July 2000

Anticoagulation for Cardiac Surgery In Patients Receiving Preoperative Heparin: Use of the High-Dose Thrombin Time.
Shore-Lesserson L, Manspeizer HE, Bolastig M, Harrington D, Vela-Cantos F, DePerio M. Anesthesia and Analgesia 2000;90:813-8

[see abstract below]

Commentary by Katherine Grichnik, M.D.

This is a very interesting article, which addresses an increasingly common clinical problem: apparent heparin resistance in the patient receiving preoperative heparin infusion when attempting full anticoagulation for cardiopulmonary bypass (CPB). Adequate anticoagulation is necessary for CPB, with prolongation of the activated clotting time (ACT) being the most common method used to demonstrate appropriate anticoagulation. However, when studies were initially done correlating various ACT levels with adequate heparinization, many patients were not in-hospital on heparin drips. It has been demonstrated that attempts to achieve apparent full anticoagulation with bolus heparin administration in patients who have had preoperative heparin administration result in less prolongation of the ACT than a similar dose in patient who have not received preoperative heparin. This is thought to be due to a relative antithrombin II deficiency, enhanced Factor VIII activity, and/or the presence of activated platelets. Thus the question becomes, is the patient adequately anticoagulated despite an ACT value which has been traditionally thought to be less than therapeutic? In the absence of an alternate test of anticoagulation, patients are often administered larger and repeated doses of heparin, are given antithrombin III concentrates and/or are administered fresh frozen plasma in an attempt to prolong the ACT.

The purpose of this study was to evaluate a different test, the high dose thrombin time (HiTT), as a monitor of anticoagulation for CPB in patients receiving and not receiving preoperative heparin. With comparison to the standard ACT, the researchers also sought to determine if "heparin resistance, characterized by a suboptimal ACT, is also correlated with a reduced HiTT response to heparin." Since the ACT pathway measures the integrity of the intrinsic coagulation pathway and the final common coagulation pathway, it was postulated that the thrombin time (TT) (which measures the conversion of fibrinogen to fibrin) would be a more specific measure of thrombin inhibition. However, this approach required modification of the TT to the high-dose TT (HiTT) to measure the effect of the high doses of heparin used for cardiopulmonary bypass. HiTT has been shown to more closely correlate with heparin concentrations than the ACT in cardiac surgery patients.

Dr. Shore-Lesserson and colleagues compared 33 patients receiving preoperative heparin (48 hours or more and continued until between 0 and 8 hours prior to surgery). The comparison group of 32 were patients who did not receive heparin preoperatively. No patients received antifibrinolytic therapy, except one in whom an unanticipated valvular procedure was also done; this patient was excluded from statistical analysis. The patients were given a standard dose of heparin (300 U/kg); ACT and HiTT were measured in all patients, and plasma markers for antithrombin III complex and fibrin monomer were measured in the last 10 patients in each group.

The ACT response to heparin was significantly lower in the group receiving heparin preoperatively, both in vivo and in vitro. The HiTT response to heparin was the same for both groups at all time points. Despite a consistently lower ACT during CPB, the group receiving heparin preoperatively and the control group did not differ during or after CPB with respect to thrombin generation or thrombin activity. The groups did not differ in chest tube, drainage or transfusion requirements; no patients required re-exploration for bleeding.

This important study challenges our long held believe that a certain "ACT" number must be achieved to conduct CPB. This belief results in patients receiving extra heparin or perhaps antithrombin II concentrates or FFP. This study should be read by all and followed up so that we all can achieve a better method for monitoring anticoagulation in our patients who present for cardiac surgery on heparin drips.

ABSTRACTS Anticoagulation for Cardiac Surgery In Patients Receiving Preoperative Heparin: Use of the High-Dose Thrombin Time. AUTHORS: Shore-Lesserson L, Manspeizer HE, Bolastig M, Harrington D, Vela-Cantos F, DePerio M SOURCE: Anesthesia and Analgesia 2000;90:813-8 Patients receiving heparin infusions have an attenuated activated clotting time (ACT) response to heparin given for cardiopulmonary bypass (CPB). We compared patients receiving preoperative heparin (Group H) to those not receiving heparin (REF group) with respect to ACT, high-dose thrombin time (HiTT), and markers of thrombin generation during CPB. Sixty-five consecutive patients (33 Group H, 32 REF group) undergoing elective CPB were evaluated. ACT and HiTT were measured at multiple time points. Plasma levels of thrombin-antithrombin III complex and fibrin monomer were determined at baseline, during CPB, and after protamine administration. Transfusion requirements and postoperative blood loss were measured and compared. ACT values after heparinization increased less in Group H and were significantly lower than those in the REF group (P < 0.01). HiTT values did not differ significantly between the two groups. Blood loss and transfusion requirements were not significantly different between the two groups. Plasma levels of thrombin-antithrombin III complexes and fibrin monomer also did not differ between groups at any time, despite a lower ACT in Group H after heparinization and during CPB. Our data suggest that thrombin formation and activity are not enhanced in patients receiving heparin therapy, despite a diminished ACT response to heparin. The utility of ACT and the threshold values indicative of adequate anticoagulation for CPB are relatively undefined in patients receiving preoperative heparin. HiTT should be investigated as a safe and accurate monitor of anticoagulation for CPB in patients receiving preoperative heparin therapy. Implications: The diminished activated clotting time response to heparin, in patients receiving preoperative heparin therapy, poses difficulties when attempting to provide adequate anticoagulation for cardiopulmonary bypass. Current data suggest that heparin resistance is not observed when high-dose thrombin time is used to monitor anticoagulation and that a lower activated clotting time value in these patients may be safe.