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Table of Contents
Year : 2020  |  Volume : 23  |  Issue : 2  |  Page : 193-199
Antifibrinolytics and cardiac surgery: The past, the present, and the future

Department of Cardiac Anesthesia, Manipal Hospitals, New Delhi, India

Click here for correspondence address and email

Date of Submission02-Nov-2018
Date of Decision05-Jan-2019
Date of Acceptance09-Mar-2019
Date of Web Publication07-Apr-2020


Cardiac surgery is usually associated with significant blood loss, which often necessitates blood transfusion. In order to decrease the risks associated with the latter, pharmacological as well as nonpharmacological strategies have been used to reduce blood loss. Among the pharmacological approaches, antifibrinolytic drugs are the mainstay. Aprotinin, which was the first ubiquitously used drug, fell into disrepute only to re-emerge after much debate. The decline of aprotinin paved the way for the lysine analogs. However, we must be aware with the side effects of these drugs as well as the dose modification required in special situations. Nonsaccharide glycosaminoglycans have been under investigation to overcome the drawbacks of the lysine analogs. It remains to be seen whether these drugs can replace the traditional antifibrinolytics.

Keywords: Aprotinin, cardiac surgery, glycosaminoglycans, lysine analogs

How to cite this article:
Aggarwal NK, Subramanian A. Antifibrinolytics and cardiac surgery: The past, the present, and the future. Ann Card Anaesth 2020;23:193-9

How to cite this URL:
Aggarwal NK, Subramanian A. Antifibrinolytics and cardiac surgery: The past, the present, and the future. Ann Card Anaesth [serial online] 2020 [cited 2022 Aug 14];23:193-9. Available from:

   Introduction Top

The issue of excessive blood loss, sometimes necessitating re-exploration, often plagues cardiac surgery. Surgical blood loss has been found to be an independent predictor of in-hospital mortality.[1] Re-exploration for bleeding has been linked to numerous adverse events, such as renal failure, infections, arrhythmias, and prolonged hospital stay.[2] Besides these, delay in re-exploration tends to use up the blood bank resources, thereby exposing the patients to the hazards of blood transfusion. Approximately 50% of cardiac surgical patients receive blood transfusion,[3] which can pose substantial risk.[4],[5] Numerous strategies have been used to decrease the same.

Pharmacological strategies have been used from time-to-time to minimize perioperative bleeding and thereby transfusion. Of these, the antifibrinolytic drugs have been the most promising. This has led to their extensive use in cardiac surgery and has been recommended by the European Association of Cardio-Thoracic Surgery and Anaesthesiology[6] and the American Heart Association.[7] Before its withdrawal, aprotinin was believed to be the most powerful and popular antifibrinolytic.[8] Tranexamic acid (TA) and epsilon-aminocaproic acid (EACA) are synthetic derivatives of lysine unlike aprotinin, which is a serine protease inhibitor derived from bovine lung.

The resurgence of aprotinin and the side effects of other antifibrinolytics, as demonstrated by some trials, have left us pondering as to which drug seems to be the most efficacious drug in controlling perioperative blood loss. In this editorial, the role of various antifibrinolytics in managing the perioperative blood loss will be discussed. We searched PubMed and Google Scholar database with the keywords as cardiac surgery and antifibrinolytic drugs for literature search.

   Hemostatic Derangements during Cardiac Surgery Top

What exactly happens during surgery that promotes bleeding? Cardiac surgery, similar to any other surgical procedure, promotes tissue damage, inflammation, and thereby bleeding. Added to this is the insult from cardiopulmonary bypass (CPB), which promotes the activation of the coagulation system due to the contact of blood with foreign surfaces. Systemic heparinization and inadequate protamine reversal too take a toll on the patient, not to forget surgical hemostasis. It has been observed that the fibrinogen levels decrease by about 40% at the end of cardiac surgery.[9],[10] The composition of the priming solution used in CPB has been shown to have an effect on the production of fibrinogen,[11] thereby impeding coagulation during on-pump surgery. The fibrinolytic activity at the surgical site has been seen to increase by eight-fold following extensive surgery.[12] The reduced generation of thrombin that occurs post cardiac surgery presents an additional insult to the bleeding patient.[13] Soluble fibrin is nonhemostatic fibrin formed due to dysregulation of hemostasis. Normally, only approximately 1% of the fibrin formed circulates as soluble fibrin with the rest residing in the wound.[14] When CPB commences, total fibrin formation is reduced because of heparinization whereas soluble fibrin formation is increased. The quality of fibrin-based clot has more impact than the reduced thrombin generation and platelet dysfunction on the magnitude of bleeding.[15]

The contact activation pathway is activated when blood comes in contact with the CPB circuit.[16] Biocompatible materials added to the CPB circuit have been shown to have an equivocal effect on bleeding and transfusion requirements.[17] However, the activation of the tissue factor (TF) pathway may be a primary reason of thrombin generation during CPB. This pathway gets activated when blood comes in contact with the pericardium and damaged tissues.[18] Washing and concentrating blood that has been aspirated from the pericardium[19] and tissue factor pathway inhibitor (TFPI) release by heparin administration[20] probably have an important role in the suppression of the TF pathway during CPB. CPB promotes the formation of bradykinin[21] that appears to be the primary stimulus for tissue plasminogen activator (tPA) secretion as documented by studies that have successfully employed bradykinin receptor blockers.[22] This tPA promotes fibrinolysis that has been shown to have a positive correlation with the magnitude of postoperative blood loss.[23],[24]

