Hemostasis Alterations in Patients With Acute Aortic Dissection

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1 ADULT CARDIAC Hemostasis Alterations in Patients With Acute Aortic Dissection Domenico Paparella, MD, Crescenzia Rotunno, BSc, Pietro Guida, PhD, Pietro Giorgio Malvindi, MD, Giuseppe Scrascia, MD, Micaela De Palo, MD, Emanuela de Cillis, MD, Alessandro S. Bortone, MD, PhD, and Luigi de Luca Tupputi Schinosa, MD Division of Cardiac Surgery, Department of Emergency and Organ Transplant, University of Bari, Bari, Italy Background. Surgery for acute aortic dissection (AAD) is frequently complicated by excessive postoperative bleeding and blood product transfusion. Blood flow through the nonendothelialized false lumen is a potential trigger for the activation of the hemostatic system; however, the physiopathology of the aortic dissection induced coagulopathy has never been precisely studied. The aim of the present study is the evaluation of the coagulation and fibrinolytic systems and platelet activation in patients undergoing surgery for AAD. Methods. Eighteen patients undergoing emergent surgery for Stanford type A AAD were enrolled in the study. The activation of the coagulation and fibrinolytic systems and platelet activation were evaluated at 6 different time points before, during, and after the operation, measuring prothrombin fragment 1.2 (F1.2), plasmin-antiplasmin complex, and platelet factor 4, respectively. Results. All measured biomarkers were increased before, during, and after the operations indicating a systemic activation of coagulation, fibrinolysis, and platelets. These changes were pronounced even preoperatively (T), and soon after the beginning of cardiopulmonary bypass (T1) when the influence of hypothermia and prolonged cardiopulmonary bypass time were not yet involved. Time from symptom onset to intervention inversely correlated with preoperative F1.2 (r.75; p.2) and plasmin-antiplasmin levels (r.57; p.34). Conclusions. Blood flow through the false lumen is a powerful activator of the hemostatic system even before the operation. This remarkable activation may influence postoperative outcome of AAD patients. (Ann Thorac Surg 211;91:1364 7) 211 by The Society of Thoracic Surgeons Acute aortic dissection (AAD) represents a dramatic event with a high risk of mortality and morbidity. Patients with dissections involving the ascending aorta (type A, according to Stanford classification) require immediate surgical correction to avoid cardiac tamponade and sudden death. Despite improvements in prompt diagnosis and appropriate surgical techniques for different clinical presentations of the pathology, surgical results are still aggravated by a higher incidence of morbidity and mortality compared with other cardiac operations [1]. Among all possible complications associated with this type of surgery, postoperative bleeding and blood products transfusion represent one of the most common and feared. It is common experience that patients undergoing surgery for AAD bleed excessively even before cardiopulmonary bypass (CPB) institution and the presence of a coagulopathy or disseminated intravascular coagulation in patients with ruptured or dissecting aortic aneurysm was suggested a long time ago [2, 3]. Blood flow through the nonendothelialized false lumen, tissue damage, and Accepted for publication Jan 2, 211. Address correspondence to Dr Paparella, University of Bari, Division of Cardiac Surgery, Dipartimento di Emergenza e Trapianti di Organo (DETO), Piazza Giulio Cesare 11 Bari 7124, Italy; dpaparella@cardiochir.uniba.it. turbulence are all valid triggers for the activation of the coagulation system; however, the physiopathology of the AAD induced coagulopathy has never been precisely studied either preoperatively or during and immediately after surgery. The aim of the present study is to document the state of the coagulation and fibrinolytic systems and platelet activation in patients undergoing emergent surgery for AAD. To this purpose we measured biomarkers that are specific for thrombin generation (prothrombin fragment 1.2, F1.2), fibrinolysis activation (plasmin-antiplasmin complex [ PAP]), and platelet activation (platelet factor 4 [PF-4]). The analysis