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Table of Contents
REVIEW ARTICLE  
Year : 2013  |  Volume : 16  |  Issue : 2  |  Page : 117-125
Antifibrinolytics in cardiac surgery


Department of Anesthesia and Perioperative Medicine, London Health Sciences Centre, University Hospital, 339 Windermere Road, London, N6A 5A5, Ontario, Canada

Click here for correspondence address and email

Date of Submission11-Sep-2012
Date of Acceptance03-Dec-2012
Date of Web Publication29-Mar-2013
 

   Abstract 

Cardiac surgery exerts a significant strain on the blood bank services and is a model example in which a multi-modal blood-conservation strategy is recommended. Significant bleeding during cardiac surgery, enough to cause re-exploration and/or blood transfusion, increases morbidity and mortality. Hyper-fibrinolysis is one of the important contributors to increased bleeding. This knowledge has led to the use of anti-fibrinolytic agents especially in procedures performed under cardiopulmonary bypass. Nothing has been more controversial in recent times than the aprotinin controversy. Since the withdrawal of aprotinin from the world market, the choice of antifibrinolytic agents has been limited to lysine analogues either tranexamic acid (TA) or epsilon amino caproic acid (EACA). While proponents of aprotinin still argue against its non-availability. Health Canada has approved its use, albeit under very strict regulations. Antifibrinolytic agents are not without side effects and act like double-edged swords, the stronger the anti-fibrinolytic activity, the more serious the side effects. Aprotinin is the strongest in reducing blood loss, blood transfusion, and possibly, return to the operating room after cardiac surgery. EACA is the least effective, while TA is somewhere in between. Additionally, aprotinin has been implicated in increased mortality and maximum side effects. TA has been shown to increase seizure activity, whereas, EACA seems to have the least side effects. Apparently, these agents do not differentiate between pathological and physiological fibrinolysis and prevent all forms of fibrinolysis leading to possible thrombotic side effects. It would seem prudent to select the right agent knowing its risk-benefit profile for a given patient, under the given circumstances.

Keywords: Anti-fibrinolytics, Aprotinin, Coagulation, Hemostasis, Lysine analogues

How to cite this article:
Dhir A. Antifibrinolytics in cardiac surgery. Ann Card Anaesth 2013;16:117-25

How to cite this URL:
Dhir A. Antifibrinolytics in cardiac surgery. Ann Card Anaesth [serial online] 2013 [cited 2019 Sep 22];16:117-25. Available from: http://www.annals.in/text.asp?2013/16/2/117/109749



   Introduction Top


One of the most common indications for blood transfusions is perioperative bleeding [1] and cardiac surgery ranks high on the list. About 50-60% of cardiac surgery patients receive blood transfusions. [2],[3] Major surgical blood loss carries a strong and independent association with in-hospital mortality. [4] Blood loss significant enough to trigger blood transfusion is harmful and the degree of damage corresponds to the amount of blood loss. [5] Red blood cell transfusion in cardiac surgical patients is strongly associated with increased morbidity, increased early as well as late mortality, hospital stay, and hospital costs. [6],[7],[8],[9] Patients taken back to the operating room for control of bleeding after cardiac surgery have a four-fold increase in mortality and sternal infection. [10] If bleeding is bad, blood transfusion worse and, re-exploration the worst, the best logical option is to reduce blood loss during cardiac surgery.

Multimodal strategies are recommended to reduce perioperative blood loss during cardiac surgery, including the use of antifibrinolytic agents. Before its withdrawal, aprotinin was the most popular agent and the mainstay for anti-fibrinolysis during cardiac surgery, the world over. A non-specific serine protease inhibitor, aprotinin is derived from bovine lung, while tranexamic acid (TA) and epsilon aminocaproic acid (EACA) are synthetic derivatives of amino acid lysine. The latest Society of Thoracic Surgeons (STS) guidelines [11] recommend the use of anti-fibrinolytic agents (only lysine analogues), as a strategy to reduce perioperative blood loss during cardiac surgery. Withdrawal of aprotinin, but its recent re-introduction in Canada (under strict and very specific indications), along with the surge in reports of the neurological side effects of TA have created confusion and controversy about the best anti-fibrinolytic agent during cardiac surgery.

This review addresses some basic questions:

  1. Does fibrinolysis occur during cardiac surgery and is it exaggerated during cardiopulmonary bypass (CPB)?
  2. Does fibrinolysis account for increased bleeding during cardiac surgery?
  3. Is there a role for antifibrinolytic agents during cardiac surgery? If yes, which agent and what doses seem reasonable?
Fibrinolysis and surgery

Surgery results in tissue damage and blood loss, and immediately the hemostatic mechanisms are activated. Hemostasis can be considered as control of bleeding, wound healing, and tissue remodeling. It is a fine balance of four physiological processes, two promoting bleeding: Anticoagulant and fibrinolytic systems, while the other two promote clotting: Pro-coagulant and antifibrinolytic activities. Under normal circumstances, these activities occur in harmony and in a very precise and autoregulated fashion by which bleeding stops without any intravascular thrombosis. There are disease states where these four components of hemostasis may be dysregulated leading to either excessive bleeding or thrombosis or both. If not for the intact fibrinolytic system, even a small thrombus that is required to prevent bleeding from a blood vessel will rapidly progress to occlude the entire vessel. Excessive activation of the fibrinolytic system leads to a bleeding tendency, whereas, impaired activation leads to thrombotic complications. [12] Reduced fibrinolytic activity or fibrinolytic shutdown in the immediate postoperative period may be responsible for venous thrombosis [13] or graft occlusion. [14],[15]

In simple surgical procedures the hemostatic changes happen locally at the surgical site. In prolonged and extensive procedures, the changes are profound and generalized. Fibrinolytic activity at the surgical site has been seen to increase as much as four-to eight-fold. [16] The degree of fibrinolytic activation is also related to tissue injury and the type of surgery. Activation is more pronounced in major orthopedic and joint surgeries, as compared to other non-cardiac surgeries. [17] When locally released Thrombin-antithrombin complexes (TAT) and other cytotoxic chemicals reach the pulmonary circulation, there is activation of coagulation in the lung. Parallel to the increased intrapulmonary coagulation, increased fibrinolytic activity has also been observed. [17]