Does off-pump cardiac surgery fare better? It should, since CPB is eliminated from the scene, but that solves only one issue. The tissue trauma, which activates the TF, is inevitable.[25] There is activation of coagulation and subsequently fibrinolysis albeit to a lesser extent during off-pump surgery.[26],[27] However, in off-pump as well as in on-pump surgeries, fibrinolytic activity is similar by the end of 24 h.[28] Therefore, cardiac surgery can be considered a hostile milieu for the patient wherein derangements of the coagulation system are encountered.

   Role of Antifibrinolytics Top

The technique of using pharmacological measures to reduce blood loss dates back to the 1980s when desmopressin and prostacyclins were introduced in cardiac surgery. However, they were found to be ineffective, except in selected cases.[29],[30] Antifibrinolytics, by inhibiting fibrinolysis, and thereby fibrin degradation product formation have been shown to reduce transfusion requirements by up to 50%. The commonly used antifibrinolytics in today's era include the protease inhibitors and lysine analogs. When aprotinin was banned in 2007, two additional pharmacological agents were clinically evaluated, namely, ecallantide and MDCO-2010. Recently, synthetic allosteric plasmin inhibitors are undergoing research as a tool to reduce perioperative bleeding.


α2-plasmin inhibitor is a natural plasmin inhibitor in our body that rapidly inactivates free plasmin with little effect on the bound form. Free plasmin is associated with pathological fibrinolysis. Hence, hemostasis is maintained and physiological clot lysis is not inhibited.[31] Aprotinin, a serine protease inhibitor, inhibits free plasmin but with little effect on bound plasmin, similar to α2-plasmin inhibitor. The initial plasma half-life is 150 min and the terminal half-life is 10 h. The kidneys eliminate aprotinin, with almost complete elimination in 4–5 h. Aprotinin clearance is reduced, and half-lives are prolonged in patients with renal insufficiency undergoing CPB.[32] A full-dose regimen consists of 2 million kallikrein international units (KIU) as a bolus, followed by the same bolus on CPB prime and a continuous infusion of 50,000 KIU. A half-dosing regimen is also available. In addition, aprotinin possesses antiinflammatory properties,[33],[34] thereby decreasing the systemic inflammatory response to cardiac surgery. There was a controversy regarding the optimal dose of aprotinin to be administered to produce the desired clinical effect. The 2 million KIU dose was found to be necessary to produce the plasma concentration of 200 KIU/ml associated with kallikrein inhibition.[35] Royston et al. demonstrated that in coronary artery bypass grafting (CABG), a full-dose regimen was associated with a lower risk of adverse cerebrovascular outcomes and a reduced need for use of vasoactive drugs.[36] Hayashida et al. opined that minimal-dose aprotinin inhibited enhanced fibrinolytic activity and reduced transfusion requirements after bypass equivalently to low-dose aprotinin.[37] Lemmer et al. concluded that low-dose and pump-prime-only aprotinin regimens provide reductions in transfusion requirements similar to those of high-dose regimens.[38] A retrospective analysis by Strouch et al. showed that half-dosing regimen was associated with a significant increase in blood products administration and re-exploration rates as compared to the full dose.[39] However, recently it has been demonstrated that a half-dosing regimen should suffice in low-risk cardiac patients.[40]

The Aprotinin saga: Introduction, decline, and resurgence

Aprotinin was isolated from bovine lung in 1936, and was first used by Royston et al.,[41] in redo cardiac surgery. Bidstrup et al.[42] used high-dose aprotinin in cardiac surgery in 1989. The Food and Drug Administration (FDA) in 1993 gave the nod for its use in high-risk CABG, which ultimately expanded to all CABG patients. Post approval it was noticed that aprotinin was associated with decreased perioperative transfusion requirements not only in cardiac surgeries but also in noncardiac surgeries. Perhaps this led to misuse of the drug, thus landing it into controversy.

In 2006, FDA issued a public health advisory regarding the use of aprotinin, based on a series of observational studies. Mangano et al.[43] reported that aprotinin use might be associated with increased risk of cardiovascular, neurological, and renal events. They further stated that aprotinin was independently predictive of 5-year mortality.[44] Karkouti et al.,[45] as well as Shaw et al.,[46] showed that patients who received aprotinin had a higher mortality rate and larger increases in serum creatinine levels than those who received EACA or no antifibrinolytic agent. By the end of 2006, FDA revised its guidelines and placed a ceiling on aprotinin's use in surgeries. In 2007, the Blood Conservation using Antifibrinolytics in a Randomized Trial (BART) study was published, which saw the demise of aprotinin.[47] Instantaneously, the manufacturer of aprotinin (Bayer Inc.) temporarily suspended production and by mid-2008, aprotinin was removed from the markets.

