Cardiac surgery, particularly when cardiopulmonary bypass (CPB) is employed, leads despite potent anticoagulation to a massive activation of the coagulation/inflammation system . This activation is caused by the surgical trauma itself which induces a massive release of tissue factor, the contact of the blood with air and the large non-endothelial surfaces of the CPB circuit, the aspiration and re-infusion of activated blood via cardiotomy suction and the generation of cytokines during ischemia . Clinical consequences of this cascade, include activation and consumption of coagulation factors and platelets which may lead to bleeding complications and transfusion requirements, an aggravation of ischemia/reperfusion (I/R) injury with potentially detrimental effects on cardiac output and microembolism of fibrin-emboli, thus contributing to post-CPB neurocognitive impairment .
Anticoagulation with unfractionated heparins (UFH), monitored with the activated clotting time (ACT) and reversed with protamine have been the fundament of anticoagulation/coagulation management in cardiac surgery since its beginnings. However, apart from limitations of the ACT as an adequate monitoring assay for the complex process of anticoagulation and drawbacks of the use of protamine, UFH are associated with significant limitations such as large differences in the preparations regarding the composition, a large inter-individual variation of the anticoagulant effect, and the development of heparin-resistance. Further disadvantages are the direct release of tissue factor pathway inhibitor, which in cardiac surgery appears to play a minor role, and the only indirect achievement of the anticoagulant effect via activation of antithrombin .
Considering the predominantly indirect anticoagulant effect of heparins and the fact that, due to hemodilution and consumption, antithrombin levels during surgery critically decrease, prompted the question of whether improved attenuation of hemostatic activation can be achieved by high dose treatment with antithrombin. The aim of this review is to present the currently available pre-clinical and clinical data on the use of antithrombin in cardiac surgery.
Assessment of antithrombin in pre-clinical studies
Hemostatic activation and ischemia are causes of massive activation of the inflammation system. The inflammatory response itself has major impact on reperfusion damage of organ systems subjected to ischemia . In a recent clinical investigation, levels of thrombin generation revealed a close correlation with markers of myocardial damage in patients after coronary artery bypass grafting, thus indicating the strong impact of thrombin generation on myocardial I/R injury .
Several pre-clinical studies have shown attenuation of I/R injury after pretreatment with antithrombin following hepatic ischemia [5-7]. Significantly elevated prostaglandin I2 levels during reperfusion suggest that this attenuation of I/R injury during antithrombin administration is mediated via the production of prostaglandins [6,7].
In a model of simulated CPB high dose (5 IU/ml) but not low-dose (1 IU/ml) antithrombin administration reduced thrombin generation, platelet activation and activation of monocytes and neutrophils, while, however, demonstrating no effect on markers of the complement system .
In another CPB animal model administration of 500 IU/kg antithrombin had no effect on myocardial I/R injury but attenuated I/R injury induced elevation of pulmonary artery pressures while having no impact on systemic and pulmonary artery vascular resistance .
All these experimental data show that potent inhibition of thrombin activation reduces inflammatory response and I/R injury. To what extent thrombin exhibits a direct effect or its mechanism is mediated via platelet activation needs further investigation.
Assessment of antithrombin in patients with heparin resistance
Heparin resistance is a condition in which increasing/excessive dosages of heparin are needed to achieve the desired anticoagulant effect. Patterns of heparin resistance in clinical studies have been associated with impaired clinical outcome . The effect of antithrombin administration on heparin resistance in patients undergoing cardiac surgery with CPB has been intensively studied (see article by G. Despotis in the current EJA issue) [11-15]. In all investigations, the administration of antithrombin (500 IU-75 IU/kg) resulted in an improved response of the ACT to heparin and increased attenuation of hemostatic activation during CPB while only in one investigation an impact on clinical outcome was observed .
