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Blood, 15 May 2004, Vol. 103, No. 10, pp. 3612. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Booth, N. A. Articles by Thomas, L. Search for Related Content PubMed Articles by Booth, N. A. Articles by Thomas, L. Related Collections Related Article in Blood Online Related Letter in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY A snip enhances 2-antiplasmin 2-Antiplasmin (2-AP, also called 2-plasmin inhibitor) is only slowly revealing its full range of subtleties. 2-AP is a member of the serpin family and the principal physiologic inhibitor of plasmin, which it rapidly inactivates. But there is more to 2-AP than its reactive center, because the inhibitor can also bind plasminogen and can be cross-linked to fibrin, both affecting its local action. In plasma, the inhibitor occurs in different forms, reflecting proteolytic cleavage. The inhibitor has a 50-residue C-terminal extension relative to the other serpins. Cleavage in the middle of this extension, by an unknown protease, removes the plasminogen-binding capacity; at any one time the nonbinding form normally constitutes about one third of plasma 2-AP. In this issue, Lee and colleagues (page 3783) clarify the other and less well-understood variation in 2-AP, which is at the amino-terminus. Originally, 2-AP was thought to have an N-terminal Asn and a 39-residue signal peptide,1 but later work suggested that the mature protein had an additional 12 residues at the amino-terminus, such that the signal peptide was 27 residues. Human plasma contained both the longer (Met-2-AP) and the shorter (Asn-2-AP) form, the latter predominating.2 Thus, questions about 2-AP synthesis and processing were raised, and these are answered satisfactorily by Lee and colleagues, who identify the protease that processes 2-AP, antiplasmin-clearing enzyme (APCE). The cleavage between Pro12-Asn13 reveals the cross-linking site (Gln14) in the inhibitor, a site that is essentially cryptic in the mature protein, where the additional 12 residues mask it. The cross-linking of 2-AP to fibrin by Factor XIIIa is crucial to its function in regulating fibrinolysis. Indeed the abnormality in 2-AP–deficient plasma was illustrated only in fibrin clots prepared in the presence of calcium, which is required for cross-linking. Fibrin from an 2-AP–deficient patient lysed rapidly, even when immersed in normal plasma, proving the efficacy of cross-linked 2-AP.3 Antibodies specific for cross-linked 2-AP greatly stimulated lysis of fibrin.4 The importance of cross-linked 2-AP is sometimes ignored because of emphasis on the relative protection from 2-AP of plasmin formed on the fibrin surface. These apparent contradictions can be reconciled if we consider that the separate effects have been demonstrated in isolation and that the actual physiologic situation will reflect some balance between them. Thus enough local 2-AP will overcome plasmin and vice versa. There are still several questions about the physical interaction between cross-linked 2-AP and fibrin-bound plasmin, but there is no doubt that cross-linking of 2-AP to fibrin decreases fibrinolysis markedly. The identification of a protease that is closely related to seprase as the 2-AP cleaving enzyme now leads to several important questions. Is the APCE activity expressed in liver cells, where 2-AP is synthesized, or on endothelial cells, where it might act on circulating 2-AP? Is its synthesis regulated in inflammatory or other conditions, such that it might have impact on the local stability of fibrin in the vessel wall? APCE is present in plasma at only trace concentrations and its isolation from plasma is an impressive feat. What is the source of this plasma APCE? The breakthrough by Lee and colleagues in identifying APCE reminds us of the many substrates in the hemostatic system that may be influenced by the emerging families of transmembrane serine proteases5 and the interesting subtleties in regulation that may yet be discovered. Nuala A. Booth, and Louise Thomas University of Aberdeen References Holmes WE, Nelles L, Lijnen HR, Collen D. Primary structure of human 2-antiplasmin, a serine protease inhibitor (serpin). J Biol Chem. 1987;262: 1659-1664.[Abstract/Free Full Text] Bangert K, Johnsen AH, Christensen U, Thorsen S. Different N-terminal forms of 2-plasmin inhibitor in human plasma. Biochem J. 1993;291: 623-625. Sakata Y, Aoki N. Significance of cross-linking of 2-plasmin inhibitor to fibrin in inhibition of fibrinolysis and in hemostasis. J Clin Invest. 1982;69: 536-542.[Medline] [Order article via Infotrieve] Reed GL, Matsueda GR, Haber E. Synergistic fibrinolysis: combinded effects of plasminogen activators and an antibody that inhibits 2-antiplasmin. Proc Natl Acad Sci U S A. 1990;87: 1114-1118.[Abstract/Free Full Text] Netzel-Arnett S, Hooper JD, Szabo R, et al. Membrane anchored serine proteases: a rapidly expanding group of cell surface proteolytic enzymes with potential roles in cancer. Cancer Metastasis Rev. 2003;22: 237-258.[CrossRef][Medline] [Order article via Infotrieve] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: A novel plasma proteinase potentiates 2-antiplasmin inhibition of fibrin digestion Kyung N. Lee, Kenneth W. Jackson, Victoria J. Christiansen, Keun H. Chung, and Patrick A. McKee Blood 2004 103: 3783-3788. [Abstract] [Full Text] [PDF] Related Letter in Blood Online: The role of PBSCT in treatment of AL amyloidosis is far from settled Hugh J. B. Goodman, Philip N. Hawkins, Angela Dispenzieri, Morie A. Gertz, Robert A. Kyle, and Jayesh Mehta Blood 2004 104: 2991-2994. [Full Text] [PDF] This article has been cited by other articles: J. Mehta Amyloidosis: graviores morbos, asperis remedii Blood, November 15, 2007; 110(10): 3490 - 3491. [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Booth, N. A. Articles by Thomas, L. Search for Related Content PubMed Articles by Booth, N. A. Articles by Thomas, L. 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