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Antifibrinolytics and cardiac surgery with cardiopulmonary bypass

Abstracts

BACKGROUND AND OBJECTIVES: Cardiac surgery is the surgical subspecialty most often associated with bleeding, bleeding disorders, and the need of blood products. Agents such as aprotinin, episilon-aminocaproic acid, and tranexamic acid are frequently used to aid the hemostasis of patients undergoing cardiopulmonary bypass. The objective of this report is to present the physiopathology of bleeding during cardiac surgeries and the current role of antifibrinolytics regarding their efficacy and complications when used in those procedures, with emphasis on tranexamic acid and aprotinin. CONTENTS: The mechanisms of changes in hemostasis caused by cardiopulmonary bypass, how antifibrinolytics decrease bleeding, and the use of alogenic blood in cardiac surgery are discussed. A review of the literature emphasizes the thromboembolism secondary to the use of those antifibrinolytics. CONCLUSION: Fibrinolysis is one of the main factors related with increased bleeding during cardiac surgery with cardiopulmonary bypass. Inhibition of fibrinolysis associated with the preservation of platelet function is, probably, the mechanism by which anti-fibrinolytics decrease bleeding. Those agents reduce bleeding in up to 50% in cardiac surgeries with cardiopulmonary bypass. Tranexamic acid and episilon-aminocaproic acid are safer than aprotinin in the prevention of thromboembolism.

BLOOD; DRUGS, Antifibrinolytic agents; SURGERY, Cardiac


JUSTIFICATIVA E OBJETIVOS: A cirurgia cardíaca é a especialidade cirúrgica que com mais freqüência está associada a sangramento, coagulopatia e necessidade de derivados de sangue. Os agentes farmacológicos aprotinina, ácido epsilon-aminocapróico e ácido tranexâmico são os mais utilizados para auxiliar na hemostasia dos pacientes submetidos à circulação extracorpórea. O objetivo deste trabalho foi apresentar a fisiopatologia do sangramento em cirurgia cardíaca e a atual situação dos antifibrinolíticos quanto à sua eficácia e complicações quando usados nesses procedimentos, dando maior ênfase ao ácido tranexâmico e à aprotinina. CONTEÚDO: São discutidos os mecanismos pelos quais a circulação extracorpórea provoca alteração na hemostasia e de que maneira os antifibrinolíticos agem para diminuir o sangramento e o uso de sangue alogênico em cirurgia cardíaca. É dada ênfase ao problema do tromboembolismo que pode ocorrer com o emprego desses antifibrinolíticos, com revisão da literatura. CONCLUSÃO: A fibrinólise é um dos principais fatores relacionados com o aumento do sangramento em cirurgia cardíaca com circulação extracorpórea. A inibição da fibrinólise, juntamente com a preservação da função plaquetária, é, provavelmente, o mecanismo pelo qual os antifibrinolíticos diminuem o sangramento. O emprego desses fármacos reduz o sangramento em cirurgia cardíaca com circulação extracorpórea num percentual que pode chegar a 50%. Com relação à preocupação com o tromboembolismo, os ácidos tranexâmico e epsilon-aminocapróico são opções que oferecem maior segurança que a aprotinina.

CIRURGIA, Cardíaca; DROGAS, Antifibrinolíticos; SANGUE


JUSTIFICATIVA Y OBJETIVOS: La cirugía cardiaca es la especialidad quirúrgica que más frecuentemente está asociada al sangramiento, cuagulopatía y con necesidad de derivados de sangre. Los agentes farmacológicos aprotinina, ácido epsilon-aminocapróico y el ácido tranexámico son los más utilizados para auxiliar en la hemostasia de los pacientes sometidos a la circulación extracorpórea. El objetivo de este trabajo fue presentar la fisiopatología del sangramiento en cirugía cardiaca y la actual situación de los antifibrinolíticos en cuanto a su eficacia y complicaciones cuando usados en estos procedimientos dando más énfasis al ácido tranexámico y a la aprotinina. CONTENIDO: Son discutidos los mecanismos por los cuales la circulación extracorpórea provoca alteración en la hemostasia y de que manera los antifibrinolíticos actúan para disminuir el sangramiento y el uso de sangre alogénica en cirugía cardiaca. Se le da énfasis al problema del trombo embolismo que puede ocurrir con el uso de esos antifibrinolíticos, con revisión de la literatura. CONCLUSIONES: La fibrinólisis es uno de los principales factores relacionados con el aumento del sangramiento en cirugía cardiaca con circulación extracorpórea. La inhibición de la fibrinólisis, conjuntamente con la preservación de la función plaquetaria es probablemente el mecanismo por el cual los antifibrinolíticos disminuyen el sangramiento. El uso de esos fármacos reduce el sangramiento en cirugía cardiaca con circulación extracorpórea en un porcentaje que puede alcanzar el 50%. Con relación a la preocupación con el trombo embolismo, el ácido tranexámico y el ácido epsilon-aminocapróico son opciones que ofrecen una mayor seguridad que la aprotinina.