Assessment of antithrombin in patients without heparin resistance
In patients scheduled for elective cardiac surgery with CPB the maintenance of high heparin concentrations during CPB resulted in reduced thrombin generation while, however, still significant amounts of fibrin were generated . This activation of the hemostatic system despite high dose heparin administration was attributed to a critical decrease of antithrombin concentrations and consequent reduced efficacy of heparin. One recent investigation demonstrated that low antithrombin levels after cardiac surgery are associated with impaired clinical outcome . The effect of antithrombin administration in non-heparin-resistant patients was the topic of several smaller clinical investigations targeting the effects of antithrombin on surrogate parameters of hemostatic activation and/or clinical outcome parameters [18-21]. While in one small investigation in 20 patients a single bolus of 50 IU/kg antithrombin had no effect on hemostatic activation and blood loss other studies showed a positive effect of antithrombin therapy . The results of this investigation are counterbalanced by three other studies: Koster et al. showed in 80 patients that administration of a single bolus of 50 IU/kg antithrombin resulted in increased attenuation of hemostatic and leukocyte activation during CPB although no impact was seen on clinical outcomes . In two other investigations the effect of administration of antithrombin in patients undergoing coronary artery bypass grafting was assessed [20,21]. In the first study a single bolus of 3000 IU antithrombin in 11 patients before aortic cannulation resulted in improved attenuation of the hemostatic activation and reduced transfusions and chest tube drainage . In the other study, of patients scheduled for coronary artery surgery with CPB, administration of antithrombin resulted in reduced bleeding in the treatment group .
Direct inhibition of thrombin as an alternative to heparin/antithrombin
The central role of thrombin in the hemostatic/inflammation system and the emerging role of direct thrombin inhibitors in percutaneous coronary artery intervention promoted the assessment of direct thrombin inhibitors (DTI) in the context of cardiac surgery. While in this indication DTIs have more often been used to treat patients with heparin-induced thrombocytopenia (HIT) as an alternative to standard anticoagulation with UFH, the bivalent, short acting DTI bivalirudin has also been evaluated in the context of cardiac surgery in patients without HIT. In pilot studies protocols for anticoagulation were assessed and later on a multicenter study was performed in 150 non-HIT patients randomized 2:1 to bivalirudin. While the results of this study demonstrated comparable clinical outcomes, the effect of bivalirudin on markers of hemostatic activation was extremely dependent on the perfusion practice during CPB [22-24]. As bivalirudin is cleaved to a major extent by thrombin itself in all areas where blood is stagnant (chest, reservoirs) and maintenance of therapeutic bivalirudin levels is not achieved, thrombin cleavage of bivalirudin results in hemostatic activation . Therefore, excellent attenuation of hemostatic activation during CPB can be achieved with the use of closed systems and avoidance of cardiotomy suction, whereas massive activation is observed when cardiotomy suction is employed . Therefore, bivalirudin appears to be a promising replacement for heparin/antithrombin anticoagulation where perfusion practice easily can be adjusted to the unique pharmacology of the drug, i.e. particularly in coronary artery bypass surgery, while its use for open heart/complex surgery may be better restricted to HIT patients.
The central role of antithrombin in the hemostatic system, inflammatory response and I/R injury during cardiac surgery with CPB is increasingly appreciated. There is convincing evidence from pre-clinical and clinical studies that administration of high dosages of antithrombin and maintenance of high antithrombin concentrations during CPB, particularly in patients diagnosed as being heparin resistant, attenuates these effects. Moreover, there are convincing data demonstrating that low concentrations of antithrombin after cardiac surgery with CPB are associated with impaired clinical outcome. However, all clinical investigations are underpowered in size to show an impact of preemptive antithrombin therapy on clinical outcomes after cardiac surgery with CPB. In view of the high cost of the therapy, before routine preemptive administration of high dose antithrombin in cardiac surgery with CPB can be advocated, demonstration of a clear benefit of antithrombin administration on clinical outcomes is essential. Therefore, such a large controlled investigation is needed to further define the impact of preemptive high dose antithrombin therapy on clinical outcomes following cardiac surgery with CPB.
Financial support and conflict of interest: none.
