Evaluation of plasma and urine pharmacokinetics of tranexamic acid for equine medication control.

This study aimed to evaluate the pharmacokinetics (PK) of tranexamic acid (TXA) in horses and estimate its irrelevant plasma and urine concentrations using the pharmacokinetic/pharmacodynamic (PK/PD) approach by applying the Pierre-Louis Toutain model. TXA was intravenously administered to eight thoroughbred mares, and plasma and urine TXA concentrations were quantified by liquid chromatography/tandem mass spectrometry. The quantified data were used to calculate the PK parameters of TXA in horses. The plasma elimination curves were best-fitted to a three-compartment model. Using the Toutain model approach, irrelevant plasma and urine TXA concentrations were estimated to be 0.0206 and 0.997 µg/mL, respectively. The typical values of clearance, steady-state volume of distribution, and steady-state urine-to-plasma ratio were 0.080 L/kg/h, 0.86 L/kg, and 49.0, respectively. The obtained irrelevant concentrations will be useful for establishing relevant regulatory screening limits for effective control of TXA use in horse racing and equestrian sports.

Pharmacokinetics of tranexamic acid after intravenous, intramuscular, and oral routes: a prospective, randomised, crossover trial in healthy volunteers.

BACKGROUND: In response to the World Health Organization call for research on alternative routes for tranexamic acid (TXA) administration in women with postpartum haemorrhage, we examined the pharmacokinetics of TXA after i.v., i.m., or oral administration. METHODS: We conducted a randomised, open-label, crossover trial in 15 healthy volunteers who received i.v. TXA 1 g, i.m. TXA 1 g, or oral TXA solution 2 g. Blood samples were drawn up to 24 h after administration. Tranexamic acid concentration was measured with liquid chromatography-mass spectrometry, and the parameters of the pharmacokinetic models were estimated using population pharmacokinetics. RESULTS: The median time to reach a concentration of 10 mg L-1 was 3.5 min for the i.m. route and 66 min for the oral route, although with the oral route the target concentration was reached in only 11 patients. Median peak concentrations were 57.5, 34.4, and 12.8 mg L-1 for i.v., i.m., and oral routes, respectively. A two-compartment open model with body weight as the main covariate best fitted the data. For a 70 kg volunteer, the population estimates were 10.1 L h-1 for elimination clearance, 15.6 L h-1 for intercompartmental clearance, 7.7 L for the volume of central compartment, and 10.8 L for the volume of the peripheral compartment. Intramuscular and oral bioavailabilities were 1.0 and 0.47, respectively, showing that i.m. absorption is fast and complete. Adverse events were mild and transient, mainly local reactions and low-intensity pain. CONCLUSIONS: The i.m. (but not oral) route appears to be an efficient alternative to i.v. tranexamic acid. Studies in pregnant women are needed to examine the impact of pregnancy on the pharmacokinetics. CLINICAL TRIAL REGISTRATION: EudraCT 2019-000285-38; NCT03777488.

Targeting delivery and minimizing epidermal diffusion of tranexamic acid by hyaluronic acid-coated liposome nanogels for topical hyperpigmentation treatment.

Hyperpigmentation is a common complaint and distressing problem in dermatology, and tranexamic acid (TA) is an effective treatment agent but limited by the delivery to melanocytes in the epidermis. Herein, a novel TA naogels (named HA/TA-LP), combining the advantages of liposomes and hyaluronic acid (HA), are prepared and assessed for topical hyperpigmentation treatment with targeting delivery and minimizing epidermal diffusion. Morphological characteristics indicate numerous TA-loaded liposomes packed in HA gels. In vitro cell studies using human A375 melanoma cells show that HA/TA-LP can promote the uptake of TA by targeting delivery with resulting inhibition of tyrosinase activity and melanin production. Guinea pigs are used to construct hyperpigmentation models and investigate the topical delivery and treatment efficacy of HA/TA-LP. In vivo topical delivery studies indicate HA/TA-LP realize the effective delivery into melanocytes with an ideal balance of effective permeability and minimizing epidermal diffusion. Subsequently, hyperpigmentation treatment assessments reveal that HA/TA-LP inhibit tyrosinase activity and melanin production under the radiation of UVB. Our study identifies favorable properties of HA/TA-LP for treating hyperpigmentation, and provides an experimental basis for further clinical application.