REVIEW ARTICLE

Antifibrinolytics and cardiac surgery with cardiopulmonary bypass* Correspondence to: Unidade de Pesquisa do IC/FUC Dr. Ari-Tadeu L. Santos Av. Princesa Isabel, 370, Santana 90620-001 Porto Alegre, RS E-mail: editoracao-pc@cardiologia.org.br

Antifibrinolíticos y cirugía cardíaca con circulación extracorpórea

Ari-Tadeu Lírio dos Santos, TSAI; João Carlos Splettstosser, TSAII; Paulo WarpechowskiIII; Mariana Mariz Pinto GaidzinskiIV

IMestre em Ciências da Saúde pelo IC/FUC; Co-Responsável pelo CET/SBA do SANE

IIInstrutor do CET/SBA do SANE

IIIAnestesiologista do SANE

IVME2 do CET/SBA do SANE

Correspondence to Correspondence to: Unidade de Pesquisa do IC/FUC Dr. Ari-Tadeu L. Santos Av. Princesa Isabel, 370, Santana 90620-001 Porto Alegre, RS E-mail: editoracao-pc@cardiologia.org.br

SUMMARY

BACKGROUND AND OBJECTIVES: Cardiac surgery is the surgical subspecialty most often associated with bleeding, bleeding disorders, and the need of blood products. Agents such as aprotinin, episilon-aminocaproic acid, and tranexamic acid are frequently used to aid the hemostasis of patients undergoing cardiopulmonary bypass. The objective of this report is to present the physiopathology of bleeding during cardiac surgeries and the current role of antifibrinolytics regarding their efficacy and complications when used in those procedures, with emphasis on tranexamic acid and aprotinin.

CONTENTS: The mechanisms of changes in hemostasis caused by cardiopulmonary bypass, how antifibrinolytics decrease bleeding, and the use of alogenic blood in cardiac surgery are discussed. A review of the literature emphasizes the thromboembolism secondary to the use of those antifibrinolytics.

CONCLUSION: Fibrinolysis is one of the main factors related with increased bleeding during cardiac surgery with cardiopulmonary bypass. Inhibition of fibrinolysis associated with the preservation of platelet function is, probably, the mechanism by which anti-fibrinolytics decrease bleeding. Those agents reduce bleeding in up to 50% in cardiac surgeries with cardiopulmonary bypass. Tranexamic acid and episilon-aminocaproic acid are safer than aprotinin in the prevention of thromboembolism.

Key Words: BLOOD: coagulation; DRUGS, Antifibrinolytic agents: aprotinin, epsilon-aminocaproic acids, tranexamic acid; SURGERY, Cardiac: cardiopulmonary bypass.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: La cirugía cardiaca es la especialidad quirúrgica que más frecuentemente está asociada al sangramiento, cuagulopatía y con necesidad de derivados de sangre. Los agentes farmacológicos aprotinina, ácido epsilon-aminocapróico y el ácido tranexámico son los más utilizados para auxiliar en la hemostasia de los pacientes sometidos a la circulación extracorpórea. El objetivo de este trabajo fue presentar la fisiopatología del sangramiento en cirugía cardiaca y la actual situación de los antifibrinolíticos en cuanto a su eficacia y complicaciones cuando usados en estos procedimientos dando más énfasis al ácido tranexámico y a la aprotinina.

