Epsilon-aminocaproic acid inhibition of fibrinolysis in vitro: should the 'therapeutic' concentration be reconsidered?
ABSTRACT The therapeutic concentration of epsilon-aminocaproic acid (EACA) has been 130 microg/ml or greater for nearly 50 years. We tested the effects on clot growth/disintegration of EACA with a plasmatic model of hyperfibrinolysis in vitro. Human plasma was exposed to 1000 U/ml tissue-type plasminogen activator containing 0, 13, 65 or 130 microg/ml EACA, with clot growth/disintegration kinetics quantified via thrombelastography. Data were analyzed with one-way analysis of variance or Kruskal-Wallis analysis of variance as appropriate. Exposure of plasma to 1000 U/ml tissue-type plasminogen activator resulted in a brief-lived clot, lasting 2 min. EACA at all concentrations tested significantly increased the rate of clot growth compared with samples with 0 microg/ml EACA. Clot strength was significantly increased by EACA in a concentration-dependent fashion. Similarly, EACA significantly prolonged the time of onset of clot lysis and decreased the rate of lysis. Samples with 130 microg/ml EACA had no sign of lysis present for 30 min. Subtherapeutic to therapeutic concentrations of EACA significantly attenuated or abolished fibrinolysis in the presence of a concentration of tissue-type plasminogen activator more than 2000-fold that encountered systemically during cardiopulmonary bypass. Further clinical investigation is warranted to determine whether smaller concentrations of EACA could provide a reduction in bleeding with a concomitant decrease in thrombotic complications.
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ABSTRACT: Microbubbles (MB) have previously demonstrated their great potential to enhance sonothrombolysis (STL) in vascular occlusions. Nonetheless the impact of MB-mediated STL on the fibrin network of clots has not been investigated up to now. The aim of this study was to evaluate the ability of combined ultrasound (US) and MB to degrade the fibrin in the presence or absence of a thrombolytic drug. Human blood clots containing radiolabeled-fibrin were exposed to different combinations of recombinant tissue plasminogen activator (rtPA), US (1.0 MHz; 1.3 MPa; 0.08% duty cycle) and MB. Three different techniques were used for the assessment of clot lysis: diameter loss, release of radioactive-fibrin degradation products (FDP) and D-Dimer assay. On one hand, the combination US + MB without rtPA induced a diameter loss (0.18 ± 0.01 mm), but no fibrin degradation, as revealed by the absence of radioactive-FDP release (0.5 ± 0.1%). On the other hand, the combination rtPA + US + MB enhanced both the diameter loss (0.77 ± 0.07 mm) and fibrin degradation (50.3 ± 2.4%) compared to rtPA alone (0.24 ± 0.01 mm and 36.5 ± 1.7%; p < 0.001), thus demonstrating a strong synergistic effect. The D-Dimer assay further confirmed the radioactivity results. Sonothrombolysis with MB greatly improves rtPA-mediated clot lysis and fibrin degradation was shown to be a key factor of the process. Studies addressing the clinical impact of this technique are warranted.Journal of Drug Delivery Science and Technology 12/2014; 25. · 1.09 Impact Factor
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ABSTRACT: To systematically examine evidence surrounding definitions and reporting of data for viscoelastic testing in veterinary medicine. Standardized, systematic evaluation of the literature, categorization of relevant articles according to level of evidence and quality, and development of consensus on conclusions for application of the concepts to clinical practice. Academic and referral veterinary medical centers. Databases searched included Medline, CAB abstracts, and Google Scholar. All 4 standard thromboelastography (TEG) and rotational thromboelastometry (ROTEM) variables should be universally reported, and the reporting of shear elastic modulus in addition to maximum amplitude (MA) is encouraged. There is insufficient evidence to support universal usage of the coagulation index at this time. The K value and clot formation time are the most variable of the 4 parameters, with alpha angle, MA, and maximum clot firmness generally the least variable. Individual studies should report sufficient data on patients and institutional controls to enable definitions of hypo- and hypercoagulability to be evaluated post-hoc, and it is recommended that all studies specifically report how these conditions were defined. In reporting data relating to fibrinolysis, the TEG variables LY30, LY60, CL30, CL60, and the ROTEM variables LI30, LI60, ML, LOT, and LT should be documented. Studies should report sufficient data on patients and controls to enable definitions of hyper- and hypofibrinolysis to be evaluated post-hoc, and we suggest that standard TEG/ROTEM assays may be unable to detect hypofibrinolysis in companion animals. We recommend that every center establish reference intervals, which are specific to either TEG or ROTEM. These reference intervals should be established using veterinary clinical pathology guidelines, standardized protocols, and a minimum of 40 healthy animals. There are currently insufficient data in companion animals to suggest a utility for Vcurve variables beyond that of standard TEG variables.Journal of veterinary emergency and critical care (San Antonio, Tex. : 2001). 01/2014; 24(1):47-56.
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ABSTRACT: Objective-To determine minimum plasma concentrations of the antifibrinolytic agents tranexamic acid (TEA) and ϵ-aminocaproic acid (EACA) needed to completely inhibit fibrinolysis in canine and human plasma after induction of hyperfibrinolysis. Samples-Pooled citrated plasma from 7 dogs and commercial pooled citrated human plasma. Procedures-Concentrations of EACA from 0 μg/mL to 500 μg/mL and of TEA from 0 μg/mL to 160 μg/mL were added to pooled citrated canine and human plasma. Hyperfibrinolysis was induced with 1,000 units of tissue plasminogen activator/mL, and kaolin-activated thromboelastography was performed in duplicate. The minimum concentrations required to completely inhibit fibrinolysis 30 minutes after maximum amplitude of the thromboelastography tracing occurred were determined. Results-Minimum plasma concentrations necessary for complete inhibition of fibrinolysis by EACA and TEA in pooled canine plasma were estimated as 511.7 μg/mL (95% confidence interval [CI], 433.2 to 590.3 μg/mL) and 144.7 μg/mL (95% CI, 125.2 to 164.2 μg/mL), respectively. Concentrations of EACA and TEA necessary for complete inhibition of fibrinolysis in pooled human plasma were estimated as 122.0 μg/mL (95% CI, 106.2 to 137.8 μg/mL) and 14.7 μg/mL (95% CI, 13.7 to 15.6 μg/mL), respectively. Conclusions and Clinical Relevance-Results supported the concept that dogs are hyperfibrinolytic, compared with humans. Higher doses of EACA and TEA may be required to fully inhibit fibrinolysis in dogs.American Journal of Veterinary Research 08/2014; 75(8):731-8. · 1.21 Impact Factor