Heart-type fatty acid binding protein levels in elderly diabetics without known cardiovascular disease
Selvihan BeyselMuhammed KızılgülMustafa ÖzbekMustafa ÇalışkanSeyfullah KanMahmut ApaydınÖzgür ÖzçelikErman Cakal
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Cardiovascular disease (CVD) is reported to be higher in elderly diabetics. Serum heart-type fatty acid binding protein (H-FABP) is a serum marker of myocardial ischemia. We aimed to investigate the association between serum H-FABP level and conventional cardiovascular risk factors, inflammatory markers and subclinical atherosclerosis in elderly diabetics without overt CVD.A total of 50 elderly diabetic patients without overt CVD and 30 age-, sex- and body mass index (BMI)-matched healthy controls were enrolled. Anthropometric and biochemical parameters, serum H-FABP, high-sensitivity C-reactive protein (hs-CRP), fibrinogen and carotid intima-media thickness (CIMT) were measured. Logistic regression analyses (adjustments for age, sex, hypertension, smoking, diabetes, BMI, blood pressure, lipid, blood glucose, hemoglobin A1c, hs-CRP and fibrinogen) were performed to evaluate the association between H-FABP and cardiovascular risk factors and atherosclerosis indices.Serum fibrinogen (421.50±85.52 mg/dL vs 319.17±30.77 mg/dL, p=0.023), CIMT (0.70±0.12 mm vs 0.59±0.06 mm, p<0.001) and hs-CRP (5.72±4.50 mg/dL vs 1.60±0.72 mg/dL, p<0.001) were significantly higher in diabetic patients than controls. The mean serum H-FABP level did not differ between groups (1571.79±604.60 ng/mL vs 1500.25±463.35 ng/mL, p=0.905). H-FABP was positively correlated with fibrinogen (r2=0.473, p<0.001), hs-CRP (r2=0.323, p=0.003) and CIMT (r2=0.467, p<0.001). After full adjustments, the serum H-FABP level was independently associated with an increase in the fibrinogen level (odds ratio [OR] =4.21, 95% confidence level [CI] =1.49-11.90).Serum H-FABP was similar in the elderly diabetic patients without known CVD when compared with the nondiabetic control group. H-FABP does not possess a high diagnostic value as a cardiovascular marker when used alone; however, it may add supplementary information in patients with a high fibrinogen level.Keywords:
Lipid Profile
Fibrinogen is a large heterogeneous family of closely related molecules consisting of three pairs of non-identical polypeptide chains: two Aα-, two Bβ- and two γ-chains, held together by disulphide bridges. The heterogeneity of fibrinogen is due to heterogeneities in all three chains. Four main types of assay are used to determine fibrinogen: clotting rate (Clauss), clottable protein, precipitation and immunological assays. Heterogeneities may differ from person to person and may affect the apparent fibrinogen concentrations in different assays. A further complicating factor was, until recently, the lack of an international fibrinogen standard. The ratio of Clauss: enzyme immunoassay (EIA) for high+low molecular weight fibrinogen decreases during therapy for acute myocardial infarction and increases again after thrombolytic therapy to above normal values. Furthermore, high molecular weight fibrinogen tends to clot more easily than low molecular weight fibrinogen. This suggests that high molecular weight fibrinogen might be associated with increased thrombotic risk. Fibrinogen assessed by a functional assay (Clauss) alone is strongly associated with ischaemic heart disease. Although not proven, it is conceivable that a fibrinogen with a Clauss: EIA ratio of >1 has an even stronger association in epidemiological studies.