The withdrawal of aprotinin was not met with a favorable response from many quarters. Though a few studies had demonstrated a poor outcome with aprotinin, others did not. Schneeweiss et al.[48] concluded that in-hospital mortality was higher with aprotinin, post cardiac surgery. Fan et al.[49] found that aprotinin did no good apart from decreasing postoperative bleeding in pediatric cardiac surgical patients. In fact, they concluded that its use was detrimental. On the contrary, Wang et al.[50] and Sniecinski et al.[51] concluded that aprotinin use was associated with less blood loss when compared to TA or no aprotinin at all. DeSantis et al.[52] in their retrospective analysis concluded that in the post aprotinin era with the exclusive use of lysine analogs, the relative risk of early postoperative outcomes such as mortality and renal dysfunction did not improve, but the risk for the intraoperative use of blood products had increased. Scott et al.[53] analyzed a retrospective data and concluded that bleeding in infant cardiac surgery increased following the change from aprotinin to EACA, thereby necessitating the use of factor VIIa. Many questions were raised regarding the validity of the studies that had disfavored aprotinin, especially the study by Mangano et al.[43],[44] and the BART trial.[47] There were several issues with the data from Mangano et al.[43],[44] First, the study was nonrandomized and used unmatched groups. Next, multivariate logistic regression analyses were used for between-group differences at baseline. This analysis did not indicate as to which type of patients received aprotinin. Finally, the details of the surgery itself were not reported. Thus, the choice of antifibrinolytic drug and the outcome were biased. This led to a meeting by the regulatory authority of Canada in December 2008. It was seen that the primary outcome in BART was not mortality but massive bleeding and that the trial was underpowered. Similarly, the exclusion of 137 patients from the study after randomization of primary endpoints was questioned. The panel concluded that the reclassification of endpoints from the original reported data were in opposite directions for aprotinin and EACA, thereby favoring EACA. These changes were magnified with the duration of the study. The anticoagulant used in the BART trial was heparin, whose effect was not monitored appropriately, as activated clotting time could be influenced by aprotinin. Thus in 2011, Health Canada lifted the ban on aprotinin and licensed its use for isolated CABG in Canada, only after balancing the risk versus benefit.[54] Following this, the European regulatory authority gave a nod for the use of aprotinin for isolated CABG in Europe.[55] Interestingly, the authors of the BART study have refuted the criticism drawn from their work.[56] The use of aprotinin, post re-introduction, in isolated CABG has been debated. Meybohm et al. found that the use of aprotinin is associated with an increased risk of mortality in low and intermediate risk cardiac surgery.[57] Likewise, the arterial revascularization trial (ART) showed a significant increased risk of early and late mortality with aprotinin.[58] However, Deloge et al. have demonstrated the superiority of aprotinin over TA in isolated CABG.[59] Currently, the European guidelines recommend the use of aprotinin only in adult patients undergoing isolated CABG, who are at a high risk of major blood loss.[60]

Although aprotinin use is associated with nephrotoxicity, Bosman et al.[61] opined that there is no evidence for an increased risk of developing new renal failure requiring dialysis/renal replacement therapy. Maslow et al. echoed similar findings in their assessment of perioperative renal outcome in cardiac surgical patients with preoperative renal dysfunction when comparing EACA with aprotinin.[62] Aprotinin-induced anaphylaxis is yet another major concern, especially after a second exposure.[63],[64] A 6 months gap between the first and the subsequent exposure might alleviate this problem.

Ecallantide and MDCO-2010

Ecallantide is a recombinant human peptide derived from the first Kunitz domain of the TF pathway inhibitor-1 that inhibits the TF pathway.[65] FDA approved it for the treatment of hereditary angioedema. It was demonstrated to decrease perioperative transfusion in cardiac surgery. Bokesch et al.[66] found out that ecallantide was less effective at reducing perioperative blood loss than TA and the study had to be prematurely terminated due to mortality in the study group.

MDCO-2010 is a synthetic molecule inhibiting plasmin, kallikrein, Xa, Xia, and protein C. It exerts more potent inhibitory activity than TA and aprotinin toward plasma kallikrein, plasmin, and FXa.[67],[68] However, further studies are needed to demonstrate its safety and efficacy.[69]

Tranexamic acid and epsilon amino caproic acid

TA and EACA are the most widely used antifibrinolytics in this era, especially following the withdrawal of aprotinin. Both are synthetic derivatives of lysine. They prevent excessive plasmin formation by binding to the lysine-binding site on plasminogen, thereby preventing fibrin from binding to plasminogen. They primarily inhibit tPA-induced physiological fibrinolysis.[70] Both are eliminated through the kidneys necessitating dose reduction in renal failure and have a half-life of 3 and 2 h, respectively. Age has been shown to be a better covariate than body weight, affecting both the distribution and the elimination of TA.[71] TA can be given as a high dose of 30 mg/kg bolus, 2 mg/kg on CPB, and 16 mg/kg/h later or as a low dose of 10 mg/kg bolus, 1–2 mg/kg on CPB, and 1 mg/kg/h. It has been approved for use in USA, Canada, and Europe. EACA is given in a dose of 100 mg/kg bolus, 5 mg/kg on CPB, and 30 mg/kg/h. TA is at least 7–10 times as potent as EACA. Both TA and EACA have been shown to reduce the need for transfusion as compared with controls.[72]

