Towards Effective and Safe Thrombolysis and Thromboprophylaxis

Abstract

Rationale: Fibrinolysis is a valuable alternative for the treatment of myocardial infarction when percutaneous coronary intervention is not available in a timely fashion. For acute ischemic stroke, fibrinolysis is the only treatment option with a very narrow therapeutic window. Clinically approved thrombolytics have significant drawbacks, including bleeding complications. Thus their use is highly restricted, leaving many patients untreated. Objective: We developed a novel targeted fibrinolytic drug that is directed against activated platelets. Methods and Results: We fused single-chain urokinase plasminogen activator (scuPA) to a small recombinant antibody (scFv SCE5 ), which targets the activated form of the platelet–integrin glycoprotein IIb/IIIa. Antibody binding and scuPA activity of this recombinant fusion protein were on par with the parent molecules. Prophylactic in vivo administration of scFv SCE5 –scuPA (75 U/g body weight) prevented carotid artery occlusion after ferric chloride injury in a plasminogen-dependent process compared with saline ( P <0.001), and blood flow recovery was similar to high-dose nontargeted urokinase (500 U/g body weight). Tail bleeding time was significantly prolonged with this high dose of nontargeted urokinase, but not with equally effective targeted scFv SCE5 –scuPA at 75 U/g body weight. Real-time in vivo molecular ultrasound imaging demonstrates significant therapeutic reduction of thrombus size after administration of 75 U/g body weight scFv SCE5 –scuPA as compared with the same dose of a mutated, nontargeting scFv–scuPA or vehicle. The ability of scFv SCE5 –scuPA to lyse thrombi was lost in plasminogen-deficient mice, but could be restored by intravenous injection of plasminogen. Conclusions: Targeting of scuPA to activated glycoprotein IIb/IIIa allows effective thrombolysis and the potential novel use as a fibrinolytic agent for thromboprophylaxis without bleeding complications.

Metal ion-assisted self-assembly of complexes for controlled and sustained release of minocycline for biomedical applications

“…Thus, local delivery of MH from the complex can potentially expose the injured neural tissue to high concentrations of MH while avoiding the deleterious side effects from systemic exposure. For applications where most neuronal loss happens in the acute stage (within 24 hr), such as traumatic brain injury [47], spinal cord injury [64, 65], and stroke [66], initial burst release of high-dose MH from the complexes can provide neuroprotection, and subsequent slow release of MH can target chronic inflammation following neural injury. For neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease which are closely associated with chronic neuroinflammation [67], sustained local delivery of MH can potentially inhibit the progression of these debilitating diseases while obviating the side effects from long term systemic exposure.…”

Coenzyme Q10 Upregulates Platelet cAMP/PKA Pathway and Attenuates Integrin αIIbβ3 Signaling and Thrombus Growth

“…Targeting the ligand binding function of integrin αIIbβ3 has been considered into the development of antithrombotic agents . These compounds may allow for effective thrombolysis and thromboprophylaxis, but they have significant side effects including thrombocytopenia and increased bleeding risks . These side effects limit the use and dose of integrin antagonists, and thus also limit their effectiveness .…”

Repurposing of Approved Cardiovascular Drugs against Ischemic Cerebrovascular Disease by Disease–Disease Associated Network-Assisted Prediction

“…60) PI3K/Akt signaling also has an important role in cerebral endothelial cells (ECs) protection and regulation of angiogenesis molecules to provide neuroprotective effects in ischemic stroke. 61,62) Urokinase-type plasminogen activator (uPA) and uPAR-mediated signaling was reported to have a role in fibrinolysis for acute ischemic stroke, as thrombolysis is the only treatment option clinically with a very narrow therapeutic window. 63) Fibrosis is concomitant with repair processes following ischemic stroke, in which pericytes are considered as an origin of fibrosis-forming cells.…”