Detection and Relevance of Crosslinked Fibrin Derivatives in Blood

Graeff, H.; Hafter, R.

doi:10.1055/s-2007-1005042

Cited by 81 publications

(45 citation statements)

References 43 publications

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“…In extracts and digests the main band was at 179 000 Da. This compares with reported molecular weights of 184 000, 21 186 000, 22 and 195 000. 23 On immunoblots of SDS-PAG, bands e, and f both reacted with a monoclonal antibody to the D-dimer link (3B6/22, kindly gifted by MabCo, through Ager Inc., Arlington, NJ); however, the antibody also reacted with a …”

Section: Bandfsupporting

confidence: 56%

“…Graeff and Hafter 21 showed experimentally in vitro that fragment DY (band e,) produced by the first pathway was larger (M, 239 000) than that produced in the simultaneous reaction {M, 226 400). In our extracts of both intima and mural thrombi, this band most frequently had an M, of 238 000; M, 226 000 was found in only two of 28 bands (Table 4, band e,), suggesting that cross-linked fibrin is formed before initiation of plasmin degradation.…”

Section: Discussionmentioning

confidence: 99%

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Fate of fibrinogen in human arterial intima.

et al. 1990

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Fibrinogen and flbrinogen/flbrin-related antigen (total FRA) was measured In human normal Intima and different types of atherosclerotic lesions and mural thrombi. The amount showed marked variation between groups of tissue samples, but within each group there was a significant correlation between levels of total FRA and low density llpoproteln (LDL), suggesting that some common factor must Influence their influx or retention. The total FRA were analyzed by gradient sodium dodecyl sutfate polyacrylamlde gel electrophoresis and ImmunoblottJng with antisera to whole fibrinogen and fragments D and E, and fibrinopeptlde A (FPA). All intimal samples (but not thrombi) contained fragment X, the first product of plasmln digestion of fibrinogen, but fragment Y was present In only half the samples, and no core-fragment E containing FPA was detected in any sample, suggesting that flbr/nogenolysis Is limited. By contrast, all samples contained fragment E, which was negative for FPA, so presumably derived from fibrin; they also contained fragments D-dlmer and DY, which are characteristic degradation products of cross-linked fibrin. There were no differences between samples obtained during reconstructive 1 The early proliferative lesions appear first as small translucent elevations but may progress to massive translucent proliferate mounds, up to 2500 tun In thickness, which are particularly characterized by their high water content; this gives them a soft and wobbly texture, and they are described as gelatinous lesions. 23 In a high proportion of these lesions, neither extracellular lipid nor lipid within fat-filled SMC or macrophages can be demonstrated in frozen microscopical sections, suggesting that lipid deposition cannot be the factor initiating SMC proliferation. These lesions contain large amounts of plasma macromolecules, including low density lipoprotein (LDL), fibrinogen and fibrin-related antigens (FRA), other components of the hemostatic system, and insoluble fibrins** In a preliminary study of the FRA fraction, Smith and Walker 6 found that about naff was comprised of intact fibrinogen, but the remainder consisted of fragments, mainly of high molecular mass, which showed characteristic patterns in different types of lesions. Different fibrin or fibrinogen degradation products have a wide range of pharmacobiological activities, including stimulation of growth of cultured cells; modification of clotting, vascular all of which might influence atherogenesis. In the present study we have attempted a detailed identification of the FRA present in lesions to relate them to particular biological activities, and, by determining if they are derived from fibrinogen or fibrin, to gain a better insight Into the handling of hemostatic factors in the arterial wall. Previously, we isolated the FRA from intimal extracts by affinity chromatography on Sepharose-antjfibrinogen columns, followed by elution with 8 M urea and separation by sodium dodecyl sutfate polyacrylamide gel electrophoresis (SDS-PAGE) and staining with Coomassie ...

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Section: Bandfsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Fate of fibrinogen in human arterial intima.

et al. 1990

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“…It is unlikely that the association between plasma fibrinogen and TOD in these patients is merely due to chance, because the strength of the association, the dose-response relationship, and the independent association demonstrated by multivariate analysis suggest causality and reduce the likelihood of confounding variables. Because fibrinogen is an acute phase reactant, it is also possible that vascular lesions with inflammatory components could be responsible for the association between fibrin- 9 and a good biochemical marker of an existing thrombophilia. Prospective epidemiological studies have demonstrated that D-dimer is independently associated with risk of myocardial infarction, 10 cerebrovascular accidents, 11 and peripheral arterial disease.…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the results of the Leigh study, in which hypertensive patients with plasma fibrinogen above 3.5 g/L had a 12-fold greater coronary risk than those with fibrinogen below 2.9 g/L, suggest that fibrinogen levels may affect prognosis in hypertension. 8 Similar to fibrinogen, elevations of D-dimer, the principle breakdown fragment of fibrin and a reliable indicator of the overall state of activation of the coagulation pathways, 9 are associated with increased risk of future myocardial infarction, 10 stroke, 11 and peripheral vascular disease. 12 These and other clinical and laboratory observations have led to the hypothesis that hypertension per se may confer a hypercoagulable state 13,14 that might be related to development of TOD and long-term prognosis.…”

