55 results on '"S. Grancha"'
Search Results
2. Native plasma-derived FVIII/VWF complex has lower sensitivity to FVIII inhibitors than the combination of isolated FVIII and VWF proteins. Impact on Bethesda assay titration of FVIII inhibitors
- Author
-
S Grancha, J. I. Jorquera, B Da Rocha-Souto, and M I Bravo
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,animal diseases ,von Willebrand factor ,Hemophilia A ,Thrombin generation ,Bethesda assay ,law.invention ,Von Willebrand factor ,thrombin generation assay ,law ,Isoantibodies ,hemic and lymphatic diseases ,Medicine ,Humans ,Blood Coagulation ,Genetics (clinical) ,Factor VIII ,biology ,Blood Coagulation Factor Inhibitors ,business.industry ,Plasma derived ,Thrombin ,FVIII inhibitors ,Hematology ,General Medicine ,Molecular biology ,In vitro ,FVIII/VWF complex ,Titer ,Drug Combinations ,Kinetics ,Immunology ,Recombinant DNA ,biology.protein ,cardiovascular system ,Titration ,Original Article ,Blood Coagulation Tests ,Antibody ,business ,circulatory and respiratory physiology ,Protein Binding - Abstract
Sensitivity to FVIII inhibitors of the native plasma-derived (pd) FVIII/VWF complex vs. the complexes formed after exogenous FVIII infusion in the haemophilic patient has not been thoroughly studied. The role of VWF in the interaction of FVIII with inhibitors was studied in vitro using different combinations of VWF and FVIII concentrates. Normal plasma, pdFVIII/VWF and isolated FVIII (recombinant FVIII, B-domain deleted and pdFVIII) were used. Titre (BU) was kinetically determined (up to 2 h) in serial dilutions of inhibitor IgG (purified from a pool of plasmas with inhibitors) mixed with VWF and then incubated with the different FVIII. Inhibitor was also added to previously mixed VWF+FVIII. Residual FVIII:C was determined. TGA assays were performed with FVIII-deficient plasma spiked with the FVIII-VWF mixtures with/without an ESH-8 antibody. Inhibitor titres for plasma and pdFVIII/VWF were comparable at all time points. Titres for all concentrates of isolated FVIII were significantly higher than those for plasma or pdFVIII/VWF (1.4–1.9 fold) even after preincubation with VWF. At t = 0 h, titres for plasma or pdFVIII/VWF were unquantifiable, but were detectable for isolated FVIII (0.6–1.6 BU). In contrast to pdFVIII/VWF, the decrease in thrombin generation parameters by isolated FVIII in the presence of ESH-8 was significant (P
- Published
- 2014
3. Neutralizing capacity of inhibitors on<scp>FVIII</scp>is lower for natural<scp>FVIII</scp>/<scp>VWF</scp>complex than for isolated<scp>FVIII</scp>:in vitrocomparative study in eleven different therapeutic<scp>FVIII</scp>concentrates
- Author
-
J. I. Jorquera, M I Bravo, Montserrat Costa, A. M. Ortiz, and S. Grancha
- Subjects
0301 basic medicine ,biology ,business.industry ,Hematology ,General Medicine ,030204 cardiovascular system & hematology ,Virology ,In vitro ,law.invention ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Von Willebrand factor ,law ,biology.protein ,Recombinant DNA ,Medicine ,business ,Genetics (clinical) - Published
- 2016
4. The burden of inhibitors in haemophilia patients
- Author
-
S. Grancha, Christopher E. Walsh, Víctor Jiménez-Yuste, and Guenter Auerswald
- Subjects
Burden of disease ,medicine.medical_specialty ,Factor VIII ,business.industry ,Hematology ,Health Care Costs ,030204 cardiovascular system & hematology ,Haemophilia ,medicine.disease ,Hemophilia A ,Poor quality ,03 medical and health sciences ,0302 clinical medicine ,Clinical evidence ,Immunology ,von Willebrand Factor ,medicine ,Immune Tolerance ,Quality of Life ,Animals ,Humans ,Cost of care ,Intensive care medicine ,business ,030215 immunology - Abstract
SummaryThe burden of disease in haemophilia patients has wide ranging implications for the family and to society. There is evidence that having a current inhibitor increases the risk of morbidity and mortality. Morbidity is increased by the inability to treat adequately and its consequent disabilities, which then equates to a poor quality of life compared with non-inhibitor patients. The societal cost of care, or `burden of inhibitors’, increases with the ongoing presence of an inhibitor. Therefore, it is clear that successful eradication of inhibitors by immune tolerance induction (ITI) is the single most important milestone one can achieve in an inhibitor patient. The type of factor VIII (FVIII) product used in ITI regimens varies worldwide. Despite ongoing debate, there is in vitro and retrospective clinical evidence to support the use of plasma-derived VWF-containing FVIII concentrates in ITI regimens in order to achieve early and high inhibitor eradication success rates.
- Published
- 2016
5. Management of bleeding disorders: basic science
- Author
-
Pascual Marco, Frederick A. Ofosu, E. Santagostino, and S. Grancha
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,biology ,business.industry ,Basic science ,animal diseases ,Haemophilia A ,Hematology ,General Medicine ,medicine.disease ,Thrombin generation ,Chronic disease ,Von Willebrand factor ,hemic and lymphatic diseases ,Immunology ,biology.protein ,Medicine ,business ,Genetics (clinical) - Abstract
Summary. Development of factor VIII (FVIII) inhibitors is the most severe and challenging complication of haemophilia A treatment and represents the highest economic burden for a chronic disease. Therefore, major research efforts are ongoing to optimize the therapeutic approaches able to minimize this complication. FVIII inhibitors have variable immuno-reactivity against different FVIII concentrates and generally have a lower reactivity against von Willebrand factor (VWF)-containing FVIII concentrates than plasma-derived FVIII (pdFVIII) or recombinant FVIII (rFVIII) that are devoid of VWF, in particular when the inhibitors are directed against the light chain of FVIII. This paper provides an overview of several in vitro and in vivo studies that compared three clinically available clinical FVIII products (Kogenate®, Bayer AG, Leverkusen, Germany; Advate®, Baxter Healthcare, Zurich, Switzerland; and Fanhdi®, Grifols S.A., Barcelona, Spain) in order to evaluate the functional actvity of the FVIII fractions in rFVIII that cannot bind VWF; explore the use of the thrombin generation assay (TGA) as a potential tool for optimizing the choice of FVIII concentrate for use in haemophilia A patients with inhibitors; compare the kinetics of the interactions between anti-FVIII antibodies and FVIII both in the presence/absence of VWF, using surface plasmon resonance.
