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Congenital and acquired disorders of coagulation
Published in Jennifer Duguid, Lawrence Tim Goodnough, Michael J. Desmond, Transfusion Medicine in Practice, 2020
Jeanne M Lusher, Roshni Kulkarni
Coagulation abnormalities in cardiopulmonary bypass (CPB) are multifactorial, resulting in intraoperative and postoperative bleeding. Dilutional coagulopathy coupled with a high concentration of heparin, platelet adhesion, thrombocytopenia, and systemic fibrinolysis all contribute to bleeding. During the first 15 minutes of bypass, the platelet count falls by 25–30% owing to exposure to the CPB devices. After initiation of CBP, plasminogen and α2-antiplasmin levels fall, reflecting dilutional coagulopathy. During CPB, activation of fibrinolytic system occurs and D-dimer levels increase.84 Administration of antifibrinolytics, prior to bypass, has significantly decreased blood loss. A similar reduction in blood loss was seen with aprotinin, a powerful inhibitor of α2-antiplasmin and other serine proteases such as trypsin, kallikreins, and chymotrypsin.85
Lipoprotein(a) and Fibrinolysis
Published in Pia Glas-Greenwalt, Fibrinolysis in Disease Molecular and Hemovascular Aspects of Fibrinolysis, 2019
Lindsey A. Miles, Edward F. Plow
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.
Coagulation Theory, Principles, and Concepts
Published in Harold R. Schumacher, William A. Rock, Sanford A. Stass, Handbook of Hematologic Pathology, 2019
Alpha-2-antiplasmin is the principal inhibitor of plasmin and is structurally related to antithrombin III. It has three major functional properties: (a) the inhibition of plasmin, (b) interference with the binding of plasminogen to fibrin, and (c) incorporation into a fibrin clot by cross-linking to the alpha chains of fibrin by the action of factor XIIIa (99–101). During clot formation approximately 20% of the alpha-2-antiplasmin cross-links to fibrin. Because of this a normal blood clot will not lyse spontaneously, despite the presence of clot-bound tPA. Clot bound alpha-2-antiplasmin is more effective in preventing clot dissolution than is the free plasma alpha-2-antiplasmin.
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.
A gottingen minipig model of radiation-induced coagulopathy
Published in International Journal of Radiation Biology, 2021
Karla D. Thrall, Saikanth Mahendra, M. Keven Jackson
Comparison of average change in coagulation factor activity levels from baseline following irradiation was compared between surviving animals and decedents. The greatest differences between these subsets of animals were observed with factors XIII (Figure 8(a)), XII (Figure 8(b)), protein C (Figure 8(c)) and antiplasmin (Figure 8(d)). The difference between coagulation factor XIII levels between surviving animals and decedents was statistically significant at post irradiation Day 20. Regardless of statistical significance, with the exception of antiplasmin, the trend indicates coagulation factor activity levels for VII, XII, XIII, and protein C decrease as the animal approaches moribund condition. Interestingly, average activity levels of factor XII observed in decedents appear to decrease as early as post irradiation Day 4. In contrast, average antiplasmin activity levels increased in decedents compared to surviving animals, possibly indicative of a fibrinolytic shutdown.
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].