was performed before, during, and immediately after the operation, providing a detailed description of the hemostatic state in this emergent situation. Material and Methods The design was a single-center and prospective study. The local Ethics Committee approved the study protocol and consent was obtained from the patients or their relatives. From April 27 to May 29, 18 patients who underwent emergent surgery for Stanford type A acute aortic dissection were enrolled in the study. Patients with known preexisting coagulative disorders, liver 211 by The Society of Thoracic Surgeons /$36. Published by Elsevier Inc doi:1.116/j.athoracsur

2 Ann Thorac Surg PAPARELLA ET AL 211;91: HEMOSTASIS IN ACUTE AORTIC DISSECTION disease, or who were receiving oral anticoagulant or antiplatelet treatment were excluded from the study. The primary endpoint of this study was to evaluate, in patients with acute aortic dissection, the state of the coagulation and fibrinolytic systems and platelet activation at hospital admission, during the operation, and in the postoperative period. Definitions Hypertension was defined as blood pressure exceeding 14 over 9 mm Hg, having a history of high blood pressure, or needing antihypertensive medications. Patients having a history of diabetes regardless of the duration of disease (or the need of antidiabetic agents) were considered diabetic. Chronic obstructive pulmonary disease (COPD) was defined as forced expiratory volume of air in 1 second less than 75% or the need of pharmacologic therapy for the treatment of chronic pulmonary compromise. Preoperative renal disease was defined as serum creatinine greater than 2. mg/dl. Death within the same hospital admission regardless of the cause was defined as operative mortality. Low cardiac output syndrome was defined as the need for postoperative inotropic support for more than 12 hours to maintain systolic blood pressure greater than 9 mm Hg, mean blood pressure greater than 6 mm Hg, or the cardiac index greater than 2.2 L min 1 m 2, despite sufficient volume implementation. Extubation criteria were hemodynamic stability, absence of surgical bleeding, fully rewarming, consciousness, optimal blood gases with fraction of inspired oxygen of.3 or less, and without the need for mechanical assistance (continued positive airway pressure-assisted spontaneous breathing less than 5 cm H 2 O). Cerebrovascular disease was regarded as any transient ischemia attack, reversible ischemic neurologic deficit, or stroke. Acute renal failure was defined as the following: (1) new onset of postoperative creatinine greater than 2. mg/dl; (2) increase of creatinine greater than twofold compared with preoperative creatinine; or (3) requirement of postoperative dialysis. During and after the operation, blood and blood products were transfused only if the patient had signs of hypovolemia (hypotension or tachycardia) and according with the following criteria: allogenic packed red blood cells were transfused if the hemoglobin value was less than 8 g/dl or the hematocrit was less than 24%. Fresh frozen plasma was infused if the Prothrombin Time - International Normalized Ratio (PT-INR) value after protamine administration was at least 1.5 times the baseline in the presence of significant bleeding, and platelet concentrates were transfused with platelet count less than 5,/mm 3. Surgical Management Patients were admitted to the Division of Cardiac Surgery of the University of Bari coming from peripheral hospitals or directly from the Emergency Department of the same hospital. Delay from symptom onset to intervention reflects the time needed for definitive diagnosis, patient transfer, and operating theatre availability. After 1365 premedication with lorazepam, anesthesia was induced with a combination of fentanyl, midazolam, and sodium thiopenthal and maintained with propofol. The surgical approach was always a median sternotomy. The AAD patients received bilateral radial artery blood pressure monitoring, near-infrared spectroscopy, bladder and nasopharyngeal temperature, and transesophageal echocardiography. Cardiopulmonary bypass was established after cannulation of femoral artery (1 patients), right axillary artery (5 patients), aortic arch (2 patients), and