Pharmacokinetics of intramuscular tranexamic acid in bleeding trauma patients: a clinical trial.

BACKGROUND: Intravenous tranexamic acid (TXA) reduces bleeding deaths after injury and childbirth. It is most effective when given early. In many countries, pre-hospital care is provided by people who cannot give i.v. injections. We examined the pharmacokinetics of intramuscular TXA in bleeding trauma patients. METHODS: We conducted an open-label pharmacokinetic study in two UK hospitals. Thirty bleeding trauma patients received a loading dose of TXA 1 g i.v., as per guidelines. The second TXA dose was given as two 5 ml (0·5 g each) i.m. injections. We collected blood at intervals and monitored injection sites. We measured TXA concentrations using liquid chromatography coupled to mass spectrometry. We assessed the concentration time course using non-linear mixed-effect models with age, sex, ethnicity, body weight, type of injury, signs of shock, and glomerular filtration rate as possible covariates. RESULTS: Intramuscular TXA was well tolerated with only mild injection site reactions. A two-compartment open model with first-order absorption and elimination best described the data. For a 70-kg patient, aged 44 yr without signs of shock, the population estimates were 1.94 h-1 for i.m. absorption constant, 0.77 for i.m. bioavailability, 7.1 L h-1 for elimination clearance, 11.7 L h-1 for inter-compartmental clearance, 16.1 L volume of central compartment, and 9.4 L volume of the peripheral compartment. The time to reach therapeutic concentrations (5 or 10 mg L-1) after a single intramuscular TXA 1 g injection are 4 or 11 min, with the time above these concentrations being 10 or 5.6 h, respectively. CONCLUSIONS: In bleeding trauma patients, intramuscular TXA is well tolerated and rapidly absorbed. CLINICAL TRIAL REGISTRATION: 2019-000898-23 (EudraCT); NCT03875937 (ClinicalTrials.gov).

Optimal use of intravenous tranexamic acid for hemorrhage prevention in pregnant women.

BACKGROUND: Every 2 minutes, there is a pregnancy-related death worldwide, with one-third caused by severe postpartum hemorrhage. Although international trials demonstrated the efficacy of 1000 mg tranexamic acid in treating postpartum hemorrhage, to the best of our knowledge, there are no dose-finding studies of tranexamic acid on pregnant women for postpartum hemorrhage prevention. OBJECTIVE: This study aimed to determine the optimal tranexamic acid dose needed to prevent postpartum hemorrhage. STUDY DESIGN: We enrolled 30 pregnant women undergoing scheduled cesarean delivery in an open-label, dose ranging study. Subjects were divided into 3 cohorts receiving 5, 10, or 15 mg/kg (maximum, 1000 mg) of intravenous tranexamic acid at umbilical cord clamping. The inclusion criteria were ≥34 week's gestation and normal renal function. The primary endpoints were pharmacokinetic and pharmacodynamic profiles. Tranexamic acid plasma concentration of >10 µg/mL and maximum lysis of <17% were defined as therapeutic targets independent to the current study. Rotational thromboelastometry of tissue plasminogen activator-spiked samples was used to evaluate pharmacodynamic profiles at time points up to 24 hours after tranexamic acid administration. Safety was assessed by plasma thrombin generation, D-dimer, and tranexamic acid concentrations in breast milk. RESULTS: There were no serious adverse events including venous thromboembolism. Plasma concentrations of tranexamic acid increased in a dose-proportional manner. The lowest dose cohort received an average of 448±87 mg tranexamic acid. Plasma tranexamic acid exceeded 10 µg/mL and maximum lysis was <17% at >1 hour after administration for all tranexamic acid doses tested. Median estimated blood loss for cohorts receiving 5, 10, or 15 mg/kg tranexamic acid was 750, 750, and 700 mL, respectively. Plasma thrombin generation did not increase with higher tranexamic acid concentrations. D-dimer changes from baseline were not different among the cohorts. Breast milk tranexamic acid concentrations were 1% or less than maternal plasma concentrations. CONCLUSION: Although large randomized trials are necessary to support the clinical efficacy of tranexamic acid for prophylaxis, we propose an optimal dose of 600 mg in future tranexamic acid efficacy studies to prevent postpartum hemorrhage.

Tranexamic acid has positive effect in early period of tendon healing by stimulating the tumor necrosis factor-alpha and matrix metalloproteinase-3 expression levels.