The optimal plasma concentration of TA to inhibit 80-85% fibrinolysis has been set at 10–20 mcg/ml. 100 mcg/ml of TA completely inhibits fibrinolysis.[73] Sharma et al. analyzed plasma TA concentrations of eight patients undergoing elective cardiac surgery with CPB and high-dose TA. The authors found that actual plasma levels of TA were significantly higher than expected, and that 100% inhibition could be achieved at lower TA doses.[74] There is also a considerable debate on its dosing. Hodgson et al. concluded that patients with a high risk of bleeding should receive high-dose TA, while those at low risk of bleeding should receive low-dose TA.[75] Sigaut et al.[73] found that although a high dose of TA does not reduce the incidence of blood product transfusion up to day 7, it is more effective than a low dose of TA in decreasing transfusion, blood loss, and repeat surgery. This study was criticized for its design and analysis, but the need for high dose was partially accepted. However, Du et al.[76] showed that lower-dose TA regimen was as effective as the higher-dose regimen in reducing postoperative bleeding and transfusion needs in patients undergoing cardiac valve surgery. Faraoni et al.[77] evaluated the effect of two doses of TA on fibrinolysis during cardiac surgery and concluded that dose does not make a difference in clinical outcome.

EACA causes inhibition of fibrinolysis at 130 mcg/ml.[78] There is no consensus on the dosage on EACA too. Different dosage regimens have been experimented by Chauhan et al.[79] and Hardy et al.[80] Sarupria et al.[81] compared two different protocols of EACA in pediatric cardiac surgery, namely continuous and discontinuous regimen. One group received 100 mg/kg of EACA after induction, upon initiation of CPB, and after protamine. Group 2 received 75 mg/kg of EACA after induction, followed by a maintenance infusion of 75 mg/kg/h until chest closure, and an additional 75 mg/kg upon initiation of CPB. Group 3 did not receive any antifibrinolytic agent or placebo. They noted that both the regimens were equally effective in reducing blood loss.

Seizures have been reported with the use of lysine analogs,[82] especially TA that could be due to γ-amino butyric acid receptor antagonism or due to cerebral vasospasm/thrombosis. However, the clinical impact of TA-induced seizures is difficult to determine. A large retrospective study reported an incidence of 0.9%, with a 2.5–3 times mortality in patients treated with TA. In this study, TA administration was shown to be an independent predictor of seizures. The occurrence of seizures has been linked to the dose, with larger doses being implicated in the development of seizures.[75],[83] Sharma et al.[84] found that independent predictors of postoperative seizures included age, female sex, redo surgery, hypothermic circulatory arrest, increased duration of aortic cross-clamp, and TA. When tested in a multivariate regression analysis, TA was a strong independent predictor of seizures. A follow-up of three patients who presented with seizures after TA administration might support the hypothesis of cerebral hypoperfusion as a cause of seizures.[85] Montes et al. linked preoperative renal dysfunction to the development of seizures and opined that the drug dose should either be reduced or completely avoided in such patients.[86] Further well-designed prospective studies are required to come to a firm conclusion on this aspect. In order to reduce these undesirable side effects, topical application of TA and EACA has been described. This has shown promising effects with some authors reporting an increased efficacy when topical and systemic methods are combined as compared to individual technique.[87],[88]

   Recent Developments Top

The lysine analogs can provoke convulsive seizures from their effects on the central GABA receptor. In particular, the variable efficacy of TA sometimes necessitating high doses causes postoperative seizures and renal dysfunction. Thus, discovering more potent and safer plasmin inhibitors became important. Research into glycosaminoglycans (GAGs), which are known to allosterically inhibit plasmin, has led to the synthesis of small, synthetic, homogenous, nonsaccharide GAG mimetics (NSGMs). Among the 55 NSGMs investigated, the flavonoid quinazoline heterodimers and bisflavanoid homodimers afford allosteric inhibition of plasmin. Advantages of these NSGMs include: (i) adequate aqueous solubility which is expected to help antifibrinolytic use during surgeries, (ii) limited cellular and central nervous system toxicity, (iii) reasonable chemical stability, and (iv) ease of chemical synthesis.[89] Further efforts are necessary to develop these sulfated NSGMs into clinically relevant molecules.[90]

   Conclusion Top

Prophylaxis for blood loss in cardiac surgery is desirable, of which antifibrinolytic drugs have been the most sought after. Literature recommends their use, albeit with other methods to prevent and treat bleeding. Their use should be driven by cost, clinician's familiarity with the drug, drug profile, and institution protocol. The development and increased use of point-of-care-based, whole-blood assays of the coagulation system may have a role in the detection of intraoperative hyperfibrinolysis and be able to guide the more rational use of antifibrinolytic agents. No particular drug is recommended, although TA is more potent than EACA. Though the regulatory agencies have licensed aprotinin only in isolated CABG, its use in other cardiac surgeries needs to be reassessed. In the absence of lucid Indian guidelines on aprotinin, we recommend that either we do not use it or use it in accordance with the European guidelines. Thus, we have to rely only on lysine analogs with low-dose TA being the most appropriate. The allosteric plasmin inhibitors seem a viable option, but warrant further research.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

