The effect of Tranexamic acid on cardiac surgery bleeding

Introduction
Bleeding and tissue damage may appear as side effects of every surgical operation which immediately activate the homeostatic mechanisms through activation of fibrinolysis and coagulation mechanisms of body to stop loosing excessive amount of blood or any thrombosis (1).
Fibrinolytic mechanism inhibits the intravascular deposition of thrombus. The level of the activation of fibrinolytic mechanism is strongly dependent on the type of surgery which is most significant in orthopedic and cardiac surgeries compared with some simple operations. In each type of surgery, there may be different factors which stimulate the activation of fibrinolysis. Manipulation of the heart, surgical trauma, and heparin are among factors that promote fibrinolysis during cardiac surgeries which finally lead to bleeding and providing the situation for blood transfusion procedure (1).
Cardiac operation is among the surgical procedures which rank high in receiving transfused blood products due to bleeding event during or after the operation. In this regard we reviewed the literature on  administrating the tranexamic acid during cardiac surgeries.

 Blood transfusion
Blood product transfusion is associated with some adverse effects. It is known as a risk factor for higher rate of mortality, infections, and length of hospital stay (2,3).
Safety, cost, and availability of blood products are other noticeable issues which necessitate the investigation of a proper solution to decrease the postoperative blood transfusion requirements. Generally, there are some major risks of recognized or mysterious pathogens along with transfusion including HIV, hepatitis B, and hepatitis C viruses (4).
 In previous surveys, a relationship was observed between blood transfusion and poor clinical outcomes. The main strategy to eliminate the need for transfusion and blood product is the administration of antifibrionlytic therapy (5).

Antifibrinolytics
There are several scientific publications which have agreed on beneficial effects of antifibrinolytic agents during hemorrhagic conditions including different types of surgeries, bleeding disorders, hereditary angio-oedema, upper gastrointestinal haemorrhage, menorrhagia, bleeding in pregnancy, etc (6-9).
Antifibrinolytics are haemostatic agents which preserve the blood content and inhibit post or during operation bleeding with different mechanisms of action in the exceptionally complex fibrinolysis pathway (10). Antifibrinolytics such as teranexonamic acid (TXA) and epsilon-aminocaproic acid (EACA), are two synthetically lysine analogue drugs which are used to reduce bleeding caused by various reasons such as several types of surgical procedures in the absence of regulatory mechanisms. Antifibrinolytics function include restraining the fibrinolysis process by blocking the lysine binding sites of plasminogen which results in reducing the interaction of fibrinogen with plasmin and subsequently inhibits the fibrin degradation.
 Beneficial effects of antifibrinolytic agents on parameters including platelet count, postoperative bleeding and coagulation are measured in several ways, yielded to a common outcome regarding reduction of the blood product transfusion eventually (11,12).
Teranexamic acid [4-(aminomethyl) cyclohexanecarboxylic acid] is one of the major lysine-like drugs which has shown considerable antifibrinolytic activity in human and firstly described in 1964. TXA has small molecular weight and short half life of about 80 minutes (13).
According to results of the 98 clinical trials performed on urologic orthopedic, gynecologic, hepatic, cranial and orthognathic, cardiac, and oral surgeries, a statistically significant decrease is evident in blood transfusion requirements due to administration of tranexamic acid which are summarized in Table1.
This is a common outcome that does not vary depending on the type of surgery (14).
Results obtained through several trials on different types of surgical operations reported that although the effect of tranexamic acid on reducing the mortality events and re-explorations is not statistically significant, it is clear that applying TXA does not increase the mortality rate (14,15).
Higher frequency of re-exploration due to bleeding during or after cardiac surgery has been observed which is noteworthy to be considered (16).
There are numerous investigations concerning the efficacy of prophylactic administration of TXA in patients experiencing cardiac surgeries since the late 1970s. Majority of the trials on cardiac surgeries for example coronary artery bypass graft, valve replacement or repeated surgeries, have tried to compare the value of TXA administration with no drug therapy or applying other drugs including aprotinin, EACA, and desmopresin, in reducing the transfusion procedure. Decrease in allogeneic blood product applying is the major result obtained through various studies.

TXA-induced seizures
All antifibrinolytic drugs have their specific risks and benefits. Although TXA is such a well-tolerated drug, there have been reported some adverse results along with using TXA in patients undergoing cardiac operations including nausea, diarrhea and orthostatic reactions, etc (12). According to some trials, TXA administration can be assumed as a risk factor of seizures after cardiac surgeries which finally lead to higher mortality. The mechanism which results in TXA-induced seizure is uncertain but based on several surveys, this association between TXA and seizure increases considerably when high dose administration of the drug is used for older patients (17-19). TXA administration has caused seizures with odd ratio of 7.4 (20). The other influential factors on TXA-induced seizures are considered to be the permeability of the blood-brain barrier, inhibiting the GABA neurotransmitter of central nervous system, renal insufficiency of patients, valve surgeries and co-administration of TXA with cephazolin (18,21).

TXA dosin
Although many trials have been performed on the prophylactic administration of TXA for cardiac cases, the optimum dosage of TXA for better effects and maintenance of the drug concentration during the operation are still under discussion. According to studies, nearly 30% of the drug will be cleared by the urine excretion within the 1 hour following administration (22).  Although high dose of TXA is observed to be along with higher and steadier plasma concentration of the drug during the surgery, it may increase the risks of different side effects. Therefore some researchers recommended the lowest dosage which is possible to be used as the safest and most appropriate dosage of TXA. A trial in 2010 proposed a bolus of 1gr followed by infusion of 1 gr overnight as a very low dose of TXA which decreases the mortality rate (23). The effective dose of TXA which reduces fibrinolysis activity during in vitro conditions is assessed to be 10 μg/ml.  
Majority of data regarding appropriate dose of TXA have been obtained empirically through previous studies which showed a wide range of applied TXA doses. There is not a considerable agreement among researchers regarding the minimum dose of TXA which leads to limiting the bleeding and blood transfusion (11,24). In open heart surgery, even moderate doses of TXA have resulted in two times increase in the rate of seizure and mortality (25). A trial showed no difference between the efficacy of high and low dosage of administrated TXA on bleeding and transfusion requirements (26). In one survey, about 5.4 mg/kg as the loading dose, 50 mg as the prime dose and 5 mg/kg/h as the amount of infusion were considered as the optimum doses which sustained a steady plasma concentration of above 20 μg/ml. The mentioned doses should be modified in renal deficiency condition (27).  
In conclusion, due to the severe risks and high cost associated with blood products and transfusion method, applying TXA has been known as the most comprehensive strategy for decreasing blood transfusion requirements and preserving blood content which has caused considerable health and economic benefits for countries. There is enough evidence to approve the use of antifibrinolytic agents in cardiac surgeries. Different clinical trials have shown the efficacy of TXA on blood transfusion, although the changing rate of mortality and thromboembolysis is yet under debate. Due to low percent of thromboembotic events in trials, obtaining a comprehensive conclusion regarding altered rate of this events by administrating TXA is difficult. Despite the better understanding about TXA effect in cardiac surgery, it is still difficult to predict the possibility of occurrence of TXA side effects in individual patients due to various genetics for fibrinolysis and thrombolysis situation.

Acknowledgement
We would like to thank Clinical Research Development Center of Ghaem Hospital for their assistant in this manuscript. This study was supported by a grant from the Vice Chancellor for Research of the Mashhad University of Medical Sciences for the research project as a medical student thesis with approval number of 910249.

Conflict of Interest
 The authors declare no conflict of interest.