Quantitation of fragment X formation during thrombolytic therapy with streptokinase and tissue plasminogen activator.

Owen, John; Friedman, Kenneth D.; Grossman, Betty A.; Wilkins, C; Berke, Andrew; Powers, Eric R.

doi:10.1172/jci113001

Cited by 51 publications

(23 citation statements)

References 33 publications

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“…Specifically, we have shown that t-PA converts a large proportion ofthe fibrinogen to fragment X (Fig. 6), a finding consistent with that of Owen and colleagues (2). Since fragment X is clottable (32), it becomes incorporated into the fibrin network of the hemostatic plug and we have demonstrated that fibrin clots formed in the presence of fragment X are more susceptible to t-PA-induced lysis (Table I).…”

Section: Discussionsupporting

confidence: 89%

“…Despite its affinity for fibrin, tissue-type plasminogen activator (t-PA) ' administration causes a systemic lytic state with fibrinogen proteolysis (1)(2)(3)(4). Although kinetic models predicted that high doses of t-PA would have this effect (5,6), recent studies suggest an additional mechanism through which even low doses of t-PA can produce fibrinogen breakdown.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

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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“…The fraction with both ␣C regions truncated is elevated in patients with peripheral vascular diseases, liver disease, or diabetes and in the elderly (27)(28)(29)45). A substantial amount of the molecules without the ␣C regions is produced during thrombolytic therapy (46). Moreover, there are a number of cases of hereditary dysfibrinogenemia in which the ␣C regions are partially or fully deleted (see the GEHT (Groupe d'Etude sur l'Hémostase et la Thrombose) Web site) (47).…”

Section: Discussionmentioning

confidence: 99%

The Assembly of Nonadhesive Fibrinogen Matrices Depends on the αC Regions of the Fibrinogen Molecule

Yermolenko

Gorkun

Fuhrmann

et al. 2012

Journal of Biological Chemistry

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Background: Surface-induced aggregation of fibrinogen results in the assembly of an extensible multilayered matrix, which prevents integrin-mediated cell adhesion. Results: Without the ␣C regions, the fibrinogen molecules assemble a defective, poorly extensible matrix supporting sustained cell adhesion. Conclusion:The assembly of nonadhesive fibrinogen multilayer requires the ␣C regions of the molecule. Significance: The molecular mechanism for the assembly of the fibrinogen multilayer is identified.

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“…With the successful cloning and expression of t-PA cDNA (9), amounts of recombinant t-PA (rt-PA) sufficient for clinical studies have recently become available. Although rt-PA is an extremely effective thrombolytic agent, its use in patients with acute myocardial infarction (10)(11)(12)(13)(14)(15) and venous thromboembolic disease (16)(17)(18)(19) results in significant fibrinogen proteolysis, albeit to a lesser extent than that produced by streptokinase (12)(13)(14)(15). Thus, large clinical studies have demonstrated that in pharmacologically effective doses, rt-PA is not fibrin-specific.…”

Section: Introductionmentioning

confidence: 99%

Soluble fibrin degradation products potentiate tissue plasminogen activator-induced fibrinogen proteolysis.

Weitz

Leslie²,

Ginsberg³

1991

J. Clin. Invest.

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Despite its affinity for fibrin, tissue plasminogen activator (t-PA) administration causes systemic fibrinogenolysis. To investigate the mechanism, t-PA was incubated with plasma in the presence or absence of a fibrin clot, and the extent of fibrinogenolysis was determined by measuring B,3142. In the presence of fibrin, there is a 21-fold increase in B,O142 levels. The potentiation of fibrinogenolysis in the presence of fibrin is mediated by soluble fibrin degradation products because (a) the extent of t-PA induced fibrinogenolysis and clot lysis are directly related, (b) once clot lysis has been initiated, fibrinogenolysis continues even after the clot is removed, and (c) lysates of cross-linked fibrin clots potentiate t-PA-mediated fibrinogenolysis. Fibrin degradation products stimulate fibrinogenolysis by binding t-PA and plasminogen because -70% of the labeled material in the clot lysates binds to both t-PA-and plasminogen-Sepharose, and only the bound fractions have potentiating activity. The binding site for t-PA and plasminogen is on the E domain because characterization of the potentiating fragments using gel filtration followed by PAGE and immunoblotting indicates that the major species is (DD)E complex, whereas minor components include high-molecular weight derivatives containing the (DD)E complex and fragment E. In contrast, D-dimer is the predominant species found in the fractions that do not bind to the adsorbants, and it has no potentiating activity. Thus, soluble products of t-PA-induced lysis of cross-linked fibrin potentiate t-PA-mediated fibrinogenolysis by providing a surface for t-PA and plasminogen binding thereby promoting plasmin generation. The occurrence of this phenomenon after therapeutic thrombolysis may explain the limited clot selectivity of t-PA. (J. Clin.

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Quantitation of fragment X formation during thrombolytic therapy with streptokinase and tissue plasminogen activator.

Cited by 51 publications

References 33 publications

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

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

The Assembly of Nonadhesive Fibrinogen Matrices Depends on the αC Regions of the Fibrinogen Molecule

Soluble fibrin degradation products potentiate tissue plasminogen activator-induced fibrinogen proteolysis.

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