Hemostatic Analysis of a Patient with Hereditary Angioedema Undergoing Coronary Artery Bypass Grafting

Hereditary angioedema (HAE), also known as hereditary angioneurotic edema, is an autosomal dominant disease with an incidence of 1 in 10,000 and is associated with episodes of acute swelling of the extremities, face, gastrointestinal tract, and airway (1). Although HAE is associated with a deficiency of functional C1 esterase inhibitor (C1INH) (2), the diagnosis of HAE is primarily based on clinical symptoms and family history. Patients with HAE may have normal or even supranormal C1INH activity but may still require chronic androgen or acute fresh-frozen plasma (FFP) administration to further increase C1INH activity to control their disease (3–6). C1INH not only regulates the initiation of the classical complement pathway but also regulates the activities of Factor XI and Factor XII, potentially enhancing the contact pathway of coagulation and fibrinolysis (3,7). Therefore, in addition to increased complement-mediated systemic inflammation associated with cardiopulmonary bypass (CPB), patients with HAE could potentially have enhanced hemostasis or exaggerated fibrinolysis during CPB. Previous reports have documented serial complement analysis during CPB in an attempt to better understand the impact this disease has on the inflammatory state associated with CPB (3,8,9). We present a case describing the impact of HAE on coagulation as assessed by serial thrombelastography (TEG®; Haemoscope, Skokie, IL) before, during and after CPB. Case Report The patient was a 58-year-old, 70-kg female with a 30-year history of HAE scheduled for coronary artery bypass grafting (CABG) surgery. She had unstable angina, symptoms of pulmonary venous hypertension, three-vessel coronary artery disease and an ejection fraction of <0.3. She had a family history of HAE (grandfather, uncle, mother, sister, and daughter) and had had multiple HAE attacks involving her extremities, face, colon, and oropharynx. She denied requiring emergent intubations or tracheotomy. Although noncompliant with her androgen therapy, she had been maintained on a prolonged course of methylprednisolone as well as antidepressants for mood control. Before the cardiothoracic anesthesia service was aware of the patient, she received a 6-day preoperative course of stanozolol 4 mg per os three times daily. The patient was administered 2 U of FFP on the morning of surgery to increase C1INH activity as recommended by the consultant hematologist. Before FFP administration, the patient had a prothrombin time of 13.1 sec (control value 12.4–14.4 sec), an activated partial thromboplastin time (aPTT) of 25 sec (control value of 25–34 sec) and a platelet count of 340,000 mm3. Preoperative TEG® analysis was performed before FFP administration via venipuncture, with the first 5 mL of blood discarded and a subsequent 2.7 mL anticoagulated with 0.129 M sodium citrate. Citrated blood was used, as it was not feasible to transport this sample to the TEG® in under 4 min. Consequently, all subsequent blood samples (obtained from a pulmonary artery catheter) were also citrated for consistency and placed into a computer-controlled TEG® within 40–60 min. The samples consisted of 330 μL of citrated blood to which was added 10 μL of normal saline or the platelet inhibitor cytochalasin D (10 μM final concentration), as has been previously described (10,11). TEG® analysis methodology is described in previous publications (10,11). Lastly, blood was recalcified with 20 μL of 2 M CaCl2, with TEG® analysis performed for 60 min. All TEG® and other hemostatic data are depicted in Table 1.Table 1: Thrombelastographic Variable, Activated Clotting Time and Platelet Concentration ValuesAnesthesia was induced with propofol and maintained with a balanced isoflurane/propofol/fentanyl technique. CABG was performed with a CPB time of 66 min at 34° and an aortic cross-clamp time of 34 min. A total of 38,000 U of heparin was administered during CPB. The patient was easily weaned from CPB, and 30 min after administration of 450 mg of protamine, 2 U of FFP, and 10 U of platelets were administered for microvascular bleeding with subsequent satisfactory hemostasis obtained. Compared with previously published control values for citrated TEG® (r = 21 min, range 18–24 min) (12), the patient’s R values were 5–10 times smaller than previously reported with citrated blood during the perioperative period (Table 1). The patient’s α values were nearly double that previously reported (α = 34°, range 28–48°) (9) and maximum amplitude (MA) values were significantly greater than formerly noted (MA = 49.5 mm, range 45–60 mm) (12) (Table 1). With regard to clot strength related to coagulation proteins (GSC), the patient’s values always exceeded a value of 10% of total clot strength previously reported (10). Total postoperative chest tube drainage was 1384 mL. There were no perioperative episodes of angioedema. The patient was discharged on postoperative day 6. Discussion The effects of CPB on patients with HAE have been anecdotally reported (7–9), with one report (7) of fatal coagulopathy observed after CPB, whereas other cases without clinically significant coagulopathy have been noted (8,9). Patients with HAE have increased Factors XI and XII activity, and an increase in the speed of clot initiation and formation was anticipated. This was evidenced by a small R time, steep α value, shortened activated clotting time (ACT), and low-normal aPTT. Further, CPB-mediated hemodilution, which has been noted to decrease α and MA (13), likely decreased this hypercoagulable state, which then reappeared after CPB with its concordant redistribution of intravascular fluid. An unanticipated finding was an increase in GSC, which is primarily mediated by fibrinogen (14). Such a finding is not unprecedented, as term parturients with increased fibrinogen concentration have been noted to have protein-mediated clot strength (15), nearly double the usual 10% of total clot strength based on changes in G (10). Of interest, stanozolol administration has been associated with a significant decrease in fibrinogen (16). Therefore, we speculate that HAE may be associated with increases in circulating fibrinogen and that the fluctuations in GSC observed in the present case were secondary to CPB-associated hemodilution. Given the hypercoagulable state observed, one might anticipate that these patients may be at risk for thrombotic disease. This is in fact not the case (3), and it has been speculated that endogenous serine protease inhibitors such as antithrombin III are capable, in concert with endogenous endothelial anticoagulant defenses, of preventing thrombosis in the presence of increased Factor XI and XII activity (3). In summary, we present the hemostatic course of a patient with HAE requiring CPB for CABG who received a typical prophylactic regimen. Throughout the perioperative period the patient was hypercoagulable (based on TEG®-derived data), primarily mediated by an increase in coagulation protein function. Of interest, no important clinical coagulopathy was noted, nor was there any significant thrombotic morbidity. Future study is warranted to obtain a better understanding of the balance of hemostasis and endogenous anticoagulants in patients with HAE.