OBJECTIVES: This study aims to evaluate the effect of tranexamic acid (TXA) application in tendon healing by using its immunohistochemical effects on tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase-3 (MMP-3), and transforming growth factor-beta (TGF-ß) expression; and to identify if TNF-α, MMP-3, and TGF-ß can be used to monitor and evaluate tendon healing or not in tenotomized rat Achilles tendons. MATERIALS AND METHODS: Twelve male Wistar-Albino rats (age 6-7-month-old; weighing 300-350 g) were used in this retrospective study conducted between November 2016 and May 2017. The rats were divided into two groups with similar weights. The right legs of the rats were determined as the study group (TXA), and the left legs as the control serum physiologic (SP) group. Under anesthesia, bilateral Achilles tenotomy was performed and surgically repaired. 1 mL of TXA was applied locally for the right side and 1 mL of SP was locally applied for the left side. Half of the rats were sacrificed at the third week (right leg-TXA3, left leg-SP3) and the other half at sixth week (right leg-TXA6, left leg-SP6) and tendon samples were taken from the extremities. Immunohistochemical findings of TNF-α, MMP-3, and TGF-ß were evaluated on the basis of the frequency and intensity of staining. RESULTS: In TNF-α and MMP-3 and TXA groups, there was a significant difference in staining compared to SP groups (p<0.05). Regarding TNF-α expression, the total index score in the TXA6 subgroup was higher than the TXA3, SP6, and SP3 subgroups (8, 7, 3, and 4, respectively). Overall scores of TNF-α showed that TXA groups had significantly higher scores when compared to SP groups (p<0.05). In addition, total MMP-3 expression scores were significantly higher in TXA groups than in SP groups, respectively; TXA3: 14, TXA6: 11, SP3: 10, and SP6: 9 (p<0.05). However, the degree of staining with TNF-α was found to be significantly lower than MMP-3 (p<0.05). Immunohistochemical reactivity was not observed with TGF-ß. CONCLUSION: Tranexamic acid has positive effect in early period of tendon healing by stimulating the TNF-α and MMP-3 expression levels. TNF-α and MMP-3 can be used to monitor and evaluate tendon healing.

Plasma Concentrations of Tranexamic Acid in Postpartum Women After Oral Administration.

OBJECTIVE: To evaluate the pharmacokinetics of tranexamic acid after oral administration to postpartum women. METHODS: We conducted a single-center pharmacokinetic study at Teaching Hospital-Jaffna, Sri Lanka, on 12 healthy postpartum women who delivered vaginally. After oral administration of 2 g of immediate-release tranexamic acid 1 hour after delivery, pharmacokinetic parameters were measured on plasma samples at 0, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, and 12 hours. Plasma tranexamic acid concentrations were determined by high-performance liquid chromatography. The outcome measures were maximum observed plasma concentration, time to maximum plasma concentration, time to reach effective plasma concentration, time period effective serum concentration lasted, area under the curve for drug concentration, and half-life of tranexamic acid. RESULTS: The mean maximum observed plasma concentration was 10.06 micrograms/mL (range 8.56-12.22 micrograms/mL). The mean time to maximum plasma concentration was 2.92 hours (range 2.5-3.5 hours). Mean time taken to reach the effective plasma concentration of 5 micrograms/mL and the mean time this concentration lasted were 0.87 hours and 6.73 hours, respectively. Duration for which plasma tranexamic acid concentration remained greater than 5 micrograms/mL was 5.86 hours. Half-life was 1.65 hours. Area under the curve for drug concentration was 49.16 micrograms.h/mL (range 43.75-52.69 micrograms.h/mL). CONCLUSION: Clinically effective plasma concentrations of tranexamic acid in postpartum women may be achieved within 1 hour of oral administration. Given the promising pharmacokinetic properties, we recommend additional studies with larger sample sizes to investigate the potential of oral tranexamic acid for the treatment or prophylaxis of postpartum hemorrhage.

Pharmacokinetics of Tranexamic Acid Given as an Intramuscular Injection Compared to Intravenous Infusion in a Swine Model of Ongoing Hemorrhage.

