The Fibrinolytic System—More Than Fibrinolysis?

Draxler, Dominik F.; Medcalf, Robert L.

doi:10.1016/j.tmrv.2014.09.006

Cited by 88 publications

(75 citation statements)

References 91 publications

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“…The anti‐fibrinolytic agent of choice is the lysine analogue, tranexamic acid (TXA) that works by binding to lysine binding sites in plasminogen, thereby blocking the capacity of plasminogen to interact with exposed lysine residues on the fibrin surface. Many non‐fibrinolytic effects of plasmin are known some of which have been highlighted in this review and elsewhere (see for further detail). Hence it is likely that plasmin inhibition may have consequences unrelated to haemostasis.…”

Section: The Influence Of the Plasminogen Activating System On The Immentioning

confidence: 90%

“…A recent publication also reported reduced lung barrier permeability by TXA in a rat model of polytrauma , while TXA was also recently reported to reduce ‘endothelialopathy’ of trauma and shock in an in vitro model . Hence it is reasonable to suggest that the blockade of plasmin generation by TXA in coagulopathic trauma patients, or indeed in other conditions associated with severe bleeding, may also have unintended consequences on outcome ; such effects could even be beneficial and may have contributed to the beneficial effects reported with TXA administration in the CRASH‐2 trial. However, there is also a potential for TXA to surprisingly promote bleeding in situations associated with high levels of urokinase.…”

Section: The Influence Of the Plasminogen Activating System On The Immentioning

confidence: 97%

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Fibrinolysis: from blood to the brain

Medcalf

2017

Journal of Thrombosis and Haemostasis

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We all know about classical fibrinolysis, how plasminogen activation by either tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA) promotes fibrin breakdown, and how this process was harnessed for the therapeutic removal of blood clots. While this is still perfectly true and still applicable to thromboembolic conditions today, another dimension to this system came to light over two decades ago that implicated the plasminogen activating system in a context far removed from the dissolution of blood clots. This unsuspected area related to brain biology where t-PA was linked to a plethora of activities in the CNS, some of which do not necessarily require plasmin generation. Indeed, t-PA either directly or via plasmin, has been shown to not only have key roles in modulating astrocytes, neurons, microglia, and pericytes, but also to have profound effects in a number of CNS conditions, including ischaemic stroke, severe traumatic brain injury and also in neurodegenerative disorders. While compelling insights have been obtained from various animal models, the clinical relevance of aberrant expression of these components in the CNS, although strongly implied, are only just emerging. This review will cover these areas and will also discuss how the use of thrombolytic agents and anti-fibrinolytic drugs may potentially have impacts outside of their clinical intention, particularly in the CNS.

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Section: The Influence Of the Plasminogen Activating System On The Immentioning

confidence: 90%

Section: The Influence Of the Plasminogen Activating System On The Immentioning

confidence: 97%

Fibrinolysis: from blood to the brain

Medcalf

2017

Journal of Thrombosis and Haemostasis

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“…The key enzyme for clot degradation is plasmin, generated from plasminogen by different proteases, most notably, tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA). Plasmin formation is increased in the presence of fibrin, as plasminogen and tPA binding to lysine residues formed in fibrin enhances the process of plasmin generation [44]. The maintenance of a precise balance between coagulation and fibrinolysis is vital for normal haemostasis.…”

Section: Dysfunction Of Fibrinolytic Mechanismsmentioning

confidence: 99%

“…The maintenance of a precise balance between coagulation and fibrinolysis is vital for normal haemostasis. The main inhibitors of the fibrinolytic process are α2-antiplasmin (which binds free plasmin), PAI-1 and PAI-2 (produced in the liver and responsible for binding free tPA and uPA and limiting fibrinolysis) and thrombin activatable fibrinolysis inhibitor (TAFI), which cleaves exposed lysine residues from fibrin and other substrates [44]. Experimental sepsis models have shown an initial transient increase in the pro-fibrinolytic response due to the release of plasminogen activators, followed by a fibrinolytic shutdown generated by increased levels of PAI-1 in plasma synthetized by endothelial cells and monocytes as a response to cytokine stimulation [41,45,46].…”