- Published
- 2012
6. Understanding FVIII/VWF complex - report from a symposium of XXIX WFH meeting 2010
- Author
-
Frederick A. Ofosu, Augusto B. Federici, Nadia P. Ewing, Alessandro Gringeri, S. Grancha, and Johannes Oldenburg
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,biology ,business.industry ,Immunogenicity ,Hematology ,General Medicine ,Haemophilia ,medicine.disease ,Immune tolerance ,Clinical trial ,Von Willebrand factor ,hemic and lymphatic diseases ,Immunology ,biology.protein ,Medicine ,In patient ,business ,Genetics (clinical) - Abstract
Summary. von Willebrand factor (VWF) has the capa-city to form a complex with factor VIII (FVIII) whichmay modulate the immunogenicity of FVIII. It has beenproposed that a significant fraction of recombinantFVIII (rFVIII) is unable to bind VWF. In an experi-mental model studied at the McMaster University inCanada, this VWF-unbound rFVIII fraction showed nocoagulant function. Sulphation of FVIII tyrosine (Tyr)1680 has been reported as essential for the interactionwith VWF. In a study performed at the Grifols andCNS-CSIC in Spain, Tyr1680 sulphation was observedto be incomplete in rFVIII and complete in plasma-derived FVIII (pdFVIII). This could explain the incap-ability of some rFVIII molecules to bind VWF.Experience with immune tolerance induction (ITI) atthe Bonn Haemophilia Centre indicates that onlyeradication of FVIII inhibitors allows safe haemostasiscontrol and the option of prophylactic treatment.Various clinical trials were planned to evaluate theclinical role VWF-containing FVIII concentrates (FVIII/VWF). RES.I.ST (an acronym for REScue Immunoto-lerance STudy) is an international, prospective studyaimed at assessing whether FVIII/VWF can induce ITI inhigh-risk haemophilia patients (RES.I.ST nai¨ve) andwhether patients who previously failed ITI with FVIIIalone can be rescued with FVIII/VWF (RES.I.STexperienced). Enrolment started in November 2009.In the FAIReSt.Will (Fanhdi and Alphanate ItalianRetrospective Study in Willebrand disease) study, 120von Willebrand disease (VWD) patients treated withFanhdi or Alphanate were retrospectively analysed.Efficacy was excellent and no side effects were reported.The ongoing PRO.Will study is a prospective, multi-center trial aimed at assessing the efficacy, safety andpharmacoeconomics of secondary long-term prophy-laxis in patients with severe inherited VWD.Keywords: factor VIII, immune tolerance induction, immu-nogenicity, inhibitors, Tyrosine 1680, von Willebrandfactor
- Published
- 2011
7. Albumin function in acute-on-chronic liver failure (ACLF): Effect of plasma exchange with albumin 5% (PE-A5%)
- Author
-
A. Páez, Javier Fernández, V. Arroyo, Raquel Horrillo, N. Afonso, M. Torres, S. Grancha, Montserrat Costa, A. Pérez, A.M. Ortiz, and L. Núñez
- Subjects
medicine.medical_specialty ,Hepatology ,business.industry ,Internal medicine ,medicine ,Albumin ,Acute on chronic liver failure ,business ,Gastroenterology ,Function (biology) - Published
- 2018
8. COLLAGEN AFFINITY TO VON WILLEBRAND FACTOR CONTAINED IN A THERAPEUTIC FVIII/VWF CONCENTRATE EVALUATED BY SURFACE PLASMON RESONANCE
- Author
-
S. Grancha and J.I. Jorquera
- Subjects
Von Willebrand factor ,biology ,Chemistry ,Biophysics ,biology.protein ,Hematology ,Surface plasmon resonance - Published
- 2007
9. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects
- Author
-
Francisco España, S. Grancha, Fernando Ferrando, Amparo Vayá, Amparo Estellés, Rafael Seguí, Cristina Falcó, Piedad Villa, Yolanda Mira, and Justo Aznar
- Subjects
Venous thrombosis ,medicine.medical_specialty ,business.industry ,Internal medicine ,Genotype ,medicine ,Hematology ,medicine.disease ,business ,Gastroenterology - Published
- 2000
10. Lipoprotein(a) Levels and Isoforms and Fibrinolytic Activity in Postmenopause – Influence of Hormone Replacement Therapy
- Author
-
S. Grancha, Justo Aznar, Juan Gilabert, Antonio Cano, Francisco España, Amparo Estellés, and Cristina Falcó
- Subjects
medicine.medical_specialty ,biology ,business.industry ,medicine.drug_class ,Plasmin ,medicine.medical_treatment ,Hematology ,Lipoprotein(a) ,Steroid hormone ,Endocrinology ,Estrogen ,Internal medicine ,Fibrinolysis ,Euglobulin lysis time ,biology.protein ,Medicine ,business ,Plasminogen activator ,Lipoprotein ,medicine.drug - Abstract
SummaryEpidemiological studies suggest that hormone replacement therapy (HRT) decreases the risk of cardiovascular disease in postmenopausal women via several mechanisms, including modifications in the fibrinolytic system and lipoprotein(a) [Lp(a)] levels. The aim of this study was to examine the influence of the levels and isoforms of Lp(a) on fibrinolytic activity in 91 postmenopausal women in comparison with premenopause and analyze the effect of HRT on those parameters. In postmenopause, an increase in plasma Lp(a) and plasminogen activator inhibitor-1 (PAI-1) levels was found. A significant inverse correlation was observed between Lp(a) or PAI-1 levels and plasmin generation. Plasma samples with low molecular weight (MW) apo(a) isoforms showed higher plasmin inhibition than plasmas with high MW apo(a) isoforms and similar levels of total Lp(a) and PAI-1. HRT induced a significant decrease in Lp(a) and PAI-1 levels and an increase in estradiol levels, as well as an increase in fibrinolytic activity. A significant correlation was found between the percentages of variation in Lp(a) levels and in plasmin generation and between the percentages of variation in PAI-1 levels and in the euglobulin lysis time under HRT. In conclusion, the increase in fibrinolytic activity observed in women under HRT could be explained by two independent mechanisms: (a) the decrease in PAI-1 and (b) the decrease in the inhibition of plasmin generation due to the decrease in Lp(a) levels.
- Published
- 1999
11. Detailed localization of type-1 plasminogen activator inhibitor mRNA expression and antigen in atherosclerotic plaque on human coronary artery
- Author
-
Francisco España, Justo Aznar, Cristina Falcó, S. Grancha, M. Chirivella, and Amparo Estellés
- Subjects
Messenger RNA ,Pathology ,medicine.medical_specialty ,business.industry ,Connective tissue ,In situ hybridization ,Coronary arteries ,medicine.anatomical_structure ,Antigen ,Immunohistochemistry ,Medicine ,business ,Plasminogen activator ,Artery - Abstract
Summary Objective : To accurately localize type-1 plasminogen activator inhibitor (PAI-1) both in atherosclerotic and normal human coronary arteries and to determine which cells are responsible for its production. Design : Immunohistochemistry and in situ hybridization over paraffin embedded samples obtained from patients subjected to heart transplant in ‘La Fe’ University Hospital, Valencia, Spain. Results : PAI-1 mRNA is clearly detectable in atherosclerotic coronary artery, both in endothelial cells and in smooth muscle cells (SMCs) in the connective tissue of the thickened intima, while in the core of the plaque macrophages are the main PAI-1 producer cells. This pattern is coincident with PAI-1 antigen localization. In arteries appearing to be normal, PAI-1 antigen and mRNA were only slightly detectable or not at all. Conclusion : PAI-1 expression and antigen are increased in endothelial cells from atherosclerotic arteries. PAI-1 mRNA and antigen are also present in the SMCs from thickened arteries and in macrophages in the core of the plaque. These results suggest that PAI-1 may be involved in the development, evolution and final outcome of the atherosclerotic plaque.
- Published
- 1998
12. Management of bleeding disorders: basic science
- Author
-
F A, Ofosu, E, Santagostino, S, Grancha, and P, Marco
- Subjects
Factor VIII ,Blood Coagulation Factor Inhibitors ,Isoantibodies ,von Willebrand Factor ,Humans ,Hemophilia A ,Recombinant Proteins - Abstract
Development of factor VIII (FVIII) inhibitors is the most severe and challenging complication of haemophilia A treatment and represents the highest economic burden for a chronic disease. Therefore, major research efforts are ongoing to optimize the therapeutic approaches able to minimize this complication. FVIII inhibitors have variable immuno-reactivity against different FVIII concentrates and generally have a lower reactivity against von Willebrand factor (VWF)-containing FVIII concentrates than plasma-derived FVIII (pdFVIII) or recombinant FVIII (rFVIII) that are devoid of VWF, in particular when the inhibitors are directed against the light chain of FVIII. This paper provides an overview of several in vitro and in vivo studies that compared three clinically available clinical FVIII products (Kogenate®, Bayer AG, Leverkusen, Germany; Advate®, Baxter Healthcare, Zurich, Switzerland; and Fanhdi®, Grifols S.A., Barcelona, Spain) in order to evaluate the functional actvity of the FVIII fractions in rFVIII that cannot bind VWF; explore the use of the thrombin generation assay (TGA) as a potential tool for optimizing the choice of FVIII concentrate for use in haemophilia A patients with inhibitors; compare the kinetics of the interactions between anti-FVIII antibodies and FVIII both in the presence/absence of VWF, using surface plasmon resonance.
