We read with interest two case reports of fatal thrombotic complications after cardiopulmonary bypass.1,2However, there are several unclear issues that the readers should become aware of. First, it is not clear whether adequate heparin levels were maintained during cardiopulmonary bypass (CPB) because activated clotting time (greater than 400–600 s*) does not necessarily reflect the efficacy of heparin anticoagulation.3 

Heparin insensitivity due to antithrombin deficiency may be masked by thrombocytopenia, hypofibrinogenemia, or other coagulation factor defects. At our institution, we administer hourly bolus doses of 100 U/kg heparin during CPB to prevent the decrease of plasma heparin levels. Furthermore, we frequently replete antithrombin during prolonged CPB (approximately 3 h) in suspected antithrombin-deficient cases by adding fresh frozen plasma or antithrombin concentrate (Thrombate III®; Talecris Biotherapeutics, Research Triangle Park, NC). We have previously shown that reduced antithrombin levels greatly enhance the rate and peak level of thrombin generation.4In patients with endocarditis, prolonged CPB, or both, plasma antithrombin levels may become critically low.5Intravascular fluidity, however, may be maintained by the balance between low procoagulant (fibrinogen, platelet) and low anticoagulant levels (antithrombin, protein C and S, thrombomodulin). Under such conditions consistent with disseminated intravascular coagulopathy, one may observe bleeding tendency. In both cases that the authors described, the administration of hemostatic blood products, platelet concentrate,1and cryoprecipitate2after heparin reversal seemed to have triggered thrombotic complications. Rapid extensions of thrombi suggest that uncontrolled “thrombin generation” occurred, and it is questionable whether thrombi could have been quickly dissolved by endogenous fibrinolytic system even in the absence of aprotinin or other antifibrinolytic agents.6In the case of afibrinogenemia referenced by the authors, it is possible that normal anticoagulant function and short CPB time (36 min) limited thrombus formation locally (i.e. , graft occlusion) without systemic thrombus extension.7 

To further stress the importance of adequate anticoagulation, the incidence of deep venous thromboses does not seem to be increased with intraoperative use of aprotinin in the orthopedic surgery when prophylaxis for deep venous thromboses (e.g. , low-molecular-weight heparin) is implemented.8These two catastrophic cases highlight the importance of balancing procoagulant and anticoagulant components of coagulation to achieve localized hemostasis while avoiding thrombotic complications. Further clinical trials must be conducted to improve our current anticoagulant strategy.9 

†Emory University School of Medicine, Atlanta, Georgia. kenichi.tanaka@emoryhealthcare.org

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; 103:215–6
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 (letter). Anesthesiology 2006; 104:213
Despotis GJ, Joist JH, Hogue CW Jr, Alsoufiev A, Kater K, Goodnough LT, Santoro SA, Spitznagel E, Rosenblum M, Lappas DG: 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
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; 99:1283–9
Heindel SW, Mill MR, Freid EB, Valley RD, White GC II, Norfleet EA: Fatal thrombosis associated with a hemi-Fontan procedure, heparin-protamine reversal, and aprotinin. Anesthesiology 2001; 94:369–71
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
Chun R, Poon MC, 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
Shiga T, Wajima Z, Inoue T, Sakamoto A: Aprotinin in major orthopedic surgery: A systematic review of randomized controlled trials. Anesth Analg 2005; 101:1602–7
Avidan MS, Levy JH, Scholz J, Delphin E, Rosseel PM, Howie MB, Gratz I, Bush CR, Skubas N, Aldea GS, Licina M, Bonfiglio LJ, Kajdasz DK, Ott E, Despotis GJ: 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. Anesthesiology 2005; 102:276–84