Plasma Levels Of Antigen Research Articles

Von Willebrand Factor, ADAMTS13 Activity, TNF-Alpha, and Their Relationships in Patients with Chronic Kidney Disease

Abstract 5312Patients with chronic kidney disease (CKD) have increased risks of endothelial dysfunction and thrombosis. Systemic inflammation may contribute to the endothelial dysfunction and accelerated thrombosis observed in CKD patients. von Willebrand factor (VWF), a well-known index of endothelial damage, has been reported to increase both in CKD and inflammatory states. ADAMTS13 is a specific VWF-cleaving protease, and some reports suggested that the ratio of VWF and ADAMTS13 maybe more useful in the diagnosis and treatment evaluation of patients in the prothrombotic state. So we assessed the relationships among endothelial dysfunction, ADAMTS13 activity, and levels of inflammatory cytokines in CKD patients. CKD patients were classified into 3 groups: chronic glomerulonephritis group (CGN, n = 31), idiopathic nephritic syndrome group (NS, n = 32), and lupus nephritis group (LN, n = 41). We measured the plasma levels of TNF-α, VWF antigen (VWF:Ag), and ADAMTS13 activity by using an ELISA-based method in CKD patients (n = 104) and normal controls (n = 32). The ratio of the VWF:Ag level to ADAMTS13 activity was calculated. The VWF:Ag level was significantly higher and the ADAMTS13 activity was significantly lower in all the disease groups than in the controls (P < 0.01). ADAMTS13 activity was lower in the NS group than in the CGN and LN groups (P < 0.05) (Table 1). The TNF-α (pg/mL) level was higher in the CKD group than in the control group (CGN: 3.19 ± 1.01; NS: 3.26 ± 1.18; LN: 3.24 ± 1.24; Control: 2.27 ± 1.23; P < 0.01; P < 0.01). TNF-α was positively correlated with the VWF:Ag level (r = 0.242, P = 0.013) and negatively correlated with the glomerular filtration rate (GFR) (r = −0.193, P = 0.049). ADAMTS13 activity was negatively correlated with the cholesterol level in CKD patients (r = −0.2, P = 0.042). TNF-α level in CKD was positively correlated with the VWF:Ag level and negatively correlated with GFR, which suggests that inflammation might be a major cause of endothelial dysfunction and an index for renal function. The VWF:Ag level increased and ADAMTS13 activity decreased in CKD patients, which indicates that CKD leads to a prothrombotic state.Table 1The plasma VWF:Ag level, ADAMTS13 activity, and the VWF/ADAMTS13 ratio in the CGN, NS, LN, and control groupsNVWF (%)ADAMTS13 (%)VWF/ADAMTS13CGN31198.25 ± 140.20**61.93 ± 22.47**,#3.83 ± 3.29**NS32149.94 ± 74.50**48.87 ± 18.63**3.42 ± 1.59**LN41234.75 ± 134.91**,##67.81 ± 22.30**,##3.79 ± 2.52**CONTROL3299.55 ± 21.3794.37 ± 23.661.12 ± 0.37vs. CONTROL**P < 0.01; vs. NS##p < 0.01,#P < 0.05 Disclosures:No relevant conflicts of interest to declare.

Mediciones seriadas de antígeno carbohidrato 125 tras un ingreso por insuficiencia cardiaca aguda y riesgo de reingreso precoz