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confidence: 99%

Relationship of Fibrinogen Levels and Hemostatic Abnormalities With Organ Damage in Hypertension

et al. 2000

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Abstract-Elevated plasma levels of fibrinogen and activated coagulation pathways are risk factors of cardiovascular disease in the general population. In a cross-sectional study of a case series, we investigated the relationship between fibrinogen and hemostatic markers with target-organ damage (TOD) in patients with arterial hypertension. Prothrombin time, partial thromboplastin time, fibrinogen, fibrin D-dimer, prothrombin fragment 1ϩ2 (F1ϩ2), and antithrombin III were measured in 352 untreated patients with mild to moderate essential hypertension and 92 normotensive controls. Staging of TOD was assessed according to W.H.O. guidelines by clinical evaluation and laboratory tests including measurements of creatinine clearance, proteinuria, ophthalmoscopy, electrocardiography, echocardiography, and ultrasound examination of major arteries. F1ϩ2 concentrations were significantly greater in hypertensive patients than normotensive controls and were positively correlated with blood pressure. Age, blood pressure levels, duration of hypertension, smoking, HDL-cholesterol, triglycerides, and plasma fibrinogen, fibrin D-dimer, and F1ϩ2 levels were significantly related to the presence and severity of TOD in univariate analysis. Plasma fibrinogen and D-dimer levels were related to organ damage independent of age, blood pressure, duration of hypertension, and smoking status. Separate analysis indicated significant association of fibrinogen and D-dimer levels with cardiac, cerebrovascular, peripheral vascular, and renal damage. In conclusion, elevated plasma levels of fibrinogen and a prothrombotic state are associated with the presence and severity of TOD in patients with essential hypertension and may contribute to the development of atherosclerotic disease in these patients. (Hypertension. 2000;36:978-985.)F requency of cardiovascular events is associated in a continuum manner with the level of blood pressure. 1 Blood pressure, however, is not the only determinant of cardiovascular damage, and the propensity of hypertensive patients to develop target-organ damage (TOD) is markedly influenced by coexisting risk factors such as age, gender, smoking, obesity, diabetes, and dyslipidemia. In addition to these factors, the hemostatic system is directly involved in the atherosclerotic process 2 and may affect the impact of hypertension on the development of TOD and thereby on cardiovascular morbidity. 3,4 Because arterial disease is the major underlying factor leading to most clinically relevant cardiovascular events and these events are usually due to formation of a thrombus at the site of an atherosclerotic plaque, research has concentrated on the state of the coagulation pathways. Fibrinogen is both a coagulation factor and an acute-phase reactant that has been identified as a major independent risk factor for coronary artery, 5,6 cerebrovascular, 6 and peripheral vascular 7 disease in the general population. Moreover, the results of the Leigh study, in which hypertensive patients with plasma fibrinogen above 3.5 g/L had a 1...

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“…24,25 The effect of terminal complement blockade with eculizumab on upstream AP activation or other markers of disease activity is unclear. We conducted a prespecified exploratory analysis as part of the C10-004 trial to investigate the effect of terminal complement blockade on biological markers associated with proximal and terminal complement activation, 22,23,26 inflammation, 27,28 endothelial cell activation and damage, [28][29][30][31][32][33][34][35] coagulation, 5,33,36,37 and renal injury [38][39][40] in patients with aHUS.…”

Section: Introductionmentioning

confidence: 99%

Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS

Cofiell

Kukreja

Bedard

et al. 2015

Blood

168

137

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• This exploratory study describes the effect of eculizumab on multiple physiologic pathways affected by complement dysregulation in aHUS.• The results highlight the importance of sustained terminal complement blockade, even in patients with improved clinical laboratory values.Atypical hemolytic uremic syndrome (aHUS) is a genetic, life-threatening disease characterized by uncontrolled complement activation, systemic thrombotic microangiopathy (TMA), and vital organ damage. We evaluated the effect of terminal complement blockade with the anti-C5 monoclonal antibody eculizumab on biomarkers of cellular processes involved in TMA in patients with aHUS longitudinally, during up to 1 year of treatment, compared with in healthy volunteers. Biomarker levels were elevated at baseline in most patients, regardless of mutational status, plasma exchange/infusion use, platelet count, or lactate dehydrogenase or haptoglobin levels. Eculizumab reduced terminal complement activation (C5a and sC5b-9) and renal injury markers (clusterin, cystatin-C, b2-microglobulin, and liver fatty acid binding protein-1) to healthy volunteer levels and reduced inflammation (soluble tumor necrosis factor receptor-1), coagulation (prothrombin fragment F112 and D-dimer), and endothelial damage (thrombomodulin) markers to near-normal levels. Alternative pathway activation (Ba) and endothelial activation markers (soluble vascular cell adhesion molecule-1) decreased but remained elevated, reflecting ongoing complement activation in aHUS despite complete terminal complement blockade. These results highlight links between terminal complement activation and inflammation, endothelial damage, thrombosis, and renal injury and underscore ongoing risk for systemic TMA and progression to organ damage. Further research regarding underlying complement dysregulation is warranted. This trial was registered at www.clinicaltrials.gov as #NCT01194973. (Blood. 2015;125(21):3253-3262)

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Detection and Relevance of Crosslinked Fibrin Derivatives in Blood

Cited by 81 publications

References 43 publications

Fate of fibrinogen in human arterial intima.

Fate of fibrinogen in human arterial intima.

Relationship of Fibrinogen Levels and Hemostatic Abnormalities With Organ Damage in Hypertension

Eculizumab reduces complement activation, inflammation, endothelial damage, thrombosis, and renal injury markers in aHUS

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