Antiphospholipid syndrome and cardiac surgery: management of anticoagulation in two patients.

Abstract

Antiphospholipid (APL) syndrome characterizes a clinical condition of arterial and venous thromboses associated with phospholipid-directed autoantibodies (1). APL syndrome occurs in 2% of the general population (2); however, one study demonstrated that 7.1% of hospitalized patients tested positive for at least one of three anticardiolipin antibody idiotypes (3). Several reports suggest that patients with APL syndrome are at increased risk of coronary artery disease and/or valvular pathology (4–5). In addition, APL antibodies often inhibit phospholipid-dependent coagulation in vitro and interfere with laboratory testing of hemostasis. The management of anticoagulation during cardiopulmonary bypass (CPB) can therefore be quite challenging in these patients; our approach in two recent cases is described. Case One A 51-yr-old woman with a history of coronary artery disease and severe mitral regurgitation was admitted for coronary artery bypass graft (CABG) surgery and mitral valve replacement. Coexisting medical conditions included hypertension, hypercholesterolemia, type II diabetes mellitus, peripheral vascular disease, depression, hypothyroidism, anemia, and a history of upper gastrointestinal bleeding. In addition, the patient reported three previous cerebrovascular accidents and four spontaneous abortions. On physical examination, the patient’s vital signs were within normal limits. A III/VI holosystolic murmur heard best at the apex was noted during cardiac auscultation. Neurologic examination was remarkable for left-sided weakness. Left heart catheterization revealed a left ventricular ejection fraction of 55% and severe mitral regurgitation. In addition, 50% stenosis of the left anterior descending coronary artery, 50% stenosis of a large first diagonal artery, and 25% stenosis of the right coronary artery were present. Preoperative transesophageal echocardiography revealed thickening of the mitral valve leaflets, a fixed posterior leaflet, perforation of the anterior leaflet, and severe regurgitation. Laboratory evaluation was unremarkable with the exception of an elevated activated partial thromboplastin time (aPTT) (52 s) and anticardiolipin immunoglobulin M (17 units). Antinuclear antibody (1:160) and lupus anticoagulant panel results were also positive. Preoperatively, a heparin-celite activated clotting time (ACT) titration curve was performed, as described below. Initiation of CPB was preceded by the administration of 400 U/kg porcine heparin. Celite® ACT (Hemochron 801 timer and diatomaceous earth [12 mg] tubes; International Technidyne, Edison, NJ) and anti-Xa concentrations (Organon Teknika, Durham, NC) were monitored throughout surgery (Fig. 1). After heparin administration, but before CPB, ε-aminocaproic acid was administered as a 10-g bolus followed by an infusion (1 g/h) which was continued until arrival in the intensive care unit. Postoperative bleeding necessitated transfusion of 3 units of packed red blood cells, 1 unit of cryoprecipitate, 2 units of fresh-frozen plasma, and 1 unit of platelets. The patient’s postoperative course was otherwise uneventful, and she was discharged home on the eighth day after surgery on prophylactic warfarin therapy (International Normalized Ratio [INR] 2.0–3.0).Figure 1: The relationship between anti-Xa concentration and activated clotting time (ACT) in Case One.Case Two A 49-yr-old woman with a history of congestive heart failure and severe mitral regurgitation was admitted for mitral valve replacement. Coexisting medical conditions included a 7-yr history of systemic lupus erythematosus, seizure disorder, anemia, hypertension, depression, hyperlipidemia, chronic renal insufficiency, gastroesophageal reflux, recurrent pneumonia/sinusitis, previous bifrontal and bioccipital watershed infarcts, and chronic steroid therapy. On physical examination, the patient’s vital signs were normal. Her skin examination was unremarkable. Lung examination revealed bibasilar crackles. On cardiac examination, a II/VI holosystolic murmur was auscultated at the apex. Right and left heart catheterization revealed a left ventricular ejection fraction of 51% and severe mitral regurgitation. No significant coronary artery stenosis was noted. Transthoracic echocardiography revealed moderate concentric left ventricular hypertrophy, thickened mitral valve leaflets with severe regurgitation, and left atrial enlargement. Laboratory evaluation was notable for the following: hemoglobin 8.6 g/dL, hematocrit 28%, platelets 220,000/μl, PT 12.9 s, INR 1.1, aPTT 45.8 s, anticardiolipin immunoglobulin G 1545, anticardiolipin immunoglobulin M 11, positive platelet neutralization and hexagonal phase phospholipid test results, and a positive lupus anticoagulant panel. Preoperatively, a heparin-Celite ACT titration curve was performed, as described below. Initiation of CPB was preceded by the administration of 400 U/kg porcine heparin. Celite ACT and anti-Xa concentrations were monitored throughout surgery (Fig. 2). After heparin administration, but before CPB, ε-aminocaproic acid was administered as a 10-g bolus followed by an infusion (1 g/h) which was continued until arrival in the intensive care unit. Three units of packed red blood cells and 1 unit of platelets were administered in the perioperative period. After an uneventful recovery, the patient was discharged home on the sixth postoperative day with prophylactic warfarin therapy (INR 2.0–3.0).Figure 2: The relationship between anti-Xa concentration and activated clotting time (ACT) in Case Two.Method for Performance of Heparin-Celite ACT Titration Curve Before the induction of anesthesia, patient-specific in vitro heparin-celite ACT titration curves were generated. Briefly, porcine heparin (identical lot to that used intraoperatively for each patient) was diluted 1:10 by adding 0.5 mL of a 1000 U/mL concentration to 4.5 mL normal saline. Twenty, 50, or 100 μL of this heparin solution was then added to 2 mL of whole blood to obtain the final heparin concentrations (1, 2.5, and 5.0 U/mL, respectively). Celite ACT’s were performed in duplicate. Based on the patient-specific titration curve, therapeutic anticoagulation (heparin