Exploitation of fibrinolytic enzymes in combating blood clotting disorders - recent advances and strategies: A comprehensive review

Abstract

Formation of blood clumps inside vessels which restrict blood circulation throughout circulatory system is known as thrombosis. This leads to origin of numerous abnormalities associated with cardiovascular system like myocardial infarction and other diseases such as cerebral stroke, acute ischaemic stroke, antiphospholipid syndrome, prothrombin G20210A deep vein thrombosis (DVT), thrombophlebitis and pulmonary embolism. As per the data reports procured from the World Health Organization, 17.7 million casualties every year due to cardiovascular disorder lead to 31% of all global deaths and in India it is about 31.6% every year. Approximately 10 million cases of venous thromboembolism (VTE) are reported worldwide (Reff). Conventionally these clot disorders are medicated by using assorted anticoagulant drugs like heparin, warfarin, rivaroxaban, edoxaban and enoxaparin. These therapeutics act by conquering the production or function of various clotting factors that are normally present in blood. Further tissue plasminogen activator (tPA) like urokinase, alteplase and streptokinase (SK) derived from group C, β-haemolytic streptococci spp., actuates plasminogen by forming a non-covalent-plasminogen activator complex. But these medications are reported to be associated with adversarial effects such as extreme bleeding, short half-life, recurrence at the site of residual thrombosis, haemorrhage, vomiting and necessitating higher therapeutic dose. These also upon intravenous administration have low specificity towards the fibrin. Besides above thrombolytic agents, fibrinolytic enzyme has gained significant attention that dissolves thrombus by triggering plasminogen which forms a cleaved product called plasmin or directly acts on fibrin and degrades blood clot. Fibrinolytic enzymes include nattokinase, serratiopeptidase and DNase derived from various microorganisms, plants, marine creatures, snake venom, insects and mushrooms. The fibrinolytic enzymes registered therapeutic potential in combating various blood clotting disorders, treatment of preeclampsia, adult parapneumonic effusions, tuberculosis, empyema, cancer therapy targeting, venous and arterial thrombosis, arterial fibrillation, prevention of postoperative adhesion formation, activators and inhibitors. The review catalogues the therapeutic role of enzymes in blood clotting disorders, numerous sources, underlying molecular mechanism, anticoagulant action, physiological function, fibrinolytic assay, bioparametric optimization by fermentation, purification, characterization, stability, adverse effects and molecular cloning and characterization of the gene encoding fibrinolytic enzyme.