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PubMed1993

[Heterocomplex formation between high and low affinity FGF receptors is mediated by the formation of a FGF dimer].

Interactions between the two classes of fibroblast growth factor receptors 1) the high affinity receptors (HAR) a membrane glycoprotein containing an intrinsic tyrosine kinase activity, 2) low affinity receptors (LAR) cell surface proteoglycans containing heparan sulfate side chains (HSPG), and aFGF (MW: 15.5 kDa) were studied in bovine lens epithelial (BEL) cells. By Scatchard analysis of the aFGF binding to the BEL cell surface, we show that heparin at 10 micrograms/ml abolishes completely aFGF binding to LAR and reduces by half the number of aFGF HAR. By using cross-linking experiments, aFGF-HAR complexes are present in two forms (150 kDa and 135 kDa). Addition of heparin at 10 micrograms/ml abolishes the formation of the 150 kDa complex and does not affect the 135 kDa complex. Furthermore, binding of aFGF to LAR induces the spontaneous formation of a 31 kDa aFGF dimer. The dimerization process of aFGF on LAR is abolished by addition of heparin. During aFGF internalization at 37 degrees C, we have shown that aFGF-dimer is internalized, accumulated and degraded in the cell as is the 15.5 kDa native form. Heparin at 10 micrograms/ml suppresses specifically aFGF dimer internalization and reduces by half the total amount of internalized aFGF native form. Moreover, after aFGF binding and internalization, the affinity of HAR for aFGF increases concomitantly with its downregulation. Heparin does not seem to affect this phenomenon. All these results strongly suggest that an heteroreceptor dimer-aFGF complex (150 kDa) is formed by one molecule of HAR associated to one molecule of LAR through their respective interaction with a very stable homodimer of aFGF. Such a three component receptor complex induced by FGF dimerization may be a general process of FGF receptor activation which could explain the diversity of the biological response to FGF of different cell type expressing different HAR and LAR or HSPG.

Animals↗
PubMed1995

The native structure of intercellular adhesion molecule-1 (ICAM-1) is a dimer. Correlation with binding to LFA-1.

In solution, intercellular adhesion molecule-1 (ICAM-1) exhibits extremely low affinity for its receptor, LFA-1, as direct binding to LFA-1 has not been reported. Furthermore, there are conflicting reports on the ability of ICAM-1 in solution to inhibit cell adhesion events. These differences could be due to the valency or an oligomeric native biochemical form of membrane-bound and soluble ICAM-1, which may correlate with its ability to bind to integrins. To test this, stimulated adenocarcinoma (A549) cells or HUVEC were labeled with 35S-methionine/cysteine and treated with a chemical cross-linker. A high m.w. form (200 kDa) of ICAM-1 but not ICAM-2 was specifically immunoprecipitated from cross-linked cell lysates and supernatants. Affinity purification of crosslinked supernatants revealed that the majority of ICAM-1 was dimeric as opposed to recombinant soluble ICAM-1, which contains a minor fraction of dimer. Gel filtration chromatography was used to isolate monomeric and dimer-rich fractions of recombinant soluble ICAM-1, and tested for direct binding to affinity-purified LFA-1. Dimer-rich fractions demonstrated an enhanced ability and estimated affinity, compared with monomeric protein, to bind to purified LFA-1. These data suggest that ICAM-1 exists in its native membrane-bound and shed form as a non-covalent dimer, and that dimerization directly correlates with enhanced binding to LFA-1.

Cross-Linking Reagents↗
PubMed1995

CNS-effects from subarachnoid injections of iohexol and the non-ionic dimers iodixanol and iotrolan in the rabbit.

