Congenital and acquired disorders of coagulation
Jennifer Duguid, Lawrence Tim Goodnough, Michael J. Desmond in Transfusion Medicine in Practice, 2020
Physiologic fibrinolysis is a localized response to thrombosis, and is necessary for re-establishment of blood flow. Plasminogen is activated to plasmin, a serine protease, by t-PA, which is primarily located on the vascular endothelium and urokinase-plasminogen activator (u-PA), which is normally present in the urine. PAI-1 inhibits t-PA and u-PA, and is synthesized by the endothelium and liver. Once plasmin is formed, it degrades fibrin and fibrinogen to several fragments (E, X, D, and Y). Crosslinked fibrin is cleaved to D-dimers, which can be assayed in the laboratory and serve as a clinical marker for fibrinolysis. α2-Antiplasmin inhibits plasmin. FXIII crosslinks α2-antiplasmin to fibrin, making it more resistant to the action of plasmin.49
Lipoprotein(a) and Fibrinolysis
Pia Glas-Greenwalt in Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
The initial interaction of plasmin with its primary inhibitor, α2-antiplasmin, is mediated by its lysine binding sites. Therefore, the interaction of Lp(a) with α2-antiplasmin has been investigated. In functional studies, Lp(a) did not affect the ability of α2-antiplasmin to inhibit plasmic cleavage of a tripeptide substrate.89 However, in this study, CNBr-derived fibrinogen fragments did suppress the inhibition of plasmin by α2-antiplasmin and the suppression was decreased by Lp(a).89 These results suggest that Lp(a) competes with plasmin(ogen) for binding to the CNBr-derived fibrinogen fragments, causing dissociation of plasmin and making it susceptible to inhibition, an antifibrinolytic effect. Contrasting results were obtained in a separate study in which plasmin and α2-antiplasmin were added to preformed fibrin clots. In the presence of Lp(a), clot lysis was promoted, presumably due to competition by Lp(a) for α2-antiplasmin.90 Thus, the status of the fibrin substrate may dictate whether Lp(a) has either pro- or antifibrinolytic effects on the plasmin: α2-antiplasmin interaction. A direct interaction between Lp(a) and α2-antiplasmin has not been demonstrated.
Fibrinolytic Enzymes for Thrombolytic Therapy
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Plasmin is the fibrin degrading enzyme which can be administered without any bleeding complication and allergic reactions. Systematically administered plasmin often gets inhibited byα2-antiplasmin, thereby losing the therapeutic benefit (Marder, 2011). But when given locally, plasmin does not get blocked by its inhibitors and will lead to fibrinolysis. Later it gets inhibited by α2-antiplasmin when it is released to circulation after thrombolysis (Marder and Novokhatny, 2010, Marder, 2011). In vivo animal models and clinical trials suggested the clinical benefit and safety of plasmin as a cardiovascular drug that could accomplish fibrinolysis (Hoefer et al., 2009; Sadeghi et al., 2003; Jahan et al., 2008; Shlansky-Goldberg et al., 2008). Plasmin is a heterodimer with an N-terminal heavy chain of molecular weight 65 kDa and a C-terminal light chain of molecular weight 25 kDa linked together by two disulfide bonds. Heavy chain contains 5 kringle domains and a 77 residue N-terminal peptide, whereas light chain carries a serine protease domain. It binds to fibrin through lysine binding sites at kringle domain, chiefly at kringle 1 domain (Wiman et al., 1979; Robbins et al., 1967; Sottrup-Jensen et al., 1978; Violand and Castellino, 1976; Wiman, 1977, Wiman and Wallen, 1977; Lucas et al., 1983; Wu et al., 1994).
Safety and efficacy of intracoronary thrombolytic agents during primary percutaneous coronary intervention for STEMI
Published in Expert Review of Cardiovascular Therapy, 2023
Natasha Kulick, Kevin A. Friede, George A. Stouffer
Thrombolytic drugs are theoretically attractive for treating coronary thrombus as they activate endogenous fibrinolysis which results in degradation of the cross-linked fibrin matrix in thrombus [43,44]. Full [45] or half dose [46] of thrombolytic agents administered IV were associated with both thrombin activation and bleeding, and thus a lower dose (approximately 20% of the systemic dose) administered directly at the site of thrombus using an IC route is hypothesized to lead to better outcomes. Currently available thrombolytic agents are plasminogen activators which work by converting the proenzyme plasminogen to plasmin, a serine protease that degrades fibrin and fibrinogen, as well as prothrombin, and factors V and VII. Fibrinolysis is regulated by plasminogen activator inhibitor type 1 (PAI-1) which inhibits plasminogen activators and α2-antiplasmin which inhibits plasmin. Plasmin is rapidly inactivated by α2-antiplasmin which exists at high concentrations in plasma but the half-life of plasmin is two to three orders of magnitude longer on a clot surface where it is relatively protected from inactivators.
Bothrops snakebites in the Amazon: recovery from hemostatic disorders after Brazilian antivenom therapy
Published in Clinical Toxicology, 2020
Sâmella Silva de Oliveira, Eliane Campos Alves, Alessandra dos Santos Santos, Elizandra Freitas Nascimento, João Pedro Tavares Pereira, Iran Mendonça da Silva, Jacqueline Sachett, Hiochelson Najibe dos Santos Ibiapina, Lybia Kássia Santos Sarraf, Jorge Carlos Contreras Bernal, Luciana Aparecida Freitas de Sousa, Mônica Colombini, Hedylamar Oliveira Marques, Marcus Vinicius Guimarães de Lacerda, Ana Maria Moura-da-Silva, Hui Wen Fan, Luiz Carlos de Lima Ferreira, Ida Sigueko Sano Martins, Wuelton Marcelo Monteiro
In Bothrops envenomation, hypofibrinogenemia returned to normal within 24 h after beginning antivenom therapy [35]. In our study, low fibrinogen and high FDP levels were almost totally normal within 24 h after beginning antivenom therapy when compared to reference values. The median concentration of D-dimer on admission showed a gradual decrease after antivenom therapy. High D-dimer reported on admission suggests that intravascular thrombin formation contributes to the coagulation disorders in Bothrops snakebites in this region by converting fibrinogen to fibrin and activating factor XIII. Plasmin cleaves cross-linked fibrin by activating factor XIII and generates D-dimer [36]. Inhibition of the fibrinolytic system at the plasmin level is a function exerted by alpha 2-antiplasmin [37]. In our study, patients showed low levels of alpha 2-antiplasmin within the first 24 h after antivenom therapy, indicating that its intravascular consumption is induced by plasmin formation [36,37]. These levels returned to normal values on discharge, accompanied by normalization of fibrinogen and FDP levels.
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].