Cardiac surgery, cardiopulmonary bypass, and fibrinolysis

Tissue trauma along with the CPB circuit provides a strong stimulus for activation of coagulation during cardiac surgery. CPB adds major insult to the injury and creates a complex clinical scenario resulting in widespread activation and dysregulation of the hemostatic system. The flow diagram below depicts the activation of the coagulation and fibrinolytic systems during cardiac surgery [Figure 1].
Figure 1: Flow diagram depicting activation of coagulation and fibrinolytic activities during cardiac surgery (PKK -Pre kallikrein; HMWK -High molecular weight kininogen; tPA -Tissue plasminogen activator; FDPs -Fibrin degradation products)

Click here to view


Normally, fibrin is present only at the site of the wound and does not circulate in the blood. Approximately, only 1% of the fibrin circulates as soluble fibrin [18] and the majority of circulating soluble fibrin is non-hemostatic, generated due to the malfunction of the hemostatic system. At the commencement of CPB, total thrombin and fibrin generation is reduced because of heparinization, but the soluble fibrin formation is increased. Non-wound related thrombin generation and soluble fibrin formation are increased five- to ten-fold and remain high throughout the CPB. [19] Fibrin is degraded into soluble degradation products by a serine protease, plasmin, which is an activated form of plasminogen. Plasminogen is activated either by a tissue plasminogen activator (t-PA) or urokinase plasminogen activator (u-PA). Under normal conditions, the vascular endothelium is the main source of t-PA release and is the major activator of fibrinolysis. It is noteworthy that thrombin also causes the release of t-PA from the vascular endothelium. There seems to be more than one source of t-PA release, and another source is bradykinin. The Factor XIIa creates kallikrein from prekallikrein (PKK) and kallikrein cleaves high molecular weight kininogen (HMWK) into bradykinin. Under normal conditions, very low levels of kallikrein activity occur at the endothelial surface, as all the kinins (including bradykinin) are degraded by plasma kinases. During CPB, plasma kallikrein creates a positive feedback loop by cleaving more factor XII, as well as producing more bradykinin from HMWK. Although active thrombin seems to be the main source of t-PA release in in-vitro studies, [20] bradykinin appears to be the main stimulus for t-PA secretion during CPB. It has been shown that by blocking bradykinin receptors, [21] or by preventing the release of bradykinin by kallikrein inhibition, [22] t-PA release can be reduced. There seems to be a variability in the activation of the fibrinolytic system during CPB. Approximately one-third of the patients show no change in the fibrinolytic activity, while others show significant activation of the fibrinolytic system during CPB. [23] Other studies have shown a five-fold increase in t-PA secretion and active t-PA levels during CPB. [23],[24],[25] The t-PA progressively increases during bypass and remains elevated even up to two hours post bypass. [18] There is a 10-fold increase in bradykinin levels during CPB, [26] and a 10- to 100-fold increase in plasmin generation at the commencement of CPB. Throughout CPB, there is a 10-to 20-fold increase in plasmin generation and fibrin degradation. [27] Under normal conditions, only 1% fibrin is degraded by the fibrinolytic system, whereas, during CPB, fibrin formation and degradation rates are equal. This increased fibrinolysis consumes fibrinogen, leaving very little available for coagulation. [19]

Off-pump cardiac surgery

It would seem logical to surmise that once CPB is taken out of the picture, there would be little fibrinolysis. However, there are other common factors promoting fibrinolysis (surgical trauma, manipulation of the heart, heparin, protamine, etc.). With off-pump coronary artery bypass (OPCAB) surgery there is activation of the fibrinolytic system, but significantly less than on pump surgery. [28] However, there is activation of coagulation (and possibly fibrinolysis) during cardiac surgery without CPB. [29] By 24 hours, thrombin generation and fibrinolytic activity are equal in OPCAB versus on pump coronary artery bypass grafting (CABG). [30],[31]

Fibrinolysis and bleeding

Fibrinolysis plays an important role in clot resolution in the later process of healing. Increased fibrinolysis that follows tissue injury is considered to be responsible for bleeding and coagulopathy. [32] Increased fibrinolytic activity during CPB was not correlated with increased bleeding during cardiac surgery in the earlier studies. [33] However, later studies have shown the correlation of bleeding and fibrinolytic activity. [34],[35],[36] Circulating plasmin is mainly inactivated by α 2-antiplasmin and to a lesser degree by α 2-macroglobin. Excessive fibrinolysis, as seen in the deficiency of α 2-antiplasmin (both the congenital or acquired forms) causes premature dissolution of the clot and bleeding. [37] Spontaneous bleeding following fibrinolytic (thrombolytic) therapy with t-PA is not uncommon and is well-known in non-cardiac [38] as well as cardiac settings. [39] Simultaneous thrombin production and fibrinolysis during CPB lead to a bleeding disorder known as consumptive coagulopathy. [40]

Role of antifibrinolytic agents during cardiac surgery

There is enough evidence in the cardiac surgical literature to support the beneficial effects of antifibrinolytic agents. Compared to placebo, EACA, TA, and aprotinin (both the low and high doses) reduce the total blood loss and decrease the number of patients requiring blood transfusion. Aprotinin in a high dose is the only agent shown to reduce the re-exploration rate. [41] Another meta-analysis comparing the use of antifibrinolytic agents with placebo in patients on aspirin, undergoing cardiac surgery, aprotinin showed reduced chest tube drainage (average benefit of 374 ml). Again, aprotinin was more effective than the lysine analogs (432 ml vs. 189 ml). Patients receiving antifibrinolytic agents are less likely to receive blood transfusion (Odds ratio 0.34 for aprotinin, 0.97 for lysine analogs, and 0.37 combined). Any re-exploration benefit with antifibrinolytic agents was not detected in this meta-analysis (However, aprotinin again showed a tendency toward this benefit). [42] On account of the convincing evidence, the Society of Cardiothoracic Surgery and the Society of Cardiovascular. Anesthesiologists (SCA) updated the 2011 guidelines on blood conservation, which recommend the use of lysine analogs (Class 1A evidence). [11]

Which agent, what dose?

