Fibrinolysis in Acute and Chronic Cardiovascular Disease

Abstract

The formation of an obstructive thrombus within an artery remains a major cause of mortality and morbidity worldwide. Despite effective inhibition of platelet function by modern antiplatelet therapies, these agents fail to fully eliminate atherothrombotic risk. This may well be related to extensive vascular disease, beyond the protective abilities of the treatment agents used. However, recent evidence suggests that residual vascular risk in those treated with modern antiplatelet therapies is related, at least in part, to impaired fibrin clot lysis. In this review, we attempt to shed more light on the role of hypofibrinolysis in predisposition to arterial vascular events. We provide a brief overview of the coagulation system followed by addressing the role of impaired fibrin clot lysis in acute and chronic vascular conditions, including coronary artery, cerebrovascular, and peripheral vascular disease. We also discuss the role of combined anticoagulant and antiplatelet therapies to reduce the risk of arterial thrombotic events, addressing both efficacy and safety of such an approach. We conclude that impaired fibrin clot lysis appears to contribute to residual thrombosis risk in individuals with arterial disease on antiplatelet therapy, and targeting proteins in the fibrinolytic system represents a viable strategy to improve outcome in this population. Future work is required to refine the antithrombotic approach by modulating pathological abnormalities in the fibrinolytic system and tailoring therapy according to the need of each individual.

Antithrombotic Therapy in Patients with Peripheral Artery Disease: A Focused Review on Oral Anticoagulation

“…The activation of fibrinolysis is inhibited by plasminogen activator inhibitor type 1 (PAI-1) released from endothelium and platelets [26,29]. If the balance of fibrinolytic activators to their inhibitors is disturbed, this may result from the depletion of PAI-1 [45] and in patients with PAD, previous studies have demonstrated and increased fibrinolysis and fibrinolysis inhibition [46][47][48].…”

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“…The underlying pathophysiological process in myocardial infarction and stroke originates from the formation of a fibrin clot and subsequent accumulation of fibrin in the blood vessels results in interference of blood flow and hence resulting in severe consequences such as irregular heartbeat, cardiac arrest, or death (Kietsiriroje et al., 2021). Currently, there exist several fibrinolytic agents used in fibrinolytic therapy to manage fibrin clot and restore blood flow such as urokinase and streptokinase enzymes which are often costly and carry undesirable side effects (Devaraj & Halami, 2021).…”

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“…Tissue factor released following vessel injury starts a cascade of reactions that culminate in the formation of thrombin that converts soluble fibrinogen into the insoluble fibrin network, which forms the skeleton of the thrombus. When the fibrin network forms, the fibrinolytic system is activated in order to limit thrombus extension, a process controlled by a fine balance between fibrinolytic and antifibrinolytic proteins, highlighting the intricacy of the system [4].…”

“…For the purpose of this review, we will adhere to the term 'plasmin inhibitor (PI)' throughout. PI is a direct inhibitor of plasmin by forming plasmin-antiplasmin (PAP) complexes, unlike other anti-fibrinolytic proteins that exert an indirect effect [4].…”