combined (axillary-femoral, 1 patient) for the arterial line and atriocaval cannulation for venous return. Mean lowest temperature during CPB was 23 4 C ( C for patients not requiring deep hypothermic circulatory arrest (DHCA) and C for those requiring DHCA. The DHCA was used in 7 patients in whom antegrade selective cerebral perfusion (6 bilateral, 1 unilateral) was also performed (mean time of circulatory arrest: minutes; mean time of antegrade selective cerebral perfusion: minutes). Myocardial protection was obtained using Custodiol (Dr F Kohler Chemie GMBH, Alsbach, Germany) solution infusion in the aortic root or directly in coronary arteries ostia. The Bentall procedure was performed in 8 patients, ascending aorta replacement in 3, ascending aorta plus aortic valve replacement in 3, and ascending aorta replacement plus aortic valve repair in 4 patients. Five patients received associated aortic arch or hemiarch replacement and 3 patients received combined coronary artery bypass grafting. Before the beginning of CPB, 3 g of tranexamic acid was administered to all patients. Heparin dosage was 3 U/kg and intraoperative heparin monitoring (ACT System, Medtronic Inc, Minneapolis, MN) was achieved using the standard activated clotting time. Additional heparin boluses (5, U) were given if the ACT values were below 4 seconds. Protamine sulfate was administered to reverse heparin. All patients were admitted postoperatively in the intensive care unit. Blood Collection Blood samples were collected at different times; before, during, and after the operation (T before surgery; T1 45 minutes after CPB; T2 before protamine administration; T3 3 minutes after protamine administration; T4 3 hours after the end of CPB; and T5 24 hours after the end of operation). Blood was taken from the central venous catheter or peripheral vein and anticoagulated with sodium citrate (.39%, final concentration) to measure plasma levels of F1.2 and PAP, with a mixture of citrate, theophylline, adenosine, and dipyridamole to measure plasma levels of PF4. Blood samples were centrifuged for 15 minutes at 3,5 rpm at 4 C and frozen at 8 C until assayed. Assays Specific assays were performed to assess the activation of coagulation, fibrinolysis, and platelets. Plasma was assayed by the monoclonal antibodies sandwich enzymelinked immunosorbent assay (ELISA) technique. Activa- ADULT CARDIAC

3 ADULT CARDIAC 1366 PAPARELLA ET AL Ann Thorac Surg HEMOSTASIS IN ACUTE AORTIC DISSECTION 211;91: tion of the coagulation system was evaluated by assessing thrombin generation through the prothrombin fragment 1.2 determination (F1.2, Enzygnost F1 2 monoclonal; Dade Behring, Marburg, Germany; median levels in normal human plasma: 115 pmol/l, range 69 to 229 pmol/l); the activation of the fibrinolytic system was measured by the PAP complex (median levels in normal human plasma is measured at 131 ng/ml with a range from to 514 ng/ml - PAP (Imuclone PAP ELISA Kit; American Diagnostica Inc, Stanford, CT) and the platelet activation by means of PF4 (concentration in normal human plasma is less than 1 UI/mL (PF4; Imuclone Platelet Factor 4 ELISA Kit, American Diagnostica Inc). Hematocrit (HKT), hemoglobin, and platelet count were measured at all sample times. All ELISA assays were doubled tested, and the mean value was used for analysis. Results were corrected for hemodilution according to the formula: (corrected assay)tx (assay)tx (HKT)T/(HKT)Tx. Statistical Analysis The data are given as mean values standard deviation unless otherwise specified; categoric variables are described as percentages. Because of the small number of patients, the continuous variables were compared using a nonparametric test. Differences within groups were analyzed by analysis of variance (Friedman test) and sign test; between-group comparisons were made by the Mann Whitney U test. The linear correlation was assessed by using the Pearson coefficient transforming values on a base 1 logarithm scale. The Spearman rank correlation test was used to assess relations between variables. The analyses were made using Statistica 6.1 software (StatSoft Inc, Tulsa, OK), and p values less than.5 were considered statistically significant. Results Patients characteristics are