Alpha 2-antiplasmin (orα2-antiplasmin orplasmin inhibitor) is aserine protease inhibitor (serpin) responsible for inactivatingplasmin.[5] Plasmin is an importantenzyme that participates infibrinolysis and degradation of various other proteins. This protein is encoded by theSERPINF2 gene.[6]
Fibrinolysis (simplified). Blue arrows denote stimulation, and red arrows inhibition.
Alpha 2-antiplasmin (α2AP) is a member of theserine protease inhibitor (serpin) superfamily and is structurally characterized by a central serpin domain flanked by uniqueN- andC-terminal extensions.[7][8] The mature human α2AP protein consists of 452 amino acids, with a 12-residue N-terminus, a central serpin domain, and a C-terminal tail of approximately 55 residues.[7][8] The reactive center loop, which is crucial for its inhibitory function, protrudes from the central serpin domain and contains the Arg364-Met365 peptide bond that is specifically targeted and cleaved by plasmin.[8] There are two main circulating forms: Met-α2AP, which hasmethionine at theN-terminus, and Asn-α2AP, which is N-terminally shortened and starts with asparagine; the latter form constitutes about 70% of plasma α2AP and is more efficiently cross-linked to fibrin.[9][8] The C-terminal region, rich in lysine residues, mediates the initial non-covalent binding to plasmin, facilitating the formation of a stable 1:1stoichiometric complex.[8] This structural arrangement allows α2AP to efficiently interact with plasmin and be incorporated into fibrin clots via cross-linking by factor XIIIa.[8][10]
Alpha 2-antiplasmin serves as the primary physiological inhibitor ofplasmin, the key enzyme responsible forfibrin degradation duringfibrinolysis.[9][10] By rapidly forming a covalent complex with plasmin, α2AP prevents excessive breakdown of fibrin clots, thereby maintaininghemostatic balance.[9][10][11] In addition to direct inhibition, α2AP interferes with the binding of plasminogen to fibrin, further regulating the initiation of fibrinolysis.[10][11] During clot formation, α2AP is cross-linked to fibrin by activatedfactor XIII, which increases the resistance of the clot to lysis and enhances clot stability.[10][11] This function is critical in preventing premature clot dissolution, but elevated levels of α2AP have been associated with increased risk of thrombotic events, such asstroke andmyocardial infarction, due to impaired fibrinolysis.[12] Conversely, α2AP deficiency leads to increased susceptibility to bleeding because of uncontrolled plasmin activity and rapid clot breakdown.[11] Thus, α2AP is essential for fine-tuning the balance between clot formation and dissolution, making it a potential therapeutic target in both thrombotic and bleeding disorders.[9]
Very few cases (<20) ofalpha-2-antiplasmin deficiency have been described. As plasmin degrades blood clots, impaired inhibition of plasmin leads to a bleeding tendency, which was severe in the cases reported.
In livercirrhosis, there is decreased production of alpha 2-antiplasmin, leading to decreased inactivation ofplasmin and an increase infibrinolysis. This is associated with an increased risk of bleeding in liver disease.[13] It has been suggested, however, that the observed decreases in alpha 2-antiplasmin levels are due to a chronic state ofdisseminated intravascular coagulation in cirrhosis rather than defective protein synthesis.[14]
^Hou Y, Okada K, Okamoto C, Ueshima S, Matsuo O (July 2008). "Alpha2-antiplasmin is a critical regulator of angiotensin II-mediated vascular remodeling".Arteriosclerosis, Thrombosis, and Vascular Biology.28 (7):1257–1262.doi:10.1161/ATVBAHA.108.165688.PMID18436805.
^Sattar H (2011).Fundamentals of Pathology. Pathoma LLC. p. 36.
^Marongiu F, Mamusa AM, Mameli G, Mulas G, Solinas A, Demelia L, et al. (Jan 1985). "α2Antiplasmin and Disseminated Intravascular Coagulation in Liver Cirrhosis".Thrombosis Research.37 (2):287–294.doi:10.1016/0049-3848(85)90017-9.PMID3975873.
Martí-Fàbregas J, Borrell M, Cocho D, Martínez-Ramírez S, Martínez-Corral M, Fontcuberta J, et al. (Jan 2008). "Change in hemostatic markers after recombinant tissue-type plasminogen activator is not associated with the chance of recanalization".Stroke.39 (1):234–236.doi:10.1161/STROKEAHA.107.493767.PMID18048863.S2CID10052168.
Nielsen VG (Oct 2007). "Hydroxyethyl starch enhances fibrinolysis in human plasma by diminishing alpha2-antiplasmin-plasmin interactions".Blood Coagulation & Fibrinolysis.18 (7):647–656.doi:10.1097/MBC.0b013e3282a167dc.PMID17890952.S2CID45608070.
Kapadia C, Yousef GM, Mellati AA, Magklara A, Wasney GA, Diamandis EP (Jan 2004). "Complex formation between human kallikrein 13 and serum protease inhibitors".Clinica Chimica Acta; International Journal of Clinical Chemistry.339 (1–2):157–167.doi:10.1016/j.cccn.2003.10.009.PMID14687906.
Magklara A, Mellati AA, Wasney GA, Little SP, Sotiropoulou G, Becker GW, et al. (Aug 2003). "Characterization of the enzymatic activity of human kallikrein 6: Autoactivation, substrate specificity, and regulation by inhibitors".Biochemical and Biophysical Research Communications.307 (4):948–955.Bibcode:2003BBRC..307..948M.doi:10.1016/S0006-291X(03)01271-3.PMID12878203.
Frank PS, Douglas JT, Locher M, Llinás M, Schaller J (Feb 2003). "Structural/functional characterization of the alpha 2-plasmin inhibitor C-terminal peptide".Biochemistry.42 (4):1078–1085.doi:10.1021/bi026917n.PMID12549929.
Uszynski M, Klyszejko A, Zekanowska E (Dec 2000). "Plasminogen, alpha(2)-antiplasmin and complexes of plasmin-alpha(2)-antiplasmin (PAP) in amniotic fluid and blood plasma of parturient women".European Journal of Obstetrics, Gynecology, and Reproductive Biology.93 (2):167–171.doi:10.1016/S0301-2115(00)00283-9.PMID11074138.
