Therapeutic Strategies for Disseminated Intravascular Coagulation Associated with Aortic Aneurysm.

Aortic aneurysms are sometimes associated with enhanced-fibrinolytic-type disseminated intravascular coagulation (DIC). In enhanced-fibrinolytic-type DIC, both coagulation and fibrinolysis are markedly activated. Typical cases show decreased platelet counts and fibrinogen levels, increased concentrations of fibrin/fibrinogen degradation products (FDP) and D-dimer, and increased FDP/D-dimer ratios. Thrombin-antithrombin complex or prothrombin fragment 1 + 2, as markers of coagulation activation, and plasmin-α2 plasmin inhibitor complex, a marker of fibrinolytic activation, are all markedly increased. Prolongation of prothrombin time (PT) is not so obvious, and the activated partial thromboplastin time (APTT) is rather shortened in some cases. As a result, DIC can be neither diagnosed nor excluded based on PT and APTT alone. Many of the factors involved in coagulation and fibrinolysis activation are serine proteases. Treatment of enhanced-fibrinolytic-type DIC requires consideration of how to control the function of these serine proteases. The cornerstone of DIC treatment is treatment of the underlying pathology. However, in some cases surgery is either not possible or exacerbates the DIC associated with aortic aneurysm. In such cases, pharmacotherapy becomes even more important. Unfractionated heparin, other heparins, synthetic protease inhibitors, recombinant thrombomodulin, and direct oral anticoagulants (DOACs) are agents that inhibit serine proteases, and all are effective against DIC. Inhibition of activated coagulation factors by anticoagulants is key to the treatment of DIC. Among them, DOACs can be taken orally and is useful for outpatient treatment. Combination therapy of heparin and nafamostat allows fine-adjustment of anticoagulant and antifibrinolytic effects. While warfarin is an anticoagulant, this agent is ineffective in the treatment of DIC because it inhibits the production of coagulation factors as substrates without inhibiting activated coagulation factors. In addition, monotherapy using tranexamic acid in cases of enhanced-fibrinolytic-type DIC may induce fatal thrombosis. If tranexamic acid is needed for DIC, combination with anticoagulant therapy is of critical importance.

Assessing Plasmin Generation in Health and Disease.

Fibrinolysis is an important process in hemostasis responsible for dissolving the clot during wound healing. Plasmin is a central enzyme in this process via its capacity to cleave fibrin. The kinetics of plasmin generation (PG) and inhibition during fibrinolysis have been poorly understood until the recent development of assays to quantify these metrics. The assessment of plasmin kinetics allows for the identification of fibrinolytic dysfunction and better understanding of the relationships between abnormal fibrin dissolution and disease pathogenesis. Additionally, direct measurement of the inhibition of PG by antifibrinolytic medications, such as tranexamic acid, can be a useful tool to assess the risks and effectiveness of antifibrinolytic therapy in hemorrhagic diseases. This review provides an overview of available PG assays to directly measure the kinetics of plasmin formation and inhibition in human and mouse plasmas and focuses on their applications in defining the role of plasmin in diseases, including angioedema, hemophilia, rare bleeding disorders, COVID-19, or diet-induced obesity. Moreover, this review introduces the PG assay as a promising clinical and research method to monitor antifibrinolytic medications and screen for genetic or acquired fibrinolytic disorders.

Rosuvastatin use increases plasma fibrinolytic potential: a randomised clinical trial.

We conducted a study to assess the effect of rosuvastatin use on fibrinolysis in patients with previous venous thromboembolism (VTE). This was a post hoc analysis within the STAtins Reduce Thrombophilia (START) study (NCT01613794). Plasma fibrinolytic potential, fibrinogen, plasmin inhibitor, plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI) were measured before and after four weeks of rosuvastatin or no treatment in participants with prior confirmed VTE, after ending anticoagulant therapy. In the non-rosuvastatin group (n = 121), plasma fibrinolytic potential and individual fibrinolysis parameters did not change at the end of the study versus the baseline, whereas in the rosuvastatin group (n = 126), plasma fibrinolytic potential increased: the mean clot lysis time decreased by 8·75 min (95% CI -13·8 to -3·72), and plasmin inhibitor levels and TAFI activity were lower at the end of the study (-0·05 U/ml; 95% CI -0·07 to -0·02 and -4·77%; 95% CI -6·81 to -2·73, respectively). PAI-1 levels did not change and fibrinogen levels were 0·17 g/l (95% CI 0·04-0·29) higher. In participants with prior VTE, rosuvastatin use led to an increased fibrinolytic potential compared with non-statin use. Our findings support the need for further studies on the possible role for statins in the secondary prevention of VTE.

