The behavior of alpha2-plasmin inhibitor in fibrinolytic states.

Aoki, Nobuo; Moroi, Masaaki; Matsuda, Michio; Tachiya, K

doi:10.1172/jci108784

Cited by 167 publications

(79 citation statements)

References 29 publications

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“…The cross-linked a2PI inhibits in situ plasmin generation on the fibrin surface by physiologically occurring fibrinassociated plasminogen activation (14,15). These properties peculiar to a2PI enable it to be a much more specific and effective inhibitor of plasmin-catalyzed fibrinolysis than any other major protease inhibitors, such as a2-macroglobulin (2,9,16,17). In individuals with a congenital deficiency of a2PI, hemostatic plugs are dissolved prematurely by physiologically occurring fibrinolytic processes before the restoration ofinjured vessels, resulting in a severe hemorrhagic tendency (18,19).…”

Section: Introductionmentioning

confidence: 99%

Organization of the human alpha 2-plasmin inhibitor gene.

Hirosawa

Nakamura

Miura

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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We have isolated overlapping phage genomic clones covering an area of 26 kilobases that encodes the human alpha 2-plasmin inhibitor. The alpha 2-plasmin inhibitor gene contains 10 exons and 9 introns distributed over approximately 16 kilobases of DNA. To our knowledge, the number of introns is the highest yet reported for a member of the serine protease inhibitor (serpin) superfamily. All introns are located in the 5'-half of the corresponding mRNA. The 5'-untranslated region and the leader sequence are interrupted by 3 introns totaling approximately equal to 6 kilobases. A "TATA box" sequence is located 17 nucleotides upstream from the proposed transcription initiation site. Multiple "GC box" sequences, G + C-rich sequences, and "CCAAT box"-like sequence, the hepatitis B virus enhancer element-like sequence and the human immunodeficiency virus enhancer-like sequence appear in the 5'-flanking region. The NH2-terminal region, which implements factor XIII-catalyzed cross-linking of alpha 2-plasmin inhibitor to fibrin, is encoded by the 4th exon. The reactive site and plasminogen-binding site, both located in the COOH-terminal region, are encoded by the 10th exon. When similar amino acids of alpha 2-plasmin inhibitor and other members of the serpin gene superfamily are aligned, the position of the 7th intron of the alpha 2-plasmin inhibitor gene aligns precisely with that of the second intron of the genes for rat angiotensinogen and human alpha 1-antitrypsin genes and is misaligned by only one nucleotide with that of the third intron of antithrombin III, suggesting that the alpha 2-plasmin inhibitor gene originates from the common ancestor of these serine protease inhibitors.

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Section: Introductionmentioning

confidence: 99%

Organization of the human alpha 2-plasmin inhibitor gene.

Hirosawa

Nakamura

Miura

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

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“…A mixture of 25 Al of act. PTA (0.5 unit/ml), 4 ,l of a2PI (500 Mg/ml) or bovine serum albumin, and 3 Mit of heparin (17 units/ml) or buffer in a 10 X 75 mm polystyrene tube was incubated at 37°C. At intervals, 4 Ml of protamine sulfate (0.2 mg/ml; Eli Lilly) or buffer was added to the tube followed by 0.27 ml of buffer (protamine sulfate was used to neutralize the action of heparin).…”

Section: Methodsmentioning

confidence: 99%

“…A mixture of 36 Ml of Celite-bound act. PTA (0.5 unit/ml) and 4 Ml of a2PI (500-1000 Mg/ml) or albumin was incubated at 37°C for 30 min. The mixture was then diluted by addition of 0.76 ml of saline and a sample was tested for act.…”

Section: Methodsmentioning

confidence: 99%

“…Ml of human Factor Xa (0.5 unit/ml) or bovine Factor Xa (4.4 ,ug/ml) and 4 ,l of a2PI (228-1740 Ag/ml) or albumin was incubated at 37°C. At intervals, portions were assayed, after appropriate dilution, for residual Factor Xa activity with Stuart factor-deficient plasma or S-2222 (see above) as a substrate.…”

Section: Methodsmentioning

confidence: 99%

“…a2PI has strong inhibitory activity against plasmin and is the first inhibitor that reacts with plasmin, whether plasminogen activation occurs in vitro or in vivo (4)(5)(6).…”

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confidence: 99%

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Inhibitory spectrum of alpha 2-plasmin inhibitor.