Fundament and objectivesThe early readmission after a hospitalization for acute heart failure (AHF) is frequent; however, factors associated are not clearly established. Plasma levels of carbohydrate antigen 125 (CA125) have shown to be associated with the presence of systemic congestion and increased risk of death in patients with AHF. The aim of this study was to assess the relationship between CA125 levels (during hospitalization, at the first outpatient visit or their changes) and readmission for AHF at 6 months follow up. Patients and methodWe analyzed 293 consecutive patients hospitalized for AHF in which CA125 was determined during the index hospitalization (T1) and the first outpatient visit after discharge (T2) (median 31 days). We examined the relationship between CA125 levels, both isolated determinations as their serial changes (absolute, relative or categorical) and readmission for AHF by Cox regression analysis adjusted for competing events. The reclassification technique integrated discrimination improvement (IDI) index was used to assess the additional discriminative power of this biomarker over the final multivariate model. ResultsAt 6 months follow up, we identified 32 (10.9%) and 54 (18.4%) deaths and readmissions for AHF, respectively. CA125 categorical changes [decrease and normalization (C1, n=153), decrease but no normalization at T2 (C2, n=72) and increase, with high levels at T2 (>35 U/ml) (C3, n=68)], followed by the isolated determination of CA125 at T2, showed the best discriminative accuracy. Thus, with respect to patients in the C1 category, patients in categories C2 and C3 showed a higher risk of readmission for AHF: C2 vs. C1: HR=3.48, 95% CI:1.84-6.59, p<0.001; C3 vs. C1: HR=3.18, 95% CI:1.62-6.21, p=0.001. On the other hand, patients with elevated levels of CA125 in T2 (>35 U/ml) (41%) tripled the risk of readmission for AHF at 6 months compared with those with normal levels of CA125 at T2: HR=3.06, 95% CI:1.79-5.23, p<0.001. The addition of the categories of serial measurements of CA125 and the presence of elevated levels of CA125 at T2 showed a significant increase in the discriminating power of 6.27% and 6.17% in the IDI index, respectively. ConclusionsAfter an episode of AHF, the elevation of CA125 levels (>35 U/ml) after the first weeks of admission is associated with an increased risk of readmission for AHF.

Plasma von Willebrand factor as a predictor of survival in pulmonary arterial hypertension associated with congenital heart disease

Biomarkers have been identified for pulmonary arterial hypertension, but are less well defined for specific etiologies such as congenital heart disease-associated pulmonary arterial hypertension (CHDPAH). We measured plasma levels of eight microvascular dysfunction markers in CHDPAH, and tested for associations with survival. A cohort of 46 inoperable CHDPAH patients (age 15.0 to 60.2 years, median 33.5 years, female:male 29:17) was prospectively followed for 0.7 to 4.0 years (median 3.6 years). Plasma levels of von Willebrand factor antigen (VWF:Ag), tissue plasminogen activator (t-PA) and its inhibitor (PAI-1), P-selectin, reactive C-protein, tumor necrosis factor alpha, and interleukin-6 and -10 were measured at baseline, and at 30, 90, and 180 days in all subjects. Levels of six of the eight proteins were significantly increased in patients versus controls (13 to 106% increase, P < 0.003). Interleukin-10 level was 2.06 times normal (P = 0.0003; Th2 cytokine response). Increased levels of four proteins (t-PA, PAI-1, P-selectin, and interleukin-6) correlated with disease severity indices (P < 0.05). Seven patients died during follow-up. An average VWF:Ag (mean of four determinations) above the level corresponding to the 95th percentile of controls (139 U/dL) was independently associated with a high risk of death (hazard ratio = 6.56, 95%CI = 1.46 to 29.4, P = 0.014). Thus, in CHDPAH, microvascular dysfunction appears to involve Th2 inflammatory response. Of the biomarkers studied, plasma vWF:Ag was independently associated with survival.

Platelet ligands and ADAMTS13 during Puumala hantavirus infection and associated thrombocytopenia

We aimed here to elucidate the role of adhesive platelet ligands and endothelial involvement during the acute phase of Puumala hantavirus (PUUV) infection. Nineteen hospital-treated patients with serologically confirmed diagnosis of acute PUUV infection were included. Patient charts were reviewed for clinical and basic laboratory data. Plasma levels of von Willebrand factor antigen (VWF:Ag), ristocetin cofactor (VWF:RCo), factor VIII (FVIII:C) and a disintegrin and metalloproteinase with a thrombospondin type 1 domain 13 (ADAMTS13) activities as well as fibrinogen and fibronectin were measured three times acutely and once during the recovery phase. VWF:Ag and VWF:RCo were nearly three-fold higher acutely compared with recovery (median 252 vs. 88%, and mean 267 vs. 98%, respectively; P<0.001 for both), whereas FVIII:C was only slightly elevated (median 118 vs. 88%, P=0.002) and remarkably failed to show association with VWF in the acute phase. ADAMTS13 activity and fibronectin concentration were lower in the acute compared with the recovery phase (median 56 vs. 63%, P=0.003, and median 221 vs. 330 μmol/l, P=0.001, respectively). Fibrinogen raised acutely (mean 5.0 vs. 3.3 g/l, P<0.001), negatively correlating with the platelet count (r=-0.468, P=0.043). Markedly upregulated fibrinogen and VWF together with decreased levels of ADAMTS13 activity and fibronectin were observed during acute PUUV infection. VWF and FVIII:C did not associate during the acute phase, whereas thrombocytopenia correlated negatively with fibrinogen. These findings imply several rearranged interactions between platelets and their ligands.

