Anesthesia & Analgesia:
Cardiovascular Anesthesiology: Research Report
The Effective Concentration of Tranexamic Acid for Inhibition of Fibrinolysis in Neonatal Plasma In Vitro
Yee, Branden E. MD, MPH*; Wissler, Richard N. MD, PhD*; Zanghi, Christine N. MD, PhD*; Feng, Changyong PhD*†; Eaton, Michael P. MD*
From the Departments of *Anesthesiology and †Biostatistics and Computational Biology, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Branden E. Yee, MD, MPH, is currently affiliated with Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri.
Accepted for publication June 10, 2013.
Published ahead of print September 10, 2013
Funding: Funded by Institutional and Departmental Resources.
The authors declare no conflicts of interest.
Reprints will not be available from the authors.
Address correspondence to Michael P. Eaton, MD, Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave., Box 604, Rochester, NY 14642. Address e-mail to email@example.com.
BACKGROUND: Neonates are at high risk for bleeding complications after cardiovascular surgery. Activation of intravascular fibrinolysis is one of the principal effects of cardiopulmonary bypass that causes poor postoperative hemostasis. Antifibrinolytic medications such as tranexamic acid are often used as prophylaxis against fibrinolysis, but concentration/effect data to guide dosing are sparse for adults and have not been published for neonates. Higher concentrations of tranexamic acid than those necessary for inhibition of fibrinolysis may have adverse effects. Therefore, we investigated the concentration of tranexamic acid necessary to inhibit activated fibrinolysis in neonatal plasma.
METHODS: We conducted an in vitro study using neonatal plasma derived from the placenta/cord units from 20 term, elective cesarean deliveries. Graded concentrations of tranexamic acid were added to aliquots of the pooled plasma before maximally activating fibrinolysis with high-dose tissue-type plasminogen activator. Thromboelastography was then performed with the primary outcome variable being lysis at 30 minutes. These procedures were repeated on pooled adult normal plasma and dilutions of neonatal plasma.
RESULTS: The minimum concentrations of tranexamic acid to completely prevent fibrinolysis were 6.54 μg/mL (95% confidence interval, 5.19–7.91) for neonatal plasma and 17.5 μg/mL (95% confidence interval, 14.59–20.41) for adult plasma. Neonatal plasma requires a significantly lower concentration than adult plasma (P < 0.0001, 2-sided Wald test).
CONCLUSIONS: Our data establish the minimal effective concentration of tranexamic acid necessary to completely prevent fibrinolysis in neonatal plasma in vitro. These data may be useful in designing a dosing scheme for tranexamic acid appropriate for neonates.
Cardiopulmonary bypass (CPB) and cardiovascular surgery produce significant impairment of hemostasis, predisposing patients to excess postoperative blood loss and transfusion. Activation of intravascular fibrinolysis is one of the principal effects of CPB that may cause poor postoperative hemostasis.1 This is often treated with antifibrinolytic medications including the lysine analog tranexamic acid (TXA).2 Optimal dosing of TXA in pediatric cardiac surgical patients is not well established.
The neonatal hemostatic system is fundamentally different from that of the adult and continues to develop in infants until at least 6 months of age.3,4 Compared with adults, newborns have significantly different levels of both procoagulant and anticoagulant proteins, including proteins relevant to fibrinolysis.5 Plasminogen and α2 antiplasmin are decreased (65% and 76% of adult values, respectively), while tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor are increased (195% and 178% adult values, respectively).3 In addition, structural differences in neonatal plasminogen makes it less sensitive to activation by tPA, but the activated plasmin in turn is less inhibited by α2 antiplasmin.6,7 These differences lead to a decrease in baseline plasmin generation and overall fibrinolytic activity.8 Given these many differences, it is apparent that neonates are likely to have an altered response to drugs that inhibit fibrinolysis. Despite this, dosing schemes used in clinical studies of TXA in pediatric cardiac surgery have been loosely based on adult doses or are simply empiric,9–13 although a recent study has suggested a pharmacokinetically based dosing regimen based on data from older children.14 Unfortunately, the only available data on the concentration of TXA required to inhibit fibrinolysis is from a 1968 study that used animal fibrin and plasminogen activator.15 It is not clear how these data are applicable to human infants and children.