Section: Dysfunction Of Fibrinolytic Mechanismsmentioning

confidence: 99%

Sepsis-Associated Coagulopathy

Scărlătescu

Tomescu

Aramă

2016

The Journal of Critical Care Medicine

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Systemic inflammatory activation in sepsis often leads to coagulation activation, but the relationship is bilateral, as coagulation also modulates the inflammatory response. This close associate has significant consequences for the pathogenesis of microvascular thrombosis and organ dysfunction in sepsis. While coagulation activation can be beneficial for immune defense, it can also be detrimental once it becomes widespread and uncontrolled. The knowledge of the pathophysiologic mechanisms involved in the interaction between infection and coagulation may lead to the better timing for the administration of targeted antithrombotic therapies in septic patients. This brief review highlights the pathophysiologic pathways leading to the prothrombotic state in sepsis and the mechanisms that play a role in the interaction between infection and coagulation.

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“…Since misfolded proteins provide the same cofactor activity as fibrin, plasmin formation can readily occur in the absence of a fibrin clot and particularly in locations where cell injury and death occur. Plasmin therefore has become recognized for its broader involvement in physiological and pathophysiological processes, which is at least in part mediated by various plasminogen receptors on leukocytes and tissue bound cells . Plasmin can also modulate the immune system on several levels .…”

Section: Introductionmentioning

confidence: 99%

Tranexamic acid modulates the cellular immune profile after traumatic brain injury in mice without hyperfibrinolysis

Draxler

Daglas

Fernando

et al. 2019

Journal of Thrombosis and Haemostasis

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Background Traumatic brain injury (TBI) is known to promote immunosuppression, making patients more susceptible to infection, yet potentially exerting protective effects by inhibiting central nervous system (CNS) reactivity. Plasmin, the effector protease of the fibrinolytic system, is now recognized for its involvement in modulating immune function. Objective To evaluate the effects of plasmin and tranexamic acid (TXA) on the immune response in wild‐type and plasminogen‐deficient (plg−/−) mice subjected to TBI. Methods Leukocyte subsets in lymph nodes and the brain in mice post TBI were evaluated by flow cytometry and in blood with a hemocytometer. Immune responsiveness to CNS antigens was determined by Enzyme‐linked Immunosorbent Spot (ELISpot) assay. Fibrinolysis was determined by thromboelastography and measuring D‐dimer and plasmin‐antiplasmin complex levels. Results Plg−/− mice, but not plg+/+ mice displayed increases in both the number and activation of various antigen‐presenting cells and T cells in the cLN 1 week post TBI. Wild‐type mice treated with TXA also displayed increased cellularity of the cLN 1 week post TBI together with increases in innate and adaptive immune cells. These changes occurred despite the absence of systemic hyperfibrinolysis or coagulopathy in this model of TBI. Importantly, neither plg deficiency nor TXA treatment enhanced the autoreactivity within the CNS. Conclusion In the absence of systemic hyperfibrinolysis, plasmin deficiency or blockade with TXA increases migration and proliferation of conventional dendritic cells (cDCs) and various antigen‐presenting cells and T cells in the draining cervical lymph node (cLN) post TBI. Tranexamic acid might also be clinically beneficial in modulating the inflammatory and immune response after TBI, but without promoting CNS autoreactivity.

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The Fibrinolytic System—More Than Fibrinolysis?

Cited by 88 publications

References 91 publications

Fibrinolysis: from blood to the brain

Fibrinolysis: from blood to the brain

Sepsis-Associated Coagulopathy

Tranexamic acid modulates the cellular immune profile after traumatic brain injury in mice without hyperfibrinolysis

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