Effect of weight loss on gelatinase levels in obese mice

1. Gelatinases (matrix metalloproteinase (MMP)-2 and MMP-9) might play a role in the development and structural organization of adipose tissue. Obese mice were subjected to caloric restriction (from 82 to 27 kJ/day) for 6 weeks, in order to investigate the effect of drastic weight loss on gelatinase mRNA, protein and activity levels. 2. Caloric restriction resulted in significantly lower bodyweight, as well as subcutaneous (SC) and gonadal (GON) fat mass (all P < 0.001). 3. The expression of MMP-2 mRNA was significantly upregulated in both SC (3.3-fold) and GON (2.2-fold) adipose tissues; however, without significant effect on total MMP-2 protein levels in fat tissues or in plasma. In contrast, MMP-9 mRNA expression in SC or GON fat was not affected by caloric restriction, whereas protein levels were reduced in SC and GON fat, but not in plasma. Zymography showed significantly elevated levels of active MMP-2 in both SC and GON adipose tissues, whereas active MMP-9 levels were reduced in GON fat. 4. These findings imply that the evaluation of the role of gelatinases in obesity and metabolic disorders requires the determination of both antigen and activity levels in plasma and fat tissues.

SPR imaging biosensor for the 20S proteasome: sensor development and application to measurement of proteasomes in human blood plasma

The 20S proteasome is a multicatalytic enzyme complex responsible for intracellular protein degradation in mammalian cells. Its antigen level or enzymatic activity in blood plasma are potentially useful markers for various malignant and nonmalignant diseases. We have developed a method for highly selective determination of the 20S proteasome using a Surface Plasmon Resonance Imaging (SPRI) technique. It is based on the highly selective interaction between the proteasome’s catalytic β5 subunit and immobilized inhibitors (the synthetic peptide PSI and epoxomicin). Inhibitor concentration and pH were optimized. Analytical responses, linear ranges, accuracy, precision and interferences were investigated. Biosensors based on either PSI and epoxomicin were found to be suitable for quantitative determination of the proteasome, with a precision of ±10% for each, and recoveries of 102% and 113%, respectively, and with little interference by albumin, trypsin, chymotrypsin, cathepsin B and papain. The proteasome also was determined in plasma of healthy subjects and of patients suffering from acute leukemia. Both biosensors gave comparable results (2860 ng·mL-1 on average for control, and 42300 ng·mL-1 on average for leukemia patients). FigureThe synthetic peptide aldehyde Z-Ile-Glu(OBut)-Ala-Leu-H (PSI) and a microbial α’,β’ epoxyketone peptide epoxomicin was used to develop SPRI biosensor for the highly selective determination of the 20S proteasome concentration, and to evaluate the sensor applicability for the determination of 20S proteasome in human blood plasma.

Pharmacokinetics, distribution, and excretion of 125I-labeled human plasma-derived-FVIIa and -FX with MC710 (FVIIa/FX mixture) in rats

Introduction MC710 is a mixture agent consisting of plasma-derived activated factor VII (FVIIa) and factor X (FX) at a weight ratio of 1:10 developed as a novel bypassing agent for the management of the bleeding of hemophilia patients with inhibitors. The pharmacokinetics, distribution, and excretion of 125I-labeled-FVIIa ( 125I-FVIIa) and -FX ( 125I-FX) were studied in male rats after a single intravenous administration of 125I-FVIIa or 125I-FX combined with MC710. Methods 125I-FVIIa or 125I-FX was administered intravenously with MC710 to male rats in a single dosage (FVIIa 0.4 mg and FX 4 mg/kg body weight) and radioactivity and antigen levels in plasma were quantified for 24 h. Urine and feces were sampled to study the excretion of radioactivity during 168 h after dosing. Whole-body autoradiography was performed to evaluate the qualitative distribution of radioactivity 168 h after dosing. Results and conclusions The half-life (t 1/2α and t 1/2β) of radioactivity and FVIIa antigen were 0.704 and 6.27 h, and 0.496 and 1.66 h, respectively and the area under the plasma concentration–time curve (AUC 0–∞) of radioactivity and FVIIa antigen were 17,932 and 8671 ng·h/mL, respectively. The t 1/2 of radioactivity and FX antigen were 4.06 and 3.05 h, respectively, and the AUC 0–∞ of radioactivity and FX antigen were 320,143 and 395,794 ng·h/mL, respectively. About 80% of the administered dose of radioactivity was excreted in urine and feces by 168 h after administration. Tissue distribution experiments showed that FVIIa- and FX-related 125I accumulated in bone and bone marrow, and disappeared slowly.