Aprotinin story


Aprotinin was discovered and isolated from bovine lung in 1936, [43],[44] and first used in humans for pancreatitis in Germany, in 1960. [45] In 1987, Royston, et al., [46] reported its use in redo cardiac surgery, while Bidstrup, et al., [47] introduced high dose aprotinin in cardiac surgery in 1989. On December 30, 1993, the Food and Drug Administration (FDA) announced its approval (limited indications) for its use in high-risk patients for CABG. [48] However, in 1998, the FDA expanded the indications for aprotinin use in all CABG patients. It became the mainstay for bleeding control and its use skyrocketed. Perhaps, this was the time when it was overused/abused. Since its introduction in cardiac surgery, aprotinin was surrounded by controversy. Studies did prove that aprotinin was very effective in reducing blood loss, but concerns were raised on its prothrombotic and renal effects as well as anaphylaxis. [49],[50],[51] In 2006, the FDA issued a Public Health Advisory for aprotinin based on two large observational studies. The first study by Mangano et al., [52] reported that aprotinin may be associated with increased risk of cardiovascular events (myocardial infarction or heart failure), cerebrovascular events (stroke, encephalopathy, or coma) and renal dysfunction/failure. The second study by Karkouti et al., [53] reported increased risk for renal toxicity with the use of aprotinin. Proponents of aprotinin argued that these studies were observational, non-randomized, and both compared aprotinin to products that were not FDA-approved at that time. On the other hand, Mangano et al., [52] pointed out that the majority of previous trials on aprotinin were insufficiently powered to detect increased mortality or rate of myocardial infarction. Most studies were sponsored and policed by the manufacturers of aprotinin, and thereby, potentially biased.

On 15 December, 2006, FDA revised aprotinin advisory, labeling to limit its use to specific situations. In 2007, Bayer Inc. released the results of its self-commissioned observational study, [54] showing an increase in kidney damage, congestive heart failure, stroke, and mortality. This quickly triggered serious safety warnings. The Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study [55] was the final nail in the coffin. Its preliminary results showed increased mortality with aprotinin compared to lysine analogues. Immediately, in November 2007, the manufacturer Bayer Inc. temporarily suspended marketing of the drug at the request of Health Canada. By May 2008, Bayer had removed the remaining stocks and withdrawn aprotinin from the world market.

Post aprotinin dilemma

The aprotinin chapter did not close there. Several studies since then have been conducted and several editorials published. Again, and as before, some favor while others refute the drug's withdrawal. [56],[57],[58]

The aprotinin case also highlights some ethical issues of drug regulation and safety with regard to the researchers, regulation bodies, and the pharmaceutical industry. The article by Katchky and Morgan [59] elaborates these ethical aspects and highlights some lesser-known facts about the aprotinin saga, the role of the researchers (Mangano), regulatory authorities (FDA), and the manufacturer (Bayer). Many physicians are dissatisfied with the removal of aprotinin from their practice. They feel that much harm is being done by not being able to use aprotinin. [60],[61] Several databases, both clinical and administrative revealed extremely divergent results. Even as some [62],[63],[64] found poor outcome with aprotinin, others [65],[66],[67],[68] did not find any adverse effects of aprotinin. In risk-adjusted models comparing aprotinin (1343 patients) with EACA (6776 patients) and no antifibrinolytics (2029 patients), worse survival was observed in the aprotinin group. [62] Schneeweiss et al., [64] analyzed the database of over 75,000 patients and observed that the aprotinin group had higher mortality within seven days of surgery compared to the EACA group. Unadjusted risk of in-hospital mortality was 83% higher with aprotinin, and the seven-day mortality was also increased by 78%. Stamou et al., [69] found that aprotinin did reduce hemorrhage-related re-exploration, but at the same time, increased the risk of in-hospital cardiac arrest and late mortality.

On the other hand, Wang et al., [70] comparing aprotinin with no aprotinin (post aprotinin era), showed higher blood loss, rate of transfusion, and re-exploration for bleeding in the no-aprotinin (or any other antifibrinolytic agent) group. Their study also showed that with aprotinin, the ventilation time was shorter with no increase in in-hospital mortality or other major adverse events. Another retrospective study by Sniecinski et al., [71] compared their center's results for hypothermic circulatory arrest. As compared to aprotinin (when it was available and used) TA (post aprotinin era) showed increased use of blood products and recombinant factor VIIa in the post aprotinin era. In neonatal cardiac surgery, increased blood loss was reported after withdrawal of aprotinin, [72] with no improvement in mortality and renal dysfunction. [73] There could be inherent flaws in the before/after studies, but these studies underscore the same dilemma.

Questions were also raised about the research methods and data analysis of the BART trial, as this was the ultimate deciding trial for aprotinin suspension. An independent analysis of the BART data and its analysis by the Bayesian statistical model did not show increased mortality in the high-risk group. [74],[75] Karkouti et al., [76] proposed the use of aprotinin in high-risk patients, as it tended to have a better risk/benefit profile in this subset of patients. In December 2008, Health Canada set up an expert advisory panel to discuss the benefit/risk issues of aprotinin and the panelists were asked very specific questions. The panel found some fundamental problems with the BART trial. First of all, the primary outcome in the BART trial was risk of massive bleeding and not the mortality. The trial was not sufficiently powered to detect the difference in mortality. Even as the BART trial was proposed for 'high-risk' patients the panel found that the patients belonged to the 'moderate-risk' group. High-risk patients were either not enrolled or excluded from the trial. Another prominent finding was the exclusion of 137 patients after randomization. Data of these excluded patients was requested and provided by the researchers. The aprotinin group in this subgroup showed lower mortality and no satisfactory explanation was provided. Combining data from both the included and the excluded patients showed that mortality in the aprotinin group was not statistically significantly higher and could have occurred by chance. The panel concluded that the risk/benefit ratio for aprotinin was still favorable as the trials responsible for its initial approval were still relevant. However, further studies were needed to define the risk/benefit of aprotinin for unauthorized indications. The panel did not find any advantage of aprotinin in low-risk patients, with an expected blood transfusion of one to three units. In these situations, blood transfusion would be safer than aprotinin. The risk of blood transfusion increased markedly when more than four units were transfused, in which case, aprotinin was better. In September 2011, Health Canada sent a letter to all health professionals informing them of the lifting of the temporary suspension of aprotinin in Canada. Aprotinin has been authorized to be used only for isolated CABG surgery in Canada, and only after careful consideration of the potential risks and benefits. [77]