- Published
- 2012
13. Kinetics of the interaction between anti-FVIII antibodies and FVIII from therapeutic concentrates, with and without von Willebrand factor, assessed by surface plasmon resonance
- Author
-
K. Hampel, S. Grancha, A. M. Ortiz, A. Moret, B. Zimmermann, C. Marañón, J. I. Jorquera, and Justo Aznar
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Kinetics ,Antigen-Antibody Complex ,Hemophilia A ,Severity of Illness Index ,law.invention ,Mice ,Von Willebrand factor ,Bacterial Proteins ,law ,hemic and lymphatic diseases ,von Willebrand Factor ,Medicine ,Animals ,Humans ,Surface plasmon resonance ,Genetics (clinical) ,Factor VIII ,biology ,business.industry ,Immunogenicity ,Hematology ,General Medicine ,Surface Plasmon Resonance ,Molecular biology ,Antibodies, Anti-Idiotypic ,Immunoglobulin G ,Immunology ,biology.protein ,Recombinant DNA ,Severe haemophilia A ,Protein G ,Antibody ,business - Abstract
Summary The presence of VWF in plasma-derived FVIII (pdFVIII/VWF) products has been pointed out as a key difference with recombinant FVIII (rFVIII) products with regard to immunogenicity. A Surface Plasmon Resonance (SPR) study was designed to characterize in detail the interaction between anti-FVIII (IgGs) from a severe haemophilia A patient, and FVIII from concentrates of different sources. Full-length rFVIII (preincubated or not with purified VWF), B domain-deleted (BDD)-rFVIII and pdFVIII/VWF were analysed. To ensure reproducible conditions for accurate determination of kinetic constants, a capture-based assay format was developed using protein G surfaces for specific and reversible coupling of endogenous anti-FVIII antibodies. Concentration ranges (nm) of FVIII products tested were 9–0.03 (rFVIII) and 6–0.024 (pdFVIII/VWF). The association with antibodies was monitored for 3–5 min, whereas dissociation of the complex was followed for 5–20–240 min. A strong interaction of rFVIII and BDD-rFVIII with patient's IgG was detected with the K D values in the low picomolar range (5.9 ± 3.0 and 12.7 ± 6.9 pm, respectively) and very slow dissociation rates, while pdFVIII/VWF showed only marginal binding signals. The VWF complexed rFVIII displayed reduced binding signals compared with uncomplexed rFVIII, but the K D was still in the picomolar range (4.1 ± 1.9 pm) indicating insufficient complex formation. rFVIII, alone or bound to exogenously added VWF, showed high affinity for anti-FVIII IgGs from a severe haemophilia A patient whereas pdFVIII/VWF did not. These results are in agreement with those studies that point towards rFVIII concentrates to be more immunogenic than pdFVIII concentrates.
- Published
- 2012
14. Altered expression of plasminogen activator inhibitor type 1 in placentas from pregnant women with preeclampsia and/or intrauterine fetal growth retardation
- Author
-
Raymond R. Schleef, M. Keeton, Juan Gilabert, Justo Aznar, Amparo Estellés, F Espna, David J. Loskutoff, S. Grancha, and Yutaka Eguchi
- Subjects
medicine.medical_specialty ,Immunology ,Syncytiotrophoblasts ,In situ hybridization ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Preeclampsia ,Endocrinology ,medicine.anatomical_structure ,Internal medicine ,Placenta ,embryonic structures ,medicine ,Immunohistochemistry ,Northern blot ,Plasminogen activator ,Immunostaining ,reproductive and urinary physiology - Abstract
Elevated plasma levels of type 1 plasminogen activator inhibitor (PAI- 1) have been implicated in mediating the fibrin deposition and occlusive lesions that occur within the placental vasculature in preeclampsia (PE) and intrauterine growth retardation (IUGR). In this report we identify the cells within the normal-appearing villous tissue that are responsible for the local production of PAI-1 in women with PE and IUGR. Levels for another fibrinolytic inhibitor (ie, type 2 plasminogen activator inhibitor [PAI-2]) were determined for comparative purposes. Elevated levels of PAI-1 were detected in placenta extracts from PE/IUGR patients (121 +/- 38 ng/mg, n = 8) when compared with the levels in placenta extracts from normal women (43 +/- 17 ng/mg, n = 10) or women with IUGR but not PE (51 +/- 22 ng/mg, n = 11). Immunohistochemical analysis of paraffin sections showed an increased immunoreactivity for PAI-1 in the placental villous syncytiotrophoblasts from PE/IUGR women compared with the immunostaining of placental samples from the normal or IUGR group. In contrast, antigen levels and immunostaining for PAI-2 were reduced in the placentas harvested from not only the PE/IUGR women (209 +/- 144 ng/mg) but also the IUGR group (169 +/- 106 ng/mg) in comparison with the PAI-2 levels in normal placentas (535 +/- 98 ng/mg). To document that the increased immunoreactivity for PAI-1 in PE/IUGR syncytiotrophoblasts was mediated by an increased production of PAI-1 within these cells, in situ hybridization analysis was performed. A strong positive signal for PAI-1 mRNA in villous syncytiotrophoblasts from PE patients (n = 5) was obtained after 2 weeks of exposure to the NTB2 emulsion in comparison with the weak signal for PAI-1 mRNA that required a 10-week exposure of the normal placenta sections (n = 10). Northern blotting for PAI-1 mRNA showed that both transcripts (ie, 3.2 and 2.3 kb) were elevated in samples of two PE patients in comparison with the PAI-1 mRNA transcripts present in a normal placenta and an IUGR placental sample. These results show increased PAI-1 and mRNA levels in placentas from PE patients and raise the possibility that localized elevated levels of PAI-1 may play a role in the initiation of placental damage, as well as in the thrombotic complications associated with this disease.
- Published
- 1994
15. Incomplete tyrosine 1680 sulphation in recombinant FVIII concentrates
- Author
-
S, Grancha, R, Navajas, C, Marañón, A, Paradela, J P, Albar, and J I, Jorquera
- Subjects
Factor VIII ,Reproducibility of Results ,Tyrosine ,Recombinant Proteins - Published
- 2011
16. Effect of temperature on plasma freezing under industrial conditions
- Author
-
M I, Bravo, S, Grancha, and J I, Jorquera
- Subjects
Cryopreservation ,Europe ,Factor IX ,Pharmacopoeias as Topic ,Plasma ,Factor VIII ,Blood Preservation ,Temperature ,Fibrinogen ,Humans ,Industry ,Blood Coagulation Tests - Abstract
The European Pharmacopoeia monograph on Human plasma for fractionation does not define the freezing process time but does define the freezing temperature (- 30 degrees C or below). Initial freezing conditions are crucial for the quality of plasma. These conditions were intended to preserve labile proteins such as fVIIl, but they can also be considered favourable for the plasma quality in general. This study evaluates the way the industrial plasma freezing affects labile coagulation factors. We have studied the freezing of plasma in industrial-size chambers at temperatures close to - 30 degrees C, - 25 degrees C and - 20 degrees C, and the possible differences between performing the freezing process in a chamber or in a freezer, in order to elucidate whether or not these parameters affect the quality of plasma. For this study, plasma bottles were frozen in industrial chambers set at - 30 degrees C, - 25 degrees C and - 20 degrees C, and in a freezer set at - 20 degrees C. The freezing rates were followed by means of probes in plasma control bottles. From this plasma, coagulation factors (fVIII, fIX and fibrinogen) were analysed before and after freezing, and cryoprecipitate was obtained in some cases. Statistically significant differences exist in fVIII:C recovery in thawed plasma between freezing at - 30 degrees C and at - 20 degrees C (n = 11; 85.4 +/- 4.3 % versus 74.6 +/- 6.0 % (chamber) or 79.3 +/- 6.3 % (freezer)). There is no difference between - 30 degrees C and - 25 degrees C, or between freezing at - 20 degrees C in a chamber or in a freezer. No significant loss of activity in thawed plasma is observed for fIX and fibrinogen at - 25 degrees C or - 20 degrees C versus - 30 degrees C. The fVIII and vWF recovery in cryoprecipitates does not show differences (464.2 IU fVIII/ml at - 30 degrees C, 446.7 IU fVIII/ml at - 25 degrees C, and 475.8 IU fVIII/ml at - 20 degrees C). The results obtained from this study support that plasma might also be frozen at - 25 degrees C or below without any impact on its quality, and that sporadic and short term deviations, from - 30 degrees C or below up to - 25 degrees C, in the currently required freezing temperature, would not have an effect on the labile factors recovery.
