Temporally and Regionally Disparate Differences inPlasmin Activity by Tranexamic Acid Daryl L. Reust, MD,* Scott T. Reeves, MD,* James H. Abernathy, III, MD,* Jennifer A. Dixon, MD,‡William F. Gaillard, II, BS,‡ Rupak Mukherjee, PhD,‡ Christine N. Koval, BS,‡ Robert E. Stroud, MS,‡and Francis G. Spinale, MD, PhD†‡ BACKGROUND: A major complication associated with cardiac surgery is excessive and pro-longed bleeding in the perioperative period. Improving coagulation by inhibiting fibrinolysis,primarily through inhibition of plasmin activity (PLact) with antifibrinolytics such as tranexamicacid (TXA), has been a pharmacological mainstay in cardiac surgical patients. Despite its almostubiquitous use, the temporal and regional modulation of PLact profiles by TXA remainsunexplored. Accordingly, we developed a fluorogenic-microdialysis system to measure in vivodynamic changes in PLact after TXA administration in a large animal model.
METHODS: Pigs (25–35 kg) were randomly assigned to receive TXA (30 mg/kg, diluted into 50mL normal saline; n ⫽ 9) or vehicle (50 mL normal saline; n ⫽ 7). Microdialysis probes wereplaced in the liver, myocardium, kidney, and quadriceps muscle compartments. The microdialy-sate infusion contained a validated plasmin-specific fluorogenic peptide. The fluorescenceemission (standard fluorogenic units [SFU]) of the interstitial fluid collected from the microdialy-sis probes, which directly reflects PLact, was determined at steady-state baseline and 30, 60,90, and 120 min after TXA/vehicle infusion. Plasma PLact was determined at the same timepoints using the same fluorogenic substrate approach.
RESULTS: TXA reduced plasma PLact at 30 min after infusion by ⬎110 SFU compared withvehicle values (P ⬍ 0.05). Specifically, there was a decrease in liver PLact at 90 and 120 minafter TXA infusion of ⬎150 SFU (P ⬍ 0.05) and 175 SFU (P ⬍ 0.05), respectively. The decreasein liver PLact occurred 60 min after the maximal decrease in plasma PLact. In contrast, kidney,heart, and quadriceps PLact transiently increased followed by an overall decrease at 120 min.
CONCLUSIONS: Using a large animal model and in vivo microdialysis measurements of PLact,the unique findings from this study were 2-fold. First, TXA induced temporally distinct PLactprofiles within the plasma and selected interstitial compartments. Second, TXA causedregion-specific changes in PLact profiles. These temporal and regional differences in the effectsof TXA may have important therapeutic considerations when managing fibrinolysis in theperioperative period. (Anesth Analg 2010;110:694 –701) tion associated with cardiothoracic, major vascular, become the major class of pharmacological intervention in liver transplantation, orthopedic spine, and trauma which antifibrinolytic therapy is indicated for the manage- surgeries. Blood products and antifibrinolytics have been ment of excessive perioperative bleeding and has likely re- effectively used to achieve needed hemostasis in these clinical sulted in an increased use of TXA for this purpose. However, scenarios.1–6 Antifibrinolytics have been the pharmacological the basic regional and temporal PLact profiles after TXA mainstay with proven efficacy in reducing blood loss and administration remain unexplored. Accordingly, the primary blood product transfusion requirements, particularly in rela- goal of this study was to characterize the effects of TXA on the tion to cardiac surgery.1,3 Common clinically used antifibrino- regional and temporal PLact profiles in plasma and selected lytics affect plasmin activity (PLact) primarily by inhibiting the enzymatic interaction of plasminogen/plasmin with Common clinically implemented weight-based TXA fibrinogen/fibrin and can be classified as either serine pro- dosing regimens are largely empirically derived and, as tease inhibitors or lysine analogues.7 The serine protease such, there is no consensus as to appropriate dosing to inhibitor aprotinin significantly inhibits fibrinolysis, but this provide optimal perioperative control of fibrinolysis.8 This drug has been removed from clinical use.7 As a consequence, lack of established clinical dosing regimens suggests thatthe modulation of fibrinolysis by TXA may be enhanced byregional and temporal measurements of PLact. Accord- From the *Department of Anesthesiology and Perioperative Medicine,Medical University of South Carolina; ‡Ralph H. Johnson Veterans Affairs ingly, we used a common weight-based TXA dosing Medical Center; and †Division of Cardiothoracic Surgery, Medical Univer- scheme to investigate the effects of TXA on regional and sity of South Carolina, Charleston, South Carolina.