Thromboelastography has been shown to be a reliable measure of fibrinolysis that correlates well with biohumoral markers in vivo16 and reflects dose-dependent activation of fibrinolysis in vitro by urokinase17 and tPA.18 This technology has been used to establish minimum effective concentrations of another lysine analog antifibrinolytic, ε-aminocaproic acid (EACA), to inhibit fibrinolysis in adult19 and neonatal plasma.20
Although TXA is commonly used to prevent excess bleeding in pediatric cardiac surgery,2 it is not known what the effective concentration of TXA is in this population. It is important to target the minimally effective concentration of TXA, because high doses of TXA have been associated with postoperative seizures in adults21,22 and children23 after cardiac surgery. High doses of EACA, which shares mechanism of action with TXA, have been associated with catastrophic intravascular thrombosis.24,25 The purpose of the current study was to determine the minimum concentration of TXA that inhibits fibrinolysis in neonatal plasma in vitro as measured by thromboelastography and compare that with the effective concentration in adult plasma.
This study was determined by the University of Rochester Research Subjects Review Board to be exempt from full board review. Because this study was to be conducted exclusively on discarded tissue (placenta/cord units) with no patient identifying information collected, informed consent was not required. Cord blood samples were collected immediately after the elective cesarean deliveries of 23 full-term (38–42 weeks) singleton live births. They were born to healthy mothers after uncomplicated pregnancies.
After the delivery of the placenta, blood was drawn from the umbilical vein and aliquoted into 4.5-mL citrated tubes and stored at 4°C. Immediately after each draw, a whole blood kaolin-activated thromboelastogram was run. Within a 4-hour period, the retained specimens were centrifuged (1700g × 15 minutes) and the platelet poor plasma was aliquoted and stored at −70°C.
The initial 23 baseline whole blood thromboelastograms were analyzed using Dixon test (confidence level = 0.95) to identify outliers for each of the 7 variables (reaction time, angle, κ, maximum amplitude, clotting index, G, lysis at 30 minutes). Two specimens were found to be outliers, and the plasma was discarded and not used for the neonatal plasma pool. This ensured that blood that had congenital or postdelivery hemostatic abnormalities would not be included in the plasma pool. One specimen’s aliquoted plasma would not provide a sufficient amount of plasma for planned testing, and this plasma was also discarded, resulting in 20 retained samples.
Before analysis, an aliquot of plasma from each of the 20 retained samples was thawed in a 37°C water bath. One milliliter of each sample was combined to form a pool of platelet poor plasma, and all further testing was performed using aliquots of this pool. All subsequent sample mixtures were prepared as previously described.20 In brief, 10 μL tPA (Activase®, Genentech, San Francisco, CA) and 5 μL TXA were added before activation with 1% kaolin. The final concentration of tPA was 1000 units/mL. TXA was added in graded concentrations with the same final volume in each thromboelastograph® cuvette (Medtel, Haemoscope Corp., Niles, IL). The initial series of thromboelastograms used the following TXA concentrations: 0, 1, 2, 4, 6, 8, 10, and 15 μg/mL. Additional thromboelastograms were run as described on adult pooled normal plasma (FACT, George King Biomedical, Overland Park, KS), after activation with 1000 units/mL tPA and TXA concentrations of 0, 1, 5, 7.5, 10, 12.5, 15, and 20 μg/mL.
Because neonatal blood is normally significantly diluted by crystalloid/colloid or adult plasma during CPB, we next performed thromboelastograms as described on aliquots of the neonatal plasma pool diluted 1:1 with normal saline or adult pooled normal plasma. TXA was added to saline dilutions in concentrations of 1, 2, 4, 6, 8, 10, and 15 μg/mL and to adult plasma dilutions in concentrations of 0, 2, 4, 6, 8, 10, 15, and 20 μg/mL. Fibrinolysis was initiated with 1000 units/mL tPA.