1. Paparella D, Brister SJ, Buchanan MR. Coagulation
disorders of cardiopulmonary bypass
: a review. Intensive Care Med
2. Raymond PD, Marsh NA. Alterations to haemostasis following cardiopulmonary bypass
and the relationship of these changes to neurocognitive morbidity. Blood Coagul Fibrinolysis
3. Hirsh J, Raschke R. Heparin and low molecular weight heparin: the seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest
4. Raivo P, Kuitinen A, Suojaranta-Ylinen R, Lassila R, Petaja J. Thrombin generation during reperfusion after coronary artery bypass associates with postoperative myocardial damage. J Thromb Haemost
5. Maksan SM, Maksan MO, Gebhard MM, Herfath C, Klar E. Reduction of reperfusion injury by antithrombin III and aprotinin. Transpl Int
Suppl 1: S562-S564.
6. Okano K, Kokudo Y, Okajima K et al
. Protective effects of antithrombin III supplementation on warm ischemia and reperfusion injury in rat liver. World J Surg
7. Harada N, Okajima K, Kushimoto S, Isobe H, Tanaka K. Antithrombin reduces ischemia/reperfusion injury of rat liver by increasing the hepatic level of prostacyclin. Blood
8. Rinder CS, Rinder HM, Smith MJ et al
. Antithrombin reduces monocyte and neutrophil CD11b up regulation in addition to blocking platelet activation during extracorporeal circulation. Transfusion
9. Jormalainen M, Vento AE, Wartiovaara-Kauto U et al
. Antithrombin reduces pulmonary hypertension during reperfusion after cardiopulmonary bypass
in a pig. Acta Anaesthesiol Scand
10. Ranucci M, Frigiola A, Menicanti L et al
. Risk factors for fatal myocardial infarction after coronary bypass grfat surgery. Eur J Anesthesiol
11. Lemmer Jr JH, Despotis GJ. Antithrombin III concentrates to treat heparin resistance in patients undergoing cardiac surgery. J Thorac Cardiovasc Surg
12. Koster A, Fischer T, Gruendel M et al
. Management of heparin résistance during cardiopulmonary bypass
: the effect of five different anticoagulation strategies on hemostatic activation. J Cardiothorac Vasc Anesth
13. Avidan MS, Levy JH, vanAken H et al
. Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation
in heparin-resistant patients during cardiopulmonary bypass
. J Thorac Cardiovasc Surg
14. Avidan MS, Levy JH, Scholz J et al
. A phase III, double blind, placebo-controlled, multicenter study on the efficacy of recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiopulmonary bypass
15. Conley JC, Plunket PF. Antithrombin III in cardiac surgery: an outcome study. J Extra Corpor Technol
16. Koster A, Fischer T, Praus M et al
. Hemostatic activation and inflammatory response during cardiopulmonary bypass
: impact of heparin management. Anesthesiology
17. Ranucci M, Frigiola A, Menicanti L, Ditta A, Boncilli A, Brozzi S. Postoperative antithrombin levels and outcome in cardiac operations. Crit Care Med
18. Slaughter TF, Mark JB, El-Moalem H et al
. Hemostatic effects of antithrombin III supplementation during cardiac surgery: results of a prospective randomized investigation. Blood Coagul Fibrinolysis
19. Koster A, Chew D, Kuebler W et al
. High antithrombin III levels attenuate hemostatic activation and leukocyte activation during cardiopulmonary bypass
. J Thorac Cardiovasc Surg
20. Rossi M, Martinelli L, Storti S et al
. The role of antithrombin III in the perioperative management of the patient with unstable angina. Ann Thorac Surg
21. Sonzongi V, Bellavita P, Carrara B et al
. The effect of antithrombin III concentrations during cardiopulmonary surgery. Minerva Anesthesiol
22. Koster A, Spiess BD, Chew DP et al
. Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass
in patients undergoing coronary artery bypass grafting. Am J Cardiol
23. Koster A, Yeter R, Buz S et al
. Assessment of hemostatic activation during cardiopulmonary bypass
for coronary artery bypass grafting with bivalirudin: results of a pilot study. J Thorac Cardiovasc Surg
24. Dyke CM, Smedira N, Koster A et al
. A comparison of bivalirudin to heparin wit protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass
: the EVOLUTION-ON study. J Thorac Cardiovasc Surg