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As evidence accumulates to implicate fibrinogen as a risk factor for cardiovascular disease (CVD) it becomes important to characterize the levels and correlates of fibrinogen in diverse populations. Knowledge of the correlates of fibrinogen may help researchers to disentangle the independent contribution of elevated fibrinogen concentrations to CVD. Characterization of the normal range and possible determinants of fibrinogen concentrations, likewise, may aid CVD risk assessment and intervention research. Fibrinogen concentrations vary widely among populations and increase with age. Levels are consistently higher in women than men and rise after menopause. Smoking is the most important lifestyle correlate of fibrinogen. People with diabetes and hypertension have elevated fibrinogen levels, as do sedentary and obese individuals. Alcohol intake and oestrogen replacement therapy are associated with lower fibrinogen levels. Most other CVD risk factors are correlated positively with fibrinogen. Fibrinogen is clearly a marker of CVD risk. Yet, the strikingly non-specific pattern of higher fibrinogen with every CVD risk factor suggests that proving an independent causal role of fibrinogen will remain elusive in the absence of trials selectively lowering fibrinogen with the aim of reducing CVD.
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Using autologous (131)I-fibrinogen, we made studies of the metabolism and distribution of fibrinogen in 10 patients with hemophilia A. In two patients simultaneous studies of autologous (131)I-fibrinogen and homologous (125)I-fibrinogen prepared from healthy donors' plasma were carried out. The average value for the plasma volume was 42.1 +/- 8.8 ml/kg; for the plasma fibrinogen concentration, 349 +/- 90 mg/100 ml; for the intravascular fibrinogen, 144 +/- 32 mg/kg; for the interstitial fibrinogen, 30 +/- 11 mg/kg; for the slower half-life of (131)I-fibrinogen, 2.34 +/- 0.17 days; for the transcapillary transfer rate of fibrinogen, 109 +/- 37 mg/kg per day; and for the catabolic and synthetic rates of fibrinogen, 51.7 +/- 13.1 mg/kg per day. Comparison of these results with those of the previous study in healthy male subjects showed that in patients with hemophilia A the catabolic and synthetic rates of fibrinogen are markedly increased, whereas the plasma fibrinogen concentration, intravascular and interstitial fibrinogen, and the transcapillary transfer rate of fibrinogen are not significantly different. The simultaneous studies of autologous (131)I-fibrinogen and normal homologous (125)I-fibrinogen in two subjects revealed that the two preparations behaved very similarly. Based on these findings, we concluded that our present findings are not due to the qualitative difference between the hemophilia A and normal fibrinogens, but that they are due to the difference in the host condition with respect to the fibrinogen metabolism, which is either an increased rate of direct breakdown of fibrinogen or an increased rate of fibrinogen breakdown after fibrin formation, or both.
Catabolism
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The effects of altered fibrinogen concentrations on fibrinogen synthesis in rabbits were evaluated by determining the rate of appearance of [75Se]selenomethionine (75SeM) in circulating fibrinogen. Fibrinogen levels were maintained at twice normal by infusion of homologous fibrinogen for either 1 or 6 days before the intravenous injection of 20 micronCi of 75SeM, and the rate of appearance of labeled fibrinogen was measured during the subsequent 24 h. In both groups, synthesis was unchanged. Five hours after induction of partial defibrinogenation by the infusion of bovine thrombin, fibrinogen synthesis was increased threefold. Stimulation was not attributable to decreased fibrinogen concentrations; synthesis was increased equally when levels were maintained above normal by infusion of fibrinogen before administration of thrombin. Heat-inactivated thrombin and diisopropylfluorophosphate-inactivated thrombin did not stimulate fibrinogen synthesis. Thrombin produced elevated titers of fibrinogen-fibrin degradation products (FDP-fdp). However, fibrinogen synthesis was not increased in rabbits that had received FDP-fdp from thrombin-treated donors. These data suggest that neither the fibrinogen concentration nor FDP-fdp influenced fibrinogen synthesis.