Epitope analysis of autoantibodies to ADAMTS13 in patients with acquired thrombotic thrombocytopenic purpura

Introduction Autoantibodies to ADAMTS13 have a pivotal role in the pathogenesis of acquired thrombotic thrombocytopenic purpura (TTP). By decreasing the function of ADAMTS13, autoantibodies impair the cleavage of ultra-large von Willebrand factor (UL-VWF) multimers into smaller sizes, leading to lethal platelet-VWF thrombi in the microcirculation. We therefore aimed to determine the sites of autoantibody recognition on ADAMTS13. Materials and Methods In this study, IgG purified from 13 acquired TTP patients were examined to determine their binding sites on ADAMTS13. Immobilized IgG on microtiter plate or proteinG beads was screened by phage library expressing various peptides of ADAMTS13. Results In screening, diverse peptide sequences were obtained from almost all of the ADAMTS13 domains, including the spacer domain, which is considered a major binding site. In particular, we detected an identical amino-acid sequence in the C-terminus of the spacer domain from Gly662 to Val687 that was recognized by autoantibodies from 5 TTP patients. The specific autoantibody was expected to be associated with the plasma levels of the ADAMTS13 antigen or activity, and with the quantity of ADAMTS13 autoantibodies or the inhibitory autoantibody titer in TTP patient plasma. These measurements, however, did not seem to be related to the presence or absence of the specific autoantibody. Conclusions These findings indicate that the specific autoantibody might be a feature of acquired TTP, although its clinical significance remains to be elucidated.

R353Q polymorphism in the factor VII gene and cardiovascular risk in Heterozygous Familial Hypercholesterolemia: a case-control study

BackgroundHeterozygous Familial Hypercholesterolemia (FH) is a genetic disorder characterized by a high risk of cardiovascular disease. Certain polymorphisms of the factor VII gene have been associated with the development of coronary artery disease and there is a known association between factor VII levels and polymorphic variants in this gene. To date, no study has evaluated the association between factor VII and coronary artery disease in patients with FH.ResultsThis case-control study comprised 720 patients (546 with FH and 174 controls). We determined the prevalence and allele frequencies of the R353Q polymorphism of factor VII, the plasma levels of factor VII antigen (FVII Ag) and whether they could be predictive factors for cardiovascular risk. 75% (410) of the patients with FH were RR, 23% (127) RQ and 1.6% (9) QQ; in the control group 75.3% (131) were RR, 21.3% (37) RQ and 3.4% (6) QQ (p = 0.32). No statistically significant associations were observed in the distribution of genotypes and allele frequencies between case (FH) and control groups. Nor did we find differences when we evaluated the relationship between the R353Q polymorphism and cardiovascular risk (including coronary disease, ischemic stroke and peripheral arterial disease), either in the univariate analysis or after adjustment for sex, age, arterial hypertension, body mass index, xanthomas, diabetes, smoking, HDLc and LDLc and lipid-lowering treatment. The FVII Ag concentrations behaved in a similar fashion, with no differences for the interaction between controls and those with FH (RR vs. RQ/QQ; p = 0.96). In the subgroup of patients with FH no association was found among cardiovascular disease, genotype and FVII Ag levels (RR vs. RQ/QQ; p = 0.97).ConclusionsOur study did not find a direct relationship between cardiovascular risk in patients with Heterozygous Familial Hypercholesterolemia, the R353Q polymorphism of factor VII and FVII Ag levels.

