches J, Belisle S. et al. Lowdose aprotinin infusion is not clinically useful to reduce bleeding and transfusion of homologous blood products in high-risk cardiac surgical patients. Can J Anaesth 1993; 40: 625-31.
22 Lemmer Jr JH, Dilling EW, Morton JR. et al. Aprotinin for primary coronary artery bypass grafting: a multicenter trial of three dose regimens. Ann Thorac Surg 1996; 62: 1659-68.
23 Speekenbrink RGH, Wildevuur CRH, Sturk A. et al. Low-dose and high-dose aprotinin improve hemostasis in coronary operations. J Thorac Cardiovasc Surg 1996; 112: 523-30.
24 Smith PK, Muhlbaier LH. Aprotinin: safe and effective only with the full-dose regimen. (editoral). Ann Thorac Surg 1996; 62: 1575-7.
25 O’Regan DJ, Giannopoulos N, Mediratta N. et al. Topical aprotinin in cardiac operations. Ann Thorac Surg 1994; 58: 778-81.
26 Tatar H, Cicek S, Demirkilic U. et al. Topical use of aprotinin in open heart operation. Ann Thorac Surg 1993; 55: 659-61.
27 Royston D. High-dose aprotinin therapy: a review of the first five years’ experience. J Cardiothorac Vasc Anesth 1991; 05: 467-74.
28 Tabuchi N, de Haan J, Boonstra PW. et al. Activation of fibrinolysis in the pericardial cavity during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993; 106: 828-33.
29 Tabuchi N, de Haan J, van Oeveren W. Topical effect of aprotinin on surgical wound in cardiac surgery. (letter to the editor, reply to the editor). J Thorac Cardiovasc Surg 1995; 109: 399-400.
30 de Hann J, Schönberger JPAM, Haan J. et al. Tissue-type plasminogen activator and fibrin monomers synergistically cause platelet dysfunction during reperfusion of shed blood after cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993; 106: 1017-23.
31 Maquelin KN, Nieuwland R, Lentjes EGWM. et al. Aprotinin adninistration in the pericardial cavity does not prevent platelet activation. J Thorac Cardiovasc Surg 2000; 120: 552-7.
32 Barthels M, Poliwoda H. Gerinnungsanalysen: Interpretation, Schnellorientierung, Therapiekontrollen. Stuttgart, New York: Thieme; 1993
33 Cicek S, Tatar H, Demirkilic U. et al. Topical use of aprotinin in cardiac surgery. (letter to the editor). J Thorac Cardiovasc Surg 1995; 110: 568-9.