Analogues of the amino acid Lysine

TA and EACA are synthetic compounds with small molecular weight and half-life of about 80-120 minutes. On a molar basis, TA is at least seven times more potent than EACA. Compared to the controls, both TA and EACA reduced the need for blood transfusion (TA more than EACA). [78] TA saved an average of 300 ml of blood per patient during cardiac surgery, with relative risk reduction of 32% in receiving blood transfusion. EACA saved an average of about 200 ml of blood during cardiac surgery, with 30% relative risk reduction in blood transfusion. In recent times, TA had also been seen to reduce blood loss during OPCAB surgery. [79] Both TA and EACA did not reduce the need for re-exploration, but at the same time, did not increase the mortality. [78] Comparing high dose TA to aprotinin, Sander et al., [80] found an increased rate of late ischemic stroke and neurological disability with aprotinin, while postoperative convulsive seizures, chest tube drainage, and re-exploration rate was higher in the TA group. Interestingly, they also found increased mortality in the TA group, in open-chamber procedures. Another meta-analysis showed that TA, in comparison to placebo, reduced blood loss (average of 298 ml), reduced the need for packed cells by 47%, other blood products by 67%, and reduced the rate of re-operations by 48%. [81] There was a wide dose range of TA in this meta-analysis, which also noticed a non-significant tendency for postoperative neurological events. New onset seizures were reported with both agents (TA more than EACA: 7.6% vs. 3.3%). [82] Both agents were also implicated in renal dysfunction during cardiac surgery (EACA: 30%, TA: 20%). Seizures associated with the use of lysine derivatives could be due to gamma-aminobutyric acid (A) receptor antagonism with possible involvement of other receptors. [83] Another hypothesis for TA-induced seizures was cerebral ischemia caused by either vasospasm or thrombosis. [84] Montes et al., [85] reported a seizure frequency of about 3.5% and its association with higher serum creatinine levels. TA, if applied directly to brain tissue or its high concentration in the cerebrospinal fluid (as observed with high doses during cardiac surgery) caused neurotoxicity. [86],[87]

TA dosing

Opinions about the optimal dose are equally controversial with a wide variety of dosing regimens. As high-dose TA is implicated in postoperative seizures, the lowest possible dosing is advised. [88] Armelin et al., [89] compared the low and high doses of TA and found no difference in blood loss or transfusion requirements. The plasma concentration of TA that is required to inhibit fibrinolysis in vitro is 10 μg/ml. [90] The dose of TA that is needed to maintain plasma concentration of above 20 μg/ml has been calculated as: Loading dose: 5.4 mg/kg, CPB prime dose: 50 mg for 2.5 L circuit, and rate of infusion: 5 mg/kg/h, with adjustment to the loading and prime dose in renal insufficiency. [91] According to Dowd et al., [92] a TA concentration of 127 μmol is sufficient to provide > 90% inhibition of the tissue activators of fibrinolysis and is the minimum therapeutic plasma concentration. In the CRASH-2 [93] trial, even a very low dose (bolus of 1 g followed by infusion of 1 g over eight hours) was effective in reducing the all-cause mortality. However, another randomized trial by Bokesch et al., [94] reported greater efficacy, fewer seizures, and lower mortality, with the same higher dosage used in the BART trial.

Epsilon-aminocaproic acid dosing

There is also no consensus as to the dosing regimens of epsilon-aminocaproic acid (EACA) and different dose regimens are recommended. [95],[96] In vitro inhibition of fibrinolysis occurs at concentrations of 130 μg/ ml [97] and the same plasma concentrations are seen to be clinically effective. This is achieved by a dose of 100 mg/kg every four hours. [98] Another regimen of 150 mg/kg at induction followed by infusion of 30 mg/kg/h consistently produces adequate plasma levels. Chauhan et al., [99] compared three doses regimens (single bolus, bolus followed by infusion, or three boluses at different time intervals) with the placebo and found all regimens to reduce blood loss, but the best effect was observed with regimens of bolus plus infusion or multiple boluses.

Genetic variation

Defects in coagulation proteins like Plasminogen Activator Inhibitor-1, factor VII, fibrinogen, and t-PA have strong heritability. Genetic disorders can lead to adverse postoperative events. Patients may also have other procoagulant states like Factor V Leiden deficiency Protein C or S deficiency. This group of patients may also show thrombotic complications, especially in the presence of antifibrinolytic agents. [100]


   Conclusions Top


To maintain vascular patency, the fibrinolytic system plays an integral part in vascular hemostasis. After extensive tissue injury and CPB, the equilibrium shifts, and increased fibrinolysis contributes to bleeding and coagulopathy. A comprehensive approach to blood conservation during cardiac surgery is highly recommended, including antifibrinolytic therapy. There is enough evidence to support the use of antifibrinolytic agents in cardiac surgery. Use of antifibrinolytic agents must be governed by an appreciation of their inherent risks and benefits. No drug is completely safe, while patient variability also plays an important role in adverse events. Despite our better understanding, it is still very difficult to predict whether any given patient is at an increased risk for bleeding or thrombosis. Antifibrinolytic therapy must be used when hyperfibrinolysis occurs and it seems attractive to have point-of-care fibrinolysis monitoring to guide the therapy. In an ideal world, it will also be nice to know the genetic variants for fibrinolysis or prothrombotic states, as some patients may not require any agent.

All three agents are effective, but are not without side effects. The degree of side effects seems to parallel the efficacy of these agents. The medical community is split over the suspension of aprotinin. Contradictory evidence must not be overlooked, but scrutinized more critically. Aprotinin is more effective in decreasing re-exploration in complex surgical procedures and is safe in patients with a very high-risk for bleeding. Health Canada does approve the use of aprotinin, but only for the isolated, high-risk CABG population. It is a remarkable drug and must be in the armamentarium of anesthesiologists managing high-risk procedures. Unfortunately, it is not yet approved due to lack of evidence. The onus is on the researchers to prove aprotinin's benefits in high-risk patients, by conducting well-designed, prospective, randomized, and placebo-controlled trials. Till then, we will have to rely on lysine analogs, which seem best suited for low-to-medium risk procedures. Choice and dose of the agent must be individualized, based on the type of patient, proposed surgery, and the risk/benefit profile of a given agent.

