Key words: Coagulation, thrombus: epsilon aminocaproic acid. Equipment: pulmonary artery catheter.
ADMINISTRATION of antifibrinolytic drugs to prevent bleeding has become an increasingly widespread practice during cardiac surgery. [1,2] The potential for antifibrinolytic therapy to promote pathologic thrombosis in the perioperative period remains unclear. A recent report describes the rapid formation of thrombus on a heparin-bonded pulmonary artery catheter after aprotinin administration.  To date, no reports have described this complication in association with the synthetic antifibrinolytics (i.e., epsilon aminocaproic acid and tranexamic acid). We describe two recent cases during which large thrombi were detected on heparin-bonded pulmonary artery catheter shortly after administration of epsilon aminocaproic acid and the subsequent precautions we have taken to minimize the risk of this complication recurring with the administration of antifibrinolytic therapy.
A 42 yr-old, 86-kg man was scheduled for coronary artery bypass graft surgery. The patient received heparin for unstable angina until 3 days before surgery. Preoperative values for prothrombin time, activated partial thromboplastin time, and platelet count were normal. Before induction of anesthesia, an 8.5-Fr introducer catheter (SI-09880), Arrow International, Reading, PA) was placed into the right internal jugular vein, followed by a 7.5-Fr thermodilution, heparin-coated pulmonary artery catheter (93A-83111–7.5F. Baxter Healthcare, Irvine, CA). Before incision, epsilon aminocaproic acid was administered through the side port of the introducer catheter (10 g over 30 min), followed by a continuous infusion of 2 g/h for 5 h. Anesthesia consisted of midazolam, fentanyl, and pancuronium. After tracheal intubation, a biplane transesophageal echocardiography probe (Hewlett Packard, Andover, MA) was placed for intraoperative monitoring. At this time (20 min after pulmonary artery catheterization and 15 min after initiation of the epsilon aminocaproic acid infusion). a 1 x 1.5-cm echo-dense, freely mobile mass with fimbriated edges adherent to the pulmonary artery chatheter was observed in the right atrium (Figure 1and Figure 2). Before aortic cannulation, 300 U/kg porcine heparin was administered via the side port of the introducer catheter. Activated coagulation time was maintained for more than 480 s. Cardiopulmonary bypass proceeded uneventfully. After cardiopulmonary bypass, the right atrial mass remained adherent to the pulmonary artery catheter as detected by transesophageal echocardiography. After administering protamine, the pulmonary artery catheter was removed during aspiration of the introducer catheter side port. Several soft dark red thrombi were recovered (Figure 3). A second pulmonary artery catheter was placed, and no subsequent thrombus formation was observed by transesophageal echocardiography. The patient's post-operative course was unremarkable, and the patient was discharged home on postoperative day 11.
A 73-yr-old, 54-kg man with a history of chronic obstructive pulmonary disease and angina pectoris was scheduled for elective coronary artery bypass graft surgery. A heparin-coated pulmonary artery catheter (93A-831H-7.5F, Baxter Healthcare) was inserted through an introducer catheter in the right internal jugular vein. Ten grams of epsilon aminocaproic acid was administered through the side port of the introducer catheter over 30 min, followed by an infusion of 1 g/h for 5 h. General anesthesia consisted of fentanyl and midazolam. After tracheal intubation, an Omniplane transesophageal echocardiographic probe was placed for intraoperative monitoring. Heparin (300 U/kg) was administered before aortic cannulation resulting in an activated coagulation time of 488 s. Cardiopulmonary bypass and myocardial revascularization proceeded uneventfully. At the conclusion of cardiopulmonary bypass, 160 mg intravenous protamine was given to neutralize the heparin. Examination by transesophageal echocardiography revealed an echodense freely mobile mass (0.3 x 1.5 cm) attached to the pulmonary artery catheter in the right atrium. Repeat examination by transesophageal echocardiography 45 min later failed to reveal the mass previously identified on the pulmonary artery catheter. The patient's postoperative course was complicated by supraventricular dysrhythmias and pulmonary lobar atelectasis; however, on postoperative day 16, the patient was discharged home in good condition.
Before the development of heparin-bonded catheters, clot formation on pulmonary artery catheters frequently occurred and occasionally caused serious complications. [4,5] Herapin bonding has been demonstrated to prevent or at least significantly delay the formation of catheter-associated clots.  Whether pharmacologic therapy aimed at reducing blood loss during heart surgery will increase the risk of clot formation on pulmonary artery catheters remains unclear. Bohrer et al. previously reported an association between high-dose aprotinin and pulmonary artery catheter thrombosis ; however, no reports of pulmonary artery catheter thrombosis after therapy with epsilon aminocaproic acid have appeared in the literature. The two cases reported here suggest that epsilon aminocaproic acid may be associated with early clot formation on pulmonary artery catheters.
Epsilon aminocaproic acid is a synthetic lysine analog with a plasma half-life of 90 min.  The mechanism of action of synthetic antifibrinolytic drugs occurs through competitive inhibition of the lysine binding sites of plasminogen and plasmin, thereby preventing the formation of a complex with fibrin.  Numerous investigations have demonstrated a hemostatic effect after the administration of epsilon aminocaproic acid before cardiac surgery. To suppress fibrinolytic activity, Hardy et al. recommended administering epsilon aminocaproic acid as a kg 100–150-mg/kg loading dose, followed by a continuous infusion of 10–15 mg *symbol* kg sup -1 *symbol* h sup -1.  However, the minimal effective dose for fibrinolytic suppression during cardiac surgery remains unclear. Prior investigations suggest that antifibrinolytic therapy must be administered before cardiopulmonary bypass to achieve an optimal hemostatic effect. [1,9].
The major concern related to antifibrinolytic therapy remains the theoretical risk of promoting pathologic thrombus formation in the perioperative period. Despite heparin administration, coronary artery bypass surgery generates increased prothrombin activation and fibrin formation.  Concomitant fibrinolytic activity may provide a protective mechanism by regulating the extent of thrombus formation. .
We hypothesize that the pulmonary artery catheter thrombosis observed in these patients was related to high localized concentrations of epsilon aminocaproic acid achieved around the pulmonary artery catheter during administration of epsilon aminocaproic acid through the side port of the introducer catheter. Subsequent to these cases, we altered our practice by infusing epsilon aminocaproic acid through a peripheral intravenous catheter after heparin administration before initiation of cardiopulmonary bypass. Administration of epsilon aminocaproic acid after heparin may decrease the risk of thrombus formation. Van Riper et al. demonstrated that antifibrinolytic therapy may be administered after heparin with no loss of hemostatic activity.  During the 6 months after our alteration in the administration of epsilon aminocaproic acid, no subsequent episodes of pulmonary artery catheter thrombosis have been observed by intraoperative transesophageal echocardiography.
In summary, this report describes two cases of early thrombus formation on heparin-bonded pulmonary artery catheters in patients receiving epsilon aminocaproic acid during cardiac surgery. We speculate that administration of epsilon aminocaproic acid into the central circulation before administration of heparin increases the risk of pulmonary artery catheter thrombosis. Although antifibrinolytic therapy has proved highly efficacious in reducing bleeding after cardiac surgery, additional investigations are needed to determine the potential risks for perioperative thrombosis.