depicted in Table 1. Most of the AAD group patients had chest pain (94%) as the predominant preoperative symptom. Time from symptom to diagnosis was 1 9 hours (range 1 to 24) and time from symptom to intervention was 14 1 hours (range 4 to 32). Preoperative routine assays demonstrate that patients with AAD have very high D-dimer levels and increased white blood cells (Table 1). Perioperative clinical course is described in Table 2. Not surprisingly, AAD patients required long cross-clamp and CPB times; postoperative clinical outcome was also complicated in these patients, with a hospital mortality of 22%. As expected, AAD patients had a high rate of postoperative bleeding and blood products transfusion. Platelet count was low on postoperative day 1 compared with preoperative values (p.5). All measured biomarkers were altered before, during, and after the operations indicating a systemic activation of coagulation, fibrinolysis, and platelets. These changes were pronounced even preoperatively (T), and soon after the beginning of CPB (T1) when the influence of hypothermia and prolonged CPB time were not yet Table 1. Preoperative Characteristics According to Study Groups Characteristic involved. Time from symptom onset to intervention inversely correlated with preoperative F1.2 ( r.75; p.2) and PAP levels (r.57; p.34). The F1.2 measurement demonstrates that thrombin generation is markedly elevated preoperatively (Fig 1A) and is amplified during CPB, reaching extremely higher levels during and after the operation. The PAP complexes displayed a fairly similar pattern with very high values observed preoperatively and postoperatively (Fig 1B). The PF4 measurement documents maximal platelet activation soon after the beginning of CPB and after crossclamp release (Fig 1C). Preoperative F1.2 values did not correlate with postoperative blood loss or blood products transfusion. Preoperative PAP levels correlated with fresh frozen plasma transfusion (r.7) but not with postoperative blood loss or red blood cell transfusion. Seven patients underwent DHCA (mean temperature: C). These patients showed lower intraoperative F1.2 and PAP values (Fig 2) compared with the remaining 11 patients (mean temperature: C). Significant differences were observed in PAP levels at T2 (p.14) and T3 (p.4). Comment Aortic Dissection (n 18) Males (%) 44 Age (years) Body mass index (kg/m 2 ) 26 4 Hypertension (%) 67 Diabetes mellitus (%) 11 Chronic obstructive pulmonary 11 disease (%) Previous myocardial infarction (%) 6 Chronic kidney disease (%) 11 Creatinine (mg/dl) Cardiac Troponin I (ng/ml) Fibrinogen (mg/dl) Prothrombin time (INR) Activated partial thromboplastin time (seconds) White Blood Cells ( 1 3 /ul) Hemoglobin (g/dl) Hematocrit (%) 36 5 Platelet ( 1 3 /ul) D-dimer (ng/ml) 4,257 4,23 Mean values standard deviation or percentage of patients. INR International Normalized Ratio. Our study specifically describes the coagulation and fibrinolytic state and platelet activation in patients undergoing surgery within 32 hours from the onset of

4 Ann Thorac Surg PAPARELLA ET AL 211;91: HEMOSTASIS IN ACUTE AORTIC DISSECTION Table 2. Intraoperative and Postoperative Variables Variable Aortic Dissection (n 18) CPB time (minutes) Cross-clamp duration (minutes) Lowest CPB temperature C 23 4 Heparin dose (U) 22,5 5,73 Protamine dose (mg) Heparinization time (minutes) Intraoperative blood (units/patient) Intraoperative fresh frozen plasma (units/patient) Intraoperative platelet (unit/patient) Overall stay (days) Intensive care unit stay (hours) Intubation (hours) Reopening for bleeding (%) 17 Chest tube drainage (ml) Pleural blood loss (ml) Postoperative blood (units/patient) Postoperative Fresh frozen plasma(units/patient) Postoperative platelet (unit/patient) Intraoperative and postoperative blood (units/patient) Intraoperative and postoperative fresh frozen plasma (units/patient) Intraoperative and postoperative platelet (unit/patient) Postoperative day 1 troponin (ng/ml) Postoperative day 1 platelet ( 13/uL) Postoperative day 1 fibrinogen (mg/dl) Atrial fibrillation (%) 33 Acute kidney injury (%) 5 Cerebrovascular disease (%) 17 Sepsis (%) 17 Multiple organ failure (%) 11 Overall mortality (%) 22 Interestingly, preoperative F1.2 