   References Top

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. 1
Ranucci M, Bozzetti G, Ditta A, Cotza M, Carboni G, Ballotta A. Surgical reexploration after cardiac operations: Why a worse outcome? Ann Thorac Surg 2008;86:1557-62.  Back to cited text no. 2
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
Shaw RE, Johnson CK, Ferrari G, Brizzio ME, Sayles K, Rioux N, et al. Blood transfusion in cardiac surgery does increase the risk of 5-year mortality: Results from a contemporary series of 1714 propensity-matched patients. Transfusion 2014;54:1106-13.  Back to cited text no. 4
Bhaskar B, Dulhunty J, Mullany DV, Fraser JF. Impact of blood product transfusion on short and long-term survival after cardiac surgery: More evidence. Ann Thorac Surg 2012;94:460-7.  Back to cited text no. 5
Pagano D, Milojevic M, Meesters MI, Benedetto U, Bolliger D, von Heymann C, et al. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. Eur J Cardiothorac Surg 2018;53:79-111.  Back to cited text no. 6
Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2011;124:2610-42.  Back to cited text no. 7
Breuer T, Martin K, Wilhelm M, Wiesner G, Schreiber C, Hess J, et al. The blood sparing effect and the safety of aprotinin compared to tranexamic acid in pediatric cardiac surgery. Eur J Cardiothorac Surg 2009;35:167-71.  Back to cited text no. 8
Blome M, Isgro F, Kiessling AH, Skuras J, Haubelt H, Hellstern P, et al. Relationship between factor XIII activity, fibrinogen, haemostasis screening tests and postoperative bleeding in cardiopulmonary bypass surgery. Thromb Haemost 2005;93:1101-7.  Back to cited text no. 9
Solomon C, Pichlmaier U, Schoechl H, Hagl C, Raymondos K, Scheinichen D, et al. Recovery of fibrinogen after administration of fibrinogen concentrate to patients with severe bleeding after cardiopulmonary bypass surgery. Br J Anaesth 2010;104:555-62.  Back to cited text no. 10
Brinkman AC, Romijn JW, van Barneveld LJ, Greuters S, Veerhoek D, Vonk AB, et al. Profound effects of cardiopulmonary bypass priming solutions on the fibrin part of clot formation: An ex vivo evaluation using rotation thromboelastometry. J Cardiothorac Vasc Anesth 2010;24:422-6.  Back to cited text no. 11
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. 12
Bosch YP, Al Dieri R, ten Cate H, Nelemans PJ, Bloemen S, de Laat B, et al. Measurement of thrombin generation intra-operatively and its association with bleeding tendency after cardiac surgery. Thromb Res 2014;133:488-94.  Back to cited text no. 13
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. 14
Solomon C, Rahe-Mayer N, Sorensen B. Fibrin formation is more impaired than thrombin generation and platelets immediately following cardiac surgery. Thromb Res 2011;128:277-82.  Back to cited text no. 15
Edmunds LH Jr. Blood-surface interactions during cardiopulmonary bypass. J Card Surg 1993;8:404-10.  Back to cited text no. 16
Marcoux JE, Mycyk TR. Are any biocompatible coatings capable of attenuating the deleterious effects of cardiopulmonary bypass? Perfusion 2013;28:433-9.  Back to cited text no. 17
Boisclair MD, Lane DA, Philippou H, Esnouf MP, Sheikh S, Hunt B, et al. Mechanisms of thrombin generation during surgery and cardiopulmonary bypass. Blood 1993;82:3350-7.  Back to cited text no. 18
Tabuchi N, de Haan J, Boonstra PW, van Oeveren W. Activation of fibrinolysis in the pericardial cavity during cardiopulmonary bypass. J Thorac Cardiovasc Surg 1993;106:828-33.  Back to cited text no. 19
Kojima T, Gando S, Kemmotsu O, Mashio H, Goda Y, Kawahigashi H, et al. Another point of view on the mechanism of thrombin generation during cardiopulmonary bypass: Role of tissue factor pathway inhibitor. J Cardiothorac Vasc Anesth 2001;15:60-4.  Back to cited text no. 20
Cugno M, Nussberger J, Biglioli P, Alamanni F, Coppola R, Agostoni A. Increase of bradykinin in plasma of patients undergoing cardiopulmonary bypass: The importance of lung exclusion. Chest 2001;120:1776-82.  Back to cited text no. 21
Witherow FN, Dawson P, Ludlam CA, Webb DJ, Fox KA, Newby DE. Bradykinin receptor antagonism and endothelial tissue plasminogen activator release in humans. Arterioscler Thromb Vasc Biol 2003;23:1667-70.  Back to cited text no. 22
Levy JH, Dutton RP, Hemphill JC, 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. 23
Ray MJ, Marsh NA, Hawson GA. Relationship of fibrinolysis and platelet function to bleeding after cardiopulmonary bypass. Blood Coagul Fibrinolysis 1994;5:679-85.  Back to cited text no. 24