- Published
- 2007
17. Incomplete tyrosine 1680 sulphation in recombinant FVIII concentrates
- Author
-
J. I. Jorquera, C. Marañón, Rosana Navajas, S. Grancha, Juan-Pablo Albar, and Alberto Paradela
- Subjects
Sulfation ,law ,business.industry ,Immunology ,Recombinant DNA ,Medicine ,Hematology ,General Medicine ,Tyrosine ,business ,Genetics (clinical) ,law.invention - Published
- 2011
18. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thrombophilic defects
- Author
-
Fernando Ferrando, Rafael Seguí, Francisco España, S. Grancha, Piedad Villa, Amparo Vayá, Justo Aznar, Amparo Estellés, Yolanda Mira, and Cristina Falcó
- Subjects
Adult ,Blood Glucose ,Male ,medicine.medical_specialty ,Pathology ,Genotype ,medicine.medical_treatment ,Thrombophilia ,Gastroenterology ,Statistics, Nonparametric ,chemistry.chemical_compound ,Risk Factors ,Internal medicine ,Plasminogen Activator Inhibitor 1 ,Fibrinolysis ,medicine ,Humans ,Genetic Predisposition to Disease ,Antigens ,Risk factor ,Allele ,Promoter Regions, Genetic ,Triglycerides ,Venous Thrombosis ,Chi-Square Distribution ,business.industry ,Thrombin ,Hematology ,Middle Aged ,medicine.disease ,Thrombosis ,Venous thrombosis ,chemistry ,Case-Control Studies ,Tissue Plasminogen Activator ,Plasminogen activator inhibitor-1 ,Female ,business ,Protein C - Abstract
Impaired fibrinolysis as a result of increased plasminogen activator inhibitor-1 (PAI-1) levels in plasma is a common finding in patients with deep vein thrombosis (DVT). A 4G/5G polymorphism in the promoter region of the PAI-1 gene has been reported to influence the levels of PAI-1. The 4G allele was found to be associated with higher plasma PAI-1 activity (act), but contradictory results on the incidence of the 4G allele in DVT patients have been reported. The aim of this study was to analyse whether the PAI-1 promoter 4G/5G genotype increases the risk of venous thrombosis in subjects with thrombophilic defects, and to determine the distribution of the PAI-1 4G/5G genotype and its relation to plasma PAI-1 levels in 190 unrelated patients with DVT in comparison with a control group of 152 healthy subjects. No differences between the 4G/5G allele distribution in the DVT group (0.43/0.57) and in the control group (0.42/0.58) were observed. However, the presence of the 4G allele significantly increased the risk of thrombosis in patients with other thrombophilic defects. Significantly higher PAI-1 levels were observed in DVT patients than in the controls. Our results also showed significant differences in the plasma levels of PAI-1 antigen (ag) and PAI-1 act among the 4G/5G genotypes in DVT patients. A multivariate analysis revealed that, in the DVT group, PAI-1 ag levels were influenced by the 4G allele dosage, triglyceride levels and body mass index (BMI). The influence of the 4G allele dosage on PAI-1 levels was independent of the triglyceride levels and BMI. In the control group, no significant correlation between PAI-1 levels and 4G allele dosage was observed. In conclusion, the PAI-1 promoter polymorphism was found to have an influence on PAI-1 levels in DVT patients and on the risk of venous thrombosis in subjects with other genetic thrombophilic defects.
- Published
- 2000
19. Lipoprotein(a) levels and isoforms and fibrinolytic activity in postmenopause--influence of hormone replacement therapy
- Author
-
A, Estellés, A, Cano, C, Falcó, F, España, J, Gilabert, S, Grancha, and J, Aznar
- Subjects
Adult ,Postmenopause ,Cardiovascular Diseases ,Hormone Replacement Therapy ,Fibrinolysis ,Humans ,Protein Isoforms ,Female ,Middle Aged ,Aged ,Lipoprotein(a) - Abstract
Epidemiological studies suggest that hormone replacement therapy (HRT) decreases the risk of cardiovascular disease in postmenopausal women via several mechanisms, including modifications in the fibrinolytic system and lipoprotein(a) [Lp(a)] levels. The aim of this study was to examine the influence of the levels and isoforms of Lp(a) on fibrinolytic activity in 91 postmenopausal women in comparison with premenopause and analyze the effect of HRT on those parameters. In postmenopause, an increase in plasma Lp(a) and plasminogen activator inhibitor-1 (PAI-1) levels was found. A significant inverse correlation was observed between Lp(a) or PAI-1 levels and plasmin generation. Plasma samples with low molecular weight (MW) apo(a) isoforms showed higher plasmin inhibition than plasmas with high MW apo(a) isoforms and similar levels of total Lp(a) and PAI-1. HRT induced a significant decrease in Lp(a) and PAI-1 levels and an increase in estradiol levels, as well as an increase in fibrinolytic activity. A significant correlation was found between the percentages of variation in Lp(a) levels and in plasmin generation and between the percentages of variation in PAI-1 levels and in the euglobulin lysis time under HRT. In conclusion, the increase in fibrinolytic activity observed in women under HRT could be explained by two independent mechanisms: (a) the decrease in PAI-1 and (b) the decrease in the inhibition of plasmin generation due to the decrease in Lp(a) levels.
- Published
- 1999
20. Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary artery disease
- Author
-
S, Grancha, A, Estellés, G, Tormo, C, Falco, J, Gilabert, F, España, A, Cano, R, Segui, and J, Aznar
- Subjects
Blood Glucose ,Genotype ,Hormone Replacement Therapy ,Myocardial Infarction ,Coronary Disease ,Estrogens ,Middle Aged ,Postmenopause ,Cholesterol ,Plasminogen Activator Inhibitor 1 ,Humans ,Female ,Antigens ,Promoter Regions, Genetic ,Triglycerides - Abstract
Increased circulating levels of type 1 plasminogen activator inhibitor (PAI-1) have been associated with coronary artery disease (CAD). However, genetic and environmental determinants of PAI-1 expression are only partially understood. The levels of PAI-1 have been found to relate to 4/5 guanosine (4G/5G) polymorphism in the promoter region of the PAI-1 gene. The 4G allele in this polymorphism has been associated with higher levels of plasma PAI-1 activity, but despite the strong correlation between PAI-1 activity and antigen, no association has been found between PAI-1 antigen levels and the PAI-1 promoter 4G/5G genotype. The aim of the present study was to analyze the influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels in post-menopause women with coronary disease in comparison with healthy women in pre and postmenopausal status, and the influence of this genotype on variations in PAI-1 levels after hormone replacement therapy (HRT). No differences between 4G/5G allele distribution in the groups studied were observed. The group of postmenopausal women with CAD showed significantly increased PAI-1 antigen and activity levels in comparison with the control groups, and the levels of PAI-1 correlated with the 4G/5G genotype. A multivariate analysis revealed that in the CAD group there was a high correlation between 4G allele dosage and PAI-1 antigen levels, which were also influenced by the triglyceride levels but not by estrogen or glucose levels. After hormone replacement therapy the decrease in PAI-1 levels was correlated with the 4G allele dosage. We conclude that in the group of postmenopausal women with CAD the influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels is more evident than in the control groups, and that the decrease in PAI-1 levels after HRT in CAD women correlates with the 4G allele dosage.
- Published
- 1999
21. Factor V Leiden and antibodies against phospholipids and protein S in a young woman with recurrent thromboses and abortion
- Author
-
F, España, P, Villa, Y, Mira, S, Grancha, M, Royo, A, Estellés, A, Vayá, and J, Aznar
- Subjects
Adult ,Abortion, Habitual ,Heterozygote ,Pregnancy Complications, Hematologic ,Factor V ,Cerebral Infarction ,Thrombophlebitis ,Antiphospholipid Syndrome ,Autoimmune Diseases ,Brain Ischemia ,Protein S ,Pregnancy Complications ,Antibody Specificity ,Pregnancy ,beta 2-Glycoprotein I ,Lupus Coagulation Inhibitor ,Antibodies, Antiphospholipid ,Humans ,Thrombophilia ,Female ,Genetic Predisposition to Disease ,Activated Protein C Resistance ,Autoantibodies ,Glycoproteins - Abstract
We describe the case of a 39-year-old woman who suffered two iliofemoral venous thromboses, a cerebral ischemic infarct and recurrent fetal loss. Initial studies showed high levels of antiphospholipid antibodies (APAs) and a moderate thrombocytopenia. After her second miscarriage, laboratory diagnosis revealed that the woman was heterozygous for the factor V Leiden mutation and had a functional protein S deficiency as well as anti-protein S and anti-beta 2-glycoprotein I antibodies. The impairment of the protein C pathway at various points could well explain the recurrent thromboses in the patient and supports the role of a disturbed protein C system in the pathophysiology of thrombosis in patients with APAs.
