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Fibrinolytic Enzymes for Thrombolytic Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Swaroop S. Kumar, Sabu Abdulhameed
The major advantage of treatment using fibrinolytic enzymes over anticoagulants and antiplatelets is that they could act upon an existing clot. The primary focus of these enzymatic actions is on the protein (fibrin) either directly or indirectly. They are often called clot busting enzymes and categorized into two types based on the mechanism of action. The first category is plasminogen activators; converting plasminogen to active plasmin that cleaves the fibrin clot formed, e.g. tissue-type plasminogen activator (t-PA) and urokinase. They are widely used for the treatment of cardiovascular diseases. t-PA was approved in 1996 by the United States Food and Drug Administration (USFDA) for intravenous injection against thrombosis. Recombinant tissue plasminogen activator alteplase (Activase®) against cardiovascular diseases is the first genetically engineered enzyme to get approved by the USFDA. Many plasminogen activators such as alteplase, reteplase, tenecteplase, urokinase, streptokinase, and anistreplase are available for clinical use and have been commonly used in treating cardiovascular diseases for the past five to six decades (Kotb, 2014). The second category of thrombolytic enzyme is plasmin-like enzymes that are direct-acting fibrinolytic enzymes which do not require the activation of plasminogen. Instead, they can perform clot dissolution by acting upon it, e.g., plasmin, nattokinase, and lumbrokinase.
Biomaterials for Scaffolds: Natural Polymers
Published in Claudio Migliaresi, Antonella Motta, Scaffolds for Tissue Engineering, 2014
Lindsay S. Wray, David L. Kaplan
Fibrin is a glycoprotein that facilitates clotting of blood and wound healing.43 Upon tissue trauma and breaching of the vascular wall, signaling cascades activate the enzyme thrombin, which cleaves the plasma protein, fibrinogen. Fibrinogen is composed of two sets of Aa, Bp, and ^-polypeptide chains, which are held together by disulfide bridges. Activated thrombin cleaves the N-terminus of the Aa and Bp chains, which exposes a region of the fibrinogen molecule that enables spontaneous self-assembly into a branching fibril network.44 This network is stabilized by non-covalent and electrostatic forces and by covalent crosslinking, which is initiated by the factor XIII enzyme. Fibrin clots provide a fibrous network over which new tissue can form and after the tissue has been regenerated, the fibrin clot is quickly degraded by plasmin.
Introduction to Host-Biomaterial Interactions
Published in Nina M. K. Lamba, Kimberly A. Woodhouse, Stuart L. Cooper, Polyurethanes in Biomedical Applications, 2017
Nina M. K. Lamba, Kimberly A. Woodhouse, Stuart L. Cooper
The fibrinolytic system is responsible for the degradation of fibrin. The zymogen plasminogen is normally circulating in the blood and is activated to plasmin via the action of either FXIIa, tissue plasminogen activator (tPA), or urokinase. In vivo, plasminogen adheres to fibrin where it is activated and lyses the fibrin into smaller, more soluble polypeptides, termed fibrin degradation products. There are two primary pathways of plasminogen activation in blood, the extrinsic and the intrinsic. The extrinsic pathway is the more physiologically important; however, the intrinsic pathway is likely to be the pathway activated by blood contacting a biomaterial surface.34–35 The fibrinolytic system is represented in Figure 4.
Acute exercise increases BDNF serum levels in patients with Parkinson’s disease regardless of depression or fatigue
Published in European Journal of Sport Science, 2022
Lílian Viana dos Santos Azevedo, Jéssica Ramos Pereira, Renata Maria Silva Santos, Natalia Pessoa Rocha, Antônio Lúcio Teixeira, Paulo Pereira Christo, Victor Rodrigues Santos, Paula Luciana Scalzo
Our results can be explained because the proBDNF is proteolytically cleaved into mBDNF by intracellular furin/proprotein convertases and extracellular proteases (plasmin/matrix metallopeptidases). Plasmin is produced by the cleavage of plasminogen by tissue plasminogen activator (tPA) (Adachi et al., 2014). Sartori et al. (2011) showed that voluntary physical activity in mice increased the levels of mBDNF protein, as well as molecules involved in proteolytic cleavage of proBDNF, such as tPA. These authors suggested that the antidepressive effect of the physical exercise may depend, at least in part, on changes in BDNF post-translational processing (Sartori et al., 2011). Thus, an intervention that promotes proBDNF transformation into mBDNF should be considered for neurodegenerative disease (Wang, Xie, & Qin, 2021).