Paparella D, Galeone A, Venneri MT, Coviello M, Scrascia G, Marraudino N, et al. Activation of the coagulation system during coronary artery bypass grafting: Comparison between on-pump and off-pump techniques. J Thorac Cardiovasc Surg 2006;131:290-7.  Back to cited text no. 25
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. 26
Mariani Ma, Gu YJ, Boonstra PW, Grandjean JG, van Oeveren W, Ebels T. Procoagulant activity after off-pump coronary operation: Is current anticoagulation adequate? Ann Thorac Surg 1999;67:1370-5.  Back to cited text no. 27
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. 28
Wademan BH, Galvin SD. Desmopressin for reducing postoperative blood loss and transfusion requirements following cardiac surgery in adults. Interact Cardiovasc Thorac Surg 2014;18:360-70.  Back to cited text no. 29
Fish KJ, Sarnquist FH, van Steennis C, Mitchell RS, Hilberman M, Jamieson SW, et al. A prospective, randomized study of the effects of prostacyclin on platelets and blood loss during coronary bypass operations. J Thorac Cardiovasc Surg 1986;91:436-42.  Back to cited text no. 30
Weitz JI, Leslie B, Hirsh J, Klement P. Alpha 2-antiplasmin supplementation inhibits tissue plasminogen activator-induced fibrinogenolysis and bleeding with little effect on thrombolysis. J Clin Invest 1993;91:1343-50.  Back to cited text no. 31
O'Connor CJ, Brown DV, Avramov M, Barnes S, O'Connor HN, Tuman KJ. The impact of renal dysfunction on aprotinin pharmacokinetics during cardiopulmonary bypass. Anesth Analg 1999;89:1101-7.  Back to cited text no. 32
Maruna P, Klein AA, Kunstyr J, Plocova KM, Mlejnsky F, Lindner J. Aprotinin reduces the procalcitonin rise associated with complex cardiac surgery and cardiopulmonary bypass. Physiol Res 2013;62:27-33.  Back to cited text no. 33
Graham EM, Atz AM, Gillis J, Desantis SM, Haney AL, Deardorff RL, et al. Differential effects of aprotinin and tranexamic acid on outcomes and cytokine profiles in neonates undergoing cardiac surgery. J Thorac Cardiovasc Surg 2012;143:1069-76.  Back to cited text no. 34
Levy JH, Bailey JM, Salmenpera M. Pharmacokinetics of aprotinin in preoperative cardiac surgical patients. Anesthesiology 1994;80:1013-8.  Back to cited text no. 35
Royston D, Levy JH, Fitch J, Dietrich W, Body SC, Murkin JM, et al. Full-dose aprotinin use in coronary artery bypass graft surgery: An analysis of perioperative pharmacotherapy and patient outcomes. Anesth Analg 2006;103:1082-8.  Back to cited text no. 36
Hayashida N, Isomura T, Sato T, Maruyama H, Kosuga K, Aoyagi S. Effects of minimal-dose aprotinin on coronary artery bypass grafting. J Thorac Cardiovasc Surg 1997;114:261-9.  Back to cited text no. 37
Lemmer JH Jr, Dilling EW, Morton JR, Rich JB, Robicsek F, Bricker DL, et al. Aprotinin for primary coronary artery bypass grafting: A multicenter trial of three dose regimens. Ann Thorac Surg 1996;62:1659-67.  Back to cited text no. 38
Strouch ZY, Drum ML, Chaney MA. Aprotinin use during cardiac surgery: Recent alterations and effects on blood product utilization. J Clin Anesth 2009;21:502-7.  Back to cited text no. 39
Beckerman Z, Shopen Y, Alon H, Cohen O, Nir RR, Adler Z, et al. Coronary artery bypass grafting after aprotinin: Are we doing better? J Thorac Cardiovasc Surg 2013;145:243-8.  Back to cited text no. 40
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. 41
Bidstrup BP, Royston D, Sapsford RN, Taylor KM. Reduction in blood loss and blood use after cardiopulmonary bypass with high dose aprotinin. J Thorac Cardiovasc Surg 1989;97:364-72.  Back to cited text no. 42
Mangano DT, Tudor IC, Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006;354:353-65.  Back to cited text no. 43
Mangano DT, Miao Y, Vuylsteke A, Tudor IC, Juneja R, Filipescu D, et al. Mortality associated with aprotinin during 5 years following coronary artery bypass grafting. JAMA 2007;297:471-9.  Back to cited text no. 44
Karkouti K, Beattie WS, Datillo 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. 45
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. 46
Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008;358:2319-31.  Back to cited text no. 47
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. 48
Fan Y, Lin R, Yang L, Ye L, Yu J, Shu Q. Retrospective cohort analysis of a single dose of aprotinin use in children undergoing cardiac surgery: A single-center experience. Paediatr Anaesth 2013;23:242-9.  Back to cited text no. 49
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. 50
