Abstract
Plasmin, the principal downstream product of tissue-type plasminogen activator (tPA), is known for its potent fibrin-degrading capacity but is also recognized for many non-fibrinolytic activities. Curiously, plasmin has not been conclusively linked to blood-brain barrier (BBB) disruption during recombinant tPA (rtPA)-induced thrombolysis in ischemic stroke. This is surprising given the substantial involvement of tPA in the modulation of BBB permeability and the co-existence of tPA and plasminogen in both blood and brain throughout the ischemic event. Here, we review the work that argues a role for plasmin together with endogenous tPA or rtPA in BBB alteration, presenting the overall controversy around the topic yet creating a rational case for an involvement of plasmin in this process.
Highlights
Tissue-type plasminogen activator[1] is a protease classically appreciated for its ability to generate the serine-protease plasmin from its inactive precursor plasminogen
Key type plasminogen activator (tPA)-dependent mechanisms for blood–brain barrier (BBB) breakdown are reported as plasmin independent, but plasmin can perform complementary or parallel actions Intravenous administration of plasmin is safer with regards to intracerebral hemorrhage (ICH) compared with plasminogen activators (PAs) Different results are obtained depending on the mode of plasmin administration Contradicting observations in plasminogen knockout mice Protective as well as deleterious effects of plasmin are seen in cultured cells of the BBB Established plasmin-dependent observations in culture are not yet backed up by solid in vivo studies Can plasmin overcome the tight control of its robust brain and blood inhibitors, even during thrombolysis?
Despite fundamental variations between observations made in rodent and in primate species, the idea that recombinant tPA (rtPA) and with less certainty endogenous tPA cause BBB alteration in humans during thrombolysis in stroke has gained solid experimental support
Summary
Plasmin-dependent modulation of the blood–brain barrier: a major consideration during tPA-induced thrombolysis?. The principal downstream product of tissue-type plasminogen activator (tPA), is known for its potent fibrin-degrading capacity but is recognized for many non-fibrinolytic activities. Plasmin has not been conclusively linked to blood– brain barrier (BBB) disruption during recombinant tPA (rtPA)-induced thrombolysis in ischemic stroke. This is surprising given the substantial involvement of tPA in the modulation of BBB permeability and the co-existence of tPA and plasminogen in both blood and brain throughout the ischemic event. We review the work that argues a role for plasmin together with endogenous tPA or rtPA in BBB alteration, presenting the overall controversy around the topic yet creating a rational case for an involvement of plasmin in this process.
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