Plasminogen Activators and Ischemic Stroke: Conditions for Acute Delivery
Division of Hematology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington.Seminars in Thrombosis and Hemostasis (Impact Factor: 3.88). 03/2013; 39(4). DOI: 10.1055/s-0033-1338126
Appropriate acute treatment with plasminogen activators (PAs) can significantly increase the probability of minimal or no disability in selected ischemic stroke patients. There is a great deal of evidence showing that intravenous recombinant tissue PAs (rt-PA) infusion accomplishes this goal, recanalization with other PAs has also been demonstrated in the development of this treatment. Recanalization of symptomatic, documented carotid or vertebrobasilar arterial territory occlusions have also been achieved by local intra-arterial PA delivery, although only a single prospective double-blinded randomized placebo-controlled study has been reported. The increase in intracerebral hemorrhage with these agents by either delivery approach underscores the need for careful patient selection, dose-appropriate safety and efficacy, proper clinical trial design, and an understanding of the evolution of cerebral tissue injury due to focal ischemia. Principles underlying the evolution of focal ischemia have been expanded by experience with acute PA intervention. Several questions remain open that concern the manner in which PAs can be applied acutely in ischemic stroke and how injury development can be limited.
- Seminars in Thrombosis and Hemostasis 06/2013; 39(4):327-328. DOI:10.1055/s-0033-1343616 · 3.88 Impact Factor
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ABSTRACT: Tissue plasminogen activator (tPA) thrombolysis, remains the only United States Food and Drug Administration(FDA) approvedtreatmentfor acute ischemia stroke. However, the use of tPA has been profoundly constraineddue to its narrow therapeutic time window and the increased risk of potentially deadly hemorrhagic complications. TPA-associated hemorrhagic transformation (HT) often occurs as a result of catastrophic failure of theblood brain barrier (BBB), wherein the affected cerebral capillaries can no longer hold blood constituents.Due to its direct contribution to edema and HT, reperfusion-associated BBB damage has been extensively studied, whileBBB damage that occurs within the thrombolytic time window is largely neglected. Of note, ischemia-induced BBB damage in the early stroke stages isincreasingly appreciated to negatively impact the safety and efficacy profiles of thrombolytic therapy for ischemic stroke. In this review, we discussed therecent findings of spatio-temporal evolution of BBB injury in the early stages of cerebral ischemia and its association with intracerebral hemorrhage following tPA thrombolysis. The increased understanding of early ischemic BBB damage and its close link to tPA-associated HT is of particular importance for developing new preventive and therapeutic strategies to reduce the hemorrhagic complications in stroke thrombolysis.Current Neurovascular Research 05/2014; 11(3). DOI:10.2174/1567202611666140530145643 · 2.25 Impact Factor
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ABSTRACT: Great advances have been made in our understanding of the fibrinolytic system from the initial discovery of proteolysis of fibrin by plasmin to the multifaceted and complex role of the plasminogen-plasmin (P-P) system. We now know that the P-P system is composed of several serine proteases and their inhibitors (serpins). This system is involved in many physiological functions, including embryogenesis, cell migration, and wound healing. They also play an important role in the pathogenesis of many diseases, including atherosclerosis, obesity, cancer, and even autoimmune disorders, and neuronal degeneration. Knowledge of their role in cancer enables their use as a prognostic factor. Therapeutic use of various forms of proteases derived from this system has been employed as thrombolytic agents. In addition, small molecules designed to inhibit many of the components of the P-P system are now available for clinical trial, aimed at treatment of these various disorders. The history of such remarkable development of our knowledge on fibrinolysis is reviewed in this article.Seminars in Thrombosis and Hemostasis 07/2014; 40(5). DOI:10.1055/s-0034-1383545 · 3.88 Impact Factor
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