Changes in von Willebrand factor and ADAMTS13 during IVF

During IVF, circulating estradiol concentrations are strongly increased, and this may have direct effects on hemostasis. Elevated von Willebrand factor levels represent an important risk factor for arterial and venous thrombosis. ADAMTS13, also known as von Willebrand factor-cleaving protease, has an important regulatory function of von Willebrand factor but has not been studied during IVF. Blood was sampled from 31 women at maximal downregulation of estradiol synthesis using gonadotropin-releasing hormone analogues and during high-level stimulation of estradiol synthesis using follicle-stimulating hormone during the first phase of IVF. Von Willebrand factor antigen, von Willebrand factor ristocetin cofactor activity, factor VIII and ADAMTS13 antigen and activity levels in plasma were determined at the time of downregulation and at high-level stimulation. Estradiol increased from a mean of 154 pg/ml at downregulation to 5889 pg/ml at high-level stimulation (range 1620-19 500 pg/ml). Factor VIII increased from 0.96 ± 0.34 to 1.26 ± 0.41 kIU/l (P < 0.001). Von Willebrand factor antigen and activity increased from 0.75 ± 0.22 to 1.06 ± 0.40 kIU/l (P < 0.001) and from 0.83 ± 0.26 to 1.24 ± 0.48 kIU/l (P < 0.001), respectively. ADAMTS13 antigen decreased from 72.2 ± 13.5 to 67.9 ± 9.9% (P < 0.05, P = 0.01) and ADAMTS13 activity from 88.6 ± 18.3 to 80.8 ± 15.7% (P < 0.01). The increments in estradiol and factor VIII during IVF were paralleled by an increase in von Willebrand factor antigen and activity, and a decrease in circulating ADAMTS13 antigen and activity, respectively. This could in part explain why these patients have an increased risk of thrombotic events.

Reduced plasma fibrinolytic potential in patients with recurrent implantation failure after IVF and embryo transfer

Recurrent implantation failure (RIF) following embryo transfer (ET) is a major continuing problem in IVF. Women with haemostatic defects may be at increased risk of miscarriage and preclinical pregnancy loss. The fibrinolytic system is considered, at present, the key to new thrombotic pathogenic mechanisms. Patients with unexplained recurrent miscarriage have an impairment of fibrinolysis, as demonstrated by prolonged clot lysis time (CLT) in association with increased plasma levels of thrombin-activatable fibrinolysis inhibitor (TAFI). In this study, we investigated fibrinolytic potential in patients with RIF. Three groups of patients were studied: 30 women with RIF (RIF group), 60 patients undergoing a first successful IVF-ET cycle (IVF group) and 60 healthy fertile women (FER group). Plasma CLT was measured using a global fibrinolysis assay. TAFI antigen plasma levels and polymorphisms in the TAFI gene (+505A/G and +1542C/G) were analysed using enzyme-linked immunosorbent assay and allele-specific PCR, respectively. CLT was significantly longer (P < 0.0001 and P < 0.0009, respectively) and TAFI antigen levels were significantly higher (both P < 0.0001) in the RIF versus the IVF and FER groups. A direct relationship between CLT and TAFI antigen levels (r = 0.40; P = 0.001) was detected in the whole study population. There were no differences in distribution of TAFI polymorphisms between groups. Patients with RIF have reduced plasma fibrinolytic potential, as shown by a prolonged CLT, and this may be explained, at least in part, by increased TAFI antigen levels.

Fully automated immunoassay for quantitative determination of FXIII

Coagulation factor XIII (FXIII) is essential for clot stabilization. Deficiency of FXIII is associated with a risk of bleeding and impaired wound healing. Substitution therapy with FXIII remedies for patients with low plasma levels of FXIII requires diagnostic quantification of the factor before and during therapy. Here, we describe a prototype of a preliminary research immunoassay for quantification of FXIII antigen on automated coagulation instruments. The prototype assay is based on a monoclonal antibody (mAb) directed against FXIII A chain, whereas the mAbs are coupled to latex particles. FXIII in a plasma specimen causes agglutination of the latex particles, which can be quantified turbidimetrically. Performance data of the assay prototype processed on BCS® XP and Sysmex® CA-1500 instruments demonstrate a good correlation to the Berichrom® factor XIII activity assay1 from Siemens Healthcare Diagnostics (r = 0.94). Comparability of instruments was excellent (r = 0.98). Coefficients of variation of total imprecision measurements ranged from 2.2 to 3.4%. Linearity was excellent over the range tested (12-121% FXIII). Analytical sensitivity was 0.51% FXIII on BCS XP and 0.44% FXIII on Sysmex CA-1500, respectively. No interference (>10% bias) was observed with haemoglobin (up to 400 mg/dl), cholesterol (up to 300 mg/dl), bilirubin (up to 60 mg/dl) or triglycerides (up to 3000 mg/dl). The preliminary research assay prototype has the potential for excellent analytical sensitivity, precision, and dynamic range suitable to measure reliably FXIII antigen levels in human plasma.

