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Ann Thorac Surg 2000;70:S9-S11
© 2000 The Society of Thoracic Surgeons
a Department of Anesthesiology, Emory University School of Medicine, Atlanta, Georgia, USA
b Division of Cardiothoracic Anesthesiology, Emory Healthcare, Atlanta, Georgia, USA
Address reprint requests to Dr Levy, Department of Anesthesiology, Emory University Hospital, 1364 Clifton Rd, NE, Atlanta, GA 30322
e-mail: jerrold_levy{at}emory.org
Presented at the "Managing the Patient Receiving Platelet Inhibitors in Cardiac Surgery" Roundtable Discussion, San Antonio, TX, Jan 22–23, 1999.
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Introduction |
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The GP IIb/IIIa receptor antagonists have assumed a pivotal role in cardiology and have had a major impact on the cardiac surgeon as well [1–3]. Patients who have been treated with GP IIb/IIIa receptor antagonists pose a challenge, not only for the cardiac surgical team, but also for all the physicians and other health care personnel involved in their management. The purpose of this monograph is to review data from the EPIC and EPILOG studies and to present therapeutic strategies aimed at managing bleeding in high-risk cardiac surgical patients. Transfusing and monitoring patients treated with GP IIb/IIIa receptor antagonists will be covered, and recommendations on the management of these patients by the cardiac surgical teams will be made.
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Therapeutic strategies to decrease bleeding and transfusion requirements |
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Proper transfusion practices
Actual transfusion practices are also very important and involve a multifaceted approach that includes avoiding prophylactic factor administration, conserving red blood cells, altering inflammatory responses, and evaluating anticoagulation and reversal issues. Cardiac surgical teams need to develop transfusion practices without empirical therapy. However, in abciximab-treated patients, platelet transfusions after CPB may not be empirical therapy. In this patient population, the circulating platelet pool may be dysfunctional; thus, platelet transfusions represent a mechanism of providing new platelets [1–3, 7]. Although algorithms can help determine specific indications for transfusing coagulation factors, unfortunately, the ideal therapy for managing patients who receive antiplatelet therapy has not yet been well established.
Conserving or increasing red cell mass
When it is necessary to conserve or increase the red cell mass in patients undergoing surgery, especially those at high risk of bleeding, scavenging shed blood using red cell-saving devices are an option, but erythropoietin and hemoglobin solutions are still experimental. For patients with an increased risk of bleeding, autologous normovolemic hemodilution may be an option, but may or may not be practical for patients receiving platelet inhibitors.
Heparin dosing and protamine reversal
Appropriate heparin dosing and protamine reversal constitute important considerations in reducing bleeding [8–13]. Greater heparin use may result in better modulation of thrombin generation because thrombin could produce coagulopathy, especially after cardiopulmonary bypass [12]. Excess protamine may be involved, not only with proinflammatory issues, but also with adverse effects of coagulation factors and platelets [14]. An important issue that anticoagulation algorithms address is the use of a heparin monitoring system. It is necessary to maintain heparin levels during extracorporeal circulation and to avoid excess protamine administration by basing administration on the exact level of circulating heparin. Excess protamine may also be an important factor in producing hemostatic dysfunction and bleeding after cardiac surgery [14].
Reversing anticoagulation
We have been investigating better ways to alter or reverse anticoagulation to improve modulation of thrombin generation during extracorporeal circulation including both purified and recombinant antithrombin. Hirudin, a new recombinant antithrombin agent, has an extremely short half-life but, because it is very tightly bound to thrombin, hirudin may still be suppressing thrombin long after the plasma levels have fallen [15]. Hirudin is one of the only solutions available for heparin-induced thrombocytopenia. Monitoring coagulation is not well established for the new thrombin inhibitors, and, despite all of the new drugs, antithrombin and heparin are still the standard for anticoagulation.
Factors that affect activated clotting time
Many cardiologists may not be aware of all the factors that can affect activated clotting time (ACT). A prolonged ACT does not necessarily indicate better anticoagulation [13]. Even in patients who have been treated with tissue plasminogen activator, streptokinase, or urokinase, the ACT may be prolonged because there is no fibrinogen to clot. If the patient is not anticoagulated with appropriate doses of heparin for CPB, thrombin may be generated, and factors and platelets sequestered into the extracorporeal circuit [12]. The importance of suppressing thrombin generation during CPB is best illustrated by a case report of dramatic thrombin generation and platelet sequestration in a patient who received ancrod for anticoagulation during CPB [16].
