The Oxidative Modification of Von Willebrand Factor Is Associated with Thrombotic Angiopathies in Diabetes Mellitus
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{"title"=>"The Oxidative Modification of Von Willebrand Factor Is Associated with Thrombotic Angiopathies in Diabetes Mellitus", "type"=>"journal", "authors"=>[{"first_name"=>"Laura", "last_name"=>"Oggianu", "scopus_author_id"=>"49061378400"}, {"first_name"=>"Stefano", "last_name"=>"Lancellotti", "scopus_author_id"=>"24780890700"}, {"first_name"=>"Dario", "last_name"=>"Pitocco", "scopus_author_id"=>"6602110238"}, {"first_name"=>"Francesco", "last_name"=>"Zaccardi", "scopus_author_id"=>"24345862000"}, {"first_name"=>"Paola", "last_name"=>"Rizzo", "scopus_author_id"=>"35316498100"}, {"first_name"=>"Francesca", "last_name"=>"Martini", "scopus_author_id"=>"57190091894"}, {"first_name"=>"Giovanni", "last_name"=>"Ghirlanda", "scopus_author_id"=>"35465821500"}, {"first_name"=>"Raimondo", "last_name"=>"de Cristofaro", "scopus_author_id"=>"7005866042"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-84873182274", "sgr"=>"84873182274", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"23383177", "doi"=>"10.1371/journal.pone.0055396", "pui"=>"368246811"}, "id"=>"f1766d7e-9b14-3b6c-bb34-926c407b75ca", "abstract"=>"The thrombogenic activity of Von Willebrand factor (VWF) is proportional to its molecular size and inversely related to its proteolysis by ADAMTS-13. Oxidation of VWF severely impairs its proteolysis by the metalloprotease. This study was aimed at assessing in patients with type 1 and type 2 diabetes whether protein carbonyls, marker of oxidative stress, are associated with both the level and oxidation status of VWF as well as with micro- and macroangiopathic complications. Eighty-three diabetic patients (41 type 1 and 42 type 2 diabetic subjects) and their respective eighty-three healthy controls were studied after verifying the availability, through institutional databases, of clinical biochemistry records spanning at least 3 years. VWF and protein carbonyls were measured by immunoassays, whereas VWF multimers were studied by SDS-agarose gel electrophoresis. Type 2 diabetic subjects had higher levels of VWF antigen (VWF:ag), VWF activity (VWF:act) and plasma proteins' carbonyls compared to both their controls and type 1 diabetic subjects. Moreover, high molecular weight VWF multimers and specific VWF-bound carbonyls were significantly increased in subjects with micro- and macro-angiopathic complications. In both type 1 and type 2 diabetic subjects, ADAMTS-13 activity was in the normal range. In a multivariable analysis, only VWF-bound carbonyls were significantly associated with any form of thrombotic angiopathy in the entire group of T1- and T2 diabetic patients. These data provide first evidence that not only high VWF levels but also its oxidation status and the presence of high molecular weight VWF multimers that are not observed in SDS-agarose gel electrophoresis of normal subjects are associated with thrombotic angiopathies in diabetes mellitus. These findings may help identify diabetic patients particularly at risk for these complications and elucidate a new pathophysiological mechanism of thrombotic angiopathies in this clinical setting.", "link"=>"http://www.mendeley.com/research/oxidative-modification-von-willebrand-factor-associated-thrombotic-angiopathies-diabetes-mellitus", "reader_count"=>21, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Librarian"=>1, "Student > Doctoral Student"=>1, "Researcher"=>4, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>2, "Student > Master"=>2, "Other"=>2, "Student > Bachelor"=>2, "Professor"=>1}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Librarian"=>1, "Student > Doctoral Student"=>1, "Researcher"=>4, "Student > Ph. D. Student"=>5, "Student > Postgraduate"=>2, "Student > Master"=>2, "Other"=>2, "Student > Bachelor"=>2, "Professor"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>4, "Agricultural and Biological Sciences"=>7, "Medicine and Dentistry"=>6, "Chemistry"=>1, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>6}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>7}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>4}, "Unspecified"=>{"Unspecified"=>1}}, "reader_count_by_country"=>{"Egypt"=>1, "Portugal"=>1}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/497179"], "description"=>"<p>The continuous line was drawn according to this phenomenological equation VWFcarb = (VWFcarb)max x (Pcarb)h/(P50h+Pcarbh), where (VWFcarb)max is the asymptotic value of VWF carbonyls (best fit value: 587±146 pmol/mg), Pcarb is the carbonyl content of plasma proteins, h is an exponential parameter (best fit = 3.6±0.6) and P50 is the concentration of plasma proteins carbonyls equal to (VWFcarb)max/2 (best fit: 706±107 pmol/mg). The vertical bars are the standard errors. In the inset, the SDS-PAGE gel (4–12%) of the purified and reduced VWF preparation is shown. On the left the molecular weight standards are also shown.