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Fibrinolytic Enzymes for Thrombolytic Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Swaroop S. Kumar, Sabu Abdulhameed
Staphylokinase is another non-t-PA variant belonging to the third-generation plasminogen activators. It is an extracellular protein produced by Staphylococcus aureus, which forms 1:1 stoichiometric complex with plasmin or plasminogen and activates more plasminogen molecules. SAK is a monomer of 136 amino acids without any disulfide bond and molecular weight is about 15.5 KDa. SAK complexes with plasminogen molecules that are bound to partially degraded fibrin [Sakharov et al., 1996]. α2-antiplasmin inhibits plasminogen-SAK complex in the absence of fibrin, however, in presence of fibrin the lysine binding domain of the complex is occupied, preventing the inhibition by α2-antiplasmin and there is a 4-fold increment in activity with presence of fibrin, thus more specificity towards fibrin (Lijnen et al., 1991).
Modulation of Tumor Matrix by Components of the Plasminogen-Plasmin System
Published in Róza Ádány, Tumor Matrix Biology, 2017
The activation of Pg is facilitated by its binding on cell surfaces, due in part, to changes in its conformation, and to its conversion to the degraded Lys-plasminogen. Further activation to plasmin may occur, with the plasmin remaining bound to the cell surface. Plasmin, when bound to the cell surface, is relatively resistant to inhibition by α2-antiplasmin, and plasmin-antiplasmin complexes may remain on the cell surface binding sites.
Alterations in platelet behavior after major trauma: adaptive or maladaptive?
Published in Platelets, 2021
Paul Vulliamy, Lucy Z. Kornblith, Matthew E. Kutcher, Mitchell J. Cohen, Karim Brohi, Matthew D. Neal
Alterations in fibrinolysis are known contributors to TIC, and platelets are intimately involved in control of both pro- and anti-fibrinolytic pathways. At one extreme, the combination of hemorrhagic shock and massive fibrinolytic activation confers an extremely high mortality [101]. Platelets harbor the fibrinolytic proteins single-chain urokinase-type [102] and tissue-type [103] plasminogen activators (uPA and tPA) on their surface, serving to modulate rates of clot lysis [104]. Conversely, reduced clot breakdown on viscoelastic testing is also associated with poor outcomes after injury [105]. Within developing thrombi, aggregated platelets augment fibrinogen binding and protect fibrin from plasmin-mediated lysis via clot retraction [106]. Activated platelets release α2-antiplasmin and plasminogen activator-inhibitor-1 (PAI-1), inhibiting plasmin-dependent clot breakdown and stabilizing nascent platelet plugs [107,108]. Clinically, impaired platelet ADP responsiveness as measured by PM-TEG is associated with increased sensitivity to tPA-mediated fibrinolysis in trauma patients [109]. Other studies have identified similar associations between injury-induced impairment in platelet aggregation and fibrinolytic shutdown phenotypes [110–113].
Role of protein deimination in cardiovascular diseases: potential new avenues for diagnostic and prognostic biomarkers
Published in Expert Review of Proteomics, 2021
Liqun Mao, Rowann Mostafa, Esra Ibili, Justyna Fert-Bober
Besides the role of NETosis in thrombosis, citrullinated protein inhibitors have been also involved in thrombosis [43]. Several serine protease inhibitor (SERPIN) superfamily members are pivotal in maintaining an orchestrated balance between clotting (coagulation) and clot dissolution (fibrinolysis). In the coagulation pathway catalyzed by thrombin, antithrombin inhibits thrombin serine protease that converts the soluble plasma fibrinogen into insoluble fibrin meshwork; in the fibrinolysis pathway catalyzed by plasmin, plasminogen activator (PA) inhibitor-1 (PAI-1) (a SERPIN superfamily member), is the main inhibitor of PAs, such as tissue-type PA (tPA) and urokinase-type PA (uPA), which cleave proenzyme plasminogen into active plasmin [141]. α2-antiplasmin (α2AP), another SERPIN superfamily member, is the primary inhibitor of plasmin and a competitor of fibrin to bind plasminogen [142]. Tilvawala et al. found that, in RA patients three SERPIN super-family members, antithrombin, antiplasmin, and PAI-1, were highly citrullinated and could hardly inhibit their cognate proteases [143]. The same group verified in plasma clotting and fibrinolysis invitro assays that, the citrullination of antithrombin and PAI-1 impaired binding to their cognate proteases, while the citrullination of antiplasmin converted it into a plasmin substrate [43]. Using a mouse model of deep vein thrombosis , they found that the citrullinated antithrombin were increased and citrullinated antiplasmin decreased, which shifted the equilibrium both in the direction of thrombosis [43]. The observation that citrullinated PAI-1 lost inhibitory activity and promoted fibrinolysis both invitro and ex vivo might imply its physiological role in balancing coagulation and fibrinolysis.
Tissue plasminogen activator-based nanothrombolysis for ischemic stroke
Published in Expert Opinion on Drug Delivery, 2018
Shan Liu, Xiaozhou Feng, Rong Jin, Guohong Li
Vascular endothelial cells are thought to be the main source of plasma tPA involved in the breakdown of blood clots (fibrinolysis), which is the major physiological function of tPA in blood. Figure 1 illustrates the in vivo thrombolytic pathway of tPA [7]. tPA has high affinity and specificity for fibrin. Fibrin binds to tPA’s F and K2 domains, plasminogen binds to tPA’s K2 domain, forming a ternary complex (plasminogen/tPA/fibrin) which catalyzes the conversion of plasminogen to plasmin. Binding of tPA to fibrin may enhance tPA’s catalytic activity by 400-fold [8]. Intravascular thrombi (blood clots) are composed of aggregation of activated platelets and fibrin monomers that are cross-linked through lysine side chains. Plasmin cleaves fibrin, thus breaking down the meshwork of blood clot and causing recanalization of the blocked vessel. The in vivo thrombolytic system could be regulated by α2-antiplasmin and plasminogen activator inhibitor-1 (PAI-1). α2-Antiplasmin is the main inhibitor of plasmin in the bloodstream, which inhibits plasmin from producing fibrin degradation products. PAI-1 is the main inhibitor of tPA in the bloodstream, which covalently binds to the C-terminal catalytic domain of tPA and forms an inactive PAI-1/tPA complex. Then, the inactive PAI-1/tPA complex can be cleared by liver through low-density lipoprotein receptor-related protein-1-mediated pathway [9]. Recombinant human tPA (alteplase) was approved by the FDA in 1996 for the treatment of acute ischemic stroke. Standard dose of tPA recommended by FDA is 0.9 mg/kg bodyweight (10% as bolus and remaining as infusion over 60 min; max 90 mg). tPA maintains a rather short therapeutic window of only 3–4.5 h after symptom onset and may increase risk of symptomatic ICH; therefore, only a few patients could receive (3–8.5%) and benefit (1–2%) from tPA treatment [10]. Although with limited efficacy and safety, tPA remains the only approved thrombolytic agent for acute ischemic stroke.