THE purpose of this case report is to alert anesthesiologists and other medical and surgical staff as to the potential for increased postoperative bleeding in patients undergoing heart surgery after having received the recently introduced low-molecular-weight heparin (LMWH) preparations (e.g. , enoxaparin) and new platelet inhibitors (e.g. , tirofiban) in the setting of acute coronary syndromes or coronary interventional procedures.
Four days after acute anterolateral myocardial infarction, a 75-yr-old, 56-kg man was scheduled for coronary arterial revascularization. His preoperative medications were 60 mg enoxaparin subcutaneously two times a day, aspirin and metoprolol orally, and intravenous infusion of the platelet glycoprotein (GP) IIb/IIIa receptor inhibitor tirofiban (Aggrastat, Merck, West Point, PA). The tirofiban infusion was discontinued at midnight before the day of operation.
Normal electrolyte and hematologic panels were obtained preoperatively: prothrombin and activated partial thromboplastin times (aPTT) of 13.9 (1.1 × control, international standardized index [ISI] 2) and 34.9 s (1.1 × control), respectively, a hematocrit of 48.1%, and a platelet count of 152,000/μl. Creatinine and blood urea nitrogen levels were normal as well (1.2 mg/dl and 10 mg/dl, respectively). During 90 min of extracorporeal support, with an ischemic time of 51 min, the surgical procedure involved anastomosis of the left internal thoracic artery to the left anterior descending coronary artery and a free reversed saphenous vein graft to the left circumflex coronary artery. During cardiopulmonary bypass (CPB), the triggers for additional heparin administration were an activated clotting time of less than 480 s and a whole blood heparin concentration less than the patients’ pre-CPB reference level (4.2 U/ml) using an automated protamine titration method (Hepcon, Medtronic Blood Management, Parker, CO). After discontinuation of CPB, the total dose (23,000 IU) of heparin was neutralized with a total of 350 mg protamine sulphate, as guided by the automated protamine titration method. Nevertheless, the surgical wound appeared diffusely “wet,” and the subjective diagnosis of microvascular bleeding was made by the staff surgeon. Based on immediately available whole blood tests, which revealed a normal activated clotting time (> 120 s); no detectable heparin (automated protamine titration heparin concentration method); a hematocrit of 22%; a platelet count of 55,000/μl; and a whole blood prothrombin/PTT of 17.8 s (1.48 × control, ISI 2)/40.9 s (1.32 × control), respectively; 2 U of packed erythrocytes and one single donor pack (apheresis) of platelets were transfused. The patient remained normothermic (36.9°C) after discontinuation of bypass. While in the cardiothoracic intensive care unit, routine hematologic assays (prothrombin/aPTT, hematocrit, and platelet count) were performed to guide transfusion therapy in the setting of excessive chest tube drainage (CTD;fig. 1) During the first 8 h, one six-pack of random donor platelets was administered for excessive bleeding (CTD: 960 ml) in the presence of a platelet count of 64,000/μl. During the next 8-h period, 4 U fresh frozen plasma were given for ongoing bleeding (CTD: 740 ml) in the setting of prothrombin/aPTT values of 15.2 s (1.2 × control)/61.7 s (1.9 × control), as well as a single donor apheresis platelet unit (six-pack equivalent) for a platelet count of 82,000/μl. Persistent excessive CTD (660 ml) during the third 8-h period necessitated the administration of an additional six-pack of random donor platelets. Despite excessive CTD (3,750 ml over 2 days), necessitating the transfusion of 7 U erythrocytes, the patient was hemodynamically stable, did not require vasopressor therapy, and was extubated the morning after surgery (15 h postoperatively). No additional hematologic assays were performed. Neither thromboelastography nor anti-Xa assay are available in our institution, and a point-of-care platelet function test, although available, was not performed by the managing physicians, who were not aware of the potential for excessive postbypass bleeding in the setting of concurrent use of LMWH and tirofiban. The patient was discharged from the intensive care unit 2 days later and from the hospital after 5 days.