- Published
- 1999
22. Plasminogen activator inhibitor-1 (PAI-1) promoter 4G/5G genotype and increased PAI-1 circulating levels in postmenopausal women with coronary artery disease - Influence of hormone replacement therapy
- Author
-
Amparo Estellés, Francisco España, G. Tormo, Cristina Falcó, R. Segui, Justo Aznar, S. Grancha, Juan Gilabert, and Antonio Cano
- Subjects
medicine.medical_specialty ,medicine.drug_class ,medicine.medical_treatment ,Hormone replacement therapy (menopause) ,Hematology ,Biology ,medicine.disease ,Coronary artery disease ,chemistry.chemical_compound ,Endocrinology ,Antigen ,chemistry ,Estrogen ,Polymorphism (computer science) ,Internal medicine ,Plasminogen activator inhibitor-1 ,Genotype ,medicine ,Allele - Abstract
SummaryIncreased circulating levels of type 1 plasminogen activator inhibitor (PAI-1) have been associated with coronary artery disease (CAD). However, genetic and environmental determinants of PAI-1 expression are only partially understood. The levels of PAI-1 have been found to relate to 4/5 guanosine (4G/5G) polymorphism in the promoter region of the PAI-1 gene. The 4G allele in this polymorphism has been associated with higher levels of plasma PAI-1 activity, but despite the strong correlation between PAI-1 activity and antigen, no association has been found between PAI-1 antigen levels and the PAI-1 promoter 4G/5G genotype. The aim of the present study was to analyze the influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels in post-menopause women with coronary disease in comparison with healthy women in pre and postmenopausal status, and the influence of this genotype on variations in PAI-1 levels after hormone replacement therapy (HRT). No differences between 4G/5G allele distribution in the groups studied were observed. The group of postmenopausal women with CAD showed significantly increased PAI-1 antigen and activity levels in comparison with the control groups, and the levels of PAI-1 correlated with the 4G/5G genotype. A multivariate analysis revealed that in the CAD group there was a high correlation between 4G allele dosage and PAI-1 antigen levels, which were also influenced by the triglyceride levels but not by estrogen or glucose levels. After hormone replacement therapy the decrease in PAI-1 levels was correlated with the 4G allele dosage. We conclude that in the group of postmenopausal women with CAD the influence of the PAI-1 promoter 4G/5G genotype on PAI-1 levels is more evident than in the control groups, and that the decrease in PAI-1 levels after HRT in CAD women correlates with the 4G allele dosage.
- Published
- 1999
23. Abnormal expression of type 1 plasminogen activator inhibitor and tissue factor in severe preeclampsia
- Author
-
Terri Thinnes, Koji Yamamoto, Juan Gilabert, Francisco España, Justo Aznar, Amparo Estellés, David J. Loskutoff, and S. Grancha
- Subjects
medicine.medical_specialty ,Placenta ,Pregnancy Complications, Cardiovascular ,Fibrin ,Preeclampsia ,Thromboplastin ,Tissue factor ,chemistry.chemical_compound ,Syncytiotrophoblast ,Pre-Eclampsia ,Pregnancy ,Internal medicine ,Plasminogen Activator Inhibitor 1 ,Medicine ,Humans ,RNA, Messenger ,Vitronectin ,reproductive and urinary physiology ,In Situ Hybridization ,biology ,business.industry ,Tumor Necrosis Factor-alpha ,Hematology ,medicine.disease ,Immunohistochemistry ,medicine.anatomical_structure ,Endocrinology ,chemistry ,Plasminogen activator inhibitor-1 ,embryonic structures ,Immunology ,biology.protein ,Tumor necrosis factor alpha ,Female ,business ,Interleukin-1 - Abstract
SummaryPreeclampsia is a multisystemic obstetric disease of unknown etiology that is commonly associated with fibrin deposition, occlusive lesions in placental vasculature, and intrauterine fetal growth retardation. We previously reported that type 1 plasminogen activator inhibitor (PAI-1) levels are significantly increased in plasma and placenta from pregnant women with preeclampsia compared to normal pregnant women. In the present report we localize the expression of placental PAI-1 in greater detail and compare it with that of tissue factor (TF), a procoagulant molecule, and vitronectin (Vn), a PAI-1 cofactor. We also examine the expression of two cytokines, tumor necrosis factor α (TNFα) and interleukin-1 (IL-1), in order to begin to define the underlying mechanisms responsible for the elevated levels of PAI-1 and fibrin deposits observed in placenta from preeclampsia. We demonstrate a significant increase in PAI-1, TF and TNFα antigen and PAI-1 and TF mRNA in placentas from preeclamptic patients. PAI-1 mRNA was increased not only in syncytiotrophoblast and infarction areas, but also in fibroblasts and in some endothelial cells of fetal vessels in placentas from preeclamptic patients. However, there was no colocalization between PAI-1, TF, Vn and TNFα in placental villi. The elevated TNFα in the placenta may induce PAI-1 and TF, and thus promote the thrombotic alterations associated with preeclampsia.
- Published
- 1998
24. Activated protein C resistance phenotype in patients with antiphospholipid antibodies
- Author
-
Francisco España, Piedad Villa, Amparo Estellés, Cristina Falcó, S. Grancha, and Justo Aznar
- Subjects
Adult ,Blood Platelets ,Male ,medicine.medical_specialty ,Abortion, Habitual ,Adolescent ,Asymptomatic ,Gastroenterology ,Pathology and Forensic Medicine ,Pregnancy ,Internal medicine ,medicine ,Humans ,Child ,Blood Coagulation ,Phospholipids ,Aged ,Lupus anticoagulant ,medicine.diagnostic_test ,business.industry ,General Medicine ,Middle Aged ,Thrombophlebitis ,medicine.disease ,Thrombosis ,Pulmonary embolism ,Venous thrombosis ,Cerebrovascular Disorders ,Phenotype ,Antibodies, Anticardiolipin ,Child, Preschool ,Lupus Coagulation Inhibitor ,Immunology ,Antibodies, Antiphospholipid ,Female ,Partial Thromboplastin Time ,medicine.symptom ,Activated protein C resistance ,business ,Protein C ,circulatory and respiratory physiology ,medicine.drug ,Partial thromboplastin time - Abstract
The effect of antiphospholipid antibodies (aPL) on the action of activated protein C (APC) was examined in 32 patients: 19 with lupus anticoagulant (LA), 6 with anticardiolipin antibodies (aCL), and 7 with LA and aCL. Eighteen patients had a ratio of activated partial thromboplastin time (APTT) with APC to APTT without APC (APTT ratio)
- Published
- 1997
25. Decreased expression of PAI-2 mRNA and protein in pregnancies complicated with intrauterine fetal growth retardation
- Author
-
Francisco España, Justo Aznar, Juan Gilabert, S. Grancha, Melitina Chirivella, and Amparo Estellés
- Subjects
Adult ,medicine.medical_specialty ,Placenta ,Syncytiotrophoblasts ,In situ hybridization ,Biology ,Pre-Eclampsia ,Pregnancy ,Internal medicine ,Gene expression ,medicine ,Plasminogen Activator Inhibitor 2 ,Humans ,RNA, Messenger ,reproductive and urinary physiology ,In Situ Hybridization ,Messenger RNA ,Fetus ,Fetal Growth Retardation ,Infant, Newborn ,Hematology ,medicine.anatomical_structure ,Endocrinology ,Gene Expression Regulation ,In utero ,embryonic structures ,Plasminogen activator inhibitor-2 ,Female - Abstract
SummaryAn increase in plasma plasminogen activator inhibitors (PAIs), fundamentally PAI type 2 (PAI-2), has been described in normal pregnancy probably because the placenta is the main source of the high plasma levels of this protein. Although we have previously described plasmatic alterations of these inhibitors in pregnancies complicated with intrauterine fetal growth retardation (IUGR), no reports have been published about placental PAI-2 mRNA expression. In the present study, the placental PAI-2 expression determined in pregnancies complicated with IUGR and in severe preeclamptic patients was compared with that of normal pregnancies in order to identify the placental cell types expressing PAI-2 and to determine whether the production of PAI-2 is altered in placentas from IUGR. In situ hybridization analyses show that the syncytiotrophoblasts are the cells with the greatest PAI-2 expression in placenta. We report that the significant decrease in plasma and placental PAI-2 levels in IUGR groups is fundamentally due to a diminished expression of PAI-2 mRNA in placenta.
