Thrombolysis: A Critical First-Line Therapy with an Unfulfilled Potential

Abstract

A blood clot or thrombus triggers the onset of most vascular diseases, like stroke or heart attack. Thrombolysis is the only treatment that can restore blood flow rapidly and easily. Unfortunately, the standard thrombolytic, tissue plasminogen activator (tPA), has proven inadequate and is being replaced by invasive endovascular procedures, which are time consuming and limited in their availability in relation to the scope of the problem. Historically, when tPA clinical trials began, it was not recognized sufficiently that without the other natural plasminogen activator, prourokinase (proUK), thrombolysis by tPA was seriously compromised. The reason is that the 2 activators have complementary mechanisms of action in fibrinolysis, making their combination a requirement for optimal efficacy and synergy. Biological fibrinolysis also uses both activators, explaining why such low endogenous concentrations are sufficient. A low-dose sequential combination of tPA and proUK was tested in acute myocardial infarction, where it was exceptionally effective and safe. Because native proUK at pharmacological doses was vulnerable to spontaneous conversion to urokinase, jeopardizing safety, a site-directed mutant was developed that improved proUK's plasma stability fivefold without interfering with its mode of action. Mini-bolus tPA followed by low-dose proUK infusion is a simple, safe, effective, and promising first-line treatment of acute thrombotic disorders.

Thrombolytic Potential of Novel Thiol-Dependent Fibrinolytic Protease from Bacillus cereus RSA1

“…These clots limit the flow of blood through veins and arteries, leading to cardiac ailments such as embolism, myocardial infarction, heart stroke, etc. [6][7][8][9]. Thrombin and Factor Xa (FXa) are identified as imperative components of blood clotting cascade [10].…”

Amifostine Pretreatment Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Apoptosis and Oxidative Stress

“…In the past decades, with the introduction of thrombolytic therapy [4], arterial bypass surgery [5], percutaneous transluminal coronary angioplasty [6], and cardiopulmonary bypass, [7] patient survival after heart attack has been significantly improved. However because of ischemia-reperfusion injury, the prognosis of patients is still grim.…”

Low concentrations of cadmium chloride promotes protein translation and improve cell line productivity

“…To explore whether it has the potential to be used as a booster of expression, we decided to conduct fed‐batch analyses with cadmium and BI‐D1870, alone and combined, on the bioproduction of secreteable protein. As an initial model for the secretable biological molecule, and to avoid confounding factors of glycoprotein assembly in the endoplasmic reticulum, we chose tPA, a serine protease glycoprotein that is expressed as a monomer and is used in the clinics for thrombotic strokes (Gurewich, ).…”

“…This is congruent with its use as a potential anticancer drug in various tumor models (Theodosakis et al, 2017). To explore whether it has the potential to be used as a booster of expression, we decided to conduct fed-batch analyses with cadmium and BI-D1870, alone and combined, on the serine protease glycoprotein that is expressed as a monomer and is used in the clinics for thrombotic strokes (Gurewich, 2016).…”