temporal PLact profiles.9 To explore the regional dynamics Accepted for publication September 27, 2009.
of PLact, we used a large animal model using established Supported in part by NIH grants HL059165 and HL078650 and a MeritAward form the Veterans' Affairs Health Administration.
microdialysis techniques.10,11 Such microdialysis tech- Address correspondence and reprint requests to Francis G. Spinale, MD, niques, utilizing a fluorogenic substrate, allowed the detec- PhD, Department of Cardiothoracic Surgery, Strom Thurmond Research tion of interstitial enzymatic activity, such as plasmin.12 Building, 114 Doughty St., Room 625, Medical University of South Carolina, Accordingly, the objectives of this study were 2-fold. The Charleston, SC 29403. Address e-mail to [email protected].
first objective was the validation and calibration of a Copyright 2010 International Anesthesia Research SocietyDOI: 10.1213/ANE.0b013e3181c7eb27 fluorogenic peptide that could be used to assess PLact in March 2010 • Volume 110 • Number 3

vivo. The second objective was the development of aporcine model to measure PLact in plasma and interstitialregions of clinical relevance using this validated fluoro-genic approach.
METHODSThis study was conducted in 2 stages. First, in vitro validationstudies were performed to develop a PLact measurementsystem using a plasmin-specific fluorogenic substrate.12 Thisvalidated PLact measurement system was used to performin vivo PLact measurements, via microdialysis probes, withintargeted regions. TXA was then infused IV and PLact wascontinuously monitored within these regions. Finally, plasmaTXA and d-dimer concentrations were measured.
In Vitro ValidationsSeveral in vitro validation studies were performed using aplasmin-specific fluorogenic substrate12 (Cat. #A8171, Sigma-Aldrich, St. Louis, MO). In particular, this substrate containeda validated fluorogenic peptide that, when specificallycleaved by plasmin, yielded a coumarin fluorescent moietywith excitation/emission wavelengths of 365/440 nm, respec-tively.12 The first in vitro validation study determined theresponse of the fluorogenic substrate to increasing concentra-tions of plasmin. Briefly, 6.25 ␮M of plasmin substrate wasinjected into a 96-well polystyrene plate (Nalge Nunc, Roch-ester, NY) with increasing concentrations of plasmin (0–31.25 ␮g/mL; Cat. #P1867, Sigma-Aldrich). After a 5-min incuba-tion at 37°C, the plate was placed into a fluorescence micro-plate reader (FLUOstar Galaxy, BMG LABTECH, Offenburg,Germany) and the fluorescence emission was recorded. Flu-orescence emission, reflective of PLact, increased with increas-ing concentrations of plasmin (Fig. 1A).
Figure 1. A, Fluorescence emission of the plasmin-specific substrate Next, a series of in vitro experiments was performed (6.25 ␮g/mL), reflective of plasmin activity (PLact), increased with using a solution of reference normal porcine plasma, which increasing concentrations of plasmin (0 –31.25 ␮g/mL) in a linearconcentration-dependent manner (n ⫽ 3, plotted values are mean ⫾ determined the TXA plasma concentration inhibition curve.
SEM; linear regression, y(x) ⫽ 1048.8 ⫻ x, r2 ⫽ 0.996, P ⫽ 0.002).