Preparation and characterization of tissue plasminogen activator-loaded liposomes
Published in Soft Materials, 2022
Katsiaryna Dubatouka, Vladimir Agabekov
Liposomes are small, nontoxic, biodegradable and biocompatible self-organized spherical vesicles consisting of one or more phospholipid bilayers that closely resemble the structure of cell membranes.[1] Due to the amphiphilic character of lipids, hydrophobic and hydrophilic substances, such as drugs, proteins, enzymes, and nucleotides can be encapsulated into liposomes that can be used in medicine as drug delivery systems.[2,3] Alteplase (tissue plasminogen activator, tPA) is a serine protease with a molecular weight of ~68 kDa, which is used for treating thromboembolic conditions. Tissue plasminogen activator converts plasminogen into fibrinolytic enzyme plasmin that then degrades fibrin, leading to clot dissolution.[4,5] It is known that tPA acts only on plasminogen associated with a thrombus, has fibrin-specificity and low immunogenicity, making it possible to reduce the dosage of the drug and use it for the treatment of acute myocardial infarction effectively.[6] At the same time, there are some limitations in the use of TPA for the treatment of thrombosis: a narrow therapeutic window, a short half-life (4–6 minutes) and poor penetration into large blood clots.[7] Moreover, tissue plasminogen activator is very sensitive to changes in pH, ionic strength, temperature, the presence of detergents, metal ions and non-aqueous solvents, which leads to denaturation, aggregation, precipitation, nonspecific adsorption and decrease in the biological activity of the substance.[8] The incorporation of tPA into liposomes protects the drug against chemical and immunological breakdown in the circulation, maintains its activity and provides prolonged effect.[4,6,9–11]
In Vitro models for thrombogenicity testing of blood-recirculating medical devices
Published in Expert Review of Medical Devices, 2019
Within seconds of blood exposure, biomaterial surfaces rapidly adsorb serum proteins onto their surface. These proteins desorb and are exchanged for higher binding affinity proteins in a process known as the Vroman Effect. Figure 1 illustrates the pro-thrombotic events catalyzed by biomaterial contact and the Vroman pattern: albumin, immunoglobulin G (IgG), fibrinogen, and high molecular weight kininogen (HMWK) [15]. Platelets interacting with these bound proteins adhere to the material and upregulate membrane-bound phosphatidylserine [16]. The downstream pro-thrombotic processes from platelet activation are illustrated in Figure 2. When serum proenzymes such as prothrombin bind at this active site, zymogen-protease conversions produce the active form of the enzyme, thrombin [17–19]. In platelet aggregates, thrombin amplifies the coagulation response. A positive feedback loop is created that increases platelet activation through platelet activation factor (PAF), proteinase-activated receptor (PAR) 1 and 4 on platelet membranes [20]. Platelets also degranulate, releasing cytokines [21] and develop pseudopodia to strengthen adherence to the surface and other platelets [22]. Thromboxane A2 diffuses across the platelet plasma membrane and acts as an activator for other platelets [23]. Under flow conditions, platelets are captured through interaction with von Willebrand factor (vWF). This interaction is mediated through two receptors: GPIb-IX-V and platelet integrin (αIIbβ3). Active thrombin cleaves at least two sites on the fibrinogen molecule making non-covalent interactions between fibrinogen molecules [24,25] producing aggregated insoluble fibrin fibers. The fibers are crosslinked by Factor XIII [26] to form an aggregated structure that can trap platelets, red blood cells, and thrombin by binding at two distinct binding sites [20]. The fibrin-mediated clot is susceptible to fibrinolysis via plasmin, an enzyme protease [24].