Solid phase microextraction coupled to mass spectrometry via a microfluidic open interface for rapid therapeutic drug monitoring.

Tranexamic acid (TXA) is an antifibrinolytic used during cardiac surgery that presents high inter-patient variability. High plasma concentrations have been associated with post-operative seizures. Due to the difficulties with maintaining acceptable concentrations of TXA during surgery, implementation of a point-of-care strategy for testing TXA plasma concentration would allow for close monitoring of its concentration during administration. This would facilitate timely corrections to the dosing schedule, and in effect tailor treatment for individual patient needs. In this work, a method for the rapid monitoring of TXA from plasma samples was subsequently carried out via biocompatible solid-phase microextraction (Bio-SPME) coupled directly to tandem mass spectrometry via a microfluidic open interface (MOI). MOI operates under the concept of a flow-isolated desorption volume and was designed with aims to directly hyphenate Bio-SPME to different detection and ionization systems. In addition, it allows the desorption of Bio-SPME fibers in small volumes while it concurrently continues feeding the ESI with a constant flow to minimize cross-talking and instabilities. The methodology was used to monitor six patients with varying degrees of renal dysfunction, at different time points during cardiac surgery. MOI proves to be a reliable and feasible tool for rapid therapeutic drug monitoring. Affording total times of analysis as low as 30 seconds per sample in its high throughput mode configuration while the single sample turn-around time was 15 minutes, including sample preparation. In addition, cross-validation against a standard thin film solid phase microextraction using liquid chromatography coupled to tandem mass spectrometry (TFME-LC-MS/MS) method was performed. Bland-Altman analysis was used to cross-validate the results obtained by the two methods. Data analysis demonstrated that 92% of the compared data pairs (n = 63) were distributed within the acceptable range. The data was also validated by the Passing Bablok regression, demonstrating good statistical agreement between these two methods. Finally, the currently presented method offers comparable results to the conventional liquid chromatography with acceptable RSDs, while only necessitating a fraction of the time. In this way, TXA concentration in plasma can be monitored in a close to real time throughput during surgery.

Safety of coagulation factor concentrates guided by ROTEM™-analyses in liver transplantation: results from 372 procedures.

BACKGROUND: Most centres use fresh frozen plasma (FFP) based protocols to prevent or treat haemostatic disturbances during liver transplantation. In the present study, we used a rotational thrombelastometry (ROTEM™, TEM, Munich, Germany) guided haemostasis management with fibrinogen concentrates, prothrombin complex concentrates (PCC), platelet concentrates and tranexamic acid without FFP usage and determined the effect on 30 day mortality. METHODS: Retrospective data analysis with 372 consecutive adult liver transplant patients performed between 2007 and 2011. RESULTS: Thrombelastometry guided coagulation management resulted in a transfusion rate for fibrinogen concentrates in 50.2%, PCC in 18.8%, platelet concentrates in 21.2%, tranexamic acid in 4.5%, and red blood cell concentrates in 59.4%. 30 day mortality for the whole cohort was 14.2%. The univariate analyses indicated that nonsurvivors received significantly more fibrinogen concentrates, PCC, red blood cell concentrates, platelet concentrates, and infusion volume, and had a higher MELD score. However, association with mortality was weak as evidenced by receiver operating characteristic curve analyses. Further univariate analyses demonstrated, that up to 8 g of fibrinogen did not increase mortality compared to patients not receiving the coagulation factor. Multivariate analysis demonstrated that platelet concentrates (p = 0.0002, OR 1.87 per unit), infused volume (p = 0.0004, OR = 1.13 per litre), and MELD score (p = 0.024; OR 1.039) are independent predictors for mortality. Fibrinogen concentrates, PCC, and red blood cell concentrates were ruled out as independent risk factors. CONCLUSIONS: ROTEM™ guided substitution with fibrinogen concentrates and PCC does not negatively affect mortality after liver transplantation, while the well-known deleterious effect associated with platelet concentrates was confirmed.

