Correspondence  |   April 2007
Vascular Thrombosis Associated with Aprotinin and Deep Hypothermic Circulatory Arrest: Where Are We in 2006?
Author Notes
  • Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
Article Information
Correspondence   |   April 2007
Vascular Thrombosis Associated with Aprotinin and Deep Hypothermic Circulatory Arrest: Where Are We in 2006?
Anesthesiology 4 2007, Vol.106, 873. doi:10.1097/01.anes.0000264779.84360.60
Anesthesiology 4 2007, Vol.106, 873. doi:10.1097/01.anes.0000264779.84360.60
To the Editor:—
I read with great interest the recent report by Shore-Lesserson and Reich1 detailing diffuse venous thromboembolism in the setting of aprotinin and adult deep hypothermic circulatory arrest. To my knowledge, this is the first reported case of venous thrombosis associated with aprotinin and adult deep hypothermic circulatory arrest in the era of adequate heparinization, as defined by standard-of-care activated clotting time and heparin levels. This case report adds to the recent reports of arterial thrombosis (both pulmonary and systemic) associated with aprotinin in adult cardiac surgery with or without deep hypothermic circulatory arrest.2–4 
Therefore, significant life-threatening thrombosis is possible throughout the cardiovascular system during complex cardiac surgery in the setting of aprotinin, despite standard-of-care heparinization. It seems to be uncommon, as evidenced by randomized controlled trials.5 
Conceptually, perioperative vascular thrombosis could cause mortality in the intraoperative or postoperative period. The case reports describe intraoperative death in this scenario.1–4 The possibility of death and/or serious morbidity in the postoperative period from vascular thrombosis associated with aprotinin has recently been raised.6,7 
Massive vascular thrombosis associated with aprotinin in complex cardiac surgery is rare, but real and catastrophic. The common factor in all the case reports is the onset during or shortly after heparin reversal with protamine, heralded by hemodynamic collapse and ventricular failure.1–5 There may or may not be an identified prothrombotic risk factor including factor V Leiden.1 Clearly, there is a net prothrombotic effect achieved during or after heparin reversal, triggering disseminated major acute intravascular thrombus. On the basis of the existing reports, further clarification of the mechanism is conjecture. However, it is also clear that this phenomenon is not only possible with aprotinin but also with aminocaproic acid.4,8 
In complex cardiac surgery, pharmacologic dampening of fibrinolysis reduces allogeneic transfusion and mediastinal reexploration for bleeding, an independent predictor for perioperative mortality.9 There is, however, a small but important risk of catastrophic cardiovascular thrombosis in the setting of antifibrinolytic exposure, despite standard-of-care anticoagulation with heparin (monitored by activated clotting time and/or heparin level).
How do we balance these risks? Should the criteria for heparin-based anticoagulation be refined? If so, how and based on what evidence? What about the role of possible concomitant antithrombin deficiency?10 Should patients be screened for underlying procoagulant conditions such as factor V Leiden?1,8,11 How are all of these considerations modified in the presence of direct thrombin inhibitors, given their arrival as alternatives to heparin for clinical anticoagulation and suppressive effects on thrombin generation?12–14 What is the clinical significance of aprotinin's effect on protein C activity?15 
These case reports together ask many important questions. There is an imperative for further data, not only an international registry but also further clinical trials, to balance the benefits and risks of antifibrinolytics in complex cardiac surgery with cardiopulmonary bypass. The BART study (blood conservation using antifibrinolytics: a randomized trial in a cardiac surgery population)1is an important step in this direction.
Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania.
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Augoustides JG, Lin J, Gambone AJ, Cheung AT: Fatal thrombosis in an adult after thoracoabdominal aneurysm repair with aprotinin and deep hypothermic circulatory arrest. Anesthesiology 2005; 103:215–6Augoustides, JG Lin, J Gambone, AJ Cheung, AT
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Donahue BS: The response to activated protein C after cardiopulmonary bypass: Impact of factor V Leiden. Anesth Analg 2004; 99:1598–603Donahue, BS
Smedira N, Dyke CM, Koster A, Jurmann M, Bhatia DS, Hu T, McCarthy HL, Lincoff M, Spiess B, Aronson S: Anticoagulation with bivalirudin for off-pump coronary artery bypass grafting: The results of the Evolution-Off study. J Thorac Cardiovasc Surg 2006; 131:686–92Smedira, N Dyke, CM Koster, A Jurmann, M Bhatia, DS Hu, T McCarthy, HL Lincoff, M Spiess, B Aronson, S
Dyke CM, Smedira N, Koster A, Aronson S, McCarthy HL, Kirschner R, Spiess B: A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: The Evolution-On study. J Thorac Cardiovasc Surg 2006; 131:533–9Dyke, CM Smedira, N Koster, A Aronson, S McCarthy, HL Kirschner, R Spiess, B
Tanaka KA, Szlam F, Katori N, Sato N, Vega JD, Levy JH: The effects of argatroban on thrombin generation and hemostatic activation in vitro  . Anesth Analg 2004; 99:1283–9Tanaka, KA Szlam, F Katori, N Sato, N Vega, JD Levy, JH
Tanaka KA, Szlam F, Levy JH: The effect of aprotinin on activated protein C-mediated downregulation of endogenous thrombin generation. Br J Haematol 2006; 134:77–82Tanaka, KA Szlam, F Levy, JH