INTRODUCTION: Tranexamic acid (TXA) improves survival in traumatic hemorrhage, but difficulty obtaining intravenous (IV) access may limit its use in austere environments, given its incompatibility with blood products. The bioavailability of intramuscular (IM) TXA in a shock state is unknown. We hypothesized that IM and IV administration have similar pharmacokinetics and ability to reverse in vitro hyperfibrinolysis in a swine-controlled hemorrhage model. METHODS: Twelve Yorkshire cross swine were anesthetized, instrumented, and subjected to a 35% controlled hemorrhage, followed by resuscitation. During hemorrhage, they were randomized to receive a 1 g IV TXA infusion over 10 min, 1 g IM TXA in two 5 mL injections, or 10 mL normal saline IM injection as a placebo group to assess model adequacy. Serum TXA concentrations were determined using liquid chromatography-mass spectrometry, and plasma samples supplemented with tissue plasminogen activator (tPA) were analyzed by rotational thromboelastometry. RESULTS: All animals achieved class III shock. There was no difference in the concentration-time areas under the curve between TXA given by either route. The absolute bioavailability of IM TXA was 97%. IV TXA resulted in a higher peak serum concentration during the infusion, with no subsequent differences. Both IV and IM TXA administration caused complete reversal of in vitro tPA-induced hyperfibrinolysis. CONCLUSION: The pharmacokinetics of IM TXA were similar to IV TXA during hemorrhagic shock in our swine model. IV administration resulted in a higher serum concentration only during the infusion, but all levels were able to successfully correct in vitro hyperfibrinolysis. There was no difference in total body exposure to equal doses of TXA between the two routes of administration. IM TXA may prove beneficial in scenarios where difficulty establishing dedicated IV access could otherwise limit or delay its use.

Tranexamic Acid for Acute Hemorrhage: A Narrative Review of Landmark Studies and a Critical Reappraisal of Its Use Over the Last Decade.

The publication of the Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage-2 (CRASH-2) study and its intense dissemination prompted a renaissance for the use of the antifibrinolytic agent tranexamic acid (TXA) in acute trauma hemorrhage. Subsequent studies led to its widespread use as a therapeutic as well as prophylactic agent across different clinical scenarios involving bleeding, such as trauma, postpartum, and orthopedic surgery. However, results from the existing studies are confounded by methodological and statistical ambiguities and are open to varied interpretations. Substantial knowledge gaps remain on dosing, pharmacokinetics, mechanism of action, and clinical applications for TXA. The risk for potential thromboembolic complications with the use of TXA must be balanced against its clinical benefits. The present article aims to provide a critical reappraisal of TXA use over the last decade and a "thought exercise" in the potential downsides of TXA. A more selective and individualized use of TXA, guided by extended and functional coagulation assays, is advocated in the context of the evolving concept of precision medicine.

Ensayo clínico sobre el efecto del ácido tranexámico en el sangrado y la fibrinólisis durante la artroplastia simple de cadera y rodilla / Clinical trial on the effect of tranexamic acid on bleeding and fibrinolysis in primary hip and knee replacement

Objetivo: La isquemia derivada de la aplicación del torniquete es un factor fibrinolítico que podría potenciar la eficacia del ácido tranexámico (ATx) en artroplastia total de rodilla (ATR) frente a la artroplastia total de cadera (ATC). Nuestro objetivo es comparar el efecto del ATx sobre sangrado y fibrinólisis en estas 2 artroplastias, valorando la incidencia de complicaciones. Método: Ensayo clínico prospectivo, aleatorizado y doble ciego. Los pacientes programados para ATR o ATC recibían ATx (2 infusiones 10mg/kg) o placebo. Se cuantificó sangrado y parámetros de fibrinólisis, y se detectaron complicaciones tromboembólicas con ecografía doppler y tomografía computarizada. Resultados: Fueron incluidos 44 pacientes (11 ATC y 11 ATR tratados con ATx; 11 ATC y 11 ATR fueron controles). El sangrado fue significativamente menor en el grupo tratado con ATx (promedio 921mL vs. 1383mL en ATC y 969mL vs. 1223mL en ATR) y se necesitaron menos transfusiones (ninguna frente a 5 unidades en grupo control). El ATx fue igualmente eficaz en la reducción del sangrado en ambas cirugías (reducción del 33% en ATC y del 21% en ATR). El gran incremento medio de dímero D entre el periodo basal y las 6h (1.004 a 10.284μg /L en ATC y 571 a 6.480μg /L en ATR) es atenuado por el uso de ATx (1.077 a 2.590μg/L en ATC y 655 a 2.535μg/L en ATR). No hubo diferencias significativas en eventos tromboembólicos. Conclusiones: El ATx profiláctico es igualmente efectivo en ATR y ATC para reducir sangrado. Ambas cirugías tienen efecto similar sobre la fibrinólisis

