Fibrinolysis: from blood to the brain

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.