 
   References Top

1.Levy JH, Ramsay JG, Guyton RA. Aprotinin in cardiac surgery. N Engl J Med 2006;354:1953-7.  Back to cited text no. 1
    
2.Mehta RH, Sheng S, O′Brien SM, Grover FL, Gammie JS, Ferguson TB, et al. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: Incidence, risk factors, time trends and outcomes. Circ Cardiovasc Qual Outcomes 2009;2:583-90.  Back to cited text no. 2
    
3.Daly DJ, Myles PS, Smith JA, Knight JL, Clavisi O, Bain DL, et al. Anticoagulation, bleeding and blood transfusion practices in Australasian cardiac surgical practice. Anaesth Intensive Care 2007;35:760-8.  Back to cited text no. 3
    
4.Karkouti K, Wijeysundera DN, Yau TM, Beattie WS, Abdelnaem E, McCluskey SA, et al. The independent association of massive blood loss with mortality in cardiac surgery. Transfusion 2004;44:1453-62.  Back to cited text no. 4
    
5.Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A, et al. A propensity score case- control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 2006;46:327-38.  Back to cited text no. 5
    
6.Murphy GJ, Reeves BC, Rogers CA, Rizvi SI, Culliford L, Angelini GD. Increased mortality, postoperative morbidity, and cost after red blood cell transfusion in patients having cardiac surgery. Circulation 2007;116:2544-52.  Back to cited text no. 6
    
7.Engoren MC, Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg 2002;74:1180-6.  Back to cited text no. 7
    
8.Rogers MA, Blumberg N, Saint SK, Kim C, Nallamothu BK, Langa KM. Allogeneic blood transfusions explain increased mortality in women after coronary artery bypass graft surgery. Am Heart J 2006;152:1028-34.  Back to cited text no. 8
    
9.Koch CG, Li L, Sessler DI, Figueroa P, Hoeltge GA, Mihaljevic T, et al. Duration of red-cell storage and complications after cardiac surgery. N Engl J Med 2008;358:1229-39.  Back to cited text no. 9
    
10.Bridges CR. Valid comparisons of antifibrinolytic agents used in cardiac surgery. Circulation 2007;115:2790-2.  Back to cited text no. 10
    
11.Society of Thoracic Surgeons Blood Conservation Guideline Task Force, Ferraris VA, Brown JR, Despotis GJ, Hammon JW, Reece TB, Saha SP, et al. 2011 Update to The Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists Blood Conservation Clinical Practice Guidelines. Ann Thorac Surg 2011;91:944-82.  Back to cited text no. 11
    
12.Booth NA. Fibrinolysis and thrombosis. Baillieres Best Pract Res Clin Haematol 1999;12:423-33.  Back to cited text no. 12
    
13.Hirsh J, Salzman EW. Pathogenesis of venous thromboembolism, In: Colman RW, Hirsh J, Marder VJ, Salman EW, editors: Hemostasis and Thrombosis: Basic Principles and Clinical Practice. 2 nd ed. Philadelphia, PA: Lippincott; 1987. p. 1199.  Back to cited text no. 13
    
14.Kauhanen P, Siren V, Carpen O, Vaheri A, Lepantalo M, Lassila R. Plasminogen activator inhibitor-1 in neointima of vein grafts: its role in reduced fibrinolytic potential and graft failure. Circulation 1997;96:1783-9.  Back to cited text no. 14
    
15.Rifon J, Paramo JA, Panizo C, Montes R, Rocha E. The increase of plasminogen activator inhibitor activity is associated with graft occlu- sion in patients undergoing aorto-coronary bypass surgery. Br J Haematol 1997;99:262-7.  Back to cited text no. 15
    
16.Davies AJ, Strachan CJ, Hurlow RA, Stuart J. Fibrinolytic activity of tissue surfaces during surgery. J Clin Pathol 1979;32:822-5.  Back to cited text no. 16
    
17.Dahl OE. The role of pulmonary circulation in the regulation of coagulation and fibrinolysis in relation to major surgery. J Cardiothorac Vasc Anesth 1997;11:322-8.  Back to cited text no. 17
    
18.Chandler WL, Velan T. Secretion of tissue plasminogen activator and plasminogen activator inhibitor 1 during cardiopulmonary bypass. Thromb Res 2003;112:185-92.  Back to cited text no. 18
    
19.Sniecinski RM, Chandler WL. Activation of the hemostatic system during cardiopulmonary bypass. Anesth Analg 2011;113:1319-33.  Back to cited text no. 19
    
20.Booyse FM, Bruce R, Dolenak D, Grover M, Casey LC. Rapid release and deactivation of plasminogen activators in human endothelial cell cultures in the presence of thrombin and ionophore A23187. Semin Thromb Hemost 1986;12:228-30.  Back to cited text no. 20
    
21.Pretorius M, Scholl FG, McFarlane JA, Murphey LJ, Brown NJ. A pilot study indicating that bradykinin B2 receptor antagonism attenuates protamine-related hypotension after cardiopulmonary bypass. Clin Pharmacol Ther 2005;78:477-85.  Back to cited text no. 21
    
22.Fuhrer G, Gallimore MJ, Heller W, Hoffmeister HE. Aprotinin in cardiopulmonary bypass: Effects on the Hageman factor (FXII)-kallikrein system and blood loss. Blood Coagul Fibrinolysis 1992;3:99-104.  Back to cited text no. 22
    
23.Chandler WL, Fitch JCK, Wall MH, Verrier ED, Cochran RP, Soltow LO, et al. Individual variations in the fibrinolytic response during and after cardiopulmonary bypass. Thromb Haemost 1995;74:1293-7.  Back to cited text no. 23
    
24.Valen G, Eriksson E, Risberg B, Vaage J. Fibrinolysis during cardiac surgery: Release of tissue plasminogen activator in arterial and coronary sinus blood. Eur J Cardiothorac Surg 1994;8:324-30.  Back to cited text no. 24
    
25.Tanaka K, Takao M, Yada I, Yuasa H, Kusagawa M, Deguchi K. Alterations in coagulation and fibrinolysis associated with cardiopulmonary bypass during open heart surgery. J Cardiothorac Anesth 1989;3:181-8.  Back to cited text no. 25
    
26.Gallimore MJ, Jones DW, Winter M, Wendel HP. Changes in high molecular weight kininogen levels during and after cardiopulmonary bypass surgery measured using a chromo- genic peptide substrate assay. Blood Coagul Fibrinolysis 2002;13:561-8.  Back to cited text no. 26
    
27.Chandler WL, Velan T. Plasmin generation and D-dimer formation during cardiopulmonary bypass. Blood Coagul Fibrinolysis 2004;15:583-91.  Back to cited text no. 27
    