All standard thromboelastographic variables were measured, and the percent clot lysis at 30 minutes (Ly30) was used as the primary outcome variable, because it reflects the total amount of clot lysis (Ly30 = [Maximum Amplitude − Amplitude at 30 minutes] ÷ [Maximum Amplitude]).
All thromboelastograms were performed in duplicate using the Thrombelastograph® Analyzer 5000 (Haemonetics, Braintree, MA) using disposable standard cuvettes and pins (Medtel; for Haemonetics). One milliliter of collected whole blood or pooled plasma was placed into a 1% kaolin vial (Medtel; for Haemonetics), which was then inverted 5 times to ensure appropriate activation of the sample. After activation, 340 μL blood was pipetted into a cuvette containing 20 μL (0.9 M) calcium chloride. Testing was conducted at 37°C. The tracing was automatically stopped 30 minutes after maximum amplitude was obtained.
Equation (Uncited)Image Tools
transformation was applied on the proportional outcome variable Ly30 to stabilize the variance of the transformed data as well as to linearize the concentration/effect curve between TXA and transformed Ly30.26 The transformed Ly30 was then modeled as a function of the concentration of TXA using linear regression. To improve model fit, only observations that provide nonredundant information or nonflooring effect were used, that is, we excluded from the model observations where Ly30 = 0 beyond the lowest TXA concentration where Ly30 was 0, because these points would only have skewed the curve. Inverse linear regression was used to determine the minimum effective concentration of TXA, that is, the minimum value of x (TXA concentration) at which y (Ly30) was zero.26 As the estimated minimum effect concentration is a function of estimated regression coefficients, the delta method27 was used to obtain its standard deviation, and the Wald test was used to calculate the 95% confidence interval. All statistical analyses were performed using R Language (R Foundation for Statistical Computing, Vienna, Austria).
Whole blood thromboelastographic values for the 20 samples included in the pool and reference variables are shown in Table 1. The addition of 1000 U/mL tPA produced rapid complete lysis (Fig. 1). Concentration-dependent inhibition of fibrinolysis by TXA was shown, with an estimated minimum completely effective concentration of 6.54 μg/mL (95% confidence interval, 5.19–7.91) for neonatal plasma and 17.50 μg/mL (95% confidence interval, 14.59–20.41) for adult plasma. The minimum effective concentrations of TXA for neonatal plasma and for adult plasma were significantly different (P < 0.0001, 2-sided Wald test). The Wald test was used to compare the coefficients of the concentration of TXA in the linear regressions (with transformed Ly30 as the dependent variables) in neonatal and adult groups. The regression analysis demonstrated that the neonatal concentration/effect curve for TXA is significantly different from the adult curve (P < 0.0001), that is, the concentration/effect relationship was significantly different between adult and neonatal plasma, with neonates requiring less TXA for inhibition of fibrinolysis (Fig. 2).
Equal volume dilutions of neonatal plasma with normal saline produced results very similar to the undiluted samples. Dilution with adult pooled normal plasma produced results between those for neonatal and adult plasma, with a minimum effective concentration of 9.83 μg/mL (95% confidence interval, 7.76–11.91).