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Fibrinogen has been reported to be a risk factor for development of myocardial infarction in patients with ischaemic heart disease. The functional properties of plasma high molecular weight (HMW) fibrinogen would suggest that this fibrinogen species is responsible for the association. In a prospective study with a follow-up period of 6 years the plasma concentrations of clottable fibrinogen and of HMW fibrinogen were related to the subsequent development of myocardial infarction in 53 patients admitted with ischaemic heart disease. Neither the concentrations of clottable fibrinogen nor of HMW fibrinogen in the 25 patients developing myocardial infarction deviated from the concentrations in the 28 patients with an uncomplicated course. A significant positive correlation between the concentrations of clottable fibrinogen and of HMW fibrinogen (rs = 0.58, p less than 0.001) suggests that HMW fibrinogen represents a major fraction of the clottable fibrinogen concentration in patients with ischaemic heart disease.
Ischaemic heart disease
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Catabolism
Afibrinogenemia
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Summary Fibrinogen Aarhus is an abnormal fibrinogen for which the clotting time with thrombin is greatly prolonged both in plasma and in the isolated fibrinogen. The whole blood clotting time is only slightly prolonged. The patient with this fibrinogen has no bleeding tendency. In this report we have investigated fibrinogen Aarhus in two alternative, thrombin independent polymerization and gelation pathways. These pathways are the factor XIII dependent oligomerization and gelation of fibrinogen, and heteropolymer (fibrinogen‐fibronectin) formation which also is catalysed by factor XIII. Both of these reactions are qualitatively the same in fibrinogen Aarhus as in normal fibrinogen, but the rate of oligomerization is somewhat slower in fibrinogen Aarhus. This may depend on impaired association between factor XIII and fibrinogen Aarhus.
Thrombin time
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In 12 patients treated with 100 mg rt-PA/3 h for acute myocardial infarction (AMI), serial fibrinogen levels were measured with the Clauss clotting rate assay ("functional fibrinogen") and with a new enzyme immunoassay for immunologically intact fibrinogen ("intact fibrinogen"). Levels of functional and "intact fibrinogen" were strikingly different: functional levels were higher at baseline; showed a more pronounced breakdown during rt-PA therapy; and a rebound phenomenon which was not seen for "intact fibrinogen". The ratio of functional to "intact fibrinogen" was calculated for each individual patient and each time point. The mean ratio (n = 12) was 1.6 at baseline, 1.0 at 90 min, and increased markedly between 8 and 24 h to a maximum of 2.1 (p < 0.01), indicating that functionality of circulating fibrinogen changes during AMI and subsequent thrombolytic therapy. The increased ratio of functional to "intact fibrinogen" seems to reflect a more functional fibrinogen at baseline and following rt-PA infusion. This is in keeping with data that the relative amount of fast clotting "intact HMW fibrinogen" of total fibrinogen is increased in initial phase of AMI. The data suggest that about 20% of HMW fibrinogen are converted to partly degraded fibrinogen during rt-PA infusion. The rebound phenomenon exhibited by functional fibrinogen may result from newly synthesized fibrinogen with a high proportion of HMW fibrinogen with its known higher degree of phosphorylation. Fibrinogen- and fibrin degradation products were within normal range at baseline. Upon infusion of the thrombolytic agent, maximum median levels of 5.88 micrograms/ml and 5.28 micrograms/ml, respectively, were measured at 90 min.(ABSTRACT TRUNCATED AT 250 WORDS)
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Objective:To evaluate the accuracy of determinating fibrinogen with Prithrombin time derived.Methods:The plasma fibrinogen of 113 patienss were determined by PT and recorded the derived fibrinogen,compared with the fibrinogen results of CLAUSS methed.Results:The within cv of PT derived fibrinogen was 3 5%.When the fibrinogen determination of PT derived was 1 50~2 99g/L,P0 05;when the fibrinogen was 3 00g/L, P 0 01,the results of PT derived fibrinogen were higher than the results of CLAUSS method.Conclusion:Plasma fibrinogen determination of PT derived is simple,economical,but not suitable for clinical application if the fibrinogen of PT derived result was over 3 00g/L.
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