Specifically, plasmin (31.25 ␮g/mL) and diluted control B, Fluorescence emission of the plasmin-specific substrate (6.25 porcine plasma (1:32) were incubated with increasing con- ␮g/mL), reflective of PLact, in the presence of plasmin (31.25 centrations of TXA (0 – 62.2 mg/mL) and subjected to the ␮g/mL) and control porcine plasma (1:32) decreased in response toincreasing concentrations of tranexamic acid (TXA) (0 – 62.2 mg/mL) in same fluorescence measurement procedure previously de- a classic logarithmic concentration-dependent manner13 (n ⫽ 3, plotted scribed. As shown in Figure 1B, the fluorescence emission, values are mean ⫾ SEM, regression, y(x) ⫽ 23,280 ⫻ e⫺0.063 ⫻ x, r2 ⫽ reflective of PLact, decreased in response to increasing con- 0.964, P ⬍ 0.001).
centrations of TXA in a classic, logarithmic, concentration-dependent manner.13 A logarithmic equation was matched tothese data using regression analysis.
After sedation with diazepam (100 mg per os, Elkins- Therefore, these in vitro studies established the optimal Sinn, Cherry Hill, NJ), general inhaled anesthesia was substrate concentration, demonstrated specificity of the induced using isoflurane (3%, Baxter Healthcare, Deerfield, substrate for plasmin, and determined the fluorescence IL) mixed with oxygen and nitrous oxide (67%:33%) and emission inhibition curve for TXA in porcine plasma. The peripheral IV access was obtained. A stable surgical plane development of this PLact measurement system was then of anesthesia was established and maintained throughout translated to the in vivo PLact studies described below.
the protocol using sufentanil (2 ␮g/kg IV, Elkins-Sinn),etomidate (0.1 mg/kg IV, Elkins-Sinn), vecuronium (10 mg Animal and Surgical Preparation IV bolus, 0.5 mg 䡠 kg⫺1 䡠 h⫺1 IV infusion, Ben Venue Labo- Yorkshire pigs (n ⫽ 16, male, 25–35 kg; Hambone Farms, ratories, Bedford, OH), morphine sulfate (3 mg 䡠 kg⫺1 䡠 h⫺1 Reevesville, SC) were instrumented to measure plasma and IV, Elkins-Sinn), and isoflurane (1%, Baxter Healthcare).
interstitial PLact. All animals were treated and cared for in Tracheal intubation was achieved via tracheostomy, and accordance with the National Institutes of Health Guide for mechanical ventilation was established (Narkomed 2B, the Care and Use of Laboratory Animals (National Institutes North American Drager, Telford, PA). Intravenous fluids of Health, 1996). Approval of all animal care and use protocols (lactated Ringer's solution) were administered per estab- was obtained from the Medical University of South Carolina lished weight-based protocols for maintenance fluids and Institutional Animal Care and Use Committee (AR# 2786).