CONTENIDO: Son discutidos los mecanismos por los cuales la circulación extracorpórea provoca alteración en la hemostasia y de que manera los antifibrinolíticos actúan para disminuir el sangramiento y el uso de sangre alogénica en cirugía cardiaca. Se le da énfasis al problema del trombo embolismo que puede ocurrir con el uso de esos antifibrinolíticos, con revisión de la literatura.

CONCLUSIONES: La fibrinólisis es uno de los principales factores relacionados con el aumento del sangramiento en cirugía cardiaca con circulación extracorpórea. La inhibición de la fibrinólisis, conjuntamente con la preservación de la función plaquetaria es probablemente el mecanismo por el cual los antifibrinolíticos disminuyen el sangramiento. El uso de esos fármacos reduce el sangramiento en cirugía cardiaca con circulación extracorpórea en un porcentaje que puede alcanzar el 50%. Con relación a la preocupación con el trombo embolismo, el ácido tranexámico y el ácido epsilon-aminocapróico son opciones que ofrecen una mayor seguridad que la aprotinina.

INTRODUCTION

Excessive bleeding is still a serious complication in cardiac surgeries. When it happens, it can increase morbidity and mortality. Besides, bleeding and reintervention increase treatment costs. The consumption of blood components and blood products is increased, as well as the length of surgery, besides increasing the length of admission in postoperative units and in the hospital. Although the frequency and criteria for blood transfusions are not uniform among different cardiac surgery departments, approximately 60% to 75% of patients receive blood transfusion 1,2. Reintervention due to bleeding in those types of procedures ranges between 2% and 6%, with a mortality rate of 10% to 22% 3,4.

The most frequent causes of hemorrhage include inadequate surgical hemostasia or change in hemostasis as a consequence of cardiopulmonary bypass (CPB).

For the reasons mentioned above, several strategies have been developed to avoid excessive bleeding and to decrease the number of transfusions.

Those strategies can be divided in pharmacological and non-pharmacological. Among the pharmacological strategies, the antifibrinolytics tranexamic acid (TA), epsilon-aminocaproic acid (EACA), and aprotinin are used and studied more often. Autologous preoperative blood donation, recovery of red blood cells by intraoperative centrifugation, and normovolemic dilution are non-pharmacologic strategies used most often.

NORMAL HEMOSTASIA

Normal hemostatic response includes three phases: primary hemostasis, clotting, and fibrinolysis. Primary hemostasis, which depends primarily on platelets and their interaction with the blood vessel, begins shortly after vascular rupture, forming a platelet plug and temporarily stopping bleeding. Clotting strengthens this friable plug with production of fibrin. This process takes up to 4 hours and stops bleeding while the blood vessel is healing. Fibrinolysis, which occurs after 24 hours, removes the clot and allows the restoration of blood flow in the affected vascular segment.

Clotting forms a fibrin net that stabilizes the platelet plug. This phase is didactically divided in two pathways: intrinsic pathway, or pathway of the contact factor, and the extrinsic pathway, or pathway of the tissue factor (TF) (Figure 1). The rigid division in two pathways is not that important anymore because there are several factors that participate in both pathways. It is important to note that, in vitro, activation of coagulation can occur by any one of those pathways. The extrinsic pathway is activated when the TF is exposed by the vascular lesion 5, and the participation of factors V and X, occurs in the common or final pathway of the coagulation cascade, whose objective the formation of thrombin (Figure 1).


It is accepted, nowadays, that clotting begins when the TF is exposed to the intravascular space after lesion of the endothelium or by the release of cytokines. This factor binds activated factor VII (FVIIa), which corresponds to 1% of the total amount of circulating factor VII. The complex TF-FVIIa activates factor X (FXa) and factor IX (FIXa). Activated factor X then activates factor V (FVa). These two factors also form a complex whose final result is the formation of a small amount of thrombin which, in turn, is capable to activate platelets, factor VIII, factor V, and factor XI. The surface of the activated platelet is the place where the complex FVIIIa-FIXa activates factor X with an efficacy 50 times greater than the complex TF-FVIIa. Activated factor FXa binds FVa in another area of the platelet surface, forming the prothrombinase complex that is capable of forming large amounts of thrombin from FXa 6. Thrombin converts fibrinogen in fibrin, promotes platelet activation, and activates factor XIII, responsible for fibrin polymerization, which makes the clot more resistant.

