Natural heterogeneity of α2-antiplasmin: functional and clinical consequences

Abstract

Human a2-antiplasmin (a2AP, also called a2-plasmin inhibitor) is the main physiological inhibitor of the fibrinolytic enzyme plasmin. a2AP inhibits plasmin on the fibrin clot or in the circulation by forming plasmin-antiplasmin complexes. Severely reduced a2AP levels in hereditary a2AP deficiency may lead to bleeding symptoms, whereas increased a2AP levels have been associated with increased thrombotic risk. a2AP is a very heterogeneous protein. In the circulation, a2AP undergoes both amino terminal (N-terminal) and carboxyl terminal (C-terminal) proteolytic modifications that significantly modify its activities. About 70% of a2AP is cleaved at the N terminus by antiplasmin-cleaving enzyme (or soluble fibroblast activation protein), resulting in a 12-amino-acid residue shorter form. The glutamine residue that serves as a substrate for activated factor XIII becomes more efficient after removal of the N terminus, leading to faster crosslinking of a2AP to fibrin and consequently prolonged clot lysis. In approximately 35% of circulating a2AP, the C terminus is absent. This C terminus contains the binding site for plasmin(ogen), the key component necessary for the rapid and efficient inhibitory mechanism of a2AP. Without its C terminus, a2AP can no longer bind to the lysine binding sites of plasmin(ogen) and is only a kinetically slow plasmin inhibitor. Thus, proteolytic modifications of the N and C termini of a2AP constitute major regulatory mechanisms for the inhibitory function of the protein and may therefore have clinical consequences. This review presents recent findings regarding the main aspects of the natural heterogeneity of a2AP with particular focus on the functional and possible clinical implications. (Blood. 2016; 127(5):538-545) Introduction a2-antiplasmin (a2AP, also called a2-plasmin inhibitor) is a key player in the fibrinolytic system (Figure 1). The fibrinolytic system is crucial for dissolving fibrin clots, facilitating tissue repair, and preventing clots from occluding vessels.1 Recent clinical studies have shown that reduced fibrinolysis (eg, due to an increase in a2AP level) is associated with an increase in both venous and arterial thrombotic risk. 2In contrast, an increase in fibrinolysis due to a2AP deficiency is associated with hemophilia-like bleeding symptoms, which typically occur after initial hemostasis as a result of the premature dissolution of fibrin. The phenotype of a2AP deficiency is heterogeneous. Complete congenital a2AP deficiency leads to severe bleeding with hemophilialike bleeding symptoms such as joint bleeding, whereas heterozygous a2AP-deficient patients typically have mild or no bleeding symptoms. 3,4 In addition, acquired a2AP deficiency may also occur in liver disease 5 and amyloidosis 6 or during fibrinolytic therapy. 7The main enzyme of the fibrinolytic system is the serine protease plasmin, which is predominantly responsible for the degradation of fibrin into rapidly cleared soluble fibrin degradation products (Figure 1). The inactive proenzyme plasminogen ca...

Efficacy of SMTP‐7, a small‐molecule anti‐inflammatory thrombolytic, in embolic stroke in monkeys

“…To seek a biomarker that predicts efficacy of SMTP‐7, we tested the following substances for their plasma levels after the drug treatment: PAP, DHET, MMP‐9, CRP, MCP‐1, and S100B (Figure A). PAP is formed from plasmin and its physiological inhibitor α 2 ‐antiplasmin, representing plasminogen activation . DHET is a product of sEH‐mediated hydrolysis of the anti‐inflammatory fatty acid epoxide epoxyeicosatrienoic acid, representing sEH inhibition .…”

Plasmin inhibitor deficiency: A case report

“…Human alpha 2‐ plasmin inhibitor « PI» is the main physiological inhibitor of the fibrinolytic enzyme plasmin. Severely reduced PI levels in hereditary PI deficiency may lead to bleeding symptoms, whereas increased PI levels have been associated with increased thrombotic risk …”

Inhibition of Fibrinolysis by Coagulation Factor XIII

“…The two chain forms of t-PA and u-PA are also efficiently inhibited by plasminogen activator inhibitor-2 (PAI-2), but the plasma levels of PAI-2 are normally low or even undetectable (except during pregnancy), and other intracellular functions of PAI-2 have been postulated [9]. Inhibition of the fibrinolytic system may also occur at the level of plasmin, mainly by α 2-antiplasmin ( α 2AP) [10]. PAI-1 and PAI-2, as well as α 2AP, are members of the serine protease inhibitor (serpin) superfamily.…”

“…In the circulation, α 2AP undergoes both N-terminal and C-terminal proteolytic modifications that significantly modify its functional properties [10]. Approximately 35% of circulating α 2AP lacks the C-terminus containing the binding site for plasmin(ogen) which is crucial for the rapid inhibitory mechanism of α 2AP [35].…”