- Published
- 1996
26. Abnormal expression of plasminogen activator inhibitors in patients with gestational trophoblastic disease
- Author
-
A, Estellés, S, Grancha, J, Gilabert, T, Thinnes, M, Chirivella, F, España, J, Aznar, and D J, Loskutoff
- Subjects
Plasminogen Inactivators ,Pregnancy ,Placenta ,embryonic structures ,Plasminogen Activator Inhibitor 1 ,Uterine Neoplasms ,Plasminogen Activator Inhibitor 2 ,Humans ,Female ,Hydatidiform Mole ,Tissue Polypeptide Antigen ,reproductive and urinary physiology ,Research Article - Abstract
We previously reported significantly elevated levels of plasminogen activator inhibitor type 1 (PAI-1) in plasma and placenta from pregnant women with severe pre-eclampsia, and pre-eclampsia is a frequent problem in molar pregnancies. As increases in PAI-1 may contribute to the placental alterations that occur in pre-eclampsia, we have begun to investigate changes in PAI-1 as well as PAI-2 and several other components of the fibrinolytic system in patients with trophoblastic disease. Significant increases in plasma PAI-1 and decreases in plasma PAI-2 levels were observed in molar pregnancies when compared with the levels in normal pregnant women of similar gestational age. PAI-1 antigen levels also were increased, and PAI-2 levels were decreased in placenta from women with molar pregnancies compared with placenta obtained by spontaneous abortion. Immunohistochemical analysis revealed strong positive and specific staining of PAI-1 in trophoblastic epithelium in molar pregnancies and relatively weak staining of PAI-2. No association between the distribution of PAI-1 and vitronectin was found, and no specific signal for tissue type PA, urokinase type PA, tumor necrosis factor-alpha, or interleukin-1 was detected. In situ hybridization revealed an increase in PAI-1 but not PAI-2 mRNAs in placenta from molar pregnancies in comparison with placenta from abortions. These results demonstrate increased PAI-1 protein and mRNA in trophoblastic disease and suggest that localized elevated levels of PAI-1 may contribute to the hemostatic problems associated with this disorder.
- Published
- 1996
27. Fibrinolytic system and reproductive process with special reference to fibrinolytic failure in pre-eclampsia
- Author
-
Amparo Estellés, Juan Gilabert, Justo Aznar, Francisco España, and S. Grancha
- Subjects
Male ,Ovulation ,medicine.medical_specialty ,medicine.medical_treatment ,Biology ,chemistry.chemical_compound ,Pre-Eclampsia ,Cell Movement ,Pregnancy ,Internal medicine ,Placenta ,Fibrinolysis ,medicine ,Humans ,Spermatogenesis ,reproductive and urinary physiology ,T-plasminogen activator ,Reproduction ,Rehabilitation ,Obstetrics and Gynecology ,Trophoblast ,Spermatozoa ,medicine.anatomical_structure ,Endocrinology ,Reproductive Medicine ,chemistry ,Plasminogen activator inhibitor-1 ,Fertilization ,embryonic structures ,Plasminogen activator inhibitor-2 ,Female ,Plasminogen activator ,Fibrinolytic agent - Abstract
Here we summarize the recent progress in research on the role of the fibrinolytic system in reproduction, with a special emphasis on the role of the plasminogen activator inhibitors in fetal development. Trophoblasts produce fibrinolytic proteins that can promote normal implantation and regulate blood flow to the fetus and placenta throughout pregnancy. Normal pregnancy is associated with a hypofibrinolytic state that is fundamentally caused by an increase in plasminogen activator inhibitors types 1 and 2. In pre-eclampsia, a fibrinolytic failure, resulting from an increase in plasma and placental concentrations of plasminogen activator inhibitor-1, was observed. The localized elevated concentrations of placenta plasminogen activator inhibitor-1 protein and mRNA observed in pre-eclamptic patients would be expected to foster the deposition of fibrin and thus play a role in the complications associated with this disease. The decreased plasminogen activator inhibitor-2 concentrations in placenta and plasma from intrauterine fetal growth retardation pregnancies and the positive correlation between plasma/placenta plasminogen activator inhibitor-2 concentration and birthweight suggest that this inhibitor could be considered an adequate marker of placental function.
- Published
- 1995
28. The effect of estrogen replacement therapy with or without progestogen on the fibrinolytic system and coagulation inhibitors in postmenopausal status
- Author
-
Miguel Tortajada, Francisco España, S. Grancha, Rosa Barrachina, Antonio Cano, Juan Gilabert, Justo Aznar, and Amparo Estellés
- Subjects
Adult ,medicine.medical_specialty ,Medroxyprogesterone ,Time Factors ,medicine.drug_class ,medicine.medical_treatment ,Administration, Oral ,Administration, Cutaneous ,Protein S ,Internal medicine ,Fibrinolysis ,Plasminogen Activator Inhibitor 1 ,medicine ,Humans ,Hormone replacement therapy ,Aged ,Urokinase ,biology ,Estradiol ,Progesterone Congeners ,business.industry ,Antithrombin ,Estrogen Replacement Therapy ,Obstetrics and Gynecology ,Lipoprotein(a) ,Middle Aged ,Postmenopause ,Endocrinology ,Estrogen ,Tissue Plasminogen Activator ,biology.protein ,Female ,Hormone therapy ,business ,Plasminogen activator ,medicine.drug ,Protein C - Abstract
OBJECTIVE: The aim of this study was to analyze several fibrinolytic components and coagulation inhibitors in postmenopausal women and to evaluate the effect of hormone replacement therapy. STUDY DESIGN: Several hemostatic parameters were evaluated in 75 postmenopausal women before and after 3 to 4 and 12 months of hormone therapy. RESULTS: An increase in plasma fibrinolytic activity primarily related to a significant increase in tissue-type plasminogen activator and a decrease in plasminogen activator inhibitor type 1 was observed in women receiving hormone replacement therapy. A significant decrease in protein S and lipoprotein(a) was detected under therapy. No modifications in tissue-type plasminogen activator/plasminogen activator inhibitor-1 and activated protein C/α 1 -antitrypsin complexes, urokinase activity, plasminogen, and antithrombin III were detected. CONCLUSIONS: The increase in fibrinolytic activity and the decrease in lipoprotein(a) levels observed in women receiving hormone replacement therapy could help decrease the risk of coronary disease associated with the postmenopausal state.
- Published
- 1995
29. Altered expression of plasminogen activator inhibitor type 1 in placentas from pregnant women with preeclampsia and/or intrauterine fetal growth retardation
- Author
-
A, Estellés, J, Gilabert, M, Keeton, Y, Eguchi, J, Aznar, S, Grancha, F, Espña, D J, Loskutoff, and R R, Schleef
- Subjects
Adult ,Fetal Growth Retardation ,Pre-Eclampsia ,Pregnancy ,Placenta ,Plasminogen Activator Inhibitor 1 ,Plasminogen Activator Inhibitor 2 ,Humans ,Female ,RNA, Messenger ,Immunohistochemistry - Abstract
Elevated plasma levels of type 1 plasminogen activator inhibitor (PAI-1) have been implicated in mediating the fibrin deposition and occlusive lesions that occur within the placental vasculature in preeclampsia (PE) and intrauterine growth retardation (IUGR). In this report we identify the cells within the normal-appearing villous tissue that are responsible for the local production of PAI-1 in women with PE and IUGR. Levels for another fibrinolytic inhibitor (ie, type 2 plasminogen activator inhibitor [PAI-2]) were determined for comparative purposes. Elevated levels of PAI-1 were detected in placenta extracts from PE/IUGR patients (121 +/- 38 ng/mg, n = 8) when compared with the levels in placenta extracts from normal women (43 +/- 17 ng/mg, n = 10) or women with IUGR but not PE (51 +/- 22 ng/mg, n = 11). Immunohistochemical analysis of paraffin sections showed an increased immunoreactivity for PAI-1 in the placental villous syncytiotrophoblasts from PE/IUGR women compared with the immunostaining of placental samples from the normal or IUGR group. In contrast, antigen levels and immunostaining for PAI-2 were reduced in the placentas harvested from not only the PE/IUGR women (209 +/- 144 ng/mg) but also the IUGR group (169 +/- 106 ng/mg) in comparison with the PAI-2 levels in normal placentas (535 +/- 98 ng/mg). To document that the increased immunoreactivity for PAI-1 in PE/IUGR syncytiotrophoblasts was mediated by an increased production of PAI-1 within these cells, in situ hybridization analysis was performed. A strong positive signal for PAI-1 mRNA in villous syncytiotrophoblasts from PE patients (n = 5) was obtained after 2 weeks of exposure to the NTB2 emulsion in comparison with the weak signal for PAI-1 mRNA that required a 10-week exposure of the normal placenta sections (n = 10). Northern blotting for PAI-1 mRNA showed that both transcripts (ie, 3.2 and 2.3 kb) were elevated in samples of two PE patients in comparison with the PAI-1 mRNA transcripts present in a normal placenta and an IUGR placental sample. These results show increased PAI-1 and mRNA levels in placentas from PE patients and raise the possibility that localized elevated levels of PAI-1 may play a role in the initiation of placental damage, as well as in the thrombotic complications associated with this disease.