Is tranexamic acid exposure related to blood loss in hip arthroplasty? A pharmacokinetic-pharmacodynamic study.

AIMS: Tranexamic acid (TXA) is an antifibrinolytic agent, decreasing blood loss in hip arthroplasty. The present study investigated the relationship between TXA exposure markers, including the time above the in vitro threshold reported for inhibition of fibrinolysis (10 mg l-1 ), and perioperative blood loss. METHODS: Data were obtained from a prospective, double-blind, parallel-arm, randomized superiority study in hip arthroplasty. Patients received a preoperative intravenous bolus of TXA 1 g followed by a continuous infusion of either TXA 1 g or placebo over 8 h. A population pharmacokinetic study was conducted to quantify TXA exposure. RESULTS: In total, 827 TXA plasma concentrations were measured in 166 patients. A two-compartment model fitted the data best, total body weight determining interpatient variability in the central volume of distribution. Creatinine clearance accounted for interpatient variability in clearance. At the end of surgery, all patients had TXA concentrations above the therapeutic target of 10 mg l-1 . The model-estimated time during which the TXA concentration was above 10 mg l-1 ranged from 3.3 h to 16.3 h. No relationship was found between blood loss and either the time during which the TXA concentration exceeded 10 mg l-1 or the other exposure markers tested (maximum plasma concentration, area under the concentration-time curve). CONCLUSION: In hip arthroplasty, TXA plasma concentrations were maintained above 10 mg l-1 during surgery and for a minimum of 3 h with a preoperative TXA dose of 1 g. Keeping TXA concentrations above this threshold up to 16 h conferred no advantage with regard to blood loss.

Comparison of tranexamic acid plasma concentrations when administered via intraosseous and intravenous routes.

INTRODUCTION: There is a lack of information regarding intraosseous (IO) administration of tranexamic acid (TXA). Our hypothesis was that a single bolus IO injection of TXA will have a similar pharmacokinetic profile to TXA administered at the same dose IV. METHODS: Sixteen male Landrace cross swine (mean body weight 27.6±2.6kg) were divided into an IV group (n=8) and an IO group (n=8). Each animal received 30mg/kg TXA via an IV or IO catheter, respectively. Jugular blood samples were collected for pharmacokinetic analysis over a 3h period. The maximum TXA plasma concentration (Cmax) and corresponding time as well as distribution half-life, elimination half-life, area under the curve, plasma clearance and volume of distribution were calculated. One- and two-way analysis of variance for repeated measures (time, group) with Tukey's and Bonferonni post hoc tests were used to compare TXA plasma concentrations within and between groups, respectively. RESULTS: Plasma concentrations of TXA were significantly higher (p<0.0001) in the IV group during the TXA infusion. Cmax occurred at 4min after initiation of the bolus in the IV group (9.36±3.20ng/µl) and at 5min after initiation of the bolus in the IO group (4.46±0.49ng/µl). Plasma concentrations were very similar from the completion of injection onwards. There were no significant differences between the two administration routes for any other pharmacokinetic variables measured. CONCLUSION: The results of this study support pharmacokinetic bioequivalence of IO and IV administration of TXA.

Comparison of tranexamic acid pharmacokinetics after intra-articular and intravenous administration in rabbits.