estimated blood loss replacement. A single-lumen catheter March 2010 • Volume 110 • Number 3

Plasmin Activity and Tranexamic Acid (8F) was placed into the right external jugular vein for fluid over 5 min, and the mobile phase consisted of 10% aceto- and drug administration. An arterial line catheter (7F) was nitrile in 2 mM ammonium acetate (pH 3.5) with a flow rate placed into the right carotid artery to continuously monitor of 0.15 mL/min. The mass spectrometer was operated in systemic blood pressures and obtain blood samples. After a positive ion mode with a capillary voltage of 3.1 kV, source 60-min baseline and stabilization period, each pig was temperature of 120°C, desolvation temperature of 400°C, assigned to receive TXA (30 mg/kg, diluted into 50 mL and nitrogen gas flow at 700 L/h. Data acquisition was normal saline; Pharmacia & Upjohn, New York, NY) or performed using MassLynx 4.1 and quantification using vehicle (50 mL normal saline) over a 10-min period using a QuanLynx 4.1 (Waters). TXA plasma concentrations were prespecified randomization protocol. This anesthesia regi- determined from precalibrated TXA standards (0.5– 40 men and surgical preparation provided a physiologically and hemodynamically stable experimental model for up to6 h as previously reported.11 D-Dimer Measurementsd-dimer measurements were made on plasma collected at Microdialysis Techniques baseline (time 0) and 120-min time intervals for vehicle and Microdialysis probes (CMA Microdialysis, North Chelms- TXA treatment groups using an enzyme-linked immu- ford, MA) with a molecular weight cutoff of 20 kDa and an nosorbent assay (Cat. #602, American Diagnostics, Stam- outer diameter of 0.5 mm were surgically placed interstitially in the anterior myocardium of the left ventricle, right lobe ofthe liver, lower pole of the right kidney, and left quadriceps muscle compartments. Placement of the microdialysis probes Comparisons for baseline steady-state as well as for net required a median sternotomy, a subxiphoid intraabdominal change in fluorescence for all time points within each incision, a subcostal flank incision, and a medial midthigh region were made using an analysis of variance followed incision with associated tissue dissections, respectively.
by pairwise tests of individual time points means using The microdialysis probes were connected to precision Bonferroni bounds. The net change in fluorescence com- infusion pumps and controller system (BASi, West Lafayette, pared with baseline for all time points within each region IN). A flow rate of 6.0 ␮L/min was established and an was determined using a 2-sample t-test. Comparisons of isoosmotic dialysis was performed. Dialysate was infused for d-dimer concentrations at baseline (time 0) and 120-min 30 min to allow for equilibration with each of the respective intervals were performed using a 2-sample t-test. All statisti- tissue compartments. The microdialysate infusion contained cal procedures were performed using STATA statistical soft- the validated fluorogenic peptide (10 ␮M, Cat. #A8171, ware (Intercooled STATA 8.0, StataCorp, College Station, TX).
Sigma-Aldrich). Preliminary studies demonstrated that this Results are presented as mean ⫾ sem with P values ⬍0.05 microdialysate concentration yielded a steady-state fluores- considered to be statistically significant.
cence emission within 30 min of the initiation of dialysis,indicative of equilibration with the interstitial space of the target tissue. The fluorescence emission of the interstitial After successful placement of microdialysis probes in all fluid collected from each of the microdialysis probes, which tissue compartments, respective steady-state baseline fluores- directly reflected PLact, was determined at steady-state cence emission measurements, reflective of PLact within each baseline and 30, 60, 90, and 120 min after TXA/vehicle compartment, were obtained (Fig. 2A). There was no signifi- infusion, using fluorescence measurement techniques as cant difference in baseline fluorescence emissions between groups, randomized to either vehicle or TXA treatment, foreach tissue compartment, reflective of equivalent PLact before initiation of treatment. Figure 2B illustrates the representative Arterial blood samples (50 mL) were collected immediately fluorescence emission for a selected tissue compartment (i.e., after a 30-min stabilization period. The plasma from these the liver) for both a representative vehicle and TXA pig blood samples was used to develop a reference normal preparation. Respective fluorescence emission measurements porcine plasma solution for in vitro validations previously were obtained at baseline (time 0) and 30, 60, 90, and 120 min described. At baselines and at 30-min intervals throughout the after either vehicle (saline) or TXA (30 mg/kg) infusion. The protocol, coinciding with the microdialysis samples, arterial differences in fluorescence emission values between the ve- blood samples (10 mL) were collected. All blood samples hicle and TXA groups at each of the respective time intervals were collected in EDTA tubes, centrifuged, and the plasma are reflective of changes in PLact induced by the administra- was decanted and frozen for subsequent measurement of tion of TXA. Therefore, to directly examine the effects of TXA PLact using the previously described fluorescence measure- on PLact, the absolute fluorescence emission values were ment system.
transformed to yield a net change in mean fluorescenceemission with respect to mean vehicle values for each of the TXA Plasma Concentration Measurements selected compartments at the specified time intervals (Fig. 3).