28.Vallely MP, Bannon PG, Bayfield MS, Hughes CF, Kritharides L. Quantitative and temporal differences in coagulation, fibrinolysis and platelet activation after on-pump and off- pump coronary artery bypass surgery. Heart Lung Circ 2009;18:123-30.  Back to cited text no. 28
    
29.Mariani MA, Gu YJ, Boonstra PW, Grandjean JG, van Oeveren W, Ebels T. Procoagulant activity after off-pump coronary operation: Is the current anticoagulation adequate? Ann Thorac Surg 1999;67:1370-5.  Back to cited text no. 29
    
30.Casati V, Gerli C, Franco A, Della Valle P, Benussi S, Alfieri O, et al. Activation of coagulation and fibrinolysis during coronary surgery: On-pump versus off-pump techniques. Anesthesiology 2001;95:1103-9.  Back to cited text no. 30
    
31.Al-Ruzzeh S, George S, Bustami M, Wray J, Ilsley C, Athanasius T, et al. Effect of off-pump coronary artery bypass surgery on clinical, angiographic, neurocognitive, and quality of life outcomes: Randomized controlled trial. BMJ 2006; 332:1365-71.  Back to cited text no. 31
    
32.Levy JH, Dutton RP, Hemphill JC 3 rd , Shander A, Cooper D, Paidas MJ, et al. Multidisciplinary approach to the challenge of hemostasis. Anesth Analg 2010;110:354-64.  Back to cited text no. 32
    
33.Bentall HH and All work SP. Fibrinolysis and increased bleeding in open-heart surgery. Lancet 1968;291:4-8.  Back to cited text no. 33
    
34.Ray MJ, Marsh NA, Hanson GA. Relationship of fibrinolysis and platelet function to bleeding after cardiopulmonary bypass. Blood Coagul Fibrinolysis 1994;5:679-85.  Back to cited text no. 34
    
35.Gram J, Janetzko T, Jespersen J, Bruhn H. Enhanced effective fibri- nolysis following the neutralization of heparin in open heart surgery increases the risk of post-surgical bleeding. Thromb Haemost 1990;63:241-5.  Back to cited text no. 35
    
36.Holloway DS, Summaria L, Sandesara J, Vagher JP, Alexander JC, Caprini JA. Decreased platelet number and function and increased fibrinolysis contribute to postoperative bleeding in cardiopulmonary bypass patients. Thromb Haemost 1988;59:62-7.  Back to cited text no. 36
    
37.Carpenter SL, Mathew P. Alpha2-antiplasmin and its deficiency: fibrinolysis out of balance. Hemophilia 2008;14:1250-4.  Back to cited text no. 37
    
38.Cross III DT, Darden CP, Moran CJ. Bleeding complications after basilar artery fibrinolysis with tissue plasminogen activator. Am J Neruradiol 2001;22:521-5.  Back to cited text no. 38
    
39.White HD, Van de Werf FJ. Thrombolysis for acute myocardial infarction. Circulation 1998;97:1632-46.  Back to cited text no. 39
    
40.Marder VJ, Feinstein DI, Colman RW, Levi M. Consumptive thrombohemorrhagic disorders. In: Hemostasis and Thrombosis, Colman RW, Marder VJ, Closes AW, George JN, Goldhaber SZ, editors. Philadelphia, 5 th ed. PA: Lippincott, Williams and Wilkins; 2006. p. 1571-600.  Back to cited text no. 40
    
41.Brown JR, Birkmeyer NJ, O′Connor GT. Meta-analysis comparing the effectiveness and adverse outcomes of antifibrinolytic agents in cardiac surgery. Circulation 2007;115:2801-13.  Back to cited text no. 41
    
42.Mcllroy DR, Myles PS, Phillips LE, Smith JA. Antifibrinolytics in cardiac surgical patients receiving aspirin: A systemic review and meta-analysis. Br J Anaesth 2009;102:168-78.  Back to cited text no. 42
    
43.Kraut E, Frey EK, Werle E. About the inactivation of Kallikrein. Hoppe-Seyler Zeitschr Physiol Chem 1930;192:1-21.  Back to cited text no. 43
    
44.Kunitz M, Nrothrop JH. Isolation from beef pancreas of crystalline trypsinogen, trypsin, a trypsin inhibitor and an inhibitor trypsin compound. J Gen Physiol 1936;19:991-1007.  Back to cited text no. 44
    
45.Asang E. Changes in the therapy of inflammatory diseases of the pancreas. A report on 1 year of therapy and prophylaxis with the kallikrein and trypsin inactivator trasylol (Bayer). Langenbecks Arch Klin Chir Ver Dtsch Z Chir 1960;293:645-70.  Back to cited text no. 45
    
46.Royston D, Bidstrup BP, Taylor KM, Sapsford RN. Effect of aprotinin on the need for blood transfusion after repeat open-heart surgery. Lancet 1987;2:1289-91.  Back to cited text no. 46
    
47.Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high-dose aprotinin (Trysalol). J Thorac Cardiovasc Surg 1989;97:364-72.  Back to cited text no. 47
    
48.US Food and Drug Administration. Approval of Aprotinin, press release. 12/30/1993. Available from: http://www.fda.gov/bbs/topics/NEWS/NEW00453.html [Last accessed on 30 Dec 1993].  Back to cited text no. 48
    
49.Cosgrove DM 3 rd , Heric B, Lytle BW, Taylor PC, Novoa R, Golding LA, et al. Aprotinin therapy for reoperative myocardial revascularization - a placebo-controlled study. Ann Thorac Surg 1992;54:1031-8.  Back to cited text no. 49
    
50.Sundt TM III, Kouchoukos NT, Saffitz JE, Murphy SF, Wareing TH, Stahl DJ. Renal dysfunction and intravascular coagulation with aprotinin and hypothermic circulatory arrest. Ann Thorac Surg 1993;55:1418-24.  Back to cited text no. 50
    
51.Dietrich W, Spath P, Ebell A, Richter JA. Prevalence of anaphylactic reactions to aprotinin: Analysis of two hundred forty-eight reexposures to aprotinin in heart operations. J Thorac Cardiovasc Surg 1997;113:194-201.  Back to cited text no. 51
    
52.Mangano DT, Tudor IC, Dietzel C; Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353-65.  Back to cited text no. 52
    
53.Karkouti K, Beattie WS, Dattilo KM, McCluskey SA, Ghannam M, Hamdy A, et al. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 2006;46:327-38.  Back to cited text no. 53
    
