Pharmacokinetics of tissue plasminogen activator in an isolated extracorporeal circuit

Geier, B.; Grossefeld, M; Barbera, L.; Mumme, A.

doi:10.1067/mva.2001.109765

Cited by 3 publications

(1 citation statement)

References 24 publications

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“…On the surface of clots both steps are affected by the structural characteristics (e. g. fibre thickness and permeability) of fibrin, and in vivo this scenario can be further complicated by a variety of blood-borne factors (reviewed in [29]). With our experiments we modelled the fibrinolytic events relevant to therapeutic thrombolysis applying tPA concentrations that have been reported in plasma of patients treated for acute myocardial infarction (150 nM) or deep vein thrombosis (300 nM) (38,39).…”

Section: Effects Of Dna Hiiis and Nets On Clot Lysismentioning

confidence: 99%

DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment

et al. 2015

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SummaryIn response to various inflammatory stimuli, neutrophils secrete neutrophil extracellular traps (NETs), web-like meshworks of DNA, histones and granular components forming supplementary scaffolds in venous and arterial thrombi. Isolated DNA and histones are known to promote thrombus formation and render fibrin clots more resistant to mechanical forces and tissue-type plasminogen activator (tPA)-induced enzymatic digestion. The present study extends our earlier observations to a physiologically more relevant environment including plasma clots and NET-forming neutrophils. A range of techniques was employed including imaging (scanning electron microscopy (SEM), confocal laser microscopy, and photoscanning of macroscopic lysis fronts), clot permeability measurements, turbidimetric lysis and enzyme inactivation assays. Addition of DNA and histones increased the median fibre diameter of plasma clots formed with 16 nM thrombin from 108 to 121 and 119 nm, respectively, and decreased their permeability constant from 6.4 to 3.1 and 3.7×10−9 cm2. Histones effectively protected thrombin from antithrombin-induced inactivation, while DNA inhibited plasminogen activation on the surface of plasma clots and their plasmin-induced resolution by 20 and 40 %, respectively. DNA and histones, as well as NETs secreted by phorbol-myristate-acetate-activated neutrophils, slowed down the tPA-driven lysis of plasma clots and the latter effect could be reversed by the addition of DNase (streptodornase). SEM images taken after complete digestion of fibrin in NET-containing plasma clots evidenced retained NET scaffold that was absent in DNase-treated clots. Our results show that DNA and histones alter the fibrin architecture in plasma clots, while NETs contribute to a decreased lytic susceptibility that can be overcome by DNase.

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Section: Effects Of Dna Hiiis and Nets On Clot Lysismentioning

confidence: 99%

DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment

et al. 2015

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Regional hyperthermic fibrinolytic perfusion after unsuccessful venous thrombectomy of extensive deep venous thrombosis

Mumme

Heinen²,

Geier³

et al. 2002

Journal of Vascular Surgery

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Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

Yaron

Zhang

Guo

et al. 2021

Front. Cardiovasc. Med.

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The making and breaking of clots orchestrated by the thrombotic and thrombolytic serine protease cascades are critical determinants of morbidity and mortality during infection and with vascular or tissue injury. Both the clot forming (thrombotic) and the clot dissolving (thrombolytic or fibrinolytic) cascades are composed of a highly sensitive and complex relationship of sequentially activated serine proteases and their regulatory inhibitors in the circulating blood. The proteases and inhibitors interact continuously throughout all branches of the cardiovascular system in the human body, representing one of the most abundant groups of proteins in the blood. There is an intricate interaction of the coagulation cascades with endothelial cell surface receptors lining the vascular tree, circulating immune cells, platelets and connective tissue encasing the arterial layers. Beyond their role in control of bleeding and clotting, the thrombotic and thrombolytic cascades initiate immune cell responses, representing a front line, “off-the-shelf” system for inducing inflammatory responses. These hemostatic pathways are one of the first response systems after injury with the fibrinolytic cascade being one of the earliest to evolve in primordial immune responses. An equally important contributor and parallel ancient component of these thrombotic and thrombolytic serine protease cascades are the serine protease inhibitors, termed serpins. Serpins are metastable suicide inhibitors with ubiquitous roles in coagulation and fibrinolysis as well as multiple central regulatory pathways throughout the body. Serpins are now known to also modulate the immune response, either via control of thrombotic and thrombolytic cascades or via direct effects on cellular phenotypes, among many other functions. Here we review the co-evolution of the thrombolytic cascade and the immune response in disease and in treatment. We will focus on the relevance of these recent advances in the context of the ongoing COVID-19 pandemic. SARS-CoV-2 is a “respiratory” coronavirus that causes extensive cardiovascular pathogenesis, with microthrombi throughout the vascular tree, resulting in severe and potentially fatal coagulopathies.

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Pharmacokinetics of tissue plasminogen activator in an isolated extracorporeal circuit

Cited by 3 publications

References 24 publications

DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment

DNA, histones and neutrophil extracellular traps exert anti-fibrinolytic effects in a plasma environment

Regional hyperthermic fibrinolytic perfusion after unsuccessful venous thrombectomy of extensive deep venous thrombosis

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

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