An Acquity UPLC coupled to a Quattro Premier XE mass Compared with vehicle values, TXA significantly reduced spectrometer (Waters, Milford, MA) was used to measure plasma PLact at 30 min after infusion. However, in the TXA plasma concentrations. Chromatographic separation interstitial compartments, temporal and regional differences was performed on an Acquity UPLC HSS C18 2.1 ⫻ 100 in PLact were observed after TXA administration. Specifically, mm (1.8 ␮m) column preceded by an Acquity UPLC HSS there was a significant decrease in liver PLact at 90 and 120 C18 (1.8 ␮m) precolumn. Samples were eluted isocratically min, which occurred 60 min after the maximal decrease in ANESTHESIA & ANALGESIA

Figure 2. A, Steady-state baseline fluo-rescence emission, reflective of plasminactivity (PLact), within each of the targettissue compartments was equivalent inpigs randomized to either vehicle (saline)or tranexamic acid (TXA) (30 mg/kg).
Thus, the baseline fluorescence emis-sions between the 2 groups was compa-rable before initiation of treatment (plot-ted values are mean ⫾ SEM, *P ⬍ 0.05).
B, Representative fluorescence emissionmeasurements within the liver tissuecompartment were obtained at baseline(time 0) and 30, 60, 90, and 120 minafter either vehicle (saline) or TXA (30mg/kg) infusion. There was a notableincrease in absolute fluorescence emis-sion over time after vehicle (saline) infu-sion. In contrast, there was an overalldecrease in fluorescence emission overtime, reflective of reduced PLact withinthe liver after TXA administration. Thesummary data reflective of PLact acrosseach target compartment and all timeintervals are shown in Figure 3.
plasma PLact. In contrast, kidney PLact was significantly at randomization (P ⫽ 0.67). The plasma d-dimer concentra- increased at 30, 60, and 90 min. Within the myocardium, PLact tion at 120 min after infusion decreased slightly, but not remained virtually unchanged. In the quadriceps muscle, significantly, from baseline (13 ⫾ 3 ␮g/mL, P ⫽ 0.49) with no PLact decreased after TXA infusion but did not reach statis- difference between vehicle or TXA (P ⫽ 0.77).
tical significance at any time point (P ⬎ 0.5).
The TXA plasma concentrations for time intervals 30, 60, 90, and 120 min after TXA infusion are shown in Figure 4.
Perioperative hemorrhage is an important risk factor for The peak TXA plasma concentration occurred at 30 min after morbidity and mortality in most major surgical procedures, TXA infusion and subsequently decreased in a negative notably cardiovascular surgery.14–17 Accordingly, blood logarithmic time-dependent manner consistent with first- transfusions, blood product and coagulation factor deliv- order elimination pharmacokinetics.13 Plasma from baseline ery, as well as pharmacological modalities targeted at the (time 0) and 120-min time intervals for vehicle and TXA coagulation/fibrinolytic mechanisms are important clinical treatment groups was subjected to d-dimer analysis. The maneuvers in the perioperative setting.3,14 However, these baseline, steady-state plasma d-dimer concentration was 20 ⫾ interventional strategies, such as pharmacological ap- 8 ␮g/mL with no difference between vehicle and TXA groups proaches, can be associated with adverse outcomes, which March 2010 • Volume 110 • Number 3

Plasmin Activity and Tranexamic Acid Figure 3. The computed net change in mean fluorescence emission, reflective of changes in plasmin activity (PLact), with respect totime-matched vehicle values after tranexamic acid (TXA) (30 mg/kg) infusion for selected compartments demonstrates the unique temporaland regional differences in the effects of TXA on PLact. Specifically, TXA significantly reduced plasma PLact at 30 min. In addition, there wasa significant decrease in liver PLact at 90 and 120 min. In contrast, kidney PLact was significantly increased at 30, 60, and 90 min. There wasno significant change in heart PLact for all time points. The PLact within the quadriceps muscle decreased after TXA infusion but did not reachstatistical significance at any time point (plotted values are mean ⫾ SEM, *P ⬍ 0.05 versus baseline).