Background: Tourniquet-induced ischaemia could increase fibrinolysis and enhance tranexamic acid (TXA) efficacy in total knee arthroplasty (TKA) compared to total hip arthroplasty (THA). The aims of this study are to compare the effect of TXA on bleeding and fibrinolysis in both types of surgery, and to record thromboembolic complications. Methods: A prospective double-blind study was conducted on patients scheduled for TKA or THA who received TXA (2 bolus of 10mg/kg) or placebo. Bleeding and fibrinolysis were evaluated. Doppler-ultrasound and computed tomography were performed in order to assess any thromboembolic complications. Results: A total of 44 patients were included (11 THA and 11 TKA treated with TXA; 11 THA and 11 TKA as controls). Blood losses were significantly lower in the TXA group (mean 921mL vs 1,383mL in THA and 969mL vs 1,223mL in TKA), and no transfusions were needed with TXA, whereas 5 blood units were transfused in controls. TXA was equally effecting in reducing bleeding in both surgeries (33% in THA and 21% in TKA). The significant mean increase in D-dimers from baseline to 6 hours after surgery (1,004 ug/L to 10,284 ug/L in THA and 571 ug/L to 6,480 ug/L in TKA) was attenuated by TXA (1,077 ug/L to 2,590 ug/L in THA and 655 ug/L to 2,535 ug/L in TKA). There were no differences in thromboembolic episodes. Conclusions: Prophylactic use of tranexamic acid is equally effective in reducing bleeding in TKA and THA. Both surgeries have a similar effect on fibrinolysis

Serum Concentrations and Pharmacokinetics of Tranexamic Acid after Two Means of Topical Administration in Massive Weight Loss Skin-Reducing Surgery.

BACKGROUND: Topical administration of tranexamic acid to reduce bleeding is receiving increasing attention, as it is inexpensive, simple, and possibly beneficial in most surgery. Concerns regarding potential systemic adverse effects such as thromboembolic events and seizures may prevent general use of tranexamic acid. Although serum concentrations after topical application are assumed to be low, proper pharmacokinetic studies of tranexamic acid after topical application are lacking. METHODS: The authors have investigated systemic absorption of tranexamic acid after two means of topical administration in patients undergoing abdominoplasty after massive weight loss: a bolus of 200 ml of 5 mg/ml into the wound cavity versus moistening the wound surface with 20 ml of 25 mg/ml. Twelve patients were recruited in each group. Serum concentrations achieved were compared with those after administration of 1 g as an intravenous bolus to arthroplasty patients. Serial blood samples for tranexamic acid analysis were obtained for up to 24 hours. RESULTS: After intravenous administration, the peak serum concentration was 66.1 ± 13.0 µg/ml after 6 ± 2 minutes. Peak serum concentration after topical moistening was 5.2 ± 2.6 µg/ml after 80 ± 33 minutes, and in the topical bolus group, it was 4.9 ± 1.8 µg/ml after 359 ± 70 minutes. Topical moistening resulted in homogenous and predictable absorption across the individuals included, whereas topical bolus administration caused variable and unpredictable serum concentrations. CONCLUSION: Topical administration of tranexamic acid in patients undergoing abdominoplasty results in low serum concentrations, which are highly unlikely to cause systemic effects.

Tranexamic acid through intravenous, intramuscular and oral routes: an individual participant data meta-analysis of pharmacokinetic studies in healthy volunteers.

Tranexamic acid (TXA) is an antifibrinolytic drug that reduces surgical blood loss and death due to bleeding after trauma and post-partum haemorrhage. One key issue for treatment success is early administration. While usually given intravenously, oral and intramuscular use would be useful in specific circumstances. Therefore, an understanding of TXA pharmacokinetics when given via different routes is valuable. The aim of this study was to perform an individual participant data meta-analysis of pharmacokinetic studies with TXA given to healthy volunteers via different routes. We searched the following databases: PubMed, Web of Science, Wiley Online Library, Elsevier Science Direct and J-STAGE. Individual subject data were extracted when available, otherwise arithmetic means were used. A population pharmacokinetic model was developed using nonlinear mixed effect modelling. Seven studies were included in the analysis with data from 10 patients for the IV route, six patients for the IM route and 114 patients for the oral route. The pharmacokinetics was ascribed to a two-compartment model, and the main covariate was allometrically scaled bodyweight. Oral and IM bioavailabilities were 46 and 105%, respectively. For a 70 kg bodyweight, the population estimates were 7.6 L/h for clearance, 17.9 L for the volume of the central compartment, 2.5 L/h for the diffusional clearance and 16.6 L for the peripheral volume of distribution. Larger well-designed studies are needed to describe the pharmacokinetics of TXA when given IM or as an oral solution before these can be recommended as alternatives to IV.