and PAP levels decrease with time from symptom onset suggesting that after an initial burst the consumption of the coagulation factors determines a subsequent reduction of thrombin and plasmin generation. This is in line with the findings of Suzuki and colleagues [6] showing, in AAD patients, higher preoperative D-dimers levels within the first 6 hours from dissection onset compared F 1.2 (pmol/l) A PAP (ng/ml) B T T1 T2 T3 T4 T5 145± ± ± ± ± ±1478 T T1 T2 T3 T4 T5 1652± ±32 341± ± ± ± ADULT CARDIAC Mean values standard deviation or percentage of patients. CPB cardiopulmonary bypass. acute aortic dissection. A few other reports have focused their attention to this topic [4, 5] but none of them described the state of AAD patients before, during, and immediately after the emergent operation. We demonstrate that blood flow through the false lumen is a powerful activator of the coagulation and fibrinolytic systems even before the operation. Preoperatively, D-dimers were markedly higher than normal as a consequence of fibrin formation and degradation, suggesting intense activation of the coagulation system. With the underlying mechanism possibly being blood contact with tissue factor-secreting fibroblast of the adventitia and tissue factor-secreting smooth muscle cells of the media layer of the aorta. We document intense preoperative thrombin generation and fibrinolysis and platelet activation. PF4 (pg/ml) C T T1 T2 T3 T4 T5 96±14 287±19 287±25 221±19 138±12 83±13 Fig 1. Mean values (standard error) of F1.2 (A), plasmin-antiplasmin (PAP) levels (B), and platelet factor 4 (C) in aortic dissection; T before surgery; T1 45 minutes after cardiopulmonary bypass (CPB); T2 before protamine administration; T3 3 minutes after protamine administration; T4 3 hours after the end of CPB; T5 24 hours after the end of operation. Dotted lines represent ranges of plasma biomarker concentration in normal population. Analysis of variance Friedman test was p.1 for each comparison. ( p.5 versus previous phase by means of sign test.)

5 ADULT CARDIAC 1368 PAPARELLA ET AL Ann Thorac Surg HEMOSTASIS IN ACUTE AORTIC DISSECTION 211;91: F 1.2 (pmol/l) A PAP (ng/ml) B T T T1 DHCA T1 with the following 18 hours [6] and may also explain why D-dimers are not always elevated in patients with AAD [7]. When these patients are then exposed to CPB surgery thrombin and plasmin generation are greatly amplified, reaching extremely higher values compared with patients undergoing standard CPB surgery [8]. In order to appreciate the magnitude of the activation of the hemostatic system observed in AAD patients, we should refer to studies in which CPB surgery was compared with off-pump procedures [8]. In these studies patients undergoing CABG operation with CPB had a remarkable generation of thrombin compared with off-pump surgery, but this reaction appears only modest compared with the reaction that we now describe in AAD. In order to demonstrate a clear influence of this process on the clinical outcome of AAD patients, a larger study group should be evaluated. In this study we could only demonstrate a significant correlation between preoperative PAP levels and fresh frozen plasma transfusion. However, some of the issues raised by our analysis have already been evaluated in other clinical context after CPB surgery. Thrombin generation has, in fact, a central role determining the CPB T2 T2 T3 T3 T4 T4 T5 No DHCA Fig 2. Mean values (standard error) of F1.2 (A) and plasmin-antiplasmin (PAP) levels (B) with ( ) and without deep hypothermic circulatory arrest (DHCA) (e); T before surgery; T1 45 minutes after cardiopulmonary bypass (CPB); T2 before protamine administration; T4 3 hours after the end of CPB; T5 24 hours after the end of operation. T3 sample was not performed in coronary artery bypass grafting patients and therefore the T3 column was omitted. ( p.5 DHCA versus No DHCA with the Mann- Whitney U test.) T5 induced coagulopathy [9]. Thrombin stimulates platelet activation and dysfunction and promotes coagulation factors consumption and excessive fibrinolysis [1], increasing postoperative blood loss and blood products transfusion [11, 12]. We may therefore speculate that massive thrombin generation before and during CPB surgery