Figure 4. Tranexamic acid (TXA) plasmaconcentrations performance liquid chromatography/ massspectrometry time intervals 30, 60, 90, and 120 minafter TXA infusion decreased in a negativelogarithmic time-dependent manner consis-tent with first-order elimination pharmacoki-netics13 (plotted values are mean ⫾ SEM,regression, y(x) ⫽ 219.37 ⫻ e⫺0.019 ⫻ x,r2 ⫽ 0.994, P ⫽ 0.003).
may be attributable to differences in dosing regimens as fluorogenic-microdialysis approach in a large animal model, well as off-target effects.14–18 One frequently used antifibrino- to provide serial assessment of PLact on a regional basis, after lytic is TXA, which can modulate the fibrinolytic pathway by a standardized dose of TXA.9 The unique finding from this inhibiting local PLact.19 However, current TXA dosing sched- study is that interstitial PLact is differentially affected after ules are largely empirical, and the regional and temporal TXA infusion in both a region- and time-dependent manner.
effects with respect to changes in PLact remain unknown.8 For example, TXA induced temporally distinct PLact profiles This study addressed this issue through the use of a validated within the plasma and selected interstitial compartments such ANESTHESIA & ANALGESIA as the kidney and the liver. These temporal and regional respect to PLact profiles was 2-fold. First, the objective of this differences in the effects of TXA on PLact may have important study was to demonstrate the proof of concept that there is therapeutic considerations when managing fibrinolysis in the regional and temporal heterogeneity regarding 1 computed perioperative period. The prophylactic use of lysine analogue dose of an antifibrinolytic, and TXA was chosen as a proto- antifibrinolytics during cardiac surgery has the potential to typical example. Second, the serine protease inhibitor, aproti- induce a hypercoagulable prethrombotic state.20 As such, nin, although historically considered the first-line drug for thrombosis (deep vein, pulmonary artery, renal pelvic and modulating PLact, has been withdrawn from clinical use, thus artery, bladder, and cerebral vascular) with respective con- leaving lysine analogues such as TXA as the pharmacological comitant organ injury and dysfunction have been associated mainstay for antifibrinolytic therapy. Lysine analogues such with the use of antifibrinolytics such as TXA.17,21–26 The as TXA affect PLact primarily by inhibiting the enzymatic primary mechanism of elimination of TXA is via renal excre- interaction of plasminogen and plasmin with fibrinogen and tion. As such, acute temporal alterations in renal function fibrin, which is key to the enzymatic induction of fibrinoly- associated with cardiac surgery further compound the com- sis.19 Thus, TXA served as a reasonable first step, with plexity of maintaining a safe hemostatic state in such clinical respect to clinical relevance, in determining the fundamen- scenarios in which TXA is indicated.27 Thus, there are several tal mechanistic underpinnings of the regional and temporal temporal and regional variables that must be considered effects of lysine analogues on PLact profiles. Comparative when attempting to balance the extensively dynamic and studies of specific antifibrinolytic drugs hold significant sensitive coagulation/fibrinolytic state(s) of cardiac surgical clinical relevance and warrant future investigation. Never- patients in the perioperative period.