- Published
- 1994
30. Evaluation of plasminogen activators and plasminogen activator inhibitors in plasma and amniotic fluid in pregnancies complicated with intrauterine fetal growth retardation
- Author
-
Francisco España, S. Grancha, Micó Jm, Justo Aznar, Ayuso Mj, Amparo Estellés, M. Chirivella, and Juan Gilabert
- Subjects
Adult ,medicine.medical_specialty ,Amniotic fluid ,Birth weight ,medicine.medical_treatment ,Preeclampsia ,Plasminogen Activators ,Pregnancy ,Internal medicine ,Fibrinolysis ,medicine ,Fetal growth ,Plasminogen Activator Inhibitor 2 ,Humans ,Urokinase ,Fetal Growth Retardation ,business.industry ,Obstetrics and Gynecology ,medicine.disease ,Amniotic Fluid ,Plasminogen Inactivators ,Endocrinology ,Reproductive Medicine ,Female ,business ,Plasminogen activator ,medicine.drug - Abstract
Several fibrinolytic parameters were determined in plasma and amniotic fluid from normotensive pregnancies complicated by intrauterine fetal growth retardation (IUGR) and severe preeclamptic (PE) patients with IUGR and compared with data from normal pregnancies. A significant decrease in plasminogen activator type 2 (PAI-2) and urokinase levels in plasma and amniotic fluid was observed in IUGR groups in comparison with normal pregnancy. No significant differences were observed between the control and IUGR groups in relation to the other fibrinolytic parameters, except for plasma PAI type 1 and tissue-type plasminogen activator levels, which were significantly increased in the PE group. A significant positive correlation was observed between birth weight and PAI-2 levels in both plasma and amniotic fluid, but the plasma PAI-2 levels showed a higher correlation. In conclusion, these results suggest that the PAI-2 level measured in plasma is a more adequate marker of placental function than the PAI-2 level measured in amniotic fluid.
- Published
- 1994
31. EVALUATION BY SURFACE PLASMON RESONANCE OF VWF EFFECT ON MONOCLONAL ANTIBODY DIRECTED TO FVIII LIGHT CHAIN REACTIVITY
- Author
-
J.I. Jorquera and S. Grancha
- Subjects
medicine.drug_class ,Chemistry ,Biophysics ,medicine ,Reactivity (chemistry) ,Hematology ,Surface plasmon resonance ,Immunoglobulin light chain ,Monoclonal antibody - Published
- 2007
32. 108 Relationship between PAI-1 promoter polymorphism and PAI-1 circulating levels in postmenopausal women with coronary artery disease (CAD)
- Author
-
J. Gilabert, Francisco España, Amparo Estellés, S. Grancha, G. Tormo, Justo Aznar, and Cristina Falcó
- Subjects
Coronary artery disease ,medicine.medical_specialty ,Postmenopausal women ,business.industry ,Internal medicine ,medicine ,Promoter polymorphism ,CAD ,medicine.disease ,business ,Gastroenterology - Published
- 1997
33. Expression of fibrinolytic components in plasmas and placentas from patients with trophoblastic disease
- Author
-
J. Gilabert, S. Grancha, Amparo Estellés, M. Chirivella, Justo Aznar, David J. Loskutoff, and Francisco España
- Subjects
Pathology ,medicine.medical_specialty ,business.industry ,Immunology ,medicine ,Hematology ,Disease ,business - Published
- 1994
34. Modifications in the fibrinolytic system by hormone-replacement therapy (HRT)
- Author
-
A. Cano, S. Grancha, J. Gilabert, Francisco España, Justo Aznar, Amparo Estellés, and M. Tortajada
- Subjects
medicine.medical_specialty ,Endocrinology ,business.industry ,Internal medicine ,medicine ,Hematology ,Hormone replacement therapy ,business - Published
- 1994
35. Technological optimization of the process of preparation of fresh frozen blood plasma to transfusion in devices for its thermal processing.
- Author
-
Lemondzhava, V. N., Lemondzhava, T. Yu., Gudkov, A. G., Shashurin, V. D., Leushin, V. Yu., and Kasyanov, A. D.
- Subjects
PLASMA products ,BLOOD transfusion ,PLASMA devices ,PROCESS optimization ,BLOOD collection ,BLOOD plasma - Abstract
The article presents the results of a study aimed at improving the safety of hemostatic parameters of donor fresh frozen blood plasma in its preparation for transfusion. The developed method of technological optimization of the process of preparation of fresh frozen blood plasma for transfusion in devices for its heat treatment is described and the results of its testing are presented. The results indicate that the use of the developed method of technological optimization of the process of preparation of fresh frozen blood plasma for transfusion leads to a reduction in the time of exposure on blood plasma in the device for its heat treatment, thereby potentially reducing the decrease in indicators of its thermolabile components. It is reasonable to continue the study to quantify the increase in their preservation with paired blood plasma samples obtained from the same donor. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
36. Genotype Variations and Association between PAI-1 Promoter Region (4G/5G and -844G/A) and Susceptibility to Acute Myocardial Infarction and Chronic Stable Angina.
- Author
-
Kumar, Sunil, Verma, Amit Kumar, Sagar, Vinay, Ranjan, Ravi, Sharma, Rahul, Tomar, Preeti, Bhatt, Deepti, Goyal, Yamini, Alsahli, Mohammed A., Almatroudi, Ahmad, Almatroodi, Saleh A., Rahmani, Arshad Husain, Alrumaihi, Faris, Muzammil, Khursheed, Dev, Kapil, Yadav, Rakesh, and Saxena, Renu
- Subjects
MYOCARDIAL infarction risk factors ,MYOCARDIAL infarction ,ANGINA pectoris ,GENETIC polymorphisms ,CASE-control method ,ALLELES ,DISEASE susceptibility ,GENOTYPES ,ENZYME-linked immunosorbent assay ,BLOOD coagulation factors ,POLYMERASE chain reaction ,DISEASE risk factors - Abstract
The present study aimed at investigating the 4G/5G and -844G/A polymorphisms and plasma concentration of PAI-1 in patients with acute myocardial infarction (AMI) and chronic stable angina (CSA) in Indian population. It included 100 patients with AMI and stable angina and 100 healthy controls. All study subjects were typed for two PAI polymorphisms (4G/5G and -844G/A) through PCR-RFLP and level of PAI through ELISA. The comparison of AMI and CSA independently with control in terms of PAI-1 level was statistically significant but not between AMI and CSA. The frequency of 4G/4G and 4G/5G genotype and 4G allele was significantly higher in AMI cases than in control and was found to increase the risk of AMI. There was a significant relationship between 4G/5G polymorphism and AMI risk under the dominant and codominant genotype. The frequency of 4G/4G genotype and 4G allele was significantly higher in CSA cases than in control group and increases the risk of CSA. There was no significant association between 4G/5G polymorphism and CSA risk under recessive, dominant, and codominant models. The genotype and allelic frequencies difference between the cases (AMI and CSA) and control with regard to -844G/A polymorphisms were statistically nonsignificant. Also, we did not detect any significant association of -844G/A polymorphism with AMI and CSA in recessive, dominant, and codominant models. Along with the traditional risk factors, the 4G/5G allele polymorphism is an independent risk factor for the development of AMI. The detection of 4G/5G allele may therefore be helpful in primary prevention. Patients who carry the 4G/5G allele polymorphism have high concentrations of PAI-1, which might be involved in incidents leading to AMI. The present study for the first time revealed significant association of 4G/5G allele polymorphism with high risk of AMI in Indian population and will be helpful in identifying the genetic risk factors associated with AMI and CSA and for better management of diagnostic measures. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
37. The progress in corneal translational medicine.
- Author
-
Hancox, Zoe, Heidari Keshel, Saeed, Yousaf, Safiyya, Saeinasab, Morvarid, Shahbazi, Mohammad-Ali, and Sefat, Farshid
