Abstract 13625: Laboratory Markers of Effective Endogenous Fibrinolysis in Intermediate-High-Risk Pulmonary Embolism
Michal MihalovičPetr RobertDenisa OdvodyováIvana MalinicovaKaterina PilikovaMichal KarpíšekJiří JarkovskýZuzana Moťovská
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Introduction: Unselected therapy with fibrinolysis in intermediate risk-pulmonary embolism (iPE) is associated with an unacceptable risk of bleeding. Early identification of iPE patients on anticoagulant therapy with ineffective endogenous fibrinolysis (eFL) could optimize treatment-strategy. Aims: The study aims to determine markers of (in)effective eFL in intermediate-risk PE initially on anticoagulant therapy with UFH. Methods: In course of 24 months, iPE patients were enrolled in the prospective study. At admission, and every 24 hours until day 5, levels of 6 selected markers of eFL (i.e., PAI-1 and tPA active assay and total antigen, TAFI, and PAP) were determined. Upon arrival and following a span of 36 hours,defined i) Clinical (heart rate >100 bpm and spontaneous oxygen saturation <90%), ii) Echo (D-shape, RVd/LVd from PLAX>0.7, RV/RA >30mmHg), and iii) CT (RV/LV>0.9) variables were obtained. An (un)successful therapy was assessed by one point for each clinical, Echo and CT criteria, as at least one parameter from initially altered has adjusted at 36 hours. We performed correlation of laboratory markers with the dynamics of clinical and imaging characteristics. Results: Study population consists of 44 patients, 22 men, mean (SD) age 60 (18.3) yr., first (38), repeat (6) PE. Plasminogen activator inhibitor-1 (PAI-1) active assay showed the most promising results. The cut-off for unsuccessful therapy from AUC for PAI-1 was ≥65 U/ml. Mean (IQR) levels of PAI-1 on day 1 were 119 U/ml (27.1 - 155.8) and were significantly higher on day 1 (p=0.019) and day 2 (p=0.055) in those with/without adjustment of initial pathological findings. PAI-1 elevation was associated with unsuccessful restoration of clinical, Echo and CT parameters at 36 hours (Table1). Overall Tx failure was associated with elevated PAI-1 (p=0.011). Conclusions: PAI-1 active assay could help us in identifying patients who would benefit from early indicated therapeutic fibrinolysis.Keywords:
Clinical endpoint
Fibrinolysis, the body's ability to degrade fibrin, is an integrated part of hemostasis. Overactivity in the fibrinolytic system causes bleeding and underactivity causes thrombosis. Tissue plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1), Article / Publication Details Published online: August 11, 2017 Issue release date: 1988 Number of Print Pages: 14 Number of Figures: 0 Number of Tables: 0 ISSN: 0013-9432 (Print) eISSN: 2504-2564 (Online) For additional information: https://www.karger.com/EZD
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Therapeutic fibrinolysis has used tissue plasminogen activator (tPA) as the fibrinolytic of choice ever since tPA was given FDA approval for the treatment of acute myocardial infarction (AMI) in 1987. This was followed in few years by its approval for ischemic stroke and tPA re-mains the treatment today based on an assumption that tPA is responsible for biological fibrinolysis. However, the evidence for this was never strong but has remained unchallenged for the past 33 years.
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Tissue-type plasminogen activator(tPA) is a highly specific serine proteinase that activates the zymogen plasminogen to the broad-specificity proteinase plasmin.Tissue-type plasminogen activator is found not only in the blood,but also in the central nervous system(CNS).There is a growing body of evidence demonstrating the participation of tPA in a number of physiological and pathological events in the CNS,as well as nonhemostatic roles of tPA in the CNS.This paper will focus on physiological function of tPA and its toxicological action in the CNS.
Zymogen
T-plasminogen activator
Nervous tissue
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Tissue plasminogen activator (tPA) has been shown to be effective at a dose of 25 micrograms in the treatment of severe postvitrectomy fibrin. However, a recent report based on an animal model indicates that retinal toxicity may occur at doses as low as 25 micrograms. This study uses a low dose (1.5 micrograms to 3 micrograms) of tPA for 34 injections in 26 eyes, and determines the lowest effective dose to be between 1.5 and 3 micrograms. Complete fibrinolysis was achieved in all 28 eyes in which 3 micrograms of tPA was administered within 10 days of vitrectomy, whereas partial fibrinolysis was achieved in eyes treated with 3 micrograms of tPA 27 days and 82 days after vitrectomy. Complete fibrinolysis occurred in only 1 of 4 eyes that receive 1.5 micrograms of tPA. A dose of 3 micrograms of tPA is recommended for treatment of severe fibrin after vitrectomy, as it has a wider margin of safety than do higher doses.
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Therapeutic fibrinolysis has used tissue Plasminogen Activator (tPA) alone since 1987,when tPA was first approved for the treatment of Acute Myocardial Infarction (AMI). The use of Tpa was based on the belief that it was responsible for fibrinolysis. However, this assumption should have been put into question from the outset when tPA was found to have the same efficacy as Streptokinase (SK). This was unexpected, since SK has an indirect, less efficient mechanism of action and SK has no fibrin clot affinity, in contrast to tPA. Nevertheless, the 30-day AMI mortality with tPA and SK were identical in the first two trials.