The neural tolerance of the new non-ionic dimer iodixanol was compared with that of the clinically used monomer iohexol and the dimer iotrolan. Behaviour of non-anaesthetised rabbits was monitored for 3 hours after intracisternal injection, at a dose-volume of 1 ml/kg of iodixanol 150 mg I/ml, iodixanol 320 mg I/ml, iohexol 350 mg I/ml, or iotrolan 300 mg I/ml (10 rabbits in each group). Iotrolan induced generalized seizures in 5 rabbits, iodixanol 320 mg I/ml in 2 rabbits, and iodixanol 150 mg I/ml in one rabbit. No excitative changes were observed in rabbits, iodixanol 320 mg I/ml in 2 rabbits, and iodixanol 150 mg I/ml in one rabbit. No excitative changes were observed in rabbits injected with iohexol, but compared with the dimeric contrast media the difference was not significant. Iohexol produced significantly more severe depressive changes than iodixanol 150 mg I/ml (p < 0.01), iodixanol 320 mg I/ml (p < 0.05), and iotrolan 300 mg I/ml (p < 0.05). The results indicate that the excitative neurotoxic potential of the dimer iodixanol is likely to be lower than that of the clinically used dimer iotrolan, but slightly higher than that of iohexol. It may be expected that both dimers will produce a lower frequency of minor neurological adverse reactions than iohexol.

Akathisia, Drug-Induced↗
PubMed1994

Covalent dimerization of vascular permeability factor/vascular endothelial growth factor is essential for its biological activity. Evidence from Cys to Ser mutations.

Vascular permeability factor, or vascular endothelial growth factor (VPF/VEGF) is an important factor in the regulation of vascular growth and vascular permeability. VPF is a secreted, dimeric protein and has 8 cysteine residues conserved with platelet-derived growth factor (PDGF). To study the role of some of these cysteine residues in maintaining the structure and function of VPF, we replaced the codons for the second, third, fourth, and fifth cysteine by serine codons, and expressed the mutant proteins in a mammalian expression system. Cysteine residues 2 and 4 in VPF were found to be directly involved in anti-parallel interchain disulfide bonds, as in PDGF. VPF mutants lacking one of these cysteins were severely impaired in their S-linked dimerization, while upon coexpression of both mutants the ability to form dimers was restored. The VPF mutants lacking cysteine residue 2 or 4 also competed poorly for receptor binding of labeled VPF and had low biological activity, but these defects were also complemented by coexpressing the two mutants, indicating that for efficient receptor binding and activation VPF needs to be a covalent dimer, unlike PDGF-BB. Furthermore, cysteine residue 5 was found to be essential for VPF dimerization and activity, while the mutant lacking cysteine residue 3 was only mildly affected in its ability to dimerize and had partial biological activity.

Binding, Competitive↗
PubMed1994

High D-dimer levels: a possible index of risk of overt disseminated intravascular coagulation and/or digestive bleeding in advanced liver cirrhosis?

The coagulation parameters of fourteen patients with advanced liver cirrhosis (3 in Child class B and 11 in class C) were prospectively determined quarterly for one year in order to evaluate the possible relationship between high D-dimer levels and incidence of disseminated intravascular coagulation (DIC) and of gastrointestinal bleeding. The values of D-dimer, fibrin(ogen) degradation products, platelets, fibrinogen, prothrombin activity and antithrombin III were fairly stable in almost all patients and no patient developed an overt DIC; one patient had a significant increase in D-dimer three months after the first control. During the one year follow-up, four patients died, one by the occurrence of hepatocellular carcinoma and three by digestive bleeding. Overall, four patients had upper digestive tract bleeding, three from esophageal varices and one from hemorrhagic gastritis. Hemorrhage was more frequent in patients with high D-dimer levels (3/7, 43%) than in patients with normal D-dimer levels (1/7, 14%). In conclusion, the detection of high D-dimer levels in patients with advanced cirrhosis is not predictive for the occurrence of a overt DIC but seems to be related with an increased risk of gastrointestinal bleeding.

Aged↗
PubMed1994

Circulating D dimer in inflammatory bowel disease.

An activated thrombogenesis has been reported in inflammatory bowel disease (IBD). In this study we evaluated whether a fibrin degradation product, the D dimer, is increased in patients with IBD. D dimer plasma levels were evaluated by sandwich ELISA in patients with Crohn's disease (24), ulcerative colitis (25), gastrointestinal (GI) disease controls (10), hospital controls (13) and healthy subjects (14). Circulating D dimer was significantly higher in ulcerative colitis (median 651; 95% CI 89-1275 ng/ml) than in healthy subjects (median 412; 95% CI 112-672 ng/ml; p = 0.002), Crohn's disease (median 466; 95% CI 6-931 ng/ml; p = 0.005) and GI disease controls (median 446; 95% CI 196-688 ng/ml; p = 0.023). In ulcerative colitis, plasma D dimer was related to inflammatory parameters such as C-reactive protein (p < 0.01) and seromucoids (p < 0.001). Circulating D dimer was age-related in all groups (p < 0.05). Fibrin degradation, as reflected by plasma D dimer, is detected in patients with ulcerative colitis exhibiting a marked acute phase response.