Our data establish the minimally effective concentration of TXA to completely prevent fibrinolysis in neonatal plasma in vitro. Although the contribution of fibrinolysis to bleeding after heart surgery in neonates is less clear than with adults,29–32 lysine analog antifibrinolytics are effective in decreasing bleeding and transfusion in pediatric heart surgery. Multiple studies of this therapy have been published with all 5 EACA studies2,33–37 and 9 of 10 TXA studies,9–13,33,38–41 demonstrating a decrease in bleeding in treated groups relative to placebo. Dosing strategies used in these studies varied widely and have been based on extrapolation of adult regimens using incorrect pharmacokinetic assumptions which ignored the relative size of the patients’ blood volume and the pump prime. In addition, since very limited adult pharmacodynamic data have been available, it has been impossible to create a dosing scheme addressing neonatal physiology. While currently used dosing schemes have largely been effective, it is important to develop a dosing regimen that inhibits fibrinolysis without producing excessive levels. Dosing schemes modeled to produce low concentrations may not be clinically effective.2 Excessive antifibrinolytic doses have been associated with adverse outcomes including excess bleeding42 and seizures.22,43
TXA has been reported to produce seizures either through an alteration of cerebral blood flow44,45 or antagonism of γ-aminobutyric acid46 or glycine47 receptors in the central nervous system. Multiple reports21,22,43 have documented significant increases in the incidence of seizures in adult cardiac surgery patients coincident with the use of TXA. Breuer et al.23 reported a similar, although nonsignificant, association between TXA treatment and seizures in a retrospective study of 199 pediatric cardiac surgery patients. Rappaport et al.48 reported an association between seizures after pediatric cardiac surgery and adverse neurodevelopmental outcomes, and this association retained significance when controlling for duration of circulatory arrest and diagnosis. Lecker et al.47 recently determined the concentration of TXA necessary to inhibit glycine receptors in mouse central nervous system neurons, a proposed mechanism for TXA-induced seizures. The TXA concentration required to inhibit these receptors at low glycine concentrations, 93.1 μM (14.6 μg/mL), was well within the concentrations found in the cerebrospinal fluid of a group of patients receiving TXA for aortic surgery (220.8 ± 116.7 μM). Serum concentrations in these surgical patients, 1.9 ± 0.4 mM (299 μg/mL), were 15-fold in excess of what we found to be effective in inhibiting fibrinolysis in adult plasma, and almost 50-fold higher than what is needed for neonatal plasma. Although it is not clear whether seizures per se are responsible for adverse neurologic outcomes or they are a marker for a greater degree of neurologic injury, it is likely important to minimize the risk of inducing iatrogenic seizures by excess doses of TXA.
The pharmacokinetics of TXA have been reasonably well established in adults, including normal volunteers,49 patients with renal failure,50 and those undergoing CPB.51 Recently, Grassin-Delyle et al.14 studied the pharmacokinetics of TXA in older children (10–30 kg) undergoing cardiac surgery and proposed a dosing scheme based on their kinetics data and concentration/effect data published by Andersson et al.15 in 1968. Andersson et al.15 investigated the pharmacokinetics and pharmacodynamics of TXA and EACA, using bovine fibrin plates with porcine tissue activator from various organs to determine the concentration/effect relationship. They found that it required a concentration of 100 μg/mL TXA for 98% inhibition of fibrinolysis and 10 μg/mL for 80% inhibition. These are essentially the only published data relating inhibition of fibrinolysis and TXA concentrations and have been used as the basis for pharmacologically based dosing schemes.14,52 Soslau et al.53 subsequently investigated the ability of TXA to block plasmin-induced platelet activation. Using porcine plasmin and human platelet–rich plasma, they showed that preincubation of plasmin with TXA reduced activation of platelets with a 50% effective dose (ED50) of 1.21 μg/mL. When the plasma was preincubated with TXA, the ED50 was 16 μg/mL, demonstrating that the effect of TXA is related to plasmin inhibition rather than a direct protective effect on platelets, and that fairly low concentrations of TXA inhibited this effect of plasmin.
The use of thromboelastography to demonstrate inhibition of fibrinolysis by lysine analog antifibrinolytics was first described in 1961.54 More recently, Spiel et al.16 used an in vivo model of endotoxin-induced fibrinolysis to demonstrate the validity of thromboelastography as a measure of fibrinolysis that correlated well with plasma levels of tPA and plasmin–antiplasmin complexes. Gallimore et al.,17 using urokinase, and Nielsen et al.,18 using tPA, have shown that thromboelastography reflects activator dose-dependent activation of fibrinolysis. Nielsen et al.19 used thromboelastography to determine the plasma concentration of EACA required for maximal inhibition of fibrinolysis in adult plasma. More recently, Yurka et al.20 used Nielsen et al.’s methods to establish the effective concentration of EACA in neonatal plasma. The concentration of EACA required to completely inhibit in vitro fibrinolysis initiated by tPA was 48 μg/mL in neonatal plasma, much lower than the 131 μg/mL required in adult plasma.