Tranexamic Acid (TXA) is commonly administered in total knee arthroplasty for reducing blood loss. There has been a growing interest in the topical use of TXA except intravenous use for prevention of bleeding in TKA. The aim of this study was to develop and validate a HPLC-MS method to detect TXA and apply to compare the pharmacokinetic profile of TXA after intravenous (IV) and topical intra-articular (IA) application of TXA at a dose of 20 mg/kg in rabbits. In order to prove intra-articular administration is better than that of intravenous administration from the point of rabbit pharmacokinetic. Two groups of rabbits (n=6/group) respectively received TXA intra-articularly or intravenously. Blood samples were collected at scheduled time. The concentration of TXA in plasma was determined by a validated HPLC-MS method. Excellent linearity was found between 0.015 and 70.0µg/ml with a lower limit of quantitation (LLOQ) of 0.015µg/ml (r>0.99); moreover, all the validation data including accuracy and precision (intra- and inter-day) were all within the required limits. The pharmacokinetic parameters in IA and IV group were: Cmax: 30.65±3.31 VS 54.05± 6.21µg/ml (p<0.01); t1/2: 1.26±0.05 VS 0.68±0.13h (p<0.05); AUC0-t: 42.98±7.73 VS 23.39±4.14µg/ml• h (p<0.01), time above the minimum effective concentration (%T > MEC): 1.5-2.2 VS 0.7-1.2h (p<0.05). HPLC-MS method is suitable for TXA pharmacokinetic studies. The results demonstrated that topical intra-articular application of TXA showed a reduced peak plasma concentration and prolonged therapeutic drug level compared with intravenous TXA from the point of rabbit pharmacokinetic.

The gender differences in the inhibitory action of UVB-induced melanocyte activation by the administration of tranexamic acid.

BACKGROUND: Tranexamic acid has an inhibitory action on ultraviolet (UV) B-induced melanocyte activation. This study examined the sex differences in the inhibitory action of tranexamic acid on UVB-induced melanocyte activation. METHODS: We irradiated the eye and ear of male and female mice with UVB at a dose of 1.0 kJ/m(2) using a 20SE sunlamp. We orally administered tranexamic acid (750 mg/kg/day) at 30 min before UVB exposure. RESULTS: Tranexamic acid inhibited the UVB-induced epidermal melanocyte activation, and the effect was more remarkable under UVB eye irradiation than under UVB ear irradiation. Furthermore, the melanocyte activity suppression effect was stronger in female mice than in male mice. Following the administration of tranexamic acid, the female displayed increased blood levels of ß-endorphin and µ-opioid receptor and estradiol receptor ß expression in comparison with the male. Furthermore, the effect of melanocyte activity suppression in the female mice was decreased by the administration of tamoxifen (antagonist of estrogen receptor) or naltrexone (antagonist of µ-opioid receptor). CONCLUSIONS: These results suggest that the suppression by tranexamic acid of the UVB-induced melanocyte activation (UVB sensitivity) is stronger in female mice than in male mice and that female hormones and ß-endorphin play an important role in this sex difference.

Major liver resection, systemic fibrinolytic activity, and the impact of tranexamic acid.

BACKGROUND: Hyperfibrinolysis may occur due to systemic inflammation or hepatic injury that occurs during liver resection. Tranexamic acid (TXA) is an antifibrinolytic agent that decreases bleeding in various settings, but has not been well studied in patients undergoing liver resection. METHODS: In this prospective, phase II trial, 18 patients undergoing major liver resection were sequentially assigned to one of three cohorts: (i) Control (no TXA); (ii) TXA Dose I - 1 g bolus followed by 1 g infusion over 8 h; (iii) TXA Dose II - 1 g bolus followed by 10 mg/kg/hr until the end of surgery. Serial blood samples were collected for thromboelastography (TEG), coagulation components and TXA concentration. RESULTS: No abnormalities in hemostatic function were identified on TEG. PAP complex levels increased to peak at 1106 µg/L (normal 0-512 µg/L) following parenchymal transection, then decreased to baseline by the morning following surgery. TXA reached stable, therapeutic concentrations early in both dosing regimens. There were no differences between patients based on TXA. CONCLUSIONS: There is no thromboelastographic evidence of hyperfibrinolysis in patients undergoing major liver resection. TXA does not influence the change in systemic fibrinolysis; it may reduce bleeding through a different mechanism of action. Registered with ClinicalTrials.gov: NCT01651182.

[Cancer treatment in elderly patients: evidence and clinical research]. / Il trattamento oncologico nel paziente anziano tra evidenze e ricerca clinica.