Adult↗
PubMed1994

Fibrinogen, D-dimer and thrombin-antithrombin complexes in a random population sample: relationships with other cardiovascular risk factors.

Fibrinogen is an independent risk factor for cardiovascular disease and both D-Dimer and Thrombin-Antithrombin complexes may be suitable as laboratory markers of deep venous thrombosis and are becoming more widespread in clinical practice. The aim of our study was to evaluate their normal range and to examine their correlation with various cardiovascular risk factors. Fibrinogen, D-Dimer and Thrombin-Antithrombin complexes were assessed in 516 normal subjects randomly selected from the National Health Service register of Trieste (Italy). In our community the mean value of fibrinogen was 283 +/- 71 mg/dl. Fibrinogen increases with age in males and was significantly higher in male smokers. In non-smokers, females had significantly higher fibrinogen values than males. The mean value of D-Dimer was 306 +/- 130 ng/ml. In females it is significantly higher. The fibrinogen and D-Dimer correlation coefficient was 0.20 (p < 0.001). The mean level of Thrombin-Antithrombin complexes was 6.25 +/- 6.8 ng/ml with a distribution markedly skewed towards the left; males had lower concentration than females (p = 0.047). Multiple regression analysis for fibrinogen as a dependent variable showed that D-Dimer, LDL-cholesterol, Body-Mass Index and Thrombin-Antithrombin complexes were poor predictors for fibrinogen plasma levels (R2 = 0.23) and that fibrinogen, ApoA1 and age can explain only about 10% of the observed variability in D-Dimer.

Adult↗
PubMed1994

Stabilization of an active dimeric form of the epidermal growth factor receptor by introduction of an inter-receptor disulfide bond.

Populations of the epidermal growth factor receptor (EGFR) with both high and low affinity for EGF are found on the surface of cells. It has been hypothesized that the high-affinity state of the EGFR represents the receptor dimer and that this is also the kinase-active form. We describe here studies aimed at addressing this question directly. To stabilize homodimers of EGFR, we have generated a mutated form of the receptor by inserting a cysteine residue in the extracellular juxtamembranous region, in order to cross-link the extracellular domains of two receptors via disulfide bond formation. The mutation resulted in ligand-induced appearance of covalently linked EGF receptor dimers and, in parallel, increased the number of high-affinity receptors present on the surface of cells expressing the mutated EGFR. Comparison of the tyrosine kinase activity of the covalently linked dimeric and the monomeric forms of the EGF receptor, separated by sucrose density gradient centrifugation, showed that the dimer was significantly more active than monomer in the phosphorylation of exogenous substrate. We conclude that the dimeric form of the EGF-receptor represents the active form, and that dimer formation is associated with the appearance of high-affinity binding EGF receptors on the cell surface.

3T3 Cells↗
PubMed1993

Thyroid hormone receptor dimerization is required for dominant negative inhibition by mutations that cause thyroid hormone resistance.

The syndrome of thyroid hormone resistance (THR) is caused by multiple distinct mutations of the ligand-binding domain of the thyroid hormone beta receptor. Although the mutant receptors are transcriptionally inactive, they inhibit normal receptor function in a dominant negative manner to cause hormone resistance. Because most of the naturally occurring mutations are clustered within two areas that lie on either side of a putative dimerization region, we hypothesized that receptor dimerization was important for dominant negative inhibition. In gel mobility shift assays, two THR mutants (G345R and P453H) formed homodimers as well as heterodimers with the retinoic acid X receptor alpha. In contrast, an artificial mutation (L428R) in one of the hydrophobic heptad repeats of the putative receptor dimerization domain impaired heterodimerization with retoinoic acid X receptor alpha without altering the formation of homodimers. Double mutants containing either of the THR mutations along with the dimerization mutation formed homodimers but not heterodimers, reflecting the properties of the dimerization mutant alone. In transient expression assays using positively (TRETKLuc) or negatively (TSH alpha Luc) regulated reporter genes, the dominant negative activity of the THR mutants was eliminated by the addition of the dimerization mutation. These results support a mechanism for dominant negative activity by THR mutants in which functionally inactive heterodimers bind to DNA to inhibit access by normal receptors.