Blood from a factor XII-deficient patient will have an ACT greater than 400 seconds. And if that patient were put on bypass, the circuit would be clotted because there would be no circulating heparin unless the patient had been heparinized to inhibit thrombin [17]. Previous heparin therapy with resultant low antithrombin levels, as well as hypothermia, interferes with the actual enzymatic process of hemostasis.
Thrombocytopenia can also prolong ACT because the platelets provide a partial tissue thromboplastin as part of the process required for clotting to occur [17]. Low platelet counts or dysfunctional platelets prolong ACT, the degree of change depending upon the ACT system used [18]. With a high platelet count, however, there may be reduced heparin levels, because platelet factor 4 is one of nature’s own heparin-reversing agents. Inhibition of platelet and platelet release reaction/activation with abciximab or prostacyclin platelet inhibitors can greatly prolong ACT because tissue thromboplastin comes from platelets.
Anticoagulation with CPB
CPB produces a very large blood-artificial surface interface and a pathologic stimulus for thrombin generation. Blood exposed to nonendothelial surfaces and anticoagulation is a key element in preventing clotting and complications. That is why it is prudent to lower the heparin dose in the cardiac catheterization lab, where bleeding is a concern. But based on the clinical studies with CPB, there is a tremendous potential for thrombin generation to produce fibrin and platelet activation. Clinicians have tried to extrapolate findings from the cardiac catheterization lab to the operating room, but this is problematic because of the extensive hemostatic activation during cardiac surgery. Appropriate anticoagulation is essential, as is complete reversal of heparin with protamine after CPB.
Aprotinin data and clinical experience have taught us the importance of maintaining adequate circulating heparin during CPB. Recommendations for anticoagulation with aprotinin evolved because of the differences in the ACT, providing a celite ACT > 750 seconds or a kaolin ACT > 480 seconds during CPB. Anticoagulation can also be accomplished with fixed heparin dosing at hourly intervals or by monitoring heparin levels using heparin-protamine titration. We have reported that keeping an adequate circulating heparin level of 
2.7 U/mL is essential when using aprotinin [19, 20]. This is supported by data from Weitz and associates suggesting that this is a reasonable heparin concentration for inhibiting some of the adverse effects of free thrombin and for potentiating an antithrombin effect [9]. The whole blood heparin level of 2.7 U/mL comes from a repeat CABG study, which demonstrated that aprotinin is safe and effective and that it reduces bleeding without perioperative complications [19]. From these data and from past experience, we believe that an adequate circulating heparin level is essential to successful cardiac surgery.
Thrombin is the center of the hemostatic universe. This is an extremely important concept, because the large nonendothelial surface and the intense hemostatic activation that occurs during extracorporeal circulation make it necessary to inhibit thrombin generation. It is unclear why there is such interest in reducing heparin levels for CPB when, in the end, the heparin must be neutralized.
During cardiac catheterization, with or without invasive procedures, heparin is not reversed with protamine, as is the case after separating from CPB. But it is important not to carry that leap of faith from the catheterization lab to the operating room, because after cardiac surgery, heparin is completely reversed so that thrombin is activated and working effectively to form a clot for the surgeon.
The idea of platelet anesthesia, of being able to decrease activation of platelets during bypass with platelet-inhibiting agents, has previously been attempted with drugs such as dipyridamole or prostaglandin E1. The more potent GP IIb/IIIa receptor inhibitors minimize platelet activation; the platelet counts were different in baboons treated with abciximab who underwent extracorporeal circulation from those who were treated with placebo [21, 22].
If a patient has a diffusely injured coronary artery that is barely open and requires urgent cardiac surgery, administering platelet transfusions will expose that patient to the possibility of acute reversal of the presurgical benefit of abciximab. And because of the possibility for adverse reactions, platelet transfusion should be avoided during transport to the operating room for urgent surgery. Finally, CPB can injure transfused platelets.
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