Engineering of plasminogen activators for targeting to thrombus and heightening thrombolytic efficacy

Abstract

Summary. Thrombotic occlusion of the coronary artery, which triggers acute myocardial infarction, is one of the major causes of death in the USA. Currently, arterial occlusions are treated with intravenous plasminogen activators (PAs), which dissolve the clot by activating plasminogen. However, PAs indiscriminately generate plasmin, which depletes critical clotting factors (fibrinogen, factor V, and factor VIII), precipitates a lytic state in the blood, and produces bleeding complications in a large patient population. PAs have been extensively investigated to achieve thrombus specificity, to attenuate the bleeding risk, and to widen their clinical applications. In this review, we discuss various strategies that have been pursued since the beginning of thrombolytic therapy. We review the biotechnological approaches that have been used to develop mutant and chimeric PAs for thrombus selectivity, including the use of specific antibodies for targeting thrombi. We discuss particulate carrier-based systems and triggered-release concepts. We propose new hypotheses and strategies to spur future studies in this research arena. Overall, we describe the approaches and accomplishments in the development of patient-friendly and workable delivery systems for thrombolytic drugs.

Prognostic impact of postoperative low platelet count after liver transplantation

“…Twenty‐eight patients were excluded because postoperative laboratory data were not fully documented. Forty‐one patients with LT from donation after cardiac death (DCD) donors were also not enrolled, because tissue plasminogen activator is typically used for DCD grafts, affecting platelet function . Thus, the final study population of 975 recipients was enrolled in this study.…”

“…Forty-one patients with LT from donation after cardiac death (DCD) donors were also not enrolled, because tissue plasminogen activator is typically used for DCD grafts, affecting platelet function. 11 Thus, the final study population of 975 recipients was enrolled in this study. All data points for this study were collected in accordance with the Henry Ford Hospital Review Board.…”

Erythrocyte‐Derived Nanoparticles as a Theranostic Agent for Near‐Infrared Fluorescence Imaging and Thrombolysis of Blood Clots

“…Alternatively, various delivery systems, including liposomal‐tPA delivery systems have been designed to improve the bioavailability of tPA . However owing to its instability in the bloodstream and poor clot lysis efficiencies, practical application of liposomal delivery systems is restricted …”

Platelet microparticle-inspired clot-responsive nanomedicine for targeted fibrinolysis

“…On the other hand, directly modifying drug molecules with ligands and antibodies may affect drug activity and may not prevent rapid plasma-induced deactivation or clearance. In this framework, several experts in the field have recently demonstrated and emphasized that advanced drug delivery systems can provide unique solutions regarding encapsulation, site-selective delivery and targeted action of thrombolytics [36–39]. Advanced drug delivery systems should be capable of carrying a therapeutic payload safely through the circulation without non-specific delivery or plasma-induced deactivation, deliver the payload preferentially at the target site via response to site-specific stimuli and biodegrade in the body for safe metabolic elimination [40].…”