In 2020 the percentage of patients with a diagnosis of cancer in people with more than 65 years will exceed 70% and 28% in ethnic minorities. The treatment of cancer in these populations is challenging for the oncologists due to socio-economic issues such as poverty, reduced access to the hospital care, level of education. The clinical pathway "diagnosis-treatment-cure", typical of the care of young patients has to be integrated in elderly patients with a more individualized treatment by means of comprehensive geriatric assessment (CGA). IADL (Instrumental Activities of Daily Living) have the best predictive role in oncological setting and their impairment significantly correlate with overall survival, chemotherapy toxicities and thirty days postoperative morbidities. The CGA is universally accepted as the most appropriate instrument to analitically evaluate the age related problems of elderly patients. The role of CGA is crucial to identify geriatric issues not easily diagnosed, to predict treatment toxicities, functional or cognitive decline, post operative complications and to estimate life expectancy. The CGA items are predictive of severe toxicity, however it is not clearly established which are the best performers and the best cut-offs points. Today CGA is integrated with physical performance tests (the most widely used is the "time up and go" test) and laboratory assay of Interleukin 6 and D-Dimer that correlate with mortality and physical decline. There are few prospective studies that evaluated the role of CGA in treatment choice. The first is a phase II study in solid tumors, the second is a haematological trial on non Hodgkin lymphoma. The largest trial is a 571 patients observational series that confirmed the role of CGA in decision making. The administration of CGA is time consuming and consequently some screening tools were developed. VES-13 is a 13 items tool that explores prevalently the functional status and the self reported health status. VES-13 showed a good sensibility (87.3%) but a low specificity (62%) with respect to CGA for the diagnosis of patients with disabilities. Overcash et al. proposed an abbreviated form of CGA using a reduced number of items of ADL, IADL, MMSE and GDS. There was a good correlation between complete and reduced scales (coefficient of correlation 0.8). G8 is a screening tool composed of 8 questions that explore functional, cognitive and nutritional status. The score with the best equilibrium between sensibility and specificity was 14 (sensibility 85% and specificity 65%). In the first observational trial age, hystotype, chemotherapy dose, haemoglobin (man: 11 g/dL; women: 10 g/dL), creatinine clearance less than 34 mL/min (Jelliffe formula), earing problems, at least a fall in the last six months, walking problems, low social activity, were related to a major risk of toxicity; in another trial IADL, diastolic blood pressure, LDH and MAX2 index were predictive of haematological toxicity, while performance status, Mini-Mental Status score, Mini-Nutritional Assessment (MNA) score and MAX2 index were predictive of non haematological toxicity. Based on these parameters a 0-2 score was developed. A recent "position article" of EORTC (European organization for Research and Treatment of Cancer) and SIOG analyzed the pro and the contra of the use of some indicators in elderly patients. The overall survival (OS) frequently used in classical clinical trial could give wrong messages as there are some competitive risks of death in elderly patients. Another important indicator is the disease specific survival (DSS). Concerning the design of clinical trials, a possible strategy is to enrol elderly patients without upper age limit and to plan stratification. An interesting trial design is the so called "extended trial" that allow to re-open the arm of a trial in which a too low number of older patients was enrolled.

Point-of-care D-dimer testing in emergency departments.

Overcrowding and prolonged patient stays in emergency departments (EDs) affect patients' experiences and outcomes, and increase healthcare costs. One way of addressing these problems is through using point-of-care blood tests, laboratory testing undertaken near patient locations with rapidly available results. D-dimer tests are used to exclude venous thromboembolism (VTE), a common presentation in EDs, in low-risk patients. However, data on the effects of point-of-care D-dimer testing in EDs and other urgent care settings are scarce. This article reports the results of a literature review that examined the benefits to patients of point-of-care D-dimer testing in terms of reduced turnaround times (time to results), and time to diagnosis, discharge or referral. It also considers the benefits to organisations in relation to reduced ED crowding and increased cost effectiveness. The review concludes that undertaking point-of-care D-dimer tests, combined with pre-test probability scores, can be a quick and safe way of ruling out VTE and improving patients' experience.

[Age features of hemostatic system in people with insulin resistance and pre-diabetes carbohydrate metabolism disorders].

In pre-diabetes disorders in which pathogenesis the insulin resistance (IR) plays a leading role, the risk of thrombosis due to increased coagulation factors, decreased concentration of physiological anticoagulants and inhibition of fibrinolysis is increased. Similar changes in the hemostatic system with aging are observed. We investigated the characteristics of the hemostatic system in middle-aged and elderly people with IR in the absence and presence of impaired glucose tolerance (IGT). It is shown that IR in middle-aged and elderly people is accompanied by increased content of plasminogen activator inhibitor type-1, which may lead to potential inhibition of fibrinolysis. An indication of significant prothrombotic changes associated with IR in the elderly are reduced a clotting time of blood plasma in the APTT test and elevated levels of soluble fibrin and D-dimer. Intensity of these changes in the hemostatic system is enhanced in the presence of IGT. The results substantiate need for correction of hemostasis by reducing the IR.