Effect of Levothyroxine Suppression Therapy on Plasma Thrombin Activatable Fibrinolysis Inhibitor Antigen Levels in Benign Thyroid Nodules

Objective: The aim of this prospective study was to investigate the effect of LT4 suppression therapy on plasma thrombin activatable fibrinolysis inhibitor (TAFI) antigen and plasminogen activator inhibitor-1 (PAI-1) levels in benign thyroid nodules. We also compared hyperthyroid patients and healthy controls. Subjects and Methods: Twenty premenopausal women with benign thyroid nodules were given LT4 suppression therapy for 1 year. Plasma TAFI and PAI-1 antigen levels were measured at baseline and after LT4 suppression treatment. The endogenous hyperthyroid group was composed of 19 premenopausal females with newly diagnosed endogenous hyperthyroidism. Eighteen age-matched euthyroid healthy premenopausal women were enrolled as the control group. Results: TAFI antigen levels decreased after LT4 suppression treatment; however, the difference was not statistically significant (p = 0.057). LT4 treatment resulted in a nonsignificant increase in PAI-1 levels. Patients with endogenous hyperthyroidism had decreased levels of TAFI antigen and increased levels of PAI-1 antigen (p < 0.05). There was a negative correlation between the FT₄ and TAFI antigen levels. Serum TSH was positively correlated with the plasma levels of TAFI antigen. Conclusion: LT4 suppression therapy for benign thyroid nodules did not result in a significant decrease in TAFI antigen levels in premenopausal women, but endogenous hyperthyroidism was associated with significantly decreased levels of TAFI antigen.

Decreased Activity of ADAMTS13 In Patients with Deep Vein Thrombosis Associated with Inflammatory Markers

AbstractAbstract 3181 Introduction:Elevated levels of inflammatory markers and clotting factors have been related to the pathogenesis of DVT. Particularly, the balance between VWF and ADAMTS 13 activity has been previously described in patients with thrombosis. VWF levels are also described to be elevated during inflammatory processes and therefore could play a role linking the activation of inflammatory and coagulation systems in patients with DVT. Objective:To evaluate the activity of ADAMTS13 and VWF in patients with DVT and its association with inflammatory markers. Patients and Methods:Fifty-five patients with DVT, 6 months to five years after the acute episode, attended at the Hematology Center of UNIFESP were included in this study and 121 normal subjects were selected as controls. The activity of ADAMTS 13 was performed by binding of residual VWF to collagen; VWF antigen, IL-6, IL-8, F1+2 and MCP1 was determined by ELISA and D-dimer and CRP was performed by turbidimetry. Continuous variables were analyzed by Mann- Whitney test, categorical variables by the chi-square test and Spearman rank test was used for correlation analysis. Results:Thirty-tree patients had DVT caused by transient risk factor, especially the use of oral contraceptives, and 22 patients had spontaneous DVT. No patient had renal, hepatic or malignant disease. The median ADAMTS 13 activity was not statistically different between patients (median= 65.8%) and controls (median=78.5%, p= 0.3043). The plasma levels of VWF antigen, IL-6 and CRP were higher in patients than in controls (p= 0.008, p= 0.0003 and p= 0.008, respectively). The levels of IL-8 and MCP1 did not differ betwee n patients and controls (p= 0.65 and p= 0.07, respectively). The levels of VWF correlated significantly with CRP (r= 0.28, p= 0.005) and F1+2 (r= 0.3, p= 0,02) in patients. There was an inverse correlation between ADAMTS13 activity and F1+2 concentrations (r= -0,33, p= 0.01). Conclusion:This study suggests that, even after the acute episode of DVT, a chronic inflammatory state would contribute to increasing levels of VWF in patients' plasma and hypercoagulability. The downregulation of ADAMTS13 activity may also contribute to the activation of the coagulation. However the role of ADAMTS13 in the interaction between inflammatory and coagulation systems in patients with thrombosis is yet to be determined. These factors together may contribute to recurrent DVT, which affects over 25% of patients within 10 years from the first episode. Disclosures:No relevant conflicts of interest to declare.