54.Report on Trasylol for Bayer Corporation and Bayer AG by Zuckerman Spaeder LLP, August 2007. Available from: http://www.pharma.bayer. com/html/pdf/BA YER_REPORT_FINAL_8-007.PDF [Last accessed on 2008 Jan 08].  Back to cited text no. 54
    
55.Fergusson DA, Hébert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. A Comparison of Aprotinin and Lysine Analogs in High-Risk Cardiac Surgery. N Engl J Med 2008;358:2319-31.  Back to cited text no. 55
    
56.Sundt TM. The demise of aprotinin: Our share of the blame. J Thorac Cardiovasc Surg 2008;135:729-31.  Back to cited text no. 56
    
57.Royston D, van Haaften N, de Vooght P. Aprotinin: Friend or foe? A review of recent medical literature. Eur J Anaesthesiol 2007;24:6-14.  Back to cited text no. 57
    
58.Tempe DK, Hasija S. Are tranexamic acid and !-aminocaproic acid adequate substitutes for aprotinin?. Ann Card Anaesth 2012;15:4-5.  Back to cited text no. 58
[PUBMED]  Medknow Journal  
59.Katchky A, Morgan C. The aprotinin story: Lessons in drug regulation and safety. UWOMJ 2008;77:12-5.  Back to cited text no. 59
    
60.McMullan V, Alston RP. The effect of the suspension of the license for aprotinin on the care of patients undergoing cardiac surgery: A survey of cardiac anesthesiologists′ and surgeons′ opinions in the United Kingdom. J Cardiothorac Vasc Anesth 2010;24:418-21.  Back to cited text no. 60
    
61.Spiess BD. Pro: The practice of cardiac anesthesia has changed after the withdrawal of aprotinin. J Cardiothorac Vasc Anesth 2010;24:875-8.  Back to cited text no. 61
    
62.Shaw AD, Stafford-Smith M, White WD, Phillips-Bute B, Swaminathan M, Milano C, et al. The effect of aprotinin on outcome after coronary-artery bypass grafting. N Engl J Med 2008;358:784-93.  Back to cited text no. 62
    
63.Olenchock SA Jr, Lee PH, Yehoshua T, Murphy SA, Symes J, Tolis G Jr. Impact of aprotinin on adverse clinical outcomes and mortality up to 12 years in a registry of 3,337 patients. Ann Thorac Surg 2008;86:560-6.  Back to cited text no. 63
    
64.Schneeweiss S, Seeger JD, Landon J, Walker AM. Aprotinin during coronary-artery bypass grafting and risk of death. N Engl J Med 2008;358:771-83.  Back to cited text no. 64
    
65.Lindvall G, Sartipy U, Ivert T, van der Linden J. Aprotinin is not associated with postoperative renal impairment after primary coronary surgery. Ann Thorac Surg 2008;86:13-9.  Back to cited text no. 65
    
66.Mouton R, Finch D, Davies I, Binks A, Zacharowski K. Effect of aprotinin on renal dysfunction in patients undergoing on-pump and off-pump cardiac surgery: A retrospective observational study. Lancet 2008;371:475-82.  Back to cited text no. 66
    
67.Pagano D, Howell NJ, Freemantle N, Cunningham D, Bonser RS, Graham TR, et al. Bleeding in cardiac surgery: The use of aprotinin does not affect survival. J Thorac Cardiovasc Surg 2008;135:495-502.  Back to cited text no. 67
    
68.Van der Linden PJ, Hardy JF, Daper A, Trenchant A, De Hert SG. Cardiac surgery with cardio- pulmonary bypass: does aprotinin affect outcome? Br J Anaesth 2007;99:646-52.  Back to cited text no. 68
    
69.Stamou SC, Reames MK, Skipper E, Stiegel RM, Nussbaum M, Geller R, et al. Aprotinin in cardiac surgery patients: is the risk worth the benefit? Eur J Cardio-thorac Surg 2009;36:869-76.  Back to cited text no. 69
    
70.Wang X, Zheng Z, Ao H, Zhang S, Wang Y, Zhang H, et al. A comparison before and after aprotinin was suspended in cardiac surgery: Different results in the real world from a single cardiac center in China. J Thorac Cardiovasc Surg 2009;138:897-903.  Back to cited text no. 70
    
71.Sniecinski RM, Chen EP, Makadia SS, Kikura M, Bolliger D, Tanaka KA. Changing from aprotinin to tranexamic acid results in increased use of blood products and recombinant factor VIIa for aortic surgery requiring hypothermic arrest. J Cardiothorac Vasc Anesth 2010;24:959-63.  Back to cited text no. 71
    
72.Martin K, Knorr J, Breuer T, Gertler R, Macguill M, Lange R, et al. Seizures after open heart surgery: Comparison of epsilon-Aminocaproic acid and tranexamic acid. J Cardiothorac Vasc Anesth 2011;25:20-5.  Back to cited text no. 72
    
73.DeSantis SM, Toole JM, Kratz JM, Uber WE, Wheat MJ, Stroud MR, et al. Early postoperative outcomes and blood product utilization in adult cardiac surgery: The post-aprotinin era. Circulation 2011;124:S62-9.  Back to cited text no. 73
    
74.Beattie WS, Karkouti K. The post-BART anti-fibrinolytic dilemma? J Cardiothorac Vasc Anesth 2011;25:3-5.  Back to cited text no. 74
    
75.Grunkemeier GL, Wu YX, Furnary AP. What is the value of a P value? Ann Thorac Surg 2009;87:1337-43.  Back to cited text no. 75
    
76.Karkouti K, Wijeysundera DN, Yau TM, McCluskey SA, Tait G, Beattie WS. The risk-benefit profile of aprotinin versus tranexamic acid in cardiac surgery. Anesth Analg 2010;110:21-9.  Back to cited text no. 76
    
77.Health Canada decision on Trasylol (aprotinin). Available from: http://www.hc-sc.gc.ca/ahc-asc/media/advisories-avis/_2011/2011_124-eng.php. [Last accessed on 21 Mar 2013].  Back to cited text no. 77
    
78.Henry DA, Carless PA, Moxey AJ, O′connell D, Stokes BJ, Fergusson DA, Ker K, et al. Anti-fibrinolytic use for minimizing perioperative allogeneic blood transfusion (Review) The Cochrane Library 2011, Issue 3.  Back to cited text no. 78
    