</p>", "links"=>[], "tags"=>["carbonyl", "plasma", "proteins", "vwf", "purified", "samples"], "article_id"=>167675, "categories"=>["Chemistry", "Biochemistry", "Hematology", "Immunology"], "users"=>["Laura Oggianu", "Stefano Lancellotti", "Dario Pitocco", "Francesco Zaccardi", "Paola Rizzo", "Francesca Martini", "Giovanni Ghirlanda", "Raimondo De Cristofaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055396.g001", "stats"=>{"downloads"=>1, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Correlation_between_total_carbonyl_content_of_plasma_proteins_and_that_of_VWF_purified_from_plasma_samples_of_type_2_diabetes_patients_/167675", "title"=>"Correlation between total carbonyl content of plasma proteins and that of VWF purified from plasma samples of type 2 diabetes patients.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 16:07:15"}
  • {"files"=>["https://ndownloader.figshare.com/files/497752"], "description"=>"<p>Legend: <sup>§</sup>The values of mean±SD are listed;</p>*<p>Comparison with respective controls;</p>**<p>Comparison between type 1 and type 2 patients;</p>***<p>v.n. <25 mg/L The parameters with significantly different (p<0.05) values are listed in bold.</p>", "links"=>[], "tags"=>["characteristics", "t1-", "t2-dm", "patients", "respective"], "article_id"=>168260, "categories"=>["Chemistry", "Biochemistry", "Hematology", "Immunology"], "users"=>["Laura Oggianu", "Stefano Lancellotti", "Dario Pitocco", "Francesco Zaccardi", "Paola Rizzo", "Francesca Martini", "Giovanni Ghirlanda", "Raimondo De Cristofaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055396.t002", "stats"=>{"downloads"=>0, "page_views"=>1, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Biochemical_characteristics_and_therapy_of_T1_and_T2_DM_patients_and_respective_controls_/168260", "title"=>"Biochemical characteristics and therapy of T1- and T2-DM patients and respective controls.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-19 16:10:31"}
  • {"files"=>["https://ndownloader.figshare.com/files/497623"], "description"=>"§<p>The values of mean±SD are listed in the table.</p>", "links"=>[], "tags"=>["oxidative", "biomarker", "t2-dm", "patients"], "article_id"=>168134, "categories"=>["Chemistry", "Biochemistry", "Hematology", "Immunology"], "users"=>["Laura Oggianu", "Stefano Lancellotti", "Dario Pitocco", "Francesco Zaccardi", "Paola Rizzo", "Francesca Martini", "Giovanni Ghirlanda", "Raimondo De Cristofaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055396.t004", "stats"=>{"downloads"=>4, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Haemostatic_and_oxidative_biomarker_parameters_167_of_T2_DM_patients_with_and_without_any_form_of_angiopathies_/168134", "title"=>"Haemostatic and oxidative biomarker parameters<sup>§</sup> of T2-DM patients with and without any form of angiopathies.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-19 16:09:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/497247"], "description"=>"<p>According to Mann-Whitney test, VWF-bound carbonyls had higher values in microangiopathic subjects than in non macroangiopathic diabetics (mean values ± SD: 92±22 vs 35±8 pmol/mg, respectively, p = 0.022).</p>", "links"=>[], "tags"=>["calculated", "vwf-bound-carbonyl", "levels", "diabetic", "patients", "microangiopathic", "complications"], "article_id"=>167752, "categories"=>["Chemistry", "Biochemistry", "Hematology", "Immunology"], "users"=>["Laura Oggianu", "Stefano Lancellotti", "Dario Pitocco", "Francesco Zaccardi", "Paola Rizzo", "Francesca Martini", "Giovanni Ghirlanda", "Raimondo De Cristofaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055396.g002", "stats"=>{"downloads"=>0, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Statistical_comparison_between_calculated_VWF_bound_carbonyl_levels_in_type_2_diabetic_patients_with_and_without_microangiopathic_complications_renal_and_retinal_/167752", "title"=>"Statistical comparison between calculated VWF-bound-carbonyl levels in type 2 diabetic patients with and without microangiopathic complications (renal and retinal).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 16:07:41"}