Amino Acid Sequence↗
PubMed1993

Steroid requirement for androgen receptor dimerization and DNA binding. Modulation by intramolecular interactions between the NH2-terminal and steroid-binding domains.

Infection of Spodoptera frugiperda Sf9 insect cells with recombinant human androgen receptor (AR) baculovirus results in expression of a 118-kDa phosphoprotein that displays high affinity androgen binding and androgen-dependent targeting to the nucleus. Using the DNA mobility shift assay, specific in vitro binding of full-length AR to androgen response element DNA (ARE) requires intracellular hormone exposure. The ability of a variety of steroids to induce ARE binding paralleled their transcriptional potential. Certain antihormones, cyproterone acetate and RU486, promote ARE binding, but a pure antiandrogen, hydroxyflutamide, inhibits AR binding to ARE DNA. AR dimerization requires incubation of recombinant baculovirus-infected insect cells with androgen, but only when one or both components of the dimer contain the NH2-terminal domain. Based on the intensities of ARE binding and lack of binding to an ARE half-site, it appears that, unlike the glucocorticoid receptor, AR binds DNA primarily as a dimer. Thus, full-length baculovirus-expressed AR requires intracellular hormone exposure for dimerization and ARE binding to overcome inhibition imposed by the AR NH2-terminal domain. Antihormones with agonist activity promote dimerization and ARE binding, while a pure antiandrogen blocks AR DNA binding. It is concluded that intramolecular interactions between the NH2-terminal and steroid-binding domains are regulated by the specificity of hormone binding and modulate receptor dimerization and DNA binding.

Androgens↗
PubMed1993

Plasma D-dimer: a useful tool for evaluating suspected pulmonary embolus.

Although ventilation-perfusion lung scanning is widely used in evaluating patients with suspected pulmonary embolus, additional rapid screening tests are needed to supplement scintigraphy in patients in whom the scan is indeterminate or the scan results are discordant with clinical suspicion. D-dimer is a fibrin degradation product which should be elevated in the presence of intravascular coagulation. We prospectively studied patients referred for lung scanning by obtaining a plasma D-dimer latex agglutination assay at the time of the scan. Of 64 patients who had pulmonary angiography to confirm the diagnosis, 16 were positive for pulmonary embolus and only one had a normal D-dimer. The D-dimer was normal in 27 of 48 patients without embolus and elevated in 21. Although an elevated D-dimer level is a nonspecific finding, we conclude that a normal D-dimer is a good negative predictor for pulmonary embolus, with a negative predictive value of 0.97.

Enzyme-Linked Immunosorbent Assay↗
PubMed1996

[Diagnosis of venous thrombosis and/or pulmonary embolism by determination of d-dimers using ELISA. Review based on a study of 80 consecutive patients hospitalized in an emergency unit].

The sensitivity and specificity of an ELISA method (Fibrinostika Fbdp Organon Teknika) for assay of D-dimers in the diagnosis of deep vein thrombosis and/or pulmonary embolism was studied in 80 consecutive patients seen at an emergency unit. Fifty-six of the patients presented clinical signs of deep vein thrombosis. Diagnosis was confirmed in 26 of the 56 patients with a D-dimer level above 370 ng/ml (sensitivity 92.3%) and 370 ng/ml for 13 of 30 patients with a negative venous ultrasound Doppler examination (specificity 43.3%). The positive predictive value was 58.5% and the negative predictive value was 87%. There was a significant difference in the level of D-dimers between distal and proximal deep vein thrombosis. In 40 cases with suspected pulmonary embolis, either alone or with suspected deep vein thrombosis, diagnosis was made in only 4 of 9 with a highly or intermediately probable ventilation/perfusion scan. D-dimer level was always above 3,000 ng/ml. Coupling the ELISA dimer test with noninvasive explorations improves negative predictive value but can also avoid invasive explorations (venography, pulmonary angiography) in certain patients. A D-dimer test as sensitive as the ELISA test and as rapid as the latex test remains to be described.