theless, it is likely that the results from this study can be Although the pharmacology of TXA has been rigorously extrapolated to some degree to other lysine analogues (i.e., described regarding mechanisms of action,19 there have ⑀-aminocaproic acid) as well as aprotinin, with respect to been no studies that have precisely quantified the effects of the regional and temporal heterogeneity observed. For TXA on interstitial PLact in vivo, the primary target for TXA example, after a single bolus dose of TXA, transient effects with respect to modulating fibrinolysis. Tissue plasminogen on PLact were observed in the heart and kidney, whereas activator is synthesized and secreted by endothelial cells there were persistent effects in the liver. Although this intraluminally and abluminally into the vascular and intersti- acute study could not address this issue directly, the tial spaces, respectively, where it catalyzes the conversion of disparate effects on PLact may in turn affect hepatic and plasminogen to plasmin and thus facilitates fibrinolysis.28 renal function, the latter of which has been identified as This microdialysis approach provides for interstitial a potential risk factor for the adverse effects of antifi- interrogation of PLact and thus a means to directly measure brinolytics such as aprotinin.17,18,29 a key determinant of fibrinolysis and avoids the interfer- The peak TXA plasma concentrations obtained in this ence of intraluminal dynamics. Furthermore, although past study are consistent with those typically reported in prior basic and clinical studies have described the utility of TXA clinical investigations.8,31,32 As such, the TXA dosing regimen in the context of cardiovascular surgery, such as that used in this study is a clinically relevant dosing approach. The associated with cardiopulmonary bypass, optimal dosing TXA plasma elimination profile obtained is congruent with strategies remain a subject of debate.8 This is the first study classic first-order pharmacokinetics,13 indicating that the large in which an approach was developed to continuously animal model used in this study holds pharmacological measure the major biological response variable relevant to relevance. The time of the peak TXA plasma at 30 min TXA administration, PLact, within the plasma as well as coincides with the occurrence of peak plasma PLact inhibi- interstitial space of critical target tissues. In this study, a tion, demonstrating the pharmacological efficacy of the TXA microdialysis approach was used to interrogate the interstitial within the vascular compartment. Thus, the large animal compartment, an approach that has been well described preparation and TXA dosing paradigm used in this study are previously in both animal and clinical studies.10,11 This mi- likely to be a clinically relevant simulation.
crodialysis method was coupled with a fluorogenic substratespecific for plasmin and therefore provided a means to Study Limitations and Conclusions quantify PLact within the interstitial space. This methodology One potential limitation of this study was that the TXA may provide a useful analytical approach to assess PLact with regimen implemented involved an initial loading dose only varying TXA dosing regimens and thereby provide a basis for without a subsequent continuous infusion of TXA. In optimal TXA administration. This study provided the funda- addition, the in vivo investigations did not include the mental temporal and regional information necessary to move context of cardiopulmonary bypass, which is a typical forward with studies aimed at TXA dosing optimization.
clinical scenario in which TXA is frequently used. Our Moreover, this study identified differences in PLact after TXA primary objective was to quantify the regional and tempo- administration in critical target organs such as the liver and ral effects of TXA on relevant compartment PLact profiles.
kidney, which may hold relevance in the clinical context of Accordingly, the TXA regimen involved an initial dose only hepatic or renal dysfunction.17,18,29 The continuous PLact to examine the compartment-specific temporal dynamics of profiling, which is described in the current study, may pro- TXA on PLact profiles, which would have been potentially vide a means by which to address these issues and further obscured by the subsequent administration of a continuous optimize current and future antifibrinolytic therapies.30 infusion of TXA. Furthermore, the context of cardiopulmo- In this study, TXA was used to investigate the effects of a nary bypass would have included requisite systemic hepa- frequently used antifibrinolytic drug on plasma and intersti- rinization, which could have added coagulation interactions tial PLact profiles. The rationale for focusing on TXA with that potentially affected de novo fibrinolytic processes. Indeed, March 2010 • Volume 110 • Number 3 Plasmin Activity and Tranexamic Acid this study demonstrated that static measurements to quan- 7. Stensrud PE, Nuttal GA. Pharmacology of antifibrinolytic tify fibrinolysis (i.e., d-dimers) were stable and not different agents (chap 8). In: Housman PR, Nuttall GA, eds. Advances in between vehicle and TXA groups. This suggests that the Cardiovascular Pharmacology. Philadelphia, PA: LipincottWilliams & Wilkins, 2008:183–204 experimental design did not evoke a substantial fibrinolytic 8. Dowd NP, Karski JM, Cheng DC, Carroll JA, Lin Y, James RL, response. Nevertheless, using a continuous interstitial Butterworth J. Pharmacokinetics of tranexamic acid during monitoring approach, this study demonstrated that there cardiopulmonary bypass. Anesthesiology 2002;97:390 –9 was heterogeneity in steady-state PLact in specific tissue 9. Chauhan S, Bisoi A, Kumar N, Mittal D, Kale S, Kiran U, compartments, which were differentially affected by TXA.
