Alpha2-Antiplasmin: The Devil You Don't Know in Cerebrovascular and Cardiovascular Disease

Abstract

Alpha2-antiplasmin (α2AP), the fast-reacting, serine protease inhibitor (serpin) of plasmin, was originally thought to play a key role in protection against uncontrolled, plasmin-mediated proteolysis of coagulation factors and other molecules. However, studies of humans and mice with genetic deficiency of α2AP have expanded our understanding of this serpin, particularly in disease states. Epidemiology studies have shown an association between high α2AP levels and increased risk or poor outcome in cardiovascular diseases. Mechanistic studies in disease models indicate that α2AP stops the body's own fibrinolytic system from dissolving pathologic thrombi that cause venous thrombosis, pulmonary embolism, arterial thrombosis, and ischemic stroke. In addition, α2AP fosters the development of microvascular thrombosis and enhances matrix metalloproteinase-9 expression. Through these mechanisms and others, α2AP contributes to brain injury, hemorrhage and swelling in experimental ischemic stroke. Recent studies also show that α2AP is required for the development of stasis thrombosis by inhibiting the early activation of effective fibrinolysis. In this review, we will discuss the key role played by α2AP in controlling thrombosis and fibrinolysis and, we will consider its potential value as a therapeutic target in cardiovascular diseases and ischemic stroke.

Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin

“…Plasmin is also inhibited by the actions of various serine protease inhibitors like α2AP [ 64 ]. High blood levels of α2AP [ 66 ], an ultrafast, covalent inhibitor of plasmin, have been linked in humans to increased risk of ischemic stroke and failure of tissue plasminogen activator therapy [ 67 ]. Furthermore, plasminogen activator inhibitor-1 (PAI-1) and α2AP, maintain a delicate homeostasis in the normal physiologic state [ 68 ].…”

“…Furthermore, plasminogen activator inhibitor-1 (PAI-1) and α2AP, maintain a delicate homeostasis in the normal physiologic state [ 68 ]. α2AP is covalently cross-linked to fibrin in the thrombus by activated factor XIII, a transglutaminase [ 69 , 70 ] which is a major source of the resistance of in vitro plasma clots to plasmin-mediated fibrinolysis [ 66 ]. It is therefore entirely plausible that, as we noted in our Long COVID/PASC samples, if there is both an acute or lingering overload of anomalous (amyloid) fibrin(ogen) microclots in circulation, and a significant fold increase in α2AP, that the endogenous activators of plasminogen and the subsequent cascade of physiological events that are driven by plasmin generation, will fail.…”

Persistent Clotting Protein Pathology in Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) is Accompanied by Increased Levels of Antiplasmin

“…Plasmin is also inhibited by the actions of various serine protease inhibitors like α2AP [57]. High blood levels of α2AP [59], an ultrafast, covalent inhibitor of plasmin, have been linked in humans to increased risk of ischemic stroke and failure of tissue plasminogen activator therapy [60]. Furthermore, plasminogen activator inhibitor-1 (PAI-1) and α2AP, maintain a delicate homeostasis in the normal physiologic state [61].…”

“…Furthermore, plasminogen activator inhibitor-1 (PAI-1) and α2AP, maintain a delicate homeostasis in the normal physiologic state [61]. α2AP is covalently crosslinked to brin in the thrombus by activated factor XIII, a transglutaminase [62,63] which is a major source of the resistance of in vitro plasma clots to plasmin-mediated brinolysis [59]. It is therefore entirely plausible that, as we noted in our Long COVID/PASC samples, if there is both an acute or lingering overload of anomalous (amyloid) brin(ogen) clotlets in circulation, and 8-fold increase in α2AP, that the endogenous activators of plasminogen and the subsequent cascade of physiological events that are driven by plasmin generation, will fail.…”

Persistent clotting protein pathology in Long COVID/ Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin

“…is covalently cross-linked to fibrin in the thrombus by activated factor XIII, a transglutaminase (Reed et al, 1991, Fraser et al, 2011 which is a major source of the resistance of in vitro plasma clots to plasmin-mediated fibrinolysis (Singh et al, 2020). It is therefore entirely plausible that, as we noted in our Long COVID/PASC samples, if there is both an acute or lingering overload of anomalous (amyloid) fibrin(ogen) clotlets in circulation, and 8-fold increase in α2AP, that the endogenous activators of plasminogen and the subsequent cascade of physiological events that are driven by plasmin generation, will fail.…”