Isolation and characterization of the clottable low-molecular-weight fibrinogen derived by limited plasmin hydrolysis of human fraction I-4

Sherman, Laurence A.; Mosesson, Michael W.; Sherry, Sol

doi:10.1021/bi00832a030

Cited by 65 publications

(15 citation statements)

References 40 publications

(42 reference statements)

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“…sequence of degradation is similar to that observed in plasmin-catalyzed digests, in that Aa-chain fragmentation precedes that of BP-chain (12,(14)(15)(16)(17)(18) Fibrinogen Degradation by a2-Macroglobulin globulin fromi urokinase-treated plasilma (500 U urokinase/ml plasmiia). Less than 0.1% of this plasimin was expresse(c as fibinogenolvtic activity.…”

Section: Resultssupporting

confidence: 66%

“…Furthermore, the suggestion that the reduction in molecular size wvas the consequence of cleavage of peptide material from the COOH-terminal region of the core imiolecule (10,11) has been confirimied (12) and extended by the demonstration that uinder physiologic circumstances such attack appears to be conifined to the Aa-chains (12,14). Sinillarities between the plasmna catabolites and early fibrinogen derivatives resulting from plasmin-catalyzed hydrolysis (14)(15)(16)(17)(18) support the notion that it is plasminii or a plasmin-like enzyme that mediates this in vivo cataholismll.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Degradation of Human Fibrinogen by Plasma α2-Macroglobulin-Enzyme Complexes

Harpel¹,

Mosesson²

1973

J. Clin. Invest.

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159

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A B S T R A C T This study demonstrates that human plasma a2-macroglobulin preparations possess an enzymic activity that degrades fibrinogen, resulting in the formation of products whose structure resembles that of circulating fibrinogen catabolites. The sequence of degradation is similar to that observed in plasmincatalyzed digests, in that Aa-chain fragmentation precedes that of B,8-chain. The addition of plasminogen activators to plasma induced an increase in the N-atosyl-L-arginine methyl ester HCl esterase and fibrinogenolytic activity associated with a2-macroglobulin purified from this plasma, indicating that the enzymic activity of the complex was preserved and could be increased in the presence of other plasma enzyme inhibitors. Immunochemical studies demonstrated that an a2-macroglobulin-plasmin complex had formed in urokinase-treated plasma. This a2-macroglobulin preparation manifested an esterolytic profile like that of a complex prepared from plasmin and purified a2-macroglobulin. After complex formation with a2-macroglobulin in plasma, plasmin retained less than 0.1% of its fibrinogenolytic activity. That plasmin expressed its activity while bound to a2-macroglobulin was suggested by immunoprecipitation of this activity with aa-macroglobulin antibody and by the demonstration that pancreatic trypsin inhibitor did not effectively inhibit its fibrinogenolytic or esterolytic activity. These results raise the possibility that, in addition to its activity as a major plasma proteolytic enzyme inhibitor, a2-macroglobulin may modThis paper was presented in part at the 15th Annual Meeting,

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Section: Resultssupporting

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Degradation of Human Fibrinogen by Plasma α2-Macroglobulin-Enzyme Complexes

Harpel¹,

Mosesson²

1973

J. Clin. Invest.

Self Cite

159

View full text Add to dashboard Cite

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“…The fragment X derivative used in this study was ( 16,17), it represents an early fragment X species because it is > 90% clottable and has a molecular mass of -Preparation ofl2I-labeledfibrinogen Fibrinogen was precipitated from barium sulfate adsorbed plasma with 2 M f3-alanine (19), and then trace labeled with '25I (20) to a specific activity of 100±5 MtCi/mg.…”

Section: Reagentsmentioning

confidence: 99%

Alpha 2-antiplasmin supplementation inhibits tissue plasminogen activator-induced fibrinogenolysis and bleeding with little effect on thrombolysis.

Weitz

Leslie²,

Hirsh³

et al. 1993

J. Clin. Invest.

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Tissue plasminogen activator (t-PA) causes fibrinogen proteolysis when a2-antiplasmin levels fall, and this may contribute to t-PA-induced hemorrhage. Because clot-bound plasmin is protected from a2-antiplasmin inhibition, we tested the possibility that a2-antiplasmin supplementation would block t-PA-induced fibrinogenolysis and bleeding without affecting thrombolysis. When added to human or rabbit plasma, a2-antiplasmin inhibits t-PA-induced fibrinogenolysis, but has little effect on the lysis of 1251-fibrin clots. To examine its effect in vivo, rabbits with preformed 125I-labeled-jugular vein thrombi were randomized to receive t-PA, t-PA and a2-antiplasmin, or saline. a2-Antiplasmin infusion produced a modest decrease in t-PAinduced thrombolysis (from 40.2% to 30.1%, P = 0.12), but reduced fibrinogen consumption from 87% to 27% (P = 0.0001), and decreased blood loss from standardized ear incisions from 5,594 to 656 ,ul (P < 0.0001). We hypothesize that a2-antiplasmin limits t-PA-induced hemorrhage by inhibiting fibrinogenolysis and subsequent fragment X formation because (a) SDS-PAGE and immunoblot analysis indicate less fragment X formation in a2-antiplasmin treated animals, and (b) when added to a solution of fibrinogen and plasminogen clotted with thrombin in the presence of t-PA, fragment X shortens the lysis time in a concentration-dependent fashion. These findings suggest that fragment X incorporation into hemostatic plugs contributes to t-PA-induced bleeding. By blocking t-PA-mediated fibrinogenolysis, a2-antiplasmin supplementation may improve the safety of fibrin-specific plasminogen activators. (J. Clin. Invest. 1993Invest. . 91:1343Invest. -1350

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“…Similar increases have been reported in fibrinogens Paris and Detroit and is present in our results with fibrinogen Zurich (Table IV). A slight increase in this ratio has been noted in the thrombin-coagulable early derivative of plasmin-induced proteolysis of fibrinogen, both in vitro (25) and in vivo (30 …”

Section: Methodsmentioning

confidence: 94%

“…Per cent nitrogen by weight was assumed to be 16.7% (24). N-terminal amino acids were determined by a previously described modification (25) of the 5-dimethylamino-1-naphthalenesulfonyl chloride (dansyl chloride) method (26).…”

Section: Methodsmentioning

confidence: 99%