Saito¹,

Goldsmith²,

Moroi³

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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ABSTRACTarPlasmin inhibitor (a2PI) has been recently characterized as a fast-reacting inhibitor of plasmin in human plasma and appears to play an important role in the regulation of fibrinolysis in vivo. We have studied the effect of purified a2PI upon various proteases participating in human blood coagulation and kinin generation. At physiological concentration (50 ;sg/ml), a2PI inhibited the clot-promoting and prekallikrein-activating activity of Hageman factor fragments, the amidolytic, kininogenase, and clot-promoting activities of plasma kallikrein, and the clot-promoting properties of activated plasma thromboplastin antecedent (PTA, Factor XIa) and thrombin. a2PI had minimal inhibitory effect on surface-bound activated PTA and activated Stuart factor (Factor Xa). a2PI did not inhibit the activity of activated Christmas factor (Factor IXa) or urinary kallikrein. Heparin (1.5-2.0 units/ml) did not enhance the inhibitory function of a2PI. These results suggest that, like other plasma protease inhibitors, a2PI possesses a broad in vitro spectrum of inhibitory properties.a2-Plasmin inhibitor (a2PI) has been recently identified as a fast-reacting inhibitor of plasmin in human plasma (1-3). a2PI has strong inhibitory activity against plasmin and is the first inhibitor that reacts with plasmin, whether plasminogen activation occurs in vitro or in vivo (4-6).Although the action of a2PI on plasmin is well characterized, relatively little information is available about the effect of this newly isolated inhibitor upon other plasma proteases (7,8). This paper reports the effect of physiologic concentrations of a2PI upon various proteases participating in blood coagulation and kinin generation and defines the in vitro spectrum of this inhibitor. We also compare the action of a2PI with that of some other plasma protease inhibitors in these systems. MATERIALS AND METHODSInhibitors. Human a2PI was prepared as described (1) and was judged greater than 95% homogeneous on disc gel electrophoresis, sodium dodecyl sulfate gel electrophoresis, and immunoelectrophoresis. The concentration of purified a2PI was determined by using 7.03 as extinction coefficient El% at 280 um. a2-Macroglobulin (a2M), isolated from human plasma (9), gave a single band by sodium dodecyl sulfate gel electrophoresis after reduction with 2-mercaptoethanol (Mr, approximately 180,000). The concentration of a2M was determined by single radial immunodiffusion on Immuno-plates (Hyland, Costa Mesa, CA). Normal serum contains approximately 2 mg of a2M per ml. a2M at 2 mg/ml was essentially free of a2PI (<0.2 ,g/ml) when tested by a sensitive radioitnmunoassay for a2PI (unpublished data). a2M (8 mg/ml) contained no detectable C1 esterase inhibitor (Clinh), a1-antitrypsin, or antithrombin III as assayed by immunodiffusion using monospecific antiserum. Purified Clinh and monospecific antiserum against Clinh were generous gifts of J. Pensky

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Increased Fibrinolysis and Amyloidosis

Liebman¹

1983

Arch Intern Med

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The behavior of alpha2-plasmin inhibitor in fibrinolytic states.

Cited by 167 publications

References 29 publications

Organization of the human alpha 2-plasmin inhibitor gene.

Organization of the human alpha 2-plasmin inhibitor gene.

Inhibitory spectrum of alpha 2-plasmin inhibitor.

Increased Fibrinolysis and Amyloidosis

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