ε-Aminocaproic acid inhibition of fibrinolysis in vitro: Should the 'therapeutic' concentration be reconsidered?

Department of Anesthesiology, The University of Alabama, Birmingham, Alabama, USA.
Blood Coagulation and Fibrinolysis (Impact Factor: 1.4). 02/2007; 18(1):35-9. DOI: 10.1097/MBC.0b013e328010a359
Source: PubMed


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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    • "The clot diameter loss was then expressed in mm as a function of time. was selected based on earlier reports [22,23]. In preliminary tests, this concentration was shown to inhibit clot fibrinolysis caused by rtPA (3 mg/mL). "
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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.
    Full-text · Article · Dec 2014 · Journal of Drug Delivery Science and Technology
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    • "Importantly, enhanced fibrinolysis contributes significantly to bleeding in trauma patients as well as patients undergoing cardiac and liver surgery and patients with obstetric complications, and this condition is readily identified by VHA (Ly (TEG), CL (ROTEM)) [45]. In addition, VHA in vitro studies have evaluated the effects of hypothermia [46], acidosis [47], different crystalloids and colloids [48], pro-haemostatic [49] and anti-fibrinolytic drugs [50], with results being highly relevant for the clinical setting. "
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    ABSTRACT: Death due to trauma is the leading cause of lost life years worldwide, with haemorrhage being responsible for 30-40% of trauma mortality and accounting for almost 50% of the deaths the initial 24 h. On admission, 25-35% of trauma patients present with coagulopathy, which is associated with a several-fold increase in morbidity and mortality. The recent introduction of haemostatic control resuscitation along with emerging understanding of acute post-traumatic coagulability, are important means to improve therapy and outcome in exsanguinating trauma patients. This change in therapy has emphasized the urgent need for adequate haemostatic assays to monitor traumatic coagulopathy and guide therapy. Based on the cell-based model of haemostasis, there is emerging consensus that plasma-based routine coagulation tests (RCoT), like prothrombin time (PT) and activated partial thromboplastin time (APTT), are inappropriate for monitoring coagulopathy and guide therapy in trauma. The necessity to analyze whole blood to accurately identify relevant coagulopathies, has led to a revival of the interest in viscoelastic haemostatic assays (VHA) such as Thromboelastography (TEG®) and Rotation Thromboelastometry (ROTEM®). Clinical studies including about 5000 surgical and/or trauma patients have reported on the benefit of using the VHA as compared to plasma-based assays, to identify coagulopathy and guide therapy. This article reviews the basic principles of VHA, the correlation between the VHA whole blood clot formation in accordance with the cell-based model of haemostasis, the current use of VHA-guided therapy in trauma and massive transfusion (haemostatic control resuscitation), limitations of VHA and future perspectives of this assay in trauma.
    Full-text · Article · Sep 2009 · Scandinavian Journal of Trauma Resuscitation and Emergency Medicine
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    ABSTRACT: Intracerebral haemorrhage (ICH) is a stroke resulting from spontaneous rupture of an intracranial vessel and is associated with high early mortality and long-term morbidity rates. With the exception of dedicated stroke units or neurocritical care, no surgical or medical intervention has been proven to effectively improve outcome following ICH. Pharmacotherapeutic considerations include optimal blood pressure control and the choice of antihypertensive agents. Acute haematoma expansion represents the most obvious acute treatment target. The use of haemostatic agents may have a role in ICH management; although it appears improved patient selection may be required before the use of these agents can be demonstrated clinically. In patients with anticoagulant-associated ICH, a number of therapeutic agents may be used to urgently reverse the coagulopathy, although further clinical trials are required. Recurrent bleeding and future thrombo-embolic event rates in patients who require anticoagulation following ICH risks are difficult to determine accurately, although risk stratification data are emerging. This article reviews the pathophysiology, natural history and the evidence supporting present therapeutic management practices for ICH. The authors' practice based on best available evidence is provided.
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