This difference is not surprising, given the differences in the fibrinolytic system of the neonate compared with that of the adult.3,5–7 Our data confirm that this effect extends to TXA as well. Our study has several limitations. First, extrapolating from an in vitro controlled experiment to the dynamic setting of an infant on CPB is problematic. The influences of anticoagulation, ongoing contact activation, platelet activation and degradation, and the effects of red and white blood cells are necessarily eliminated. It is very likely that the methods used for CPB, including the degree of hemodilution by crystalloid prime solution and inclusion of adult fresh frozen plasma in the prime volume, significantly alter the hemostatic and fibrinolytic systems and ultimately the response to antifibrinolytics. We were able to show that dilution with saline has a minimal effect on the effective concentration of TXA in this model. However, dilution with adult plasma (reflecting the common practice of including fresh frozen plasma in the pump prime at many institutions) produced a result intermediate between adult and neonatal responses. The relevance of our findings should be interpreted based on the usual pump prime constituents used at any individual center. We also used specimens from cord/placenta units which may conceivably have been different than blood drawn directly from neonates. Using this source allowed us to obtain significantly larger volumes of blood than would have been reasonable to obtain from neonates. We eliminated any specimens that were outliers on baseline whole blood thromboelastograms to avoid including samples that may have begun to clot. In addition, Edwards et al.55 published normal values for neonatal thromboelastograms which were performed in cord samples. Despite the purely in vitro nature of our data, it should be noted that currently used pharmacologically based adult dosing schemes are based on concentration/effect data derived in vitro,14,52 and our data are at least specific to neonates. Second, the plasma pool we used was selected from normal neonates. It is likely that newborns with congenital heart disease have multiple coagulation abnormalities, including ongoing activation of fibrinolysis.56,57 This may limit applicability of our results in the congenital heart surgery population, especially cyanotic patients. Third, the concentrations of tPA we used to initiate fibrinolysis were ≥100 times that normally encountered during pediatric CPB.58 Clearly what we have established is the concentration of TXA necessary to inhibit maximal activation of fibrinolysis. Given that the minimally effective TXA concentration we found is significantly lower than that targeted by currently recommended dosing schemes,2 this distinction is less important. It is possible that concentrations even <6.54 μg/mL may be effective clinically, but levels higher than this are likely to be unnecessary and excessive. Finally, this work does not establish a dose of TXA that is theoretically effective in neonates, only a concentration. Pharmacokinetic data for TXA in neonates have not been published and are needed to suggest a dosing scheme targeting a concentration of at least 7.91 μg/mL to address the upper 95% confidence limits of our findings.
In summary, we investigated the in vitro concentration/effect relationship of TXA in neonatal plasma using thromboelastography. We found the minimal concentration that completely inhibits fibrinolysis to be 6.54 μg/mL, significantly lower than that required for adults and much lower than the concentration targeted by currently used dosing schemes. Although there are some limitations to the generalizability of these data, they are equally valid with the data used to establish adult doses and may guide future antifibrinolytic therapy for neonates.
Name: Branden E. Yee, MD, MPH.
Contribution: This author helped conduct the study, analyze the data, and write the manuscript.
Attestation: Branden E. Yee has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Richard N. Wissler, MD, PhD.
Contribution: This author helped design and conduct the study, and write the manuscript.
Attestation: Richard N. Wissler has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Christine N. Zanghi, MD, PhD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Christine N. Zanghi has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Changyong Feng, PhD.
Contribution: This author helped analyze the data and write the manuscript.
Attestation: Changyong Feng has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.
Name: Michael P. Eaton, MD.
Contribution: This author helped design and conduct the study, analyze the data, and write the manuscript.
Attestation: Michael P. Eaton has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.
This manuscript was handled by: Jerrold H. Levy, MD, FAHA, FCCM.
The authors would like to acknowledge the technical assistance of Joshua Jensen, and William Voter, Research Assistant, Department of Anesthesiology, University of Rochester School of Medicine and Dentistry, Rochester, NY
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