A novel method to quantify fibrin-fibrin and fibrin-α2-antiplasmin cross-links in thrombi formed from human trauma patient plasma.

BACKGROUND: The widespread use of the antifibrinolytic agent, tranexamic acid (TXA), interferes with the quantification of fibrinolysis by dynamic laboratory assays such as clot lysis, making it difficult to measure fibrinolysis in many trauma patients. At the final stage of coagulation, factor (F)XIIIa catalyzes the formation of fibrin-fibrin and fibrin-α2-antiplasmin (α2AP) cross-links, which increases clot mechanical strength and resistance to fibrinolysis. OBJECTIVES: Here, we developed a method to quantify fibrin-fibrin and fibrin-α2AP cross-links that avoids the challenges posed by TXA in determining fibrinolytic resistance in conventional assays. METHODS: Fibrinogen alpha (FGA) chain (FGA-FGA), fibrinogen gamma (FGG) chain (FGG-FGG), and FGA-α2AP cross-links were quantified using liquid chromatography-mass spectrometry (LC-MS) and parallel reaction monitoring in paired plasma samples from trauma patients prefibrinogen and postfibrinogen replacement. Differences in the abundance of cross-links in trauma patients receiving cryoprecipitate (cryo) or fibrinogen concentrate (Fg-C) were analyzed. RESULTS: The abundance of cross-links was significantly increased in trauma patients postcryo, but not Fg-C transfusion (P < .0001). The abundance of cross-links was positively correlated with the toughness of individual fibrin fibers, the peak thrombin concentration, and FXIII antigen (P < .05). CONCLUSION: We have developed a novel method that allows us to quantify fibrin cross-links in trauma patients who have received TXA, providing an indirect measure of fibrinolytic resistance. Using this novel approach, we have avoided the effect of TXA and shown that cryo increases fibrin-fibrin and fibrin-α2AP cross-linking when compared with Fg-C, highlighting the importance of FXIII in clot formation and stability in trauma patients.

Routine micromethod for the determination of vitamin K1 in human plasma.

BACKGROUND: A selective and sensitive high-performance liquid chromatographic method with fluorescence detection after postcolumn reduction is described for the routine measurement of vitamin K1 in plasma samples of 100 µL of volume. METHODS: Liquid-liquid extraction was used for the sample preparation with vitamin K2 as an internal standard. For the chromatographic separation, a standard C18 column was applied. The calibration range used was from 2 to 500 ng/mL. RESULTS: At the low level (5 ng/mL), a coefficient of variation of 14.9% was observed interday in the quality control samples, whereas at the intermediate (50 ng/mL) and high (200 ng/mL) levels such of 6.8% and 8.7% were found. CONCLUSIONS: The method has proven robust and convenient for the analysis of samples from clinical pharmacological studies.

Population pharmacokinetics of tranexamic acid in adults undergoing cardiac surgery with cardiopulmonary bypass.

BACKGROUND: Interest in antifibrinolytic tranexamic acid (TA) has grown since the widespread removal of aprotinin, but its dosing during cardiac surgery is still debated. The objectives of this study were to investigate the population pharmacokinetics (PK) of TA given with either low- or high-dose continuous infusion schemes in adult cardiac surgery patients during cardiopulmonary bypass (CPB). METHODS: Patients were randomized to receive either low-dose (10 mg kg(-1) followed by an infusion of 1 mg kg(-1) h(-1) throughout the operation, and 1 mg kg(-1) into the CPB) or high-dose (30 mg kg(-1), then 16 mg kg(-1) h(-1), and 2 mg kg(-1) into the CPB) TA. Serum TA concentrations were measured in 61 patients and the data were modelled using Monolix. RESULTS: TA concentrations were 28-55 µg ml(-1) in the low-dose group and 114-209 µg ml(-1) in the high-dose group throughout surgery. TA PK was best described by a two-compartment open model. The main covariate effect was bodyweight, whereas the CPB did not influence the PK. Assuming a bodyweight of 70 kg, the population estimates were 4.8 litre h(-1) for clearance, 6.6 litre for the volume of the central compartment, 32.2 litre h(-1) for the diffusional clearance, and the peripheral volume of distribution was 10.8 litre. CONCLUSIONS: The PK of TA was satisfactorily described by an open two-compartmental model, which was used to propose a dosing scheme suitable for obtaining and maintaining the desired plasma concentration in a stable and narrow range in cardiac surgery patients.