Adolescent↗
PubMed1996

[Level of D-dimer and comparison with cell count in pleural effusion from tuberculosis and neoplasms].

The examinations were carried out in 33 patients (aged 21-69 years) with tuberculous and neoplastic effusions, before and during the treatment. 10 subjects with circulatory failure and pleural effusion a consisted control group. D-dimer level was detected using semiquantitative method (D-dimer Latex Test, Diagnostica Stago-Boehringer Mannheim), cells number and composition-using light microscope. All the groups demonstrated significant differences in the effusion D-dimer level before and during the treatment. Cells number was significantly higher in tuberculous and carcinomatous pleural effusion than in the control group. D-dimer level correlated with neutrophils percentage only in tuberculous effusions before the treatment. We found no correlation in D-dimer level and cells number and composition in neoplastic pleural effusion. We did not find any correlation in D-dimer level and cells number in blood.

Adult↗
PubMed1997

[A coagulation of fibrinolytic study in children with nephrotic syndrome: evaluation of hypercoagulability by measuring with plasmin- alpha 2 plasmin inhibitor complex and FDP D-dimer].

Increased plasma plasmin-alpha 2 plasmin inhibitor complex (PIC) and FDP D-dimer (D-dimer) reflect in vivo activation of the coagulation and fibrinolytic systems. We measured plasma PIC, D-dimer and other coagulation and fibrinolytic parameters in 42 children with nephrotic syndrome. Higher levels of both plasma PIC (0.67 +/- 0.48 micrograms/ml, P < 0.01) and D-dimer (154 +/- 105 ng/ml, P < 0.001) were observed at the active stage of nephrotic syndrome, compared to the remission stage (0.43 +/- 0.18 micrograms/ml, 72 +/- 48 ng/ml, respectively). In addition, plasma D-dimer correlated significantly with serum albumin, urinary protein, plasma fibrinogen, aPTT, and plasma antithrombin III activity. Although no thromboembolic complication was diagnosed clinically in the study period, increased plasma PIC or D-dimer may reflect a hypercoagulable state or subclinical thrombosis in nephrotic syndrome.

Adolescent↗
PubMed1997

A reference material for harmonisation of D-dimer assays. Fibrinogen Subcommittee of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis.

The term "D-dimer assay" suggests, that these assays report the concentrations of the end-stage degradation product of crosslinked fibrin. This hardly occurs in patients. Degradation products of cross-linked fibrin rather occur with a wide range of molecular weights, and comprise various numbers of the D-dimer motif. Moreover, the numerical values obtained with different "D-dimer" assays vary widely. The variations are probably due to differences in reactivity of the various monoclonal antibodies used with the various D-dimer containing degradation products as they occur in patients; and to the various calibrators with a value assigned by the manufacturers. For the reasons indicated above a calibrator in the strict sense (e.g., pure D-dimer) is not feasible. This study shows that: it appears feasible to generate a conversion factor for each of the "D-dimer" assays studied, which will make the widely varying results obtained with these kits comparable; that the conversion factors can be based on a pool of real patient samples; and that the conversion factors are pool-independent. The next and final step in this study is to prepare and make available an international reference material for use by manufacturers and others facing a comparison problem. This is being carried out, in collaboration with the NIBSC (Dr. P. Gaffney), and the material is expected to be available in early 1997.

Antifibrinolytic Agents↗
PubMed1998

Evaluation of D-dimer ELISA test in elderly patients with suspected pulmonary embolism.

