POSTOPERATIVE bleeding after cardiopulmonary bypass using deep hypothermic circulatory arrest (DHCA) is a significant cause of morbidity and mortality. The pathogenesis of this hemorrhagic tendency is complex and multifactorial, resulting from hypothermia, consumption of clotting factors, platelet destruction, platelet dysfunction, hyperfibrinolysis, and surgical factors. The use of antifibrinolytic agents, such as aprotinin, ε-aminocaproic acid (EACA), and tranexamic acid, have been demonstrated to reduce postoperative blood loss and transfusion requirements in cardiac surgery. 1–7The benefits of antifibrinolytic use in DHCA are less well-established because of anecdotal and retrospective reports of renal dysfunction and thrombosis. 8–14We present two cases in which patients treated intraoperatively with EACA during aortic replacement surgery presented with massive, fatal aortic thrombosis.
A 70-yr-old man with previous aortic valve replacement presented several months postoperatively with bacterial endocarditis and an aortic root abscess. He was scheduled for an aortic root replacement (Bentall) procedure using cardiopulmonary bypass (CPB) and DHCA. At the time of surgery, his vital signs were normal; his coagulation, hematology, and biochemical profiles were normal; and he was taking the following medications: spironolactone, furosemide, digoxin, metoprolol, oxacillin, and verapamil. General anesthesia was induced and maintained with midazolam, sufentanil, pancuronium, and isoflurane. Cefazolin (1,000 mg) and vancomycin (1,000 mg) were also administered. Monitoring included standard anesthesia monitoring plus a radial arterial line, a pulmonary artery catheter, jugular bulb saturation monitoring, and transesophageal echocardiography. EACA (150 mg/kg) was administered as a loading dose soon after induction, and a maintenance infusion of 15 mg · kg−1· h−1was continued until after protamine administration.
The patient’s intraoperative course was uneventful. Activated clotting time (ACT) was maintained at more than 500 s with bovine lung heparin using an initial dose of 300 U/kg and ACT testing every 30 min thereafter. The Bentall procedure was performed with a mechanical prosthetic aortic valve and composite graft. The aortic root graft was a Hemashield®(Boston Scientific, Oakland, NJ) graft, and the coronary arteries were reimplanted successfully. CPB time was 311 min, DHCA was 25 min, and the patient initially separated successfully from CPB with 5 μg · kg−1· min−1dopamine for inotropic support. Protamine sulphate (7 mg/kg) was administered over 15 min to neutralize a total heparin dose of 700 U/kg. After 5 min of protamine administration, the mean arterial blood pressure decreased to 40 mmHg, and protamine administration was stopped to evaluate the etiology of the severe hypotension. Transesophageal echocardiography revealed a large thrombus, which occupied the entire lumen of the ascending aorta, the aortic arch, and the descending aorta. This thrombus and fibrinous material was also visualized in the left atrium and ventricle (fig. 1). The patient rapidly progressed to cardiac arrest, CPR was commenced, heparin was readministered, and a futile attempt to reinstitute CPB was made. Resuscitative efforts were unsuccessful.
At the time of death, blood sampling was performed to evaluate for the possibility of a previously undiagnosed hypercoagulable state. The patient was negative for anticardiolipin antibodies, anti–thrombin III deficiency, and protein C or S deficiency. Laboratory analysis revealed that the patient had a heterozygous mutation of Factor V, FV:R506Q, also known as Factor V Leiden.
A 76-yr-old woman presented for repair of an ascending aortic aneurysm. At the time of surgery, her vital signs were normal; her coagulation, hematology, and biochemical profiles were normal; and she was taking the following medications: hydroxyzine, furosemide, benazepril hydrochloride, and metoprolol. General anesthesia was induced and maintained with etomidate, midazolam, sufentanil, pancuronium, and isoflurane. Cefazolin (1,000 mg) and vancomycin (1,000 mg) were also administered. Monitoring included standard anesthesia monitoring plus a radial arterial line, a pulmonary artery catheter, jugular bulb saturation monitoring, and transesophageal echocardiography. EACA (150 mg/kg) was administered as a loading dose soon after induction, and a maintenance infusion of 15 mg · kg−1· h−1was continued until after protamine administration. Her intraoperative course was uneventful. ACT was maintained at greater than 500 s with bovine lung heparin using an initial dose of 300 U/kg and ACT testing every 30 min thereafter. The aortic arch graft was a Hemashield®graft. CPB time was 233 min, DHCA was 46 min, and the patient initially separated successfully from bypass using 5 μg · kg−1· min−1dopamine.