Besides this mechanism, called extrinsic pathway, which triggers coagulation in response to trauma, another pathway also activates coagulation, and involves factor XII, high-molecular weight kininogens, pre-kallikrein, and factor XI, followed by the activation of factor IX. The importance of this pathway is not completely understood, since factor XII deficiency does not cause changes in coagulation. On the contrary, factor XI deficiency could cause moderate bleeding 7. According to Roberts et al. 6, factor XI deficiency causes changes in coagulation, which have little clinical importance.

Coagulation should be controlled in order to remain restricted to the area of vascular lesion.

Several mechanisms prevent disseminated coagulation. Since blood remains in the form of a liquid, despite intense stimulus, as can be seen in polytraumatized patients, it demonstrates that these mechanisms are effective. The antithrombin III system (ATIII) is the most important of them. Heparin potentiates the actions of ATIII. In the absence of ATIII, heparin does not have anticoagulation activity, and plasma should be administered to the patient.

Fibrinolysis is the process that destroys thrombi. Plasminogen and tissue plasminogen activator (t-PA), a protease that transforms plasminogen in plasmin, participate in this process. Since it is a wide-spectrum proteolytic enzyme, plasmin digests fibrin, fibrinogen, and most coagulation factors and co-factors 8. Fibrin is stabilized by the formation of cross links stimulated by factor XIII. Lysis of the clot before cross links are formed, originates fibrin and fibrinogen degradation products (FDP). Lysis of the clot after fibrin stabilization originates D-dimers.

CHANGES IN HEMOSTASIS DURING CPB

When blood circulates within the cardiovascular system, it is always in contact with a continuous layer of endothelium, capable of maintaining it in liquid form. The endothelium is extremely important for the hemostatic system because it participates in all three phases of hemostasis 9. Endothelial cells release factors that control platelet activation and inhibition, clotting, and fibrinolysis.

During cardiopulmonary bypass, blood is in contact with artificial surfaces, measuring approximately 12 m2, that form the CPB system. The lining material of oxygenators, filters, lines, and other components of the system, derives from chemical compounds, such as polyvinyl chloride, silicon, polyurethane, polycarbonate, and polyesterene 10. Despite attempts to improve the biocompatibility of those materials, this system still activates blood cells, leading to the release of TF.

Until recently, artificial CPB surfaces were considered the greatest stimulus for thrombin formation. Currently, evidence indicates that tissue lesion is more important. The extrinsic pathway is activated whenever blood is in contact with the pericardium and damaged tissues rich in TF 11-13. For this reason, Tabuchi et al. 14 recommended that, whenever possible, blood accumulated in the pericardium should neither be aspirated nor mixed with circulating perfusate. This blood should be washed and concentrated, allowing only red blood cells to return to the circulation, except in critical bleeding situations. Another alternative is the addition of antibodies against TF or administration of the inhibitor of the TF pathway directly in the blood that accumulates in the pericardium, to avoid the activation of the intrinsic pathway 15.

The intrinsic pathways probably do not promote the formation of thrombin in vivo, but whenever blood gets in contact with CPB materials, the process of thrombin formation is activated 16.

Heparin is not the ideal anticoagulant to be used during CPB because it does not prevent completely the formation of thrombin. Kojima et al. 17 demonstrated that during CPB the levels of thrombin are elevated. It is important to stress that fibrin is formed, and consequently fibrinolysis is present, whenever thrombin is activated. Besides converting fibrinogen in fibrin, thrombin is a potent platelet activator by causing a conformational change in the platelet receptor IIb/IIIa, allowing fibrinogen to bind to this place, with consequent platelet aggregation and release of ADP and serotonin, and induction of the synthesis of prostaglandins and formation of thromboxane A218. Thrombin also activates factors V, VIII, and XI 19, promoting the formation of more thrombin and activation of factor XIII 20.