  • {"files"=>["https://ndownloader.figshare.com/files/497667"], "description"=>"*<p>Adjusted for age and sex.</p>", "links"=>[], "tags"=>["logistic", "regression", "thrombotic", "angiopathies", "haemostatic", "oxidation", "variables", "t2dm", "patients"], "article_id"=>168170, "categories"=>["Chemistry", "Biochemistry", "Hematology", "Immunology"], "users"=>["Laura Oggianu", "Stefano Lancellotti", "Dario Pitocco", "Francesco Zaccardi", "Paola Rizzo", "Francesca Martini", "Giovanni Ghirlanda", "Raimondo De Cristofaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055396.t005", "stats"=>{"downloads"=>0, "page_views"=>4, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Multivariable_adjusted_logistic_regression_for_thrombotic_angiopathies_with_haemostatic_and_oxidation_variables_in_T1_and_T2DM_patients_n_83_/168170", "title"=>"Multivariable-adjusted<sup>*</sup> logistic regression for thrombotic angiopathies with haemostatic and oxidation variables in T1– and T2DM patients (n = 83).", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-19 16:10:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/497507"], "description"=>"<p>The continuous line represents the linear regression (R2 = 0.908, p = 0.0002). The arrow shows the mean value of the parameter in age- and sex- matched healthy controls (MMW = 6.2±0.7), all having carbonyl content of VWF<20 pmol/mg (Δ). Notably, all the patients with VWF-bound carbonyls>100 pmol/mg suffered from both micro- and macrovascular complications.</p>", "links"=>[], "tags"=>["carbonyl", "purified", "vwf", "mmw", "parameter", "t2-dm", "patients", "macrovascular"], "article_id"=>168012, "categories"=>["Chemistry", "Biochemistry", "Hematology", "Immunology"], "users"=>["Laura Oggianu", "Stefano Lancellotti", "Dario Pitocco", "Francesco Zaccardi", "Paola Rizzo", "Francesca Martini", "Giovanni Ghirlanda", "Raimondo De Cristofaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055396.g005", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_of_carbonyl_content_of_purified_VWF_with_the_MMW_parameter_for_T2_DM_patients_with_macrovascular_complications_/168012", "title"=>"Association of carbonyl content of purified VWF with the MMW parameter for T2-DM patients with macrovascular complications.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 16:09:08"}
  • {"files"=>["https://ndownloader.figshare.com/files/497562"], "description"=>"<p>Purified VWF multimers were digested by 5 nM ADAMTS-13 for 60 min in the presence of 1.2 mg/ml ristocetin under the experimental conditions detailed in the text. The same protein amounts were loaded on the gels. The samples from diabetic patients had the highest VWF carbonyl content (380 pmol/mg), whereas the controls had a lower carbonyl content (40 pmol/mg).</p>", "links"=>[], "tags"=>["adamts-13", "vwf", "multimers", "t2dm", "patients", "subjects"], "article_id"=>168077, "categories"=>["Chemistry", "Biochemistry", "Hematology", "Immunology"], "users"=>["Laura Oggianu", "Stefano Lancellotti", "Dario Pitocco", "Francesco Zaccardi", "Paola Rizzo", "Francesca Martini", "Giovanni Ghirlanda", "Raimondo De Cristofaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055396.g006", "stats"=>{"downloads"=>0, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cleavage_by_ADAMTS_13_of_VWF_multimers_in_a_pool_obtained_from_two_T2DM_patients_and_two_healthy_subjects_Ctrl_/168077", "title"=>"Cleavage by ADAMTS-13 of VWF multimers in a pool obtained from two T2DM patients and two healthy subjects (Ctrl).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 16:09:30"}
  • {"files"=>["https://ndownloader.figshare.com/files/497793"], "description"=>"*<p>Comparison with respective controls;</p>**<p>Comparison between type 1 and type 2 patients.</p>§<p>The values of mean±SD are listed in the table.</p>", "links"=>[], "tags"=>["oxidative", "biomarker", "levels", "t1-", "t2-dm", "patients", "respective"], "article_id"=>168305, "categories"=>["Chemistry", "Biochemistry", "Hematology", "Immunology"], "users"=>["Laura Oggianu", "Stefano Lancellotti", "Dario Pitocco", "Francesco Zaccardi", "Paola Rizzo", "Francesca Martini", "Giovanni Ghirlanda", "Raimondo De Cristofaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055396.t003", "stats"=>{"downloads"=>3, "page_views"=>6, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Haemostatic_and_oxidative_biomarker_levels_in_T1_and_T2_DM_patients_and_respective_controls_/168305", "title"=>"Haemostatic and oxidative biomarker levels in T1- and T2-DM patients and respective controls.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-19 16:10:45"}