for AAD correction is one of the causes of coagulopathy and bleeding, complicating this type of surgery. Moreover, our data show that platelet activation, evaluated by measuring PF4 plasma concentration, was significantly increased in AAD patients before the operation, and 45 minutes after CPB it remained elevated during the operation and decreased after protamine administration. The PF4, which is found within platelet -granules and on the endothelium, is a member of the C-X-C subfamily of chemokines and is released in plasma as a consequence of platelet activation and degranulation. Platelet activation, in the context of our study, is certainly induced also by the concurrent contribution of hypothermia and prolonged CPB time; nonetheless thrombin is the most powerful platelet activator in vivo [9] and can be considered one of the main causes of platelet dysfunction in this context. Fibrinolysis, evaluated by PAP complex, is extremely more activated in AAD patients at the end of the operation despite antifibrinolytic prophylaxis with tranexamic acid given preoperatively. Excessive fibrinolysis is associated with postoperative bleeding [12] and can be a cofactor leading to hemorrhagic complications in AAD patients. We found decreased thrombin and plasmin generation in patients undergoing DHCA compared with patients receiving moderately hypothermic CPB. This interesting finding certainly deserves further analysis; however, the effects of hypothermia on the hemostatic system are known and may support it. Hypothermia, in fact, slows the activity of the coagulation cascade, an enzymatic process, reduces the synthesis of coagulation factors, and affects platelet function [13]. Our data seem to suggest that the preservation of the hemostatic system should be one of the objectives in the surgical treatment of AAD. How can this be achieved represents, certainly, a difficult question to answer. Theoretically, thrombin generation should be reduced before the operation but the anticoagulation of patients with an elevated hemorrhagic risk is a difficult task. Nevertheless, all efforts should be made to reduce CPB induced inflammatory response and coagulopathy, adopting those strategies known to be protective in this regard (ie, closed and coated circuits, limited cardiotomy suction). Recently, the benefit of steroid prophylaxis reducing postoperative complication (including postoperative bleeding) has been highlighted [14, 15], and their use in AAD patients should be the object of adequately designed prospective studies. Study Limitations Beginning with the third sample time (T2), it is difficult to separate the effects of the false lumen and those of extended CPB, hypothermia, and abundant blood prod-

6 Ann Thorac Surg PAPARELLA ET AL 211;91: HEMOSTASIS IN ACUTE AORTIC DISSECTION ucts transfusion. It would be useful to have a control group, consisting of patients undergoing elective complex ascending aorta and aortic arch repairs, in order to highlight the differences in the coagulative-fibrinolytic state between patients with AAD and patients requiring complex CPB surgery. Conclusion Acute aortic dissection is associated with an intense activation of the coagulation and fibrinolytic systems and platelets. During and after the operation with cardiopulmonary bypass this reaction is enormously amplified, possibly explaining the coagulopathy frequently observed during this kind of surgery. This study was supported in part by a Regione Puglia Government research grant (Progetto Esplorativo 127) and in part by University of Bari internal research funds. The authors wish to express their deep gratitude to Nicola Semeraro, MD (University of Bari) for kindly reviewing the manuscript. References 1. Trimarchi S, Nienaber CA, Rampoldi V, et al. Contemporary results of surgery in acute type A aortic dissection: the International Registry Of Acute Aortic Dissection experience. J Thorac Cardiovasc Surg 25;129: ten Cate JW, Timmers H, Becker AE. Coagulopathy in ruptured or dissecting aortic aneurysms. Am J Med 1975;59: Fisher DF, Yawn DH, Crawford ES. Preoperative disseminated intravascular coagulation associated with aortic aneurysms: a prospective study of 76 cases. Arch Surg 1983;118: Nomura F, Tamura