Another effect of thrombin that occurs in the third phase of hemostasis is the release of t-PA, produced by the endothelium, with conversion of plasminogen in plasmin and consequent activation of the fibrinolytic system. Plasmin degrades fibrin, forming FDP and D-dimers. Fibrinogen degradation products inhibit platelet aggregation, probably by binding to the platelet receptor GPIIb/IIIa, which is important for platelet aggregation (Figure 2) 21. Fibrinogen degradation products have other actions that favor anticoagulation, such as degradation of factors V and VIII and interference with fibrin polymerization, i.e., interferes with the formation of cross links stimulated by factor XIII 22.


Evidence indicates that besides its action on fibrin, plasmin causes changes in platelet receptors, especially glycoprotein Ib-IX, the main receptor of the von Willebrand 23 factor, leading to the destruction of factors V and VIII 24.

Cardiopulmonary bypass induces changes in the complex fibrinolysis system, because it promotes imbalances between t-PA and plasminogen activator inhibitor-1. Initially, fibrinolysis predominates, which might be followed by a tendency for thrombosis. This explains the theoretical risk of postoperative thrombotic complications after CPB.

The heparin used during CPB participates in the changes in platelet function that occur in this period. Platelets are activated by heparin, with an increase in its aggregation capacity. Activated platelets form macroaggregates and disappear rapidly from the circulation, explaining the reduction in platelet number that is seen during CPB 25. Besides, heparin causes changes in platelet function by inducing a temporary refractoriness to ADP stimulus 26.

The CPB system, through its rollers, filters, aspirators, oxygenator, and other components of the perfusion equipment, causes mechanical lesions of the platelets, therefore contributing to the altered hemostasis.

ANTIFIBRINOLYTICS

Pharmacological strategies with antifibrinolytics to reduce bleeding in cardiac surgeries take into consideration the changes in hemostasis caused by CPB and the mechanism of action of the drugs.

Until the middle of the decade of 1980, pharmacological strategies used more often to reduce surgical bleeding consisted of desmopressin and prostacyclins, which were not very effective 27-29.

Antifibrinolytics inhibit fibrinolysis and, consequently, prevent or reduce the formation of FDP, which have deleterious effects on platelet function. Besides, they also decrease the conversion of plasminogen in plasmin that has proteolytic actions on platelet receptors.

Currently, three antifibrinolytic agents are used more often. Aprotinin, a wide spectrum inhibitor of serum proteases, and two analogs of the amino acid lysine, EACA and TA, that inhibit fibrinolysis. In most studies, those drugs cause a 30% to 50% reduction in bleeding.

APROTININ

Aprotinin is a wide spectrum polypeptide that inhibits serum proteases, isolated from bovine lungs. Its efficacy is related to its wide spectrum. It inhibits several plasma proteases: plasmin, serum and tissue kallikrein, trypsin, and urokinase 30. Its antifibrinolytic action is related with the inhibition of plasmin. The inhibition of proteases seems to be dose-dependent 31. It is currently the pharmacological strategy used more often to decrease bleeding in cardiac surgeries after ECC.

In vitro studies show that a serum concentration of 125 KIU (kallikrein inhibitor units).mL-1 inhibits more than 90% of plasmin activity. To inhibit kallikrein it is necessary a serum concentration of 300-500 KIU.mL-1 32. Aprotinin is eliminated by the kidneys. In 4 hours, 80% of the drug has already been eliminated.

The use of aprotinin as a blood-sparing drug has been demonstrated in several clinical studies, with random distribution of patients, and 3 meta-analyses 33-35. It has been demonstrated that aprotinin is effective in reducing bleeding and blood transfusions in cardiac surgeries with CPB, even in patients with increased risk of bleeding 36-38.

Aprotinin is used, mostly, in high doses, as established by Roystron et al. 36 at the Hammersmith Hospital. Since its elimination half-life is between 1 and 7 hours, the recommended regimen consists of an initial dose of 2 x 106 KIU (2,000,000 KIU), followed by the same dose in the CPB, and continuous infusion of 5 x 105 KIU.h-1 during surgery. Several studies demonstrated that this regimen reduces blood loss by up to 50% and the need of transfusion in 40% to 80% of the cases of cardiac surgery with CPB 39-42.

Besides this regimen, the one used more often and that has been studied the most, regimens with lower doses have been used. The initial administration is 1x106 KIU, similar dose at CPB, and continuous infusion of 2.5 x 105 KIU during surgery. Studies have demonstrated that this dose decreases the loss of blood and the need of blood transfusion 43-46.