Based on results of the ESSENCE trial, 1the combination of LMWH and aspirin is increasingly being used for patients with acute coronary syndromes. LMWHs, such as enoxaparin, are derived from unfractionated heparin (UFH) and produce their major anticoagulant effect by accelerating the binding of antithrombin III (AT III) to predominantly factor Xa (enoxaparin has an anti-Xa:anti-IIa activity ratio of 3.8:1.0). 2LMWHs generally have enhanced bioavailability, a longer half-life (two to four times as long as that of UFH), a dose-independent renal clearance, and a slightly decreased incidence of heparin-induced thrombocytopenia. 3LMWHs exhibit an antithrombotic effect that is assessed most accurately by measuring anti-Xa activity (which is often unavailable). The inability of routine doses of protamine to completely reverse the anti-Xa activity represents a significant limitation. 2In an animal study, the dose of protamine sulfate necessary to fully minimize bleeding was 10-fold greater for LMWH than for UFH. 4In addition, excessive CTD was observed, 5,6when enoxaparin was used as an alternative to UFH in patients with heparin-induced thrombocytopenia undergoing CPB.
Platelet aggregation has been implicated as one of the major causes in the development of unstable angina and acute myocardial infarction. Activation of the platelet IIb/IIIa GP receptor represents a crucial step in platelet aggregation, and 80–100% blockade of this receptor should completely suppress platelet aggregation. Therefore, potent platelet inhibitors, such as the intravenous GP IIb/IIIa inhibitors have been developed, and their clinical effectiveness is supported by several studies. 7
Recent data showed that substantially increased blood usage was associated with use of the GP IIb/IIIa inhibitor abciximab, especially if surgery was performed within 24 h after receiving the medication. 8However, these findings have not been universal. 9Platelet transfusions, which will reduce the drug's receptor occupancy on platelet surfaces to less than the critical 50% threshold associated with prolongation of the bleeding time, 10is the most appropriate therapy.
Although postbypass bleeding can have a multifactorial cause, several important factors, such as prolonged duration of CPB and type of procedure, are associated with transfusion of hemostatic blood products and increased CTD. 11The postoperative CTD of our patient, 2,360 ml over the first 24 h and 1,380 during the second 24 h, far exceeded the previously reported mean 24-h cumulative chest tube output of 986 ± 581 ml. 11In the case presented, the CPB duration was rather short, bleeding from the two distal anastomoses should have been easily detected, and normothermia was maintained after CPB. The role of tirofiban with respect to excessive bleeding is uncertain based on its short half-life time of about 90 min, 12and the infusion was discontinued the night before. Use of this agent may be important because the patient also received enoxaparin on the day of the surgery. The peak anti-Xa activity after subcutaneous LMWH administration occurs within 3–4 h, and the anti-Xa levels are approximately 50% of peak levels 12 h later. 13
When patients who are receiving a LMWH preparation are scheduled to undergo a surgical procedure, such as coronary revascularization, it would be prudent to discontinue the LMWH at least 24 h before surgery or to replace the LMWH with an intravenous infusion of UFH. This approach may be even more important in the setting of concurrent administration of a potent platelet inhibitor, such as tirofiban. In the setting of concurrent use of LMWH and platelet inhibitors, routine coagulation results (prothrombin, aPTT, activated clotting time, platelet count) will most likely not be helpful in guiding appropriate therapy. Further studies are needed to evaluate the relation between concomitant use of these new antithrombotic agents and perioperative bleeding, as well as the use of new monitoring systems and heparin reversal agents. Future advances in coagulation monitoring may help in the evaluation of patients with residual anti-Xa activity, such as the HepTest anti-Xa (Haemachem, St. Louis, MO), a test that directly measures the inhibition of factors Xa and IIa. 14Point-of-care tests of platelet function, such as platelet activating factor–mediated acceleration of coagulation (hemoSTATUS 15; Medtronic Blood Management, Parker, CO), thromboelastography (Haemoscope, Skokie, IL), 16agglutination of fibrinogen-coated beads (Ultegra; Accumetrics, San Diego, CA), and platelet-force development (Hemodyne, Richmond, VA), may facilitate evaluation of the degree of residual platelet inhibition as well as the degree of CPB-related platelet dysfunction. Novel reversal agents, such as the [+18RGD] protamine variant, which reverses conventional UFH and enoxaparin, may be clinically useful in reversing the anticoagulant effects of LMWH. 17