  • {"files"=>["https://ndownloader.figshare.com/files/497421"], "description"=>"<p>A) SDS-agarose gel electrophoresis and western blot of VWF multimers from a pool (n = 10) of type 2 diabetic patients without microangiopathy and low VWF-bound carbonyls (<50 pmol/mg) (1) and with high levels of VWF-bound carbonyls (>100 pmol/mg) and several forms of microangiopathies (2: nefropathy; 3: nefropathy+grade 3 retinopathy; 4: nefropathy+retinopathy+autonomic neuropathy; 5: nefropathy+grade 3 retinopathy; autonomic neuropathy+coronary microangiopathy). The agarose gel was discontinuous (0.4% agarose in stacking gel and 1.2% agarose in running gel. The amount of loaded VWF was similar in all samples (about 2 µg). B) SDS-agarose gel electrophoresis and western blot of VWF multimers from type 2 diabetic patients without macroangiopathy (1) and with several forms of macroangiopathies (2–4: coronaropathy; 5: coronaropathy+PAD). The presence of UL-VWF in samples is indicated between the dashed lines.</p>", "links"=>[], "tags"=>["sds-agarose", "gel", "electrophoresis", "blot", "vwf", "multimers", "diabetic", "patients", "vwf-bound", "carbonyls", "microangiopathy", "levels", "forms"], "article_id"=>167924, "categories"=>["Chemistry", "Biochemistry", "Hematology", "Immunology"], "users"=>["Laura Oggianu", "Stefano Lancellotti", "Dario Pitocco", "Francesco Zaccardi", "Paola Rizzo", "Francesca Martini", "Giovanni Ghirlanda", "Raimondo De Cristofaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055396.g004", "stats"=>{"downloads"=>2, "page_views"=>88, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_SDS_agarose_gel_electrophoresis_and_western_blot_of_VWF_multimers_between_type_2_diabetic_patients_with_low_VWF_bound_carbonyls_without_microangiopathy_and_those_with_high_levels_of_VWF_bound_carbonyls_and_several_forms_of_microangiopathies/167924", "title"=>"Comparison of SDS-agarose gel electrophoresis and western blot of VWF multimers between type 2 diabetic patients with low VWF-bound carbonyls without microangiopathy and those with high levels of VWF-bound carbonyls and several forms of microangiopathies.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 16:08:36"}
  • {"files"=>["https://ndownloader.figshare.com/files/497327"], "description"=>"<p>According to Mann-Whitney test, all these parameters showed higher values in macroangiopathics than in non macroangiopathic diabetics (mean values ± SD: A) total carbonyl content of plasma proteins, 380±37 pmol/mg vs 270±25 pmol/mg, p = 0.0234; B) VWF-bound carbonyls, 82±20 vs 33±9 pmol/mg, p = 0.028; C) and 177±16% vs 132±12%, p = 0.032, respectively.</p>", "links"=>[], "tags"=>["carbonyl", "plasma", "vwf-bound", "carbonyls", "diabetic", "patients", "macroangiopathies"], "article_id"=>167834, "categories"=>["Chemistry", "Biochemistry", "Hematology", "Immunology"], "users"=>["Laura Oggianu", "Stefano Lancellotti", "Dario Pitocco", "Francesco Zaccardi", "Paola Rizzo", "Francesca Martini", "Giovanni Ghirlanda", "Raimondo De Cristofaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055396.g003", "stats"=>{"downloads"=>2, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Comparison_of_total_carbonyl_content_of_plasma_proteins_VWF_bound_carbonyls_and_VWF_act_between_type_2_diabetic_patients_with_and_without_macroangiopathies_AMI_stroke_and_PAD_/167834", "title"=>"Comparison of total carbonyl content of plasma proteins, VWF-bound carbonyls and VWF:act between type 2 diabetic patients with and without macroangiopathies (AMI, stroke and PAD).", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-19 16:08:09"}
  • {"files"=>["https://ndownloader.figshare.com/files/497709"], "description"=>"<p>Legend: <sup>§</sup>The values of mean±SD are listed;</p>*<p>Comparison with respective controls;</p>**<p>Comparison between type 1 and type 2 patients. The parameters with significantly different (p<0.05) values are listed in bold.</p>", "links"=>[], "tags"=>["biochemical", "characteristics", "t2-dm", "patients", "respective"], "article_id"=>168219, "categories"=>["Chemistry", "Biochemistry", "Hematology", "Immunology"], "users"=>["Laura Oggianu", "Stefano Lancellotti", "Dario Pitocco", "Francesco Zaccardi", "Paola Rizzo", "Francesca Martini", "Giovanni Ghirlanda", "Raimondo De Cristofaro"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0055396.t001", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Clinical_and_biochemical_characteristics_of_T1_T2_DM_patients_and_respective_controls_/168219", "title"=>"Clinical and biochemical characteristics of T1-, T2-DM patients and respective controls.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-02-19 16:10:17"}

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Relative Metric

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