Venugopal P. Dose comparison of tranexamic acid in pediatriccardiac surgery. Asian Cardiovasc Thorac Ann 2004;12:121– 4 These observations suggest that continuous PLact monitor- 10. Spinale FG, Koval CN, Deschamps AM, Stroud RE, Ikonomidis ing would be of much greater importance in the context of JS. Dynamic changes in matrix metalloprotienase activity a heightened fibrinolytic state such as cardiopulmonary within the human myocardial interstitium during myocardial bypass. The primary focus of this preliminary study was to arrest and reperfusion. Circulation 2008;118:S16 –23 determine the fundamental mechanistic underpinnings of 11. Deschamps AM, Zavadzkas J, Murphy RL, Koval CN, McLean the regional and temporal effects of TXA on PLact profiles JE, Jeffords L, Saunders SM, Sheats NJ, Stroud RE, Spinale FG.
Interruption of endothelin signaling modifies membrane type in a de novo, nonpathological, fibrinolytic state. Logically, 1 matrix metalloproteinase activity during ischemia and reper- one may anticipate an even greater magnitude of effect by fusion. Am J Physiol Heart Circ Physiol 2008;294:H875– 83 TXA in a pathological fibrinolytic state such as that induced 12. Smith RE, Bissell ER, Mitchell AR, Pearson KW. Direct photo- by cardiopulmonary bypass. The extension of the current metric or fluorometric assay of proteinases using substrates findings will provide a basis for the pursuit of similar PLact containing 7-amino-4-trifluoromethylcoumarin. Thromb Res investigations involving a clinically relevant cardiopulmo- 1980;17:393– 402 13. Buxton ILO. Pharmacokinetics and pharmacodynamics: the dy- nary bypass model. Nevertheless, this study demonstrated namics of drug absorption, distribution, action, and elimination in a clinically relevant large animal model that there is (chap 1). In: Brunton LL, Lazo JS, Parker KL, eds. Goodman & regional and temporal heterogeneity in PLact after a single Gilman's The Pharmacological Basis of Therapeutics. 11th ed.
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Inter national Organization for Succulent Plant Study para el Estudio de Plantas Suculentas de Recherche sur les Plantes Succulentes Inter nationale Organisation A short history of Repertorium Plantarum Succulentarum The first issue of Repertorium Plantarum Succulentarum (RPS) was produced in 1951 byMichael Roan (1909−2003), one of the founder members of the International Organizationfor Succulent Plant Study (IOS) in 1950. It listed the ‘majority of the new names [ofsucculent plants] published the previous year'. The first issue, edited by Roan himself withthe help of A.J.A Uitewaal (1899−1963), was published for IOS by the National Cactus &Succulent Society, and the next four (with Gordon Rowley as Associate and later JointEditor) by Roan's newly formed British Section of the IOS. For issues 5−12, GordonRowley became the sole editor. Issue 6 was published by IOS with assistance by theAcclimatisation Garden Pinya de Rosa, Costa Brava, Spain, owned by Fernando Riviere deCaralt, another founder member of IOS.


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