The high cost of aprotinin is one of the problems that hinder its use. Besides, it has a higher incidence of allergic reaction than synthetic antifibrinolytics 47. Pinosky et al. alerted that the repeated use of aprotinin may cause anaphylactic reaction in 5% to 6% of the patients 48. The prevalence of allergic reactions during the first exposure is lower. In the work of Levy et al. with 287 patients, 215 received this drug, and the incidence of allergic reaction was of 0.5%. This reaction was characterized by cutaneous reaction restricted to the thorax and neck, without hemodynamic changes 49.

Aprotinin accumulates in the renal tubules, raising the concern of renal complications. In animal studies, the administration of aprotinin caused a reduction in glomerular filtration, renal plasma flow, and excretion of sodium and potassium 50. The actions of aprotinin in renal function are complex and cause important changes in human kidneys 51.

TRANEXAMIC ACID

Tranexamic acid (TA), along with EACA, belongs to the group of antifibrinolytics derived from lysine. The structural formula of those synthetic antifibrinolytics is similar (Figure 3).


Figure 4


Tranexamic acid is 6 to 10 times more potent than EACA 52. It has more affinity for plasminogen, its antifibrinolytic activity is more sustained, and it has a longer duration. The volume of distribution of this drug varies from 9 to 12 liters, and the elimination half-life is approximately 2 hours 53. After intravenous administration, only 3% bind to proteins. More than 95% of the drug are eliminated in the urine 54; therefore, the dose should be reduced in patients with renal failure.

Several recent, comparative, clinical studies between TA and aprotinin failed to show any differences in postoperative bleeding and transfusion of alogenic blood 55-58.

As for EACA, several studies have also demonstrated a reduction in bleeding after cardiac surgery with CPB 59-61. In comparative studies with TA and EACA, TA had better results 48,62.

The dose of TA used prophylactically to prevent excessive bleeding in cardiac surgeries with CPB varies among the different institutions. The doses vary between a single dose of 150 mg.kg-1 to an initial dose of up to 10 mg.kg-1 followed by the infusion of 1 mg.kg-1.h-1. The larger prospective, double-blind study that compared 5 different doses, undertaken by Horrow et al. 63, demonstrated that an initial dose of 10 mg.kg-1 followed by the infusion of 1 mg.kg-1.h-1, is the most adequate. This dose provides serum levels above 10 µg.ml-1, enough to suppress fibrinolytic activity 64. In a recent study by Fischer et al. 65, the dose described maintained adequate levels ( 10 µg.mL-1). This administration regimen was questioned by a preliminary study by Dowd et al. 66, who measured serum levels of TA during CPB. The administration of 10 mg.kg-1 of TA followed by the infusion of 1 mg.kg-1.h-1 did not maintain therapeutic levels in isolated moments of CPB. The study by Karski et al. 67 also questioned the dose used. They compared three groups with doses of 50 mg.kg-1, 100 mg.kg-1, and 150 mg.kg-1, administered 20 minutes before CPB. Bleeding was significantly greater in the group that received 50 mg.kg-1.

When the administration is instituted also influences the results. In two studies that demonstrated that TA did not reduce bleeding in cardiac surgeries with CPB by Filipescu et al. 68 and Ævrum et al. 69 this methodological matter must have been important. Tranexamic acid was not instituted after the incision of the skin, which hindered its efficacy. Soslau 70 compared two groups, one in which TA was started before the incision of the skin and the other after CPB. Bleeding and serum levels of FDP were greater in the second group.

Besides the dose and when the administration is instituted, another variable is the duration of the administration. Casati et al. 71 demonstrated that prolonging the infusion of TA beyond the surgery does not add advantages regarding bleeding or the number of homologous transfusions. The explanation is based on the elimination half-life of TA of 80 minutes. Approximately 30% of the drug appear in the urine in 1 hour, and 45% in the following 2 hours, and 90% are eliminated in 24 hours. Therefore, the amount administered during surgery is enough for the immediate postoperative period, when the stimulus that leads to changes in hemostasis is over. Treatment with TA increases the precipitation of fibrin, and can cause thrombosis and decrease renal function in patients with glomerular disease. The use of this drug is potentially dangerous in patients with glomerulonephritis or nephrotic syndrome, being able to trigger renal failure by intratubular fibrin precipitation. In theory, TA can also potentiate the problem in patients with hematuria in the upper urinary tract because it prevents the dissolution of the clots by urokinase. These clots can obstruct the urinary tract 72.

