Structure of fragment E species from human crosslinked fibrin

Olexa, Stephanie A.; Budzynski, Andrei Z.; Doolittle, Russell F.; Cottrell, Barbara A.; Greene, Thomas C.

doi:10.1021/bi00524a035

Cited by 72 publications

(50 citation statements)

References 34 publications

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“…The other minor peak identified by gel filtration (peak C) has a molecular weight of -60,000 D and represents predominantly fragment E. Analysis under nondissociating conditions indicates that more than one fragment E species is present (Fig. 8 A, (44,45).…”

Section: Discussionmentioning

confidence: 98%

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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Section: Discussionmentioning

confidence: 98%

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

Weitz

Leslie²,

Ginsberg³

1991

J. Clin. Invest.

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“…It is synthesized as plasminogen and activated by proteolysis via tissue-type (t) or urokinase-type (u) plasminogen activator (tPA or uPA). Activated plasmin in turn cleaves fibrin at various cleavage sites resulting in X and Y fragments, D-dimers, D and E fragments, Bβ15-42 and smaller fragments mostly derived from the α chain (19)(20)(21). Figure 1 schematically depicts fibrinogen, fibrin, its domains, cleavage sites and the resulting plasmic derivatives.…”

Section: Fibrinogen and Fibrin Structurementioning

confidence: 99%

“…NDSKII is generated synthetically via the cleavage of fibrinogen by cyanogen bromide and thrombin digestion. The resulting product is similar-but not identical-to the physiological FnE (FnE: Aα17-78, Bβ15-122 and γ1-62; NDSKII: Aα17-51, Bβ15-118, γ1-78) (19,64). Bach et al studied the interaction of NDSKII using human umbilical vein endothelial cells (HUVECs).…”

Section: Fibrin Fragmentsmentioning

confidence: 99%

Novel Aspects of Fibrin(ogen) Fragments during Inflammation

Jennewein

Tran

Paulus

et al. 2011

Mol Med

208

139

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Coagulation is fundamental for the confinement of infection and/or the inflammatory response to a limited area. Under pathological inflammatory conditions such as arthritis, multiple sclerosis or sepsis, an uncontrolled activation of the coagulation system contributes to inflammation, microvascular failure and organ dysfunction. Coagulation is initiated by the activation of thrombin, which, in turn, triggers fibrin formation by the release of fibrinopeptides. Fibrin is cleaved by plasmin, resulting in clot lysis and an accompanied generation of fibrin fragments such as D and E fragments. Various coagulation factors, including fibrinogen and/or fibrin [fibrin(ogen)] and also fibrin degradation products, modulate the inflammatory response by affecting leukocyte migration and cytokine production. Fibrin fragments are mostly proinflammatory, however, Bβ15-42 in particular possesses potential antiinflammatory effects. Bβ15-42 inhibits Rho-kinase activation by dissociating Fyn from Rho and, hence prevents stress-induced loss of endothelial barrier function and also leukocyte migration. This article summarizes the state-of-the-art in inflammatory modulation by fibrin(ogen) and fibrin fragments. However, further research is required to gain better understanding of the entire role fibrin fragments play during inflammation and, possibly, disease development.

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“…Along with this, the fibrinolysis system is activated, leading to a significant amount of fibrin degradation products (Lord 2007;Mosesson 2005). Namely, X and Y fragments, D-dimers, D and E fragments, Bβ15-42 and smaller fragments (Olexa et al 1981;Smith et al 1990;Walker and Nesheim 1999).…”

Section: Fibrin Degradation Productsmentioning

confidence: 99%