79.Wang G, Xie G, Jiang T, Wang Y, Wang W, Ji H, et al. Tranexamic acid reduces blood loss after off-pump coronary surgery: A prospective, randomized, double-blind, placebo-controlled study. Anesth Analg 2012;115:239-43.  Back to cited text no. 79
    
80.Sander M, Spies CD, Martiny V, Rosenthal C, Wernecke KD, von Heymann C. Mortality associated with administration of high-dose tranexamic acid and aprotinin in primary open-heart procedures: A retrospective analysis. Crit Care 2010;14:R148.  Back to cited text no. 80
    
81.Ngaage DL, Bland JM. Lessons from aprotinin: Is the routine use and inconsistent dosing of tranexamic acid prudent? Meta-analysis of randomized and large matched observational studies. European J Cariothorac Surg 2010;37:1375-83.  Back to cited text no. 81
    
82.Martin K, Gertler R, Liermann H, Mayr NP, Macguill M, Schreiber C, et al. Switch from aprotinin to {varepsilon}-aminocaproic acid: Impact on blood loss, transfusion, and clinical outcome in neonates undergoing cardiac surgery. Br J Anaesth 2011;107:934-9.  Back to cited text no. 82
    
83.Furtmüller R, Schlag MG, Berger M, Hopf R, Huck S, Sieghart W, et al. Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gamma-aminobutyric acid (A) receptor antagonistic effect. J Pharmacol Exp Ther 2002;301:168-73.  Back to cited text no. 83
    
84.Iplikcioglu AC, Berkman MZ. The effect of short-term antifibrinolytic therapy on experimental vasospasm. Surg Neurol 2003;59:10-6.  Back to cited text no. 84
    
85.Montes FR, Pardo DF, Carreño M, Arciniegas C, Dennis RJ, Umaña JP. Risk factors associated with postoperative seizures in patients undergoing cardiac surgery who received tranexamic acid: A case-control study. Ann Card Anaesth 2012;15:6-12.  Back to cited text no. 85
[PUBMED]  Medknow Journal  
86.Fremes SE, Wong BI, Lee E, Mai R, Christakis GT, McLean RF, et al. Meta-analysis of prophylactic drug treatment in the prevention of postoperative bleeding. Ann Thorac Surg 1994;58:1580-8.  Back to cited text no. 86
    
87.Karski JM, Dowd NP, Joiner R, Carroll J, Peniston C, Bailey K, et al. The effect of three different doses of tranexamic acid on blood loss after cardiac surgery with mild systemic hypothermia (32 degrees C). J Cardiothorac Vasc Anesth 1998;12:642-6.  Back to cited text no. 87
    
88.Manji RA, Grocott HP, Leake J, Ariano RE, Manji JS, Menkis AH, et al. Seizures following cardiac surgery: The impact of tranexamic acid and other risk factors. Can J Anest 2012;59:6-13.  Back to cited text no. 88
    
89.Armellin G, Vinciguerra A, Bonato R, Pittarello D, Giron GP. Tranexamic acid in primary CABG surgery: High vs low dose. Minerva Anestesiol 2004;70:97-107.  Back to cited text no. 89
    
90.Andersson L, Nilsoon IM, Colleen S, Granstrand B, Melander B. Role of urokinase and tissue activator in sustaining bleeding and the management thereof with EACA and AMCA. Ann N Y Acad Sci 1968;146:642-58.  Back to cited text no. 90
    
91.Fiechtner BK, Nuttall GA, Johnson ME, Dong Y, Sujirattanawimol N, Oliver WC Jr, et al. Plasma tranexamic acid concentrations during cardiopulmonary bypass. Anesth Analg 2001;92:1131-6.  Back to cited text no. 91
    
92.Dowd NP, Karski JM, Cheng DC, Carroll JA, Lin Y, James RL, et al. Pharmacokinetics of tranexamic acid during cardiopulmonary bypass. Anesthesiology 2002;97:390-9.  Back to cited text no. 92
    
93.The CRASH-2 Collaborators. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): A randomised, placebo-controlled trial. Lancet 2010;376:23-32.  Back to cited text no. 93
    
94.Bokesch PM, Szabo G, Wojdyga R, Grocott HP, Smith PK, Mazer CD, et al. A phase 2 prospective, randomized, double-blind trial comparing the effects of tranexamic acid with ecallantide on blood loss from high-risk cardiac surgery with cardiopulmonary bypass (CONSERV-2 Trial). J Thorac Cardiovasc Surg 2012;143:1022-9.  Back to cited text no. 94
    
95.Hardy JF, Belisle S, Dupont C, Havel F, Robitaille D, Roy M, et al. Prophylactic tranexamic acid and E aminocaproic acid for primary myocardial revascularization. Ann Thorac Surg 1998;65:371-8.  Back to cited text no. 95
    
96.Daily PO, Lamphere JA, Dembitsky WP, Adamson RM, Dans NF. Effect of prophylactic epsilon aminocaproic acid on blood loss and transfusion requirements in patients undergoing first time coronary artery bypass grafting. J Thorac Cardiovasc Surg 1997;108:99-108.  Back to cited text no. 96
    
97.Elliot BG, Jonathan GS, Canada AT, Ayuso L, Newman MF, Reves GJ, et al. Epsilon- aminocaproic acid plasma levels during cardiopulmonary bypass. Anesth Analg 1997;85:248-51.  Back to cited text no. 97
    
98.Verstraete M. Clinical application of inhibitors of fibrinolysis. Drugs 1985;29:236-61.  Back to cited text no. 98
    
99.Chauhan S, Bisoi AK, Rao BH, Rao MS, Saxena N, Venugopal P, et al. Dosage of Epsilon-Aminocaproic Acid to reduce postoperative blood loss. Asian Cardiovasc Thorac Ann 2000;8:15-8.  Back to cited text no. 99
    
100.Augoustides JG. Fatal intraoperative thrombosis in contemporary adult thoracic aortic surgery requiring deep hypothermic circulatory arrest: Observations from the literature 1993-2006. J Thorac Cardiovasc Surg 2007;134:1069-70.  Back to cited text no. 100
    

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Correspondence Address:
Achal Dhir
Department of Anesthesia and Perioperative Medicine, London Health Sciences Centre, University Hospital, 339 Windermere Road, London, N6A 5A5, Ontario
Canada
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DOI: 10.4103/0971-9784.109749

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