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. 51
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 (11 Suppl):S62-9.  Back to cited text no. 52
Scott JP, Costigan DJ, Hoffman GM, Simpson PM, Dasgupta M, Punzalan R, et al. Increased recombinant activated factor VII use and need for surgical reexploration following a switch from aprotinin to epsilon-aminocaproic acid in infant cardiac surgery. J Clin Anesth 2014;26:204-11.  Back to cited text no. 53
Health Canada decision on Trasylol (aprotinin). Available from: [Last accessed on 2018 Aug 17].  Back to cited text no. 54
European Medicines Agency recommends lifting suspension of aprotinin. Available from: [Last accessed on 2018 Aug 17].  Back to cited text no. 55
Fergusson DA, Hebert PC, Mazer CD, Fremes S, MacAdams C, Murkin JM, et al. Regulatory decisions pertaining to aprotinin may be putting patients at risk. CMAJ 2014;186:1379-86.  Back to cited text no. 56
Meybohm P, Herrmann E, Nierhoff J, Zacharowski K. Aprotinin may increase mortality in low and intermediate risk but not in high risk cardiac surgical patients compared to tranexamic acid and ε-aminocaproic acid—A meta-analysis of randomised and observational trials of over 30.000 patients. PLoS One 2013;8:e58009.  Back to cited text no. 57
Benedetto U, Altman DG, Gerry S, Gray A, Lees B, Angelini GD, et al. Safety of perioperative aprotinin administration during isolated coronary artery bypass graft surgery: Insights from the ART. J Am Heart Assoc 2018;7:e7570.  Back to cited text no. 58
Deloge E, Amour J, Provenchere S, Rozec B, Scherrer B, Ouattara A. Aprotinin vs Tranexamic acid in isolated coronary artery bypass surgery: A multicenter observational study. Eur J Anaesthesiol 2017;34:280-7.  Back to cited text no. 59
De Hert S, Gill R, Habre W, Lance M, Llau J, Meier J, et al. Aprotinin: Is it time to reconsider? Eur J Anaesthesiol 2015;32:591-5.  Back to cited text no. 60
Bosman M, Royston D. Aprotinin and renal dysfunction. Expert Opin Drug Saf 2008;7:663-77.  Back to cited text no. 61
Maslow AD, Chaudrey A, Bert A, Schwartz C, Singh A. Perioperative renal outcome in cardiac surgical patients with preoperative renal dysfunction: Aprotinin versus epsilon aminocaproic acid. J Cardiothorac Vasc Anesth 2008;22:6-15.  Back to cited text no. 62
Dietrich W, Ebell A, Busley R, Boulesteix AL. Aprotinin and anaphylaxis: Analysis of 12,403 exposures to aprotinin in cardiac surgery. Ann Thorac Surg 2007;84:1144-50.  Back to cited text no. 63
Scheule AM, Jurmann MJ, Wendel HP, Häberle L, Eckstein FS, Ziemer G. Anaphylactic shock after aprotinin reexposure: Time course of aprotinin-specific antibodies. Ann Thorac Surg 1997;63:242-4.  Back to cited text no. 64
Lehmann A. Ecallantide (DX-88), a plasma kallikrein inhibitor for the treatment of hereditary angioedema and the prevention of blood loss in on-pump cardiothoracic surgery. Expert Opin Biol Ther 2008;8:1187-99.  Back to cited text no. 65
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. 66
Szabó G, Veres G, Radovits T, Haider H, Krieger N, Bährle S, et al. The novel synthetic serine protease inhibitor CU-2010 dose-dependently reduces postoperative blood loss and improves postischemic recovery after cardiac surgery in a canine model. J Thorac Cardiovasc Surg 2010;139:732-40.  Back to cited text no. 67
Dietrich W, Nicklisch S, Koster A, Spannagl M, Giersiefen H, van de Locht A. CU-2010: A novel small molecule protease inhibitor with antifibrinolytic and anticoagulant properties. Anesthesiology 2009;110:123-30.  Back to cited text no. 68
Englberger L, Dietrich W, Eberle B, Erdoes G, Keller D, Carrel T. A novel blood-sparing agent in cardiac surgery?First in-patient experience with the synthetic serine protease inhibitor MDCO-2010: A phase II, randomized, double-blind, placebo-controlled study in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass. Anesth Analg 2014;119:16-25.  Back to cited text no. 69
Fears R, Greenwood J, Hearn J, Howard BS, Morrow G, Standring R. Inhibition of fibrinolytic and fibrinogenolytic activity of plasminogen activators in vitro by antidotes, aminocaproic acid, tranexamic acid and aprotinin. Fibrinolysis 1992;6:79-86.  Back to cited text no. 70
Wesley MC, Pereira LM, Scharp LA, Emani SM, McGowan FX Jr, DiNardo JA. Pharmacokinetics of tranexamic acid in neonates, infants, and children undergoing cardiac surgery with cardiopulmonary bypass. Anesthesiology 2015;122:746-58.  Back to cited text no. 71