Sex Hormones and Colorectal Cancer: What Have We Learned So Far?

Sex Hormones and Colorectal Cancer: What Have We Learned So Far?

BAS/BSCR13 Increased plasminogen activator inhibitor-1 may explain dexamethasone-induced thrombosis as site of intraluminal wire injury

We have previously shown that high-dose glucocorticoid treatment reduces neointimal proliferation following arterial injury in mice, but is associated with increased local thrombosis. Clinically, glucocorticoid excess, either in Cushing's syndrome...

Polymorphisms in the factor VII gene and ischemic stroke in young adults

Polymorphic configurations of the coagulation factor VII gene (F7) are associated with plasma levels of FVII antigen (FVII:Ag) and FVII coagulant activity (FVII:C). Our aim was to determine whether F7 polymorphisms influence risk of ischemic stroke in young adults. One hundred and fifty survivors of ischemic stroke before the age of 45 and an equal number of age and sex-matched controls were genotyped for five F7 polymorphisms: the -A670C transversion, -323 decanucleotide insertion (P + 10), the number (which varies between five and eight) of a 37 base pair repeat polymorphisms in intron 7 (IVS7), amino acid substitution R353Q, and +154AA insertion. 353Q, P + 10 and +154AA were demonstrated to associate with significantly decreased plasma FVII:Ag, whereas -670C and IVS7 seven or higher were associated with a tendency towards increased plasma FVII:Ag. The former three polymorphisms were significantly more common in control individuals than in patients, whereas the latter two were significantly more common in patients than in control individuals. The multiple logistic regression analysis revealed that two F7 polymorphisms, -670C and IVS7 seven or higher, are independent risk factors for ischemic stroke in young adult patients.

Circulating angiogenic factors determined by electrochemiluminescence immunoassay in relation to the clinical features and laboratory parameters in women with pre-eclampsia

The purpose of this study was to determine whether increased serum soluble fms-like tyrosine kinase-1 (sFlt-1) and decreased placental growth factor (PlGF) levels in pre-eclampsia are related to the clinical features and laboratory parameters of the patients, including markers of inflammation, endothelial activation and injury, oxidative stress and trophoblast debris. A total of 54 pre-eclamptic patients, 58 healthy pregnant and 52 healthy non-pregnant women were involved in this case-control study. Serum sFlt-1 and PlGF levels were measured by electrochemiluminescence immunoassay. Serum levels of sFlt-1 and PlGF were significantly higher in pre-eclamptic patients and healthy pregnant women than in healthy non-pregnant women. In addition, pre-eclamptic patients had significantly higher sFlt-1 levels and significantly lower PlGF concentrations compared with healthy pregnant women. According to the subgroup analyses, sFlt-1 levels were significantly higher in severely pre-eclamptic patients than in those with mild pre-eclampsia, whereas pre-eclamptic patients with fetal growth restriction or preterm onset of the disease had significantly lower PlGF concentrations compared with those without intrauterine growth restriction or with a disease onset at term. In the pre-eclamptic group, there were significant positive correlations between serum sFlt-1 levels and systolic and diastolic blood pressure, serum levels of blood urea nitrogen and creatinine, as well as plasma levels of von Willebrand factor antigen, fibronectin and cell-free fetal DNA. Furthermore, serum PlGF concentrations of pre-eclamptic patients showed significant positive correlations with gestational age at disease onset and delivery, as well as with fetal birth weight, and significant inverse correlations with levels of blood urea nitrogen, creatinine and fibronectin. In conclusion, increased serum sFlt-1 and decreased PlGF levels are associated with blood pressure, renal and endothelial dysfunction, trophoblast deportation, as well as with a shorter duration of pregnancy, fetal growth restriction, the severity and preterm onset of the disease in pre-eclampsia. These findings indicate the central role of an angiogenic imbalance in the pathogenesis of this pregnancy-specific disorder.