Immunohistochemical Grading of Epidural Fibrosis with CD105 Antibody.

OBJECTIVE: Grading of epidural fibrosis (EF) is usually performed by histopathologic staining in experimental studies. Immunohistochemical methods for grading are not available in routine practice yet. In our study, the effect of tranexamic acid (TXA), a commonly used hemostatic agent in surgical interventions, was evaluated for use against the development of EF with classical histopathologic methods and immunohistochemistry using the CD105 antibody, a marker of angiogenesis. METHODS: Sixteen rats were used. The rats were assigned to 2 groups, control and TXA. Laminectomy was performed on the control group. In the treatment group, laminectomy + topical TXA was applied. After sacrificing the rats in the sixth week, histopathologic and immunohistochemical examinations and grading of the EF tissue were performed. RESULTS: Conventional histopathologic parameters of fibroblast count, intensity of fibrosis density, and inflammatory cell density, as well as immunohistochemical evaluation with CD105, showed that the grading of EF was comparable between groups I and II (P < 0.001). DISCUSSION: The results of our study have demonstrated that CD105 is compatible with the conventional histopathologic grading methods and can be used as a marker to determine the grades of angiogenesis and fibrosis in experimental studies. The results of our study have also shown that TXA, administered locally for hemostasis, reduces the grade of EF in rats following laminectomy. TXA has been observed to cause no toxic effects on neural tissue as it is already commonly used in clinical practice.

Pharmacokinetics of Tranexamic Acid via Intravenous, Intraosseous, and Intramuscular Routes in a Porcine (Sus scrofa) Hemorrhagic Shock Model.

BACKGROUND: Intravenous (IV) tranexamic acid (TXA) is an adjunct for resuscitation in hemorrhagic shock; however, IV access in these patients may be difficult or impossible. Intraosseous (IO) or intramuscular (IM) administration could be quickly performed with minimal training. We investigated the pharmacokinetics of TXA via IV, IO, and IM routes in a swine model of controlled hemorrhagic shock. METHODS: Fifteen swine were anesthetized and bled of 35% of their blood volume before randomization to a single 1g/10mL dose of IV, IO, or IM TXA. Serial serum samples were obtained after TXA administration. These were analyzed with high-pressure liquid chromatography-mass spectrometry to determine drug concentration at each time point and define the pharmacokinetics of each route. RESULTS: There were no significant differences in baseline hemodynamics or blood loss between the groups. Peak concentration (Cmax) was significantly higher in IV and IO routes compared with IM (p = .005); however, the half-life of TXA was similar across all routes (p = .275). CONCLUSION: TXA administration via IO and IM routes during hemorrhagic shock achieves serum concentrations necessary for inhibition of fibrinolysis and may be practical alternatives when IV access is not available.

The antifibrinolytic and anti-inflammatory effects of multiple doses of oral tranexamic acid in total knee arthroplasty patients: a randomized controlled trial.