The topic administration of TA in the central nervous system, in humans and animals, has been related with seizures 73,74. However, this observation has not been reported in clinical studies and meta-analysis of cardiac surgeries. We found only one study in humans, by Couto et al. 75, that reported a possible correlation between TA and seizures, because one patient in the TA group developed seizures.

The antifibrinolytic activity is due to the formation of reversible complexes with plasminogen. Tranexamic acid and EACA block almost completely the interaction of t-PA, plasminogen, and the fibrin monomer due to the high affinity for binding places on the lysine in the plasminogen 76. This process inhibits or delays fibrinolysis because, although plasmin is formed, it cannot bind to fibrin.

EPSILON-AMINOCAPROIC ACID

Epsilon-aminocaproic acid (EACA), similar to TA, is a competitive inhibitor of plasminogen activation. It has been used in different doses and regimens. The dose recommended, and used, in most cases varies from 100-150 mg.kg-1, intravenous, followed by the infusion of 10-15 mg.kg1 during the surgery. Serum levels of 70 to 75 µg.mL-1 inhibit fibrinolysis in 50%, and blood levels around 130 µg.mL-1 have the maximal effect 77. It has a redistribution of 10 to 25 minutes and an elimination half-life of 1 to 3 hours. Most of the drug is eliminated by the kidneys, and about 35% is metabolized in the liver 78.

Epsilon-aminocaproic acid has a small, synthetic molecule, assuring a very small risk of allergic reaction. The most frequent side effect is hypotension, which is usually associated with fast administration 79.

DISCUSSION

One of the main concerns about the use of antifibrinolytics in myocardial revascularization with CPB is the risk of obstruction of the coronary grafts and myocardial infarction (MI). Suppression of fibrinolysis without reduction in thrombin formation can, in theory, lead to hypercoagulability and, consequently, MI.

Aprotinin is the antifibrinolytic drug studied the most. The use of low doses has been questioned for a long time. Currently, this regimen is not recommended due to the concern of thromboembolic complications 80. The use of aprotinin, even in the high doses regimen, has been questioned regarding the increase in thromboembolic complications. In the multicenter study, IMAGE 81, sponsored by the manufacturer of aprotinin, with 870 patients undergoing primary myocardial revascularization, occlusion of the graft of saphenous vein was greater in the aprotinin group. The incidence of graft occlusion in the aprotinin group was 15.4% and 10.9% in the placebo group (p = 0.03). After a questionable statistical analysis, adjusted for risk factors of saphenous graft occlusion, that included among the factors analyzed even the possible use of blood with aprotinin to preserve the graft, the relationship decreased. The percentage rate in the aprotinin group ended up as being 1.7%, and in the placebo group it was 1,09%. The authors stated that aprotinin can affect the permeability of grafts with vessels whose diameter is below 1.5 mm or in patients with compromised distal vascular bed, which is very common nowadays with the change in the population undergoing this procedure, due to the increase in the frequency of therapeutic hemodynamic interventions that treat less severe cases.

The meta-analysis by Laupacis et al., 5,808 patients of clinical studies with random distribution of patients, comparing groups that received aprotinin with placebo groups, showed a tendency, which was not statistically significant, for a greater incidence of MI in the group treated with aprotinin 34.

In another meta-analysis, undertaken in 1999, with 72 clinical studies with random distribution of 8,409 patients, the authors demonstrated that the frequency of MI was twice as high in patients who received conventional (high) doses of aprotinin than those who received low doses, and this difference was statistically significant. When patients who received aprotinin (regardless of the dose) were compared with the placebo group, the incidence of MI was greater in the aprotinin group, but this difference was not statistically significant. However, despite of this tendency, in-hospital mortality in this meta-analysis was always lower in the aprotinin group. Comparing patients who received aprotinin, regardless of the dose, with the placebo group, the in-hospital mortality was twice as high in the placebo group 82. It is important to stress that the scientific value of the mortality evaluation would be higher if the follow-up were not restricted to the hospitalization period.