After separation from CPB, 5 mg/kg protamine sulphate was administered by slow infusion to neutralize a total heparin dose of 500 U/kg. Five units pooled platelet concentrates were administered without incident to treat microvascular bleeding. Forty-one minutes after successful separation from CPB, during transfusion of 1 unit fresh frozen plasma, the patient became profoundly hypotensive. Fresh frozen plasma transfusion was discontinued, and the patient’s hemodynamics initially responded to commencement of epinephrine and norepinephrine infusions. A dose of steroids was administered in case anaphylaxis to fresh frozen plasma had caused the hypotension. Transesophageal echocardiography revealed large thrombi in the right atrium, the main pulmonary artery, and the entire lumen of the descending aorta. The patient did not respond to further resuscitative efforts.
Postmortem analysis showed that the patient had normal alleles for Factor V Leiden by prothrombin assay. There was insufficient sera for further testing for other causes of previously undiagnosed hypercoagulable states.
Blood loss minimization in patients undergoing CPB with DHCA has been attempted with the use of either the lysine analog antifibrinolytic agents (EACA and tranexamic acid) or the nonspecific serine protease inhibitor, aprotinin. The literature suggests that these agents are effective in reducing blood loss after CPB. However, their safety and efficacy in DHCA are controversial because some reports suggest that thrombotic events and renal dysfunction are potential risks that outweigh any benefits. 9–12,14–18The risks of thrombosis in DHCA have prompted some clinicians to stop using aprotinin in these patients. Others recommend using aprotinin after deep hypothermia and circulatory arrest have been completed. 13Specifically, aprotinin has been reported to be associated with renal glomerular thrombi 14and other thrombi 19in CPB both with and without DHCA. Careful analysis of these events has more accurately attributed them to inadequate heparinization, inappropriate aprotinin dosing regimes, or flawed study methodology. 10–12,14,17,19,20There are fewer reports of catastrophic thrombotic events using EACA or tranexamic acid, but it is unclear whether these events are truly less frequent or underreported. 21One case report describes massive thrombosis after a hypovolemic cardiac arrest in a patient treated with EACA while undergoing CPB. 22Another report of fatal aortic thrombosis occurred in a neonate treated with EACA during extracorporeal life support. 23Data regarding the use of the lysine analogs EACA or tranexamic acid given during DHCA are even more scarce and inconclusive about safety outcomes. 9
ε-Aminocaproic acid is a lysine analog that inhibits fibrinolysis by attaching to lysine binding sites on plasminogen and plasmin, thereby inhibiting their activities. In secondary fibrinolysis states, such as that which occurs during CPB, EACA may potentially precipitate a prothrombotic state with unopposed coagulation. 24,25
The two cases that we present suggest that certain patients may be prone to thrombosis when given lysine analog antifibrinolytic agents during DHCA. In both of our patients, Hemoshield®aortic grafts were used. These grafts are collagen-impregnated and have hemostatic properties but have not been associated with acute aortic intravascular thrombosis. 26,27Though we did monitor ACT to assure adequate anticoagulation during CPB, we did not measure or maintain a specific heparin concentration. It is possible that a combination of disseminated intravascular coagulation after hypothermic CPB, the use of an antifibrinolytic agent, low heparin concentrations, and the presence of hemostatic graft material combined to produce the hypercoagulable state that led to the fatal thrombotic events in these two patients. In the first patient, the presence of a heterozygous mutation associated with hypercoagulability (Factor V Leiden) was almost certainly contributory.
Factor V Leiden is reported to occur in 3–5% of the population and is associated with hypercoagulable states. This abnormality produces a resistance to activated protein C, which is involved in anticoagulation and thrombolysis. The use of an antifibrinolytic agent in the presence of abnormal thrombolysis could be expected possibly to enhance the likelihood of thrombosis.
Both patients received a standard 300-U/kg dose of heparin and had ACT monitoring every 30 min. Although the ACT was maintained at more than 500 s, in profound hypothermia, ACT correlates poorly with plasma heparin concentrations. 28,29This is our standard method of heparin management in a referral center in which we perform hundreds of DHCA operations per year. However, it is possible that low heparin concentrations were present in each patient and that the development of a subclinical disseminated intravascular coagulation contributed to the postprotamine fatal thrombotic events. 28,29The optimal ACT and heparin management protocol in the presence of antifibrinolytic therapy and DHCA remains unknown.
In summary, we have presented two cases of fatal thrombosis after EACA administration and DHCA. Previously, such cases had only been described with aprotinin usage. These cases provide a warning that the lysine analogs may also cause unopposed coagulation by virtue of their antifibrinolytic properties, especially in patients who have a second risk factor for thrombosis. Screening for subclinical procoagulant states, such as Factor V Leiden abnormality, is costly but may be considered in patients undergoing DHCA in which the use of antifibrinolytics is planned. The optimal heparin dosage and maintenance in this patient group also need to be further investigated. The benefits of reduced blood loss need to be carefully weighed against the risks of intravascular thrombosis when selecting an anesthetic and surgical plan for aortic surgery using deep hypothermic circulatory arrest.