concentration >3.0 U/mL) for CPB was achieved in both patients at celite ACT values exceeding 550 s. Discussion APL syndrome characterizes an autoimmune disorder in which antibodies are directed against anionic phospholipid/protein complexes. These antibodies are often associated with autoimmune diseases, such as systemic lupus erythematosus; however, they may occur independently. APL syndrome comprises a diverse array of diagnostic features including venous and/or arterial thromboses, recurrent fetal loss, and thrombocytopenia. In addition, neurologic manifestations of APL syndrome have been reported to include recurrent cerebral infarcts, headaches, and visual disturbances (1–2). Patients with APL syndrome often experience valvular heart disease with a predilection for mitral valvular dysfunction (5). Monitoring anticoagulation in the patient with APL syndrome requiring cardiac surgery remains problematic. APL antibodies often interfere with in vitro tests of hemostasis by impeding the anchoring of coagulation proteins to phospholipid surfaces (6). Initial identification of this artifact in patients with systemic lupus erythematosus resulted in the misnomer “lupus anticoagulant” being applied to what is a more generalized phenomenon. There is no consensus in the literature as to the optimal method for assuring adequate perioperative anticoagulation in APL syndrome. Sheikh et al. (7) elected to empirically double the ACT to more than 999 seconds; obtaining factor Xa or plasma heparin concentrations was considered impractical. A second report measured both the ACT and plasma heparin levels during CPB (8). Interestingly, in this case, the patient’s plasma heparin level decreased to 1.5 mg/kg at one point during CPB despite an ACT greater than 999 seconds. Previous reports suggest that heparin concentrations of 2–3 U/mL minimize activation of coagulation during CPB (9); however, in our cases, point-of-care heparin concentration monitoring was unavailable. We elected to perform heparin-celite ACT titration curves preoperatively on each patient to assess the effect of APL antibodies on ACT monitoring. In addition, the titration curves provided a “target” ACT concentration correlating with appropriate heparin concentrations for institution of CPB for each patient. As a secondary confirmatory measure, laboratory-based anti-Xa monitoring was performed concurrently during CPB. Lack of point-of-care testing for plasma anti-Xa concentrations required transport of samples to our central laboratory; however, with advance planning, turnaround time was reduced to approximately 30 minutes. Anti-Xa monitoring is generally considered the “gold standard” laboratory measure of heparin therapy for use in situations in which the aPTT may be adversely affected. By using this testing method, known concentrations of purified coagulation factor Xa and antithrombin are mixed with a sample of the patient’s heparin-containing plasma. After the heparin and antithrombin within the sample have been allowed to inhibit a proportional amount of factor Xa in the patient sample, a chromogenic substrate which is cleaved by factor Xa is added to the sample, the concentration of factor Xa remaining is quantitated by spectrophotometry, and a standard reference curve is used to determine the quantity of heparin within the patient’s plasma sample before testing. In our patients, the celite ACT appeared relatively unaffected by the presence of APL antibodies; however, the potential for APL antibody interference with the ACT necessitates preoperative confirmatory testing to verify that the ACT is unaffected before instituting this form of monitoring. This report is the first published description of perioperative antifibrinolytic drug administration in patients with APL syndrome. Thrombotic complications intermittently accompany the diagnosis of APL syndrome and appear to result from APL-mediated displacement of annexin-V from phospholipid surfaces (6). Annexin-V is an anticoagulant protein which binds to phospholipids blocking coagulation factors from obtaining binding sites to allow activation. Displacement of annexin-V by APL antibodies increases the quantity of coagulation factor binding sites potentially leading to a procoagulant state. CPB induces multiple hemostatic defects including dilution of clotting factors, qualitative and quantitative disorders of platelet function, and fibrinolysis (10). There is considerable evidence to suggest that prophylactic antifibrinolytic therapy decreases bleeding associated with cardiac surgery (11), and the synthetic antifibrinolytic drug, ε-aminocaproic acid, is routinely administered to all adult patients undergoing primary elective coronary artery bypass graft surgery at our institution. The mechanism by which ε-aminocaproic acid inhibits fibrinolysis, namely competitive inhibition of plasmin(ogen) lysine binding sites (12), differs from the mechanism by which APL antibodies are proposed to induce a hypercoagulable state (6). Given this information, and the fact that no outcome-based investigations with the synthetic antifibrinolytics have suggested an increased thrombotic risk, we elected to administer ε-aminocaproic acid in both patients. In our opinion, the risk for bleeding-related complications after cardiac surgery outweighed the remote theoretical risk of perioperative thrombosis. Neither patient experienced clinically apparent thrombotic complications in the postoperative period. APL syndrome is a relatively common diagnosis in hospitalized patients with the potential to adversely affect multiple forms of anticoagulation monitoring in the perioperative setting. In this report, we have demonstrated the feasibility of performing heparin-ACT titration curve testing preoperatively to assess APL antibody effects on the celite-ACT and to determine patient-specific target ACT levels before initiating CPB. Preoperative heparin-ACT titration testing offers a simple, inexpensive option for evaluating the feasibility of ACT monitoring in the setting of APL syndrome. In addition, we report uncomplicated administration of antifibrinolytic therapy in two patients with APL syndrome requiring cardiac surgery with CPB. Further investigation of the safety of antifibrinolytics in conjunction with APL syndrome is needed.