The study by Cosgrove et al. demonstrated a tendency for a higher prevalence of MI in patients treated with aprotinin who underwent myocardial revascularization 83. Heparin was administered to maintain the PTT above 400 seconds, and it is now known that aprotinin prolongs, artificially, the PTT activated with celite. In this study, the justification for the higher incidence of MI observed in the aprotinin group was inadequate anticoagulation. The dose of heparin was lower than usual, and it would have caused greater formation of fibrin, with an increase in the consumption of coagulation factors and reduction in platelet function, according to the mechanisms explained before.

In a recent study with 4,374 patients with worldwide repercussion, which also originated a recommendation in the site of the Society of Cardiovascular Anesthesiologists, Mangano et al. 51 demonstrated that the use of aprotinin is associated with renal lesion, MI, heart failure, and strokes, contrasting with the use of TA and EACA, which are recommended as less expensive and safer alternatives. These drugs are not associated with increased risk of renal, cardiac, or cerebral events.

Due to its cost, which makes the routine use of aprotinin in cardiac surgeries with CPB impracticable, sensitization with the possibility of an allergic reaction on future exposures, and the risk of thromboembolic and renal complications, the interest for TA and EACA has increased, since the reduction in postoperative bleeding in cardiac surgeries is not different among those drugs.

Fibrinolysis is related to changes in hemostasis that occur during CPB. To detect the severity of fibrinolysis, the dosage of D-dimers, specific to measure fibrinolysis, is one of the tests used most often 53,84,85; it quantifies the lysis of fibrin with cross-links. Elevated serum levels of D-dimers reflect and increase in the lysis of fibrin, i.e., increased fibrinolysis. In a recent study with patients undergoing cardiac surgery with CPB, the concentration of D-dimers was significantly lower in the group that received TA, demonstrating reduced fibrinolytic activity, when compared with the placebo group 86.

The thromboelastograph, easy and fast to use, is another way of measuring fibrinolysis after CPB 87.

As mentioned before, the risk of MI is one of the main concerns about the use of antifibrinolytics. Suppression of fibrinolysis without reducing the formation of thrombin can, in theory, lead to a hypercoagulable state; however, studies with TA have not demonstrated increased risk or tendency of thromboembolic complications, such as MI.

In the meta-analysis by Laupacis et al. 34 of 12 studies with 882 patients, the prevalence of MI was 0.4% in the TA group and 1.8% in the control group. In another meta-analysis, undertaken by Levi et al. 35, comparing TA and EACA together, as lysine analogues, to placebo, demonstrated a tendency for decreased prevalence of MI in the group treated with lysine analogues than in the placebo group.

CONCLUSION

The risk of MI did not increase with the use of antifibrinolytics and lysine analogues (TA and EACA), according to several studies and meta-analysis. However, fibrinolysis and bleeding decreased significantly, demonstrating that the use of those drugs is safe and beneficial to patients undergoing cardiac surgeries with CPB. The routine use of these antifibrinolytics can be recommended for their low cost and safety.

REFERENCES

Submitted em 21 de agosto de 2006

Accepted para publicação em 22 de junho de 2007

* Received from Serviço de Cirurgia Cardiovascular do Instituto de Cardiologia do Rio Grande do Sul/Fundação Universitária de Cardiologia (IC/FUC)

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  • Correspondence to:
    Unidade de Pesquisa do IC/FUC
    Dr. Ari-Tadeu L. Santos
    Av. Princesa Isabel, 370, Santana
    90620-001 Porto Alegre, RS
    E-mail:
  • Publication Dates

    • Publication in this collection
      14 Sept 2007
    • Date of issue
      Oct 2007

    History

    • Accepted
      22 June 2007
    • Received
      21 Aug 2006
    Sociedade Brasileira de Anestesiologia R. Professor Alfredo Gomes, 36, 22251-080 Botafogo RJ Brasil, Tel: +55 21 2537-8100, Fax: +55 21 2537-8188 - Campinas - SP - Brazil
    E-mail: bjan@sbahq.org