K, Yoshitatsu M, Katayama A, Katayama K, Ihara K. Changes in coagulation condition, cytokine, 1369 adhesion molecule after repair of type A aortic dissection. Eur J Cardiothorac Surg 24;26: Nakajima T, Kin H, Minagawa Y, Komoda K, Izumoto H, Kawazoe K. Coagulopathy associated with residual dissection after surgical treatment of type A aortic dissection. J Vasc Surg 1997;26: Suzuki T, Distante A, Zizza A, et al. Diagnosis of acute aortic dissection by d-dimer. The international registry of acute aortic dissection substudy on biomarkers (IRAD-Bio) experience. Circulation 29;119: Paparella D, Malvindi PG, Scrascia G, et al. D-dimers are not always elevated in patients with acute aortic dissection. J Cardiovasc Med (Hagerstown) 29;1: Paparella D, Galeone A, Venneri MT, et al. Activation of the coagulation system during coronary artery bypass grafting: comparison between on-pump and off-pump techniques. J Thorac Cardiovasc Surg 26;131: Edmunds LH Jr, Colman RW. Thrombin during cardiopulmonary bypass. Ann Thorac Surg 26;82: Paparella D, Brister SJ, Buchanan MR. Coagulation disorders of cardiopulmonary bypass: a review. Intensive Care Med 24;3: Despotis GJ, Joist JH, Hogue CW Jr, et al. More effective suppression of hemostatic system activation in patients undergoing cardiac surgery by heparin dosing based on heparin blood concentrations rather than ACT. Thromb Haemost 1996;76: Edmunds LH Jr. Managing fibrinolysis without aprotinin. Ann Thorac Surg 21;89: Hardy JF, De Moerloose P, Samama M; Groupe d intérêt en Hémostase Périopératoire. Massive transfusion and coagulopathy: pathophysiology and implications for clinical management. Can J Anaesth 24;51: Whitlock RP, Chan S, Devereaux PJ, et al. Clinical benefit of steroid use in patients undergoing cardiopulmonary bypass: a meta-analysis of randomized trials. Eur Heart J 28;29: Cappabianca G, Rotunno C, de Luca Tupputi Schinosa L, Ranieri VM, Paparella D. Protective effects of steroids in cardiac surgery. A meta-analysis of randomized double blind trials. J CardiothoracVasc Anesth 211;25: ADULT CARDIAC INVITED COMMENTARY It has been known for some time that intravascular coagulation with thrombin and platelet activation, coupled with fibrinolysis, is present in patients presenting with symptomatic aortic dissection. The differential diagnosis of myocardial infarction and aortic dissection has received a diagnostic boost from the development of point-of-care testing, which rapidly reports plasma Troponin T and D-dimer levels from a small blood sample. Thus, it is not surprising that the authors of this paper [1] have demonstrated the rather remarkable levels of D-dimer, plasmin-antiplasmin ratio, and platelet factor IV levels in their group of patients who underwent operation for acute aortic dissection. It is also not surprising that patients who present to the operating room with ongoing consumptive coagulopathy would be a bleeding risk with a large aortic resection and grafting procedure. Therefore, their data regarding this process sets the stage for potential studies to assess treatment or, at least, amelioration of this condition. It is well known now that contact of blood with tissue factor from the patient s wound causes thrombin formation and platelet activation, which causes the coagulopathy during cardiopulmonary bypass. The administration of drugs, such as Alpha-Amino Caproic acid, can diminish the fibrinolysis associated with this process, which accentuates bleeding. Unfortunately, the actual dosing schedule of this compound has not been completely worked out (especially in complicated, high risk operations), and comparing postbypass D-dimer levels and using increasing doses of Alpha-Amino Caproic acid to treat ongoing fibrinolysis has not been systematically studied. The other commonly used anti-fibrinolytic agent, Tranexamic acid, has also had very few studies regarding effectiveness against ongoing fibrinolysis, and large doses have been shown to be associated with a high incidence of seizures. The most powerful antifibrinolytic agent, Aprotinin, is now off the market and out of the picture. There are other recombinant proteinase inhibitors be- 211 by The Society of Thoracic Surgeons /$36. Published by Elsevier Inc doi:1.116/j.athoracsur