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The plasminogen-activating enzyme system has been exploited and harnessed for therapeutic thrombolysis for nearly three decades. Tissue-type plasminogen activator is still the only thrombolytic agent approved for patients with ischemic stroke. While tissue-type plasminogen activator-induced thrombolysis is proven to be of clear benefit in these patients if administered within 4·5 h poststroke onset, it is surprisingly underused in clinics despite international guidelines and improved acute stroke systems, a situation that requires urgent attention. While tissue-type plasminogen activator has also been shown to have unforeseen roles in the brain that have presented new challenges, tissue-type plasminogen activator and related fibrinolytic agents are currently being assessed over extended time frames. This review will focus on the therapeutic experience and controversies of tissue-type plasminogen activator. Furthermore, we will also provide an overview of recent and current trials assessing tissue-type plasminogen activator and related thrombolytic agents as well as novel approaches for the treatment of ischemic stroke.
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T-plasminogen activator
Fibrinolytic agent
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Seventy patients with different stages of hepatosplenic schistosomiasis and 18 non-bilharzial normal controls were studied. Plasminogen, plasminogen activators (PA), tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA), α2-antiplasmin (α2-AP), plasminogen activator inhibitor (PAI), fibrinogen/fibrin degradation products (FDP) and D-dimer were determined to elucidate the role of plasminogen activators and inhibitors in the pathogenesis of accelerated fibrinolysis in schistosomiasis. There was a progressive increase in the levels of PA, t-PA, u-PA, FDP and D-dimer indicating enhanced fibrinolytic activity with advancing disease. In addition, there was progressive decrease of plasminogen, α2-AP and PAI levels which might be due to decreased hepatic synthesis and/or increased peripheral consumption. These findings suggest that the pathogenesis of accelerated fibrinolysis in schistosomiasis is multifactorial, but may be due to the progressive increase in the levels of plasminogen activators. In addition, the increase of FDP and D-dimer levels are evidence of secondary fibrinolysis following thrombin generation.
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Plasminogen activator inhibitor-1
D-dimer
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Immunoradiometric assay
T-plasminogen activator
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To identify factors responsible for the decline of plasma tissue-type plasminogen activator (t-PA)-specific activity that we have observed after infusions of the activator and to define the potential usefulness of selected variants of t-PA in obviating them in patients with infarction, serial plasma samples from patients (n = 4) and rabbits (n = 15) given t-PA were assayed for total t-PA antigen, t-PA activity, and free as opposed to type-1 plasminogen activator inhibitor (PAI-1)--complexed t-PA. In patients, attenuation of t-PA specific activity after infusions was evident with concentrations of total t-PA antigen that were as much as sevenfold greater than pretreatment values (62 compared with 9 ng/ml). Attenuation of t-PA activity corresponded with the disappearance of free t-PA from plasma and was associated with persistence of complexes of t-PA with PAI-1. In normal rabbits (n = 4) given wild-type t-PA by bolus injection, PAI-1 activity was 4 +/- 1 arbitrary units/ml. Attenuation of t-PA activity was not evident until 60 minutes after injection at a time when total plasma t-PA antigen concentration was as low as 13 +/- 8 ng/ml. Under these conditions, plasma t-PA was composed predominantly of free t-PA. In rabbits (n = 5) given lipopolysaccharide to increase plasma PAI-1 activity to 193 +/- 84 arbitrary units/ml, the specific activity of t-PA was attenuated as early as 15 minutes after injection at a time when total t-PA antigen concentration was as high as 164 +/- 79 ng/ml. As was the case with samples from patients, attenuation was associated with the disappearance of free t-PA and the persistence of complexes of t-PA with PAI-1. A genetically engineered variant of t-PA with comparable specific activity and a comparable rate constant of association with PAI-1 but designed to persist in the circulation manifested prolonged clearance from plasma of normal rabbits (n = 3) (t1/2 = 24.6 +/- 1.6 minutes compared with an alpha phase t1/2 of 1.9 minutes for wild-type t-PA). The variant lacked the epidermal growth factor and kringle one domains and contained a duplicated kringle two domain.(ABSTRACT TRUNCATED AT 400 WORDS)
T-plasminogen activator
Bolus (digestion)
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Corn trypsin inhibitor (CTI) has been considered the molecule of choice to inhibit activated factor XII (FXIIa) during the conduct of experimentation focusing on tissue factor-initiated coagulation. However, CTI-mediated attenuation of fibrinolysis following celite activation of coagulation was observed in pilot studies with the clot lifespan model. The goal of the present study was thus to characterize the mechanism(s) responsible for CTI-mediated hypofibrinolysis. Normal plasma was exposed to 0 or 49.6 μg/ml CTI, with coagulation initiated with celite or tissue factor. Fibrinolysis was initiated with tissue-type plasminogen activator (tPA). Additional experiments utilized plasminogen activator inhibitor 1 deficient or α2-antiplasmin-deficient plasma. Coagulation/fibrinolysis kinetics were monitored with the thrombelastography-based clot lifespan model. In addition to delaying the initiation of coagulation, CTI prolonged clot growth time, delayed the onset of lysis, and prolonged clot lysis time in normal plasma after celite activation. Conversely, CTI increased the speed of clot growth, clot strength, and prolonged clot lysis time after tissue factor activation. Experiments with plasma deficient in antifibrinolytic proteins supported a primary inhibition of tPA by CTI. In addition to anti-FXIIa effects following celite activation, CTI likely exerts an anti-tPA effect, which contributed to hypofibrinolysis in this model.
Thrombelastography
Factor XII
Fibrinolytic agent
T-plasminogen activator
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