Essentials Perioperative blood loss and inflammatory response can significantly affect recovery after surgery. We studied the effects of multiple-dose oral tranexamic acid on blood loss and inflammatory response. A postoperative four-dose regimen brought about maximum reduction in postoperative blood loss. A postoperative four-dose regimen reduced inflammatory response and promoted early rehabilitation. SUMMARY: Background Tranexamic acid (TXA) can reduce blood loss and the inflammatory response at multiple doses in total knee arthroplasty patients. However, the optimal regimen has not been determined. Objectives To identify the most effective regimen for achieving maximum reductions in blood loss and the inflammatory response. Patients/Methods Two hundred and seventy-five patients were randomized to receive a placebo (group A), a single 2-g oral dose of TXA 2 h preoperatively followed by 1 g of oral TXA 3 h postoperatively (group B), a single dose followed by 1 g of oral TXA 3 h and 7 h postoperatively (group C), a single dose followed by 1 g of oral TXA 3 h, 7 h and 11 h postoperatively (group D), or a single dose followed by 1 g of oral TXA 3 h, 7 h, 11 h and 15 h postoperatively (group E). The primary outcome was total blood loss on postoperative day (POD) 3. Secondary outcomes included a decrease in the hemoglobin level, coagulation parameters, inflammatory marker levels, and thromboembolic complications. Results Groups D and E had significantly lower blood loss and smaller decreases in hemoglobin level than groups A, B, and C, with no significant difference on POD 3 between groups D and E. Significantly enhanced coagulation was identified for the four multiple-dose regimens; however, all thromboelastographic parameters remained within normal ranges. Group E had the lowest inflammatory marker levels and pain, and the greatest range of motion. No thromboembolic complications were identified. Conclusion The four-dose regimen yielded the maximum reductions in blood loss and inflammatory response, improved analgesia, and promoted early rehabilitation. Further studies are required to ensure that these findings are reproducible.

Pharmacokinetics of tranexamic acid in healthy dogs and assessment of its antifibrinolytic properties in canine blood.

OBJECTIVE To assess pharmacokinetics of tranexamic acid (TXA) in dogs and assess antifibrinolytic properties of TXA in canine blood by use of a thromboelastography-based in vitro model of hyperfibrinolysis. ANIMALS 6 healthy adult dogs. PROCEDURES Dogs received each of 4 TXA treatments (10 mg/kg, IV; 20 mg/kg, IV; approx 15 mg/kg, PO; and approx 20 mg/kg, PO) in a randomized crossover-design study. Blood samples were collected at baseline (time 0; immediately prior to drug administration) and predetermined time points afterward for pharmacokinetic analysis and pharmacodynamic (thromboelastography) analysis by use of an in vitro hyperfibrinolysis model. RESULTS Maximum amplitude (MA [representing maximum clot strength]) significantly increased from baseline at all time points for all treatments. The MA was lower at 360 minutes for the 10-mg/kg IV treatment than for other treatments. Percentage of clot lysis 30 minutes after MA was detected was significantly decreased from baseline at all time points for all treatments; at 360 minutes, this value was higher for the 10-mg/kg IV treatment than for other treatments and higher for the 20-mg/kg IV treatment than for the 20-mg/kg PO treatment. Maximum plasma TXA concentrations were dose dependent. At 20 mg/kg, IV, plasma TXA concentrations briefly exceeded concentrations suggested for complete inhibition of fibrinolysis. Oral drug administration resulted in a later peak antifibrinolytic effect than did IV administration. CONCLUSIONS AND CLINICAL RELEVANCE Administration of TXA improved clot strength and decreased fibrinolysis in blood samples from healthy dogs in an in vitro hyperfibrinolysis model. Further research is needed to determine clinical effects of TXA in dogs with hyperfibrinolysis.

Effects of Tranexamic Acid Based on its Population Pharmacokinetics in Pediatric Patients Undergoing Distraction Osteogenesis for Craniosynostosis: Rotational Thromboelastometry (ROTEMTM) Analysis.

Background: Distraction osteogenesis for craniosynostosis is associated with significant hemorrhage. Additionally, patients usually require several transfusions. Tranexamic acid (TXA) is effective for reducing blood loss and the need for transfusions during surgeries. However, the significance of TXA infusion has not been thoroughly described yet. Methods: Forty-eight children undergoing distraction osteogenesis for craniosynostosis were administered intraoperative TXA infusion (loading dose of 10 mg/kg for 15 min, followed by continuous infusion at 5 mg/kg/h throughout surgery; n = 23) or normal saline (control, n = 25). Rotational thromboelastometry (ROTEMTM) was conducted to monitor changes in coagulation perioperatively. Results: Blood loss during surgery was significantly lower in the TXA-treated group than it was in the control group (81 vs. 116 mL/kg, P = 0.003). Furthermore, significantly fewer transfusions of red blood cells and fresh frozen plasma were required in the TXA group. In the control group, clotting time during the postoperative period was longer than it was during the preoperative period. Similarly, clot strength was weaker during the postoperative period. D-dimer levels dramatically increased in the control group compared with the TXA group after surgery. The duration of mechanical ventilation and the number of postoperative respiratory-related complications were significantly greater in the control group than they were in the TXA group. Conclusions: TXA infusion based on population pharmacokinetic analysis is effective in reducing blood loss and the need for transfusions during the surgical treatment of craniosynostosis. It can also prevent the increase in D-dimer levels without affecting systemic hemostasis.

