Targeting Extracellular Matrix Proteolysis for Hemorrhagic Complications of tPA Stroke Therapy

Abstract

To date, tPA-based thrombolytic therapy is the only FDA-approved treatment for achieving vascular reperfusion and clinical benefit, but this agent is given to only about 2-5% of stroke patients in the United States of America. This may be related, in part, to the elevated risks of symptomatic intracranial hemorrhage, and the consequently reduced therapeutic time window. Recent efforts have aimed at identifying new combination strategies that might increase thrombolytic efficacy of tPA to benefit reperfusion, while reducing its associated neurotoxicity and hemorrhagic complications. Emerging experimental studies demonstrate that the breakdown of neurovascular matrix initiates blood-brain barrier disruption with edema and/or hemorrhage. Perturbation of extracellular homeostasis triggered by dysregulated extracellular proteases may underlie processes responsible for the hemorrhagic complications of thrombolytic stroke therapy. This short review summarizes experimental investigations of this field in pre-clinical stroke models. The data strongly suggest that targeting the extracellular matrix proteolytic imbalance within the neurovascular unit may provide new approaches for improving the safety and efficacy of thrombolytic reperfusion therapy of stroke.

Plasminogen Activator Inhibitor-1 and Thrombotic Cerebrovascular Diseases

“…34,35 Besides the clearly beneficial role of tPA as a thrombolytic molecule in ischemic stroke, tPA may also play detrimental roles at the blood–brain interface, where it can mediate blood–brain barrier leakage, edema, and hemorrhagic transformation. 36 …”

Annexin A2

“…Plasmin, in turn, degrades cross-linked fibrin and, possibly, intact fibrinogen, a process called fibrinogenolysis19. However, recent vascular biology studies have revealed that tPA interacts with cellular receptors that allow it to carry out additional biological functions and to activate specific signal transduction pathways20. A central tenet of cell surface fibrinolysis is the concept of fibrinolytic assembly, in which the tPA-dependent conversion of plasminogen to active plasmin is precisely orchestrated through the formation of a multimolecular complex, consisting of tPA, the annexin A2 heterotetramer, and plasminogen (Figure 1)21.…”

Recovery of neurological function of ischemic stroke by application of conditioned medium of bone marrow mesenchymal stem cells derived from normal and cerebral ischemia rats

“…A major limitation of r-tPA therapy for acute stroke is its narrow therapeutic window of 4.5 hours after stroke onset [1]. Beyond this timing of administration, rt-PA presents with deleterious side effects, in particular increase risk of intra-cerebral hemorrhage which can exacerbate stroke injury and counteract the benefits provided by reperfusion of the occluded artery in many patients [3]. …”