Henry DA, Carless PA, Moxey AJ, O'Connell D, Stokes BJ, Fergusson DA, et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2011:CD001886. doi: 10.1002/14651858.  Back to cited text no. 72
Sigaut S, Tremey B, Ouattara A, Couturier R, Taberlet C, Grassin-Delyle S, et al. Comparison of two doses of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass. Anesthesiology 2014;120:590-600.  Back to cited text no. 73
Sharma V, Fan J, Jerath A, Pang KS, Bojko B, Pawliszyn J, Karski JM, et al. Pharmacokinetics of tranexamic acid in patients undergoing cardiac surgery with use of cardiopulmonary bypass. Anaesthesia 2012;67:1242-50.  Back to cited text no. 74
Hodgson S, Larvin JT, Dearman S. What dose of tranexamic acid is most effective and safe for adult patients undergoing cardiac surgery? Interact Cardiovasc Thorac Surg 2015;21:384-8.  Back to cited text no. 75
Du Y, Xu J, Wang G, Shi J, Yang L, Shi S, et al. Comparison of two tranexamic acid dose regimens in patients undergoing cardiac valve surgery. J Cardiothorac Vasc Anesth 2014;28:1233-7.  Back to cited text no. 76
Faraoni D, Cacheux C, Van Aelbrouck C, Ickx BE, Barvais L, Levy JH. Effect of two doses of tranexamic acid on fibrinolysis evaluated by thromboelastography during cardiac surgery: A randomised, controlled study. Eur J Anaesthesiol 2014;31:491-8.  Back to cited text no. 77
Bennett-Guerrero E, Sorohan JG, Canada AT, Ayuso L, Newman MF, Reves JG, et al. Epsilon-Aminocaproic acid plasma levels during cardiopulmonary bypass. Anesth Analg 1997;85:248-51.  Back to cited text no. 78
Chauhan S, Bisoi AK, Rao BH, Rao MS, Saxena N, Venugopal P. Dosage of epsilon-aminocaproic acid to reduce postoperative blood loss. Asian Cardiovasc Thorac Ann 2000;8:15-8.  Back to cited text no. 79
Hardy JF, Belisle S, Dupont C, Harel F, Robitaille D, Roy M, et al. Prophylactic tranexamic acid and epsilon-aminocaproic acid for primary myocardial revascularization. Ann Thorac Surg 1998;65:371-6.  Back to cited text no. 80
Sarupria A, Makhija N, Lakshmy R, Kiran U. Comparison of different doses of ε-aminocaproic acid in children for tetralogy of Fallot surgery: Clinical efficacy and safety. J Cardiothorac Vasc Anesth 2013;27:23-9.  Back to cited text no. 81
Murkin JM, Falter F, Granton J, Young B, Burt C, Chu M. High-dose tranexamic acid is associated with nonischemic clinical seizures in cardiac surgical patients. Anesth Analg 2010;110:350-3.  Back to cited text no. 82
Kalavrouziotis D, Voisine P, Mohammadi S, Dionne S, Dagenais F. High-dose tranexamic acid is an independent predictor of early seizure after cardiopulmonary bypass. Ann Thorac Surg 2012;93:148-54.  Back to cited text no. 83
Sharma V, Katznelson R, Jerath A, Garrido-Olivares L, Carroll J, Rao V, Wasowicz M, et al. The association between tranexamic acid and convulsive seizures after cardiac surgery: A multivariate analysis in 11529 patients. Anaesthesia 2014;69:124-30.  Back to cited text no. 84
Gofton TE, Chu MW, Norton L, Fox SA, Chase L, Murkin JM, et al. A prospective observational study of seizures after cardiac surgery using continuous EEG monitoring. Neurocrit Care 2014;21:220-7.  Back to cited text no. 85
Montes FR, Pardo DF, Carreno M, Arciniegas C, Dennis RJ, Umana 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. 86
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Mahaffey R, Wang L, Hamilton A, Phelan R, Arellano R. A retrospective analysis of blood loss with combined topical and intravenous tranexamic acid after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth 2013;27:18-22.  Back to cited text no. 87
Fawzy H, Elmistekawy E, Bonneau D, Latter D, Errett L. Can local application of Tranexamic acid reduce post-coronary bypass surgery blood loss? A randomized controlled trial. J Cardiothorac Surg 2009;4:25.   Back to cited text no. 88
Liang, A, Thakkar JN, Desai UR. Study of physico-chemical properties of novel highly sulfated, aromatic, mimetics of heparin and heparan sulfate. J Pharm Sci 2010;99:1207-16.  Back to cited text no. 89
Afosah DK, Al-Horani RA, Sankaranarayanan NV, Desai UR. Potent, selective, allosteric inhibition of human plasmin by sulfated non-saccharide glycosaminoglycan mimetics. J Med Chem 2017;60:641-57.  Back to cited text no. 90

Correspondence Address:
Arun Subramanian
Department of Cardiac Anesthesia, Manipal Hospitals, Sector-6, Dwarka, New Delhi - 110 075
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/aca.ACA_205_18

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