Population pharmacokinetics of epsilon-aminocaproic acid in infants undergoing craniofacial reconstruction surgery.

BACKGROUND: Understanding the clinical pharmacology of the antifibrinolytic epsilon-aminocaproic acid (EACA) is necessary for rational drug administration in children. The aim of this study is to determine the pharmacokinetics (PKs) of EACA in infants aged 6-24 months undergoing craniofacial reconstruction surgery. METHODS: Cohorts of six infants were enrolled sequentially to one of the three escalating loading dose-continuous i.v. infusion (CIVI) regimens: 25 mg kg(-1), 10 mg kg(-1) h(-1); 50 mg kg(-1), 20 mg kg(-1) h(-1); 100 mg kg(-1), 40 mg kg(-1) h(-1). Plasma EACA concentrations were determined using a validated high-performance liquid chromatography-tandem mass spectrometry assay. A population non-linear mixed effects modelling approach was used to characterize EACA PKs. RESULTS: Population PK parameters of EACA were estimated using a two-compartment disposition model with weight expressed as an allometric covariate and an age effect. The typical patient in this study had an age of 38.71 weeks and a weight of 8.82 kg. PK parameters for this typical patient were: pre-/postoperative plasma drug clearance of 32 ml min(-1) (3.6 ml kg(-1) min(-1)), inter-compartmental clearance of 42.4 ml min(-1) (4.8 ml min(-1) kg(-1)), central volume of distribution of 1.27 litre (0.14 litre kg(-1)), and peripheral volume of distribution of 2.53 litre (0.29 litre kg(-1)). Intra-operative clearance and central volume of distribution were 89% and 80% of the pre-/postoperative value, respectively. CONCLUSIONS: EACA clearance increased with weight and age. The dependence of clearance on body weight supports weight-based dosing. Based on this study, a loading dose of 100 mg kg(-1) followed by a CIVI of 40 mg kg(-1) h(-1) is appropriate to maintain target plasma EACA concentrations in children aged 6-24 months undergoing these procedures.

The effective concentration of tranexamic acid for inhibition of fibrinolysis in neonatal plasma in vitro.

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.

Impaired fibrinolysis as a risk factor for Budd-Chiari syndrome.

In Budd-Chiari syndrome (BCS), thrombosis develops in the hepatic veins or inferior vena cava. To study the relationship between hypofibrinolysis and BCS, we measured plasma levels of fibrinolysis proteins in 101 BCS patients and 101 healthy controls and performed a plasma-based clot lysis assay. In BCS patients, plasminogen activator inhibitor 1 (PAI-1) levels were significantly higher than in controls (median, 6.3 vs 1.4 IU/mL, P < .001). Thrombin-activatable fibrinolysis inhibitor and plasmin inhibitor levels were lower than in controls (13.8 vs 16.9 microg/mL and 0.91 vs 1.02 U/L, both P < .001). Median plasma clot lysis time (CLT) was 73.9 minutes in cases and 73.0 minutes in controls (P = .329). A subgroup of cases displayed clearly elevated CLTs. A CLT above the 90th or 95th percentile of controls was associated with an increased risk of BCS, with odds ratios of 2.4 (95% confidence interval, 1.1-5.5) and 3.4 (95% confidence interval, 1.2-9.7), respectively. In controls, only PAI-1 activity was significantly associated with CLT. Analysis of single nucleotide polymorphisms of fibrinolysis proteins revealed no significant differences between cases and controls. This case-control study provides the first evidence that an impaired fibrinolytic potential, at least partially caused by elevated PAI-1 levels, is related to the presence of BCS.