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| The thrombotic and thrombolytic cascades and primordial immune response. The thrombotic pathways (intrinsic and extrinsic) and the thrombolytic (fibrinolysis) pathway involve a complex cascade of protease activation. Solid arrows indicate the conversion to an active protease, while dotted line arrows indicate the activity of the activating upstream protease. A variety of inhibitors are shown, with serpin inhibitors denoted by a serpin protein structural image. Examples of early primordial immune response origins are noted in context of the pathways. MYA, million years ago.

| The thrombotic and thrombolytic cascades and primordial immune response. The thrombotic pathways (intrinsic and extrinsic) and the thrombolytic (fibrinolysis) pathway involve a complex cascade of protease activation. Solid arrows indicate the conversion to an active protease, while dotted line arrows indicate the activity of the activating upstream protease. A variety of inhibitors are shown, with serpin inhibitors denoted by a serpin protein structural image. Examples of early primordial immune response origins are noted in context of the pathways. MYA, million years ago.

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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...

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... much has been discovered in the developmental biology-based study of clotting across Animalia, the clotting "toolkit" has been found to differ greatly amongst animals. Exploration of the ancient roots of clotting now reveals that the coagulation pathways may originally have had central roles in innate immune responses, or inflammation (Figure 1). Mammals (Class Mammalia) harbor the most complex coagulation system, with the classically defined contact activation or "intrinsic" pathway and the tissue factor/factor VII system or the "extrinsic" pathway (13,14). ...
Context 2
... (Class Mammalia) harbor the most complex coagulation system, with the classically defined contact activation or "intrinsic" pathway and the tissue factor/factor VII system or the "extrinsic" pathway (13,14). The pathways converge, resulting in a complex downstream cascade of protease activation events leading to the activation of factor X and thrombin, conversion of fibrinogen to fibrin, and ultimate generation of a stable fibrin clot (Figure 1). In the vascular system, thrombi form on the surface of activated platelets, damaged endothelium in the lining of the arterial wall, and activated macrophage cells adherent to damaged endothelium. ...
Context 3
... careful examination of other animals reveals a distinct role for coagulation in the immune response. For example, despite the presence of components of the kallikrein-kinin system in birds (Class Aves), amphibians (Class Amphibia) and fish (Class Actinopterygii), evidence suggests these components do not drive clot formation, but rather, regulate angiogenesis and the immune response system (Figure 1). The process of clotting in these Classes is regulated by the extrinsic tissue factordirected pathway (15). ...
Context 4
... Ascidiacea, which include sac-like marine invertebrate filter feeders, is among the most ancient coagulation systems investigated. While their plasma contains some blood clotting components (such as von Willebrand factor, vWF), blood in Ascidacea animals does not clot, and these components are predominantly used to regulate innate immune responses (Figure 1) (17,18). ...
Context 5
... similar primordial role in innate immunity can be found for fibrinolysis, a cascade that balances and is complementary to the coagulation cascade which is responsible for dissolution of a fibrin clot. In Mammalia, fibrinolysis is initiated by the conversion of inactive, circulating plasminogen into active plasmin by serine proteases referred to as the plasminogen activators, tissue-and urokinase-type plasminogen activators (tPA and uPA, respectively) (Figure 1). Activated plasmin then breaks down cross-linked fibrin, resulting in dissolution of the thrombus. ...

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... A PEGylated version of the Myxomavirus derived SERPIN Serp-1 has also been developed demonstrating improved efficacy in a mouse model of diffuse alveolar hemorrhage (259). Serp-1 is a broad acting SERPIN with anti-inflammatory and antifibrinolytic activities (260). In addition, however, Serp-1 also functions as a heparin dependent inhibitor of thrombin (261,262). ...
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In tissue engineering, cell origin is important to ensure outcome quality. However, the impact of the cell type chosen for seeding in a biocompatible matrix has been less investigated. Here, we investigated the capacity of primary and immortalized fibroblasts of distinct origins to degrade a gelatin/alginate/fibrin (GAF)-based biomaterial. We further established that fibrin was targeted by degradative fibroblasts through the secretion of fibrinolytic matrix-metalloproteinases (MMPs) and urokinase, two types of serine protease. Finally, we demonstrated that besides aprotinin, specific targeting of fibrinolytic MMPs and urokinase led to cell-laden GAF stability for at least several days. These results support the use of specific strategies to tune fibrin-based biomaterials degradation over time. It emphasizes the need to choose the right cell type and further bring targeted solutions to avoid the degradation of fibrin-containing hydrogels or bioinks.
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