STUDY OBJECTIVE: To determine the clinical usefulness of D-dimer ELISA test in elderly patients with clinically suspected pulmonary embolism (PE). DESIGN: Prospective cohort study. PATIENTS: Ninety-six consecutive outpatients older than 70 years with a duration of symptoms shorter than one week and without metastatic cancer or recent surgery, trauma, infection, stroke, myocardial infarction, deep vein thrombosis (DVT) or PE, or treatment with curative doses of heparin or oral anticoagulant. INTERVENTION: All patients underwent at least ventilation/perfusion scan and bilateral ultrasonic duplex scan and a blood sample collection within 24 hours of admission. When necessary a pulmonary angiography and/or a bilateral venography were also performed. Patients were classified as follows: (1) PE-positive: positive angiography or high probability V/Q scan and deep vein thrombosis (proven either by venography or by ultrasonic duplex scan) or non high probability V/Q scan and either DVT (proven at presentation by venography or by ultrasonic duplex scan) or symptomatic thromboembolic event within 3 months of follow-up; or (2) PE-negative; normal V/Q scan or normal angiography or non high probability V/Q scan and either negative ultrasonic duplex scan or normal venography and low clinical probability and absence of symptomatic thromboembolism within 3 months of follow-up. D-dimer measurements were performed using both a conventional and a single semi-quantitative ELISA test (Asserachrom D-di, Instant I.A.D-dimer). RESULTS: Using a cutoff value of 500 ng/ml, the conventional ELISA D-dimer test showed a sensitivity and a negative predictive value of 100% with poor specificity and positive predictive value of 14.3% and 45.5% respectively. The new rapid semi-quantitative D-dimer test displays worse results with sensitivity, negative predictive value, specificity and positive predictive value of 92.3%, 82.4%, 25% and 46% respectively. CONCLUSION: In a geriatric population, conventional ELISA D-dimer is a good marker to exclude PE but, due to the comorbid conditions, only a few patients presented with D-dimer values less than 500 ng/ml.

Aged↗
PubMed1997

[Determination of plasma D-dimer in patients with pregnancy induced hypertension].

OBJECTIVE: To investigate the changes and the clinical significance of plasma D-dimer in normal pregnant women and patients with pregnancy induced hypertension (PIH). METHODS: Using ELISA method, we measured the level of plasma D-dimer in 160 cases, including 106 normal pregnant women and 25 patients with mild and moderate PIH, 18 patients with preeclampsia and 11 patients with eclampsia. RESULTS: The value (2.27 +/- 0.92 mg/L) of plasma D-dimer in mild and moderate PIH patients was markedly higher than that of normal third trimester pregnant women (1.45 +/- 0.38 mg/L, P < 0.01). The value (3.09 +/- 1.65 mg/L) of plasma D-dimer in preeclampsia patients was markedly higher than that of mild and moderate PIH patients (P < 0.01). The value (5.62 +/- 1.34 mg/L) of plasma D-dimer in eclampsia patients was markedly higher than that of preeclampsia patients. CONCLUSION: Determination of plasma D-dimer level in second and third trimester pregnant women was of great significance in diagnosing early PIH and predicting the prognosis of PIH.

Adult↗
PubMed1997

[The role of D-dimer determination in clinical evaluation with pulmonary perfusion scintigraphy].

The diagnosis of pulmonary embolism is even in contemporary clinical practice problematical. Pulmonary angiography is used in our departments very little due to its invasive character. The method of choice for diagnosis remains therefore perfusion scintigraphy of the lungs, in this country frequently without ventilation scintigraphy as it is not available in the majority of our departments of nuclear medicine. In recent years in the diagnostic algorithms also assessment of D-dimers was started, i.e. assessment of products of fibrinolysis assessed by monoclonal antibodies. The authors tried to find out how many patients admitted to the medical department for diagnosis of pulmonary embolization may have a false positive diagnosis on the basis of pulmonary scintigraphy. During the period III/96 to V/96 a total of 18 patients from the medical clinic with suspected pulmonary embolism were examined where the value of D-dimers(latex test) was assessed and at the same time perfusion scintigraphy was performed. With regard to the highly negative predictive value of D-dimer assessment the authors focused their attention on patients with a suspect or positive lung scan (i.e. treated on account of pulmonary embolism) while D-dimers were negative. Of 13 patients with suspect or possible pulmonary embolism, as assessed by scintigraphy, four had negative dimers(30%). With regard to the 90% reported negative predictive value, based on the literature, thus three of these patients were unnecessarily admitted to hospital and treated. The authors assume that assessment of D-dimers should be part of the examination protocol due to its non-pretentious character and low price as compared with costs of hospitalization.

Biomarkers↗