The effects of hemorrhage on the pharmacokinetics of tranexamic acid in a swine model.

BACKGROUND: The early use of tranexamic acid (TXA) is strongly advocated in patients who are likely to require massive transfusion to decrease mortality. This study determines the influence of hemorrhage on the pharmacokinetics of TXA in a porcine model. METHODS: The investigation was a prospective experimental study in Yucatan minipigs. First, in vitro plasma-cell partitioning of TXA was evaluated by inoculating whole blood with known aliquots, centrifuging, and measuring the supernatant with high-performance liquid chromatography with mass spectrometry (HPLC-MS). Then, using in vivo modeling, normovolemic and hypovolemic (35% reduction in blood volume) swine (n = 4 per group) received 1 g of intravenous TXA and had blood sampled at 14 time points over 4 hours to determine baseline clearance via HPLC-MS. Additional swine (n = 4) were hemorrhaged 35% of their blood volume, and TXA was administered as a 15 mg/kg infusion over 10 minutes followed by infusion of 1.875 mg/kg per hour to simulate massive hemorrhage scenario. During the first hour of TXA administration, one total blood volume was hemorrhaged and simultaneously replaced with TXA free blood. Serial blood samples and the hemorrhaged blood were analyzed by HPLC-MS to determine the percentage of dose lost via hemorrhage. RESULTS: Clearance of TXA was diminished in the hypovolemic group compared with the normovolemic group (115 ± 4 vs 70 ± 7 mL/min). Percentage of dose lost via hemorrhage averaged 25%. The lowest measured plasma level during the exchange transfusion was 34 µg/mL. CONCLUSION: Mean 25% of the present 2017 Joint Trauma System Clinical Practice Guideline dosing of TXA can be lost to hemorrhage if a blood volume is transfused within an hour of initiating therapy. In the case of TXA, which has limited distribution and is administered during active hemorrhage and massive blood transfusions, replacement strategies should be developed and tested to find simple methods of adjusting the current dosing guidelines to maintain therapeutic plasma concentrations. LEVEL OF EVIDENCE: Therapeutic, level II.

Therapeutic and pharmaco-biological, dose-ranging multicentre trial to determine the optimal dose of TRAnexamic acid to reduce blood loss in haemorrhagic CESarean delivery (TRACES): study protocol for a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal death worldwide. Tranexamic acid (TA), an antifibrinolytic drug, reduces bleeding and transfusion need in major surgery and trauma. In ongoing PPH following vaginal delivery, a high dose of TA decreases PPH volume and duration, as well as maternal morbidity, while early fibrinolysis is inhibited. In a large international trial, a TA single dose reduced mortality due to bleeding but not the hysterectomy rate. TA therapeutic dosages vary from 2.5 to 100 mg/kg and seizures, visual disturbances and nausea are observed with the highest dosages. TA efficiency and optimal dosage in haemorrhagic caesarean section (CS) has not been yet determined. We hypothesise large variations in fibrinolytic activity during haemorrhagic caesarean section needing targeted TA doses for clinical and biological efficacy. METHODS/DESIGN: The current study proposal is a blinded, randomised controlled trial with the primary objective of determining superiority of either 1 g of TXA or 0.5 g of TXA, in comparison to placebo, in terms of 30% blood-loss reduction at 6 h after non-emergency haemorrhagic caesarean delivery (active PPH > 800 mL) and to correlate this clinical effect in a pharmacokinetics model with fibrinolysis inhibition measured by an innovative direct plasmin measurement regarding plasmatic TA concentration. A sample size of 342 subjects (114 per group) was calculated, based on the expected difference of 30% reduction of blood loss between the placebo group and the low-dose group, out of which 144 patients will be included blindly in the pharmaco-biological substudy. A non-haemorrhagic reference group will include 48 patients in order to give a reference for peak plasmin level. DISCUSSION: TRACES trial is expected to give the first pharmacokinetics data to determinate the optimal dose of tranexamic acid to reduce blood loss and inhibit fibrinolysis in hemorrhagic cesarean section. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02797119 . Registered on 13 June 2016.