Association between reduced ADAMTS13 and diabetic nephropathy

Introduction Deficiency of Von Willebrand factor (VWF)-cleaving protease (ADAMTS13) causes platelet thrombosis in the microcirculation. Intrarenal coagulation is thought to be associated with the development and progression of diabetic nephropathy. Our aim was to clarify the association between plasma ADAMTS13 antigen (ADAMTS13Ag) levels and diabetic nephropathy. Material and Methods We measured the plasma levels of VWF antigen (VWFAg) and ADAMTS13Ag, and calculated the VWF/ADAMTS13 ratio in 86 type 2 diabetic patients and 26 healthy volunteers, to investigate the relationship between these levels and renal function. With regard to diabetic macroangiopathy, the relationship between these levels and carotid intima-media thickness (IMT) was also investigated. Results and Conclusions A significant positive and negative correlation was noted between ADAMTS13Ag and the estimated glomerular filtration rate (eGFR), vWF/ADAMTS13 ratio and eGFR, respectively. The diabetic patients were divided into normoalbuminuria (n = 50), microalbuminuria (n = 8) and overt nephropathy (n = 28) groups. Compared among these three groups and the 26 healthy volunteers, ADAMTS13Ag was significantly lower only in the overt nephropathy group. The mean carotid IMT was measured in 69 patients and was significantly negatively correlated with ADAMTS13Ag and positively correlated with VWF/ADAMTS13 ratio. When these 69 patients were divided into four groups according to eGFR and ADAMTS13 levels (ADAMTS13/eGFR; low/low: n = 12; high/low: n = 7; low/high: n = 25; high/high: n = 25), the mean carotid IMT was increased in patients with a low ADAMTS13Ag in the same eGFR group. The present study suggests that reduced ADAMTS13 might be associated with diabetic nephropathy.

PSA doubling time for prediction of [11C]choline PET/CT findings in prostate cancer patients with biochemical failure after radical prostatectomy

Previous studies have shown that the positive detection rate of [(11)C]choline positron emission tomography/computed tomography (PET/CT) depends on prostate-specific antigen (PSA) plasma levels. This study compared PSA levels and PSA doubling time (PSADT) to predict [(11)C]choline PET/CT findings. PSADT was retrospectively calculated in 170 prostate cancer (PCa) patients with biochemical failure after radical prostatectomy who underwent [(11)C]choline PET/CT. PSADT was calculated as PSADT = ln2/m, where m is the slope of the linear regression line of the natural log of PSA values. At least three PSA measurements were used (median: 4; range: 3-16), separated by at least 3 months, each with a minimum increase of 0.20 ng/ml. PET/CT findings were validated using criteria based on histological analysis and clinical and imaging data. Statistical analysis was performed using the t test, chi-square test, analysis of variance and binary logistic regression. Regression-based coefficients were used to develop a nomogram predicting the probability of positive [(11)C]choline PET/CT and 200 bootstrap resamples were used for internal validation. The median PSA was 1.25 ng/ml (range: 0.23-48.6 ng/ml), and the median PSADT was 7.0 months (range: 0.97-45.3 months). [(11)C]choline PET/CT was positive in 75 of 170 patients (44%). PET/CT findings were validated using histological criteria (11%) and clinical and imaging criteria (89%). The overall accuracy of [(11)C]choline PET/CT was 88%. Multivariate logistic regression showed that high PSA and short PSADT were significant (p < 0.05) predictors of positive [(11)C]choline PET/CT [PSA: odds ratio (OR) = 1.43; 95% confidence interval (CI): 1.15-1.78; PSADT: OR = 1.12; 95% CI: 1.04-1.21]. The percentage of patients with positive [(11)C]choline PET/CT was 27% for PSADT >6 months, 61% for PSADT between 3 and 6 months and 81% for PSADT <3 months. The percentage of patients who displayed pathological [(11)C]choline uptake in the skeleton significantly increased (p < 0.05) from 3% for PSADT >6 months to 52% for PSADT <3 months. Conversely, patients who displayed pathological [(11)C]choline uptake in the prostatectomy bed were 0% for PSADT <3 months and 17% for PSADT >6 months (p < 0.05). A nomogram based on age, PSA, PSADT, time to trigger PSA, Gleason score, pathological stage and androgen deprivation therapy demonstrated bootstrap-corrected predictive accuracy of 81%. Like PSA, PSADT is an independent predictor of [(11)C]choline PET/CT. [(11)C]choline PET/CT is very sensitive to PCa tumour growth, as reflected by PSA kinetics. PSADT should be taken into account by physicians when referring PCa patients for [(11)C]choline PET/CT.