- Published
- 2020
- Full Text
- View/download PDF
38. Albumin: An Emerging Opportunity in Drug Delivery.
- Author
-
Rahimizadeh, Parastou, Yang, Sungtae, and Lim, Sung In
- Subjects
ALBUMINS ,TARGETED drug delivery ,BLOOD proteins ,DRUG carriers ,BIOLOGICAL transport - Abstract
Albumin, the most abundant and long-lived serum protein, exhibits novel features as a carrier that can greatly enhance the pharmacological action of therapeutic payloads. Besides passive trafficking by enhanced permeability and retention effect, albumin has been shown to accumulate within the tumor environment or inflamed tissues by receptor-mediated active transport, lending itself to being a promising scaffold for targeted drug delivery. Albumin has recently been found to be a scavenger for amyloid-β with the potential to treat neurodegenerative diseases. The hydrophobic binding pockets, conjugatable thiol residue, and surface-exposed N- and C-termini in albumin inherently serve as useful spots for carrying various kinds of peptidyl and non-peptidyl drugs. Beyond its long-standing role as a half-life extender, albumin is emerging as a versatile drug carrier to aid numerous therapeutic agents that have poor pharmacokinetics, targetability, solubility, and instability in vivo. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
39. plasma product release testing vs plasma pool screening and approval studies of plasma donors
- Author
-
Hierzenhofer, Patricia
- Subjects
plasma derivative ,Richtlinien ,EMA ,Plasmaderivate ,guideline ,FDA - Abstract
Bei der Herstellung von Arzneimitteln aus biologischen Materialen sind immer Risiken gegeben. Besonders bei aus humanem Plasma hergestellten Produkten müssen wegen der Heterogenität des Startmaterials für die Fraktionierung strenge Richtlinien befolgt werden. Diese Arbeit behandelt den Vergleich ebendieser Richtlinien aus Europa und USA und um etwaige Unterschiede festzustellen. Dazu wurden die entsprechenden Richtlinien der European Medicines Agency (EMA) und U.S. Food and Drug Administration (FDA) in einer formal wissenschaftlichen Arbeitsweise durch Recherche im Internet erfasst, ausgearbeitet und verglichen. Dabei ergaben die Recherchen, dass jeweils die Gute Herstellungspraxis [1, 2] zu beachten ist, Blutspendeeinrichtungen zugelassen sein müssen und für die Spenderauswahl die Zulassungskriterien, welche sich nur in den Details unterscheiden, beachtet werden müssen [3, 4]. Die Einzelspenden und Plasmapools für die Fraktionierung müssen auf die Infektionsmarker von Hepatitis B, Hepatitis C und HIV getestet werden [5, 6]. Die Kontrollen im Prozess müssen vorab definiert werden, Reprocessing darf nur erfolgen, wenn dies schon prospektiv in der Prozessvalidierung berücksichtigt worden ist und die Stabilität der Produkte während der Haltbarkeitsdauer muss durch Stabilitätsstudien bewiesen sein [1, 7]. Weiters wurde noch ermittelt, dass Faktor VIII (FVIII) Plasmaderivate gegenüber rekombinant hergestellten Proteinen eine geringere Immunogenität beim Patienten hervorruft [8]. Auch zeigte sich, dass die Einführung des Nukleinsäure-Amplifikations-Verfahrens (NAT) eine große Auswirkung auf die sichere und frühere Testung von HIV, HCV und HBV Infektionen hat [9]. Bezüglich der Richtlinien zeigte sich, dass in Europa und USA diese weitgehend vereinheitlicht sind und die Unterschiede nur in den Details liegen. Im Weiteren wäre ein internationaler Vergleich interessant, inwieweit die international gültigen Leitfäden der internationalen Harmonisierungs-Kommission (ICH) umgesetzt worden sind und welche Länder noch Handlungsbedarf zeigen. [1] EudraLex, Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 14 Manufacture of Medicinal Products Derived from Human Blood or Plasma. Brussels, SANCO/C8/AM/an D(2010) 380358, Revision 1, 30 November 2011 [2] electronic Code Of Federal Regulations, PART 606—Current Good Manufacturing Practice For Blood And Blood Components, eCFR data is current as of June 10, 2016 [3] RICHTLINIE 2002/98/EG DES EUROPÄISCHEN PARLAMENTS UND DES RATES vom 27. Januar 2003 zur Festlegung von Qualitäts- und Sicherheitsstandards für die Gewinnung, Testung, Verarbeitung, Lagerung und Verteilung von menschlichem Blut und Blutbestandteilen und zur Änderung der Richtlinie 2001/83/EG [4] electronic Code Of Federal Regulations, PART 607—Establishment Registration And Product Listing For Manufacturers Of Human Blood And Blood Products, eCFR data is current as of June 10, 2016 [5] Eu.Pharm.8 01/2014:0853 HUMAN PLASMA FOR FRACTIONATION - Plasma humanum ad separationem [6] electronic Code Of Federal Regulations, PART 640—Additional Standards For Human Blood And Blood Products, eCFR data is current as of June 10, 2016 [7] Guidance for Industry: For the Submission of Chemistry, Manufacturing and Controls and Establishment Description Information for Human Plasma-Derived Biological Products, Animal Plasma or Serum-Derived Products - U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research (CBER) - February 1999 [8] M.I. Bravo, B. da Rocha-Souto, S. Grancha and J.I. Jorquera: Native plasma-derived FVIII/VWF complex has lower sensitivity to FVIII inhibitors than the combination of isolated FVIII and VWF proteins. Impact of Bethesda assay titration of FVIII inhibitors. Haemophilia 2014, Vol.20, 905-911, DOI: 10.1111/hae.12494 [9] M. Müller et al: Evaluation of two, commercial, multi-dye, nucleic acid amplification technology tests, for HBV/HCV/HIV-1/HIV-2 and B19V/HAV, for screening blood and plasma for further manufacture. VoxSanguinis 2013, Vol.104, 19-29, DOI: 10.1111/j.1423-0410.2012.01635.x The production of biological products includes several risks, especially if they are produced of human plasma. Therefore, strict guidelines have to be followed. This script compares guidelines from the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA). It is a formal scientific work, the information was acquired by research of several internet websites. The Results showed that Good Manufacturing Practise [1, 2] has to be followed and the registered blood establishments have to select donors by required acceptance criteria [3, 4]. The single donations and plasma pools for fractionation have to be tested for infection markers of Hepatitis B, Hepatitis C and HIV [5, 6]. In-process-controls have to be defined in advance, reprocessing is allowed if the criteria were laid down prospectively to the process validation and the products stability during shelf life needs to be proven by stability studies [1, 7]. Furthermore, it was determined that plasma-derived Factor VIII (FVIII) induce less immunogenicity than recombinant FVIII proteins. However, it was also shown that the introduction of the nucleic acid amplification technology (NAT) reduced the window period of HIV, HCV and HBV [9]. Regarding the guidelines of Europe and USA, it was found that most of the standards are harmonized, and the differences are just in details. In the future, an international comparison of guidelines would be interesting, to see how far the guidelines of the International Council for Harmonisation (ICH) are already implemented. [1] EudraLex, Volume 4, EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 14 Manufacture of Medicinal Products Derived from Human Blood or Plasma. Brussels, SANCO/C8/AM/an D(2010) 380358, Revision 1, 30 November 2011 [2] electronic Code Of Federal Regulations, PART 606—Current Good Manufacturing Practice For Blood And Blood Components, eCFR data is current as of June 10, 2016 [3] RICHTLINIE 2002/98/EG DES EUROPÄISCHEN PARLAMENTS UND DES RATES vom 27. Januar 2003 zur Festlegung von Qualitäts- und Sicherheitsstandards für die Gewinnung, Testung, Verarbeitung, Lagerung und Verteilung von menschlichem Blut und Blutbestandteilen und zur Änderung der Richtlinie 2001/83/EG [4] electronic Code Of Federal Regulations, PART 607—Establishment Registration And Product Listing For Manufacturers Of Human Blood And Blood Products, eCFR data is current as of June 10, 2016 [5] Eu.Pharm.8 01/2014:0853 HUMAN PLASMA FOR FRACTIONATION - Plasma humanum ad separationem [6] electronic Code Of Federal Regulations, PART 640—Additional Standards For Human Blood And Blood Products, eCFR data is current as of June 10, 2016 [7] Guidance for Industry: For the Submission of Chemistry, Manufacturing and Controls and Establishment Description Information for Human Plasma-Derived Biological Products, Animal Plasma or Serum-Derived Products - U.S. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research (CBER) - February 1999 [8] M.I. Bravo, B. da Rocha-Souto, S. Grancha and J.I. Jorquera: Native plasma-derived FVIII/VWF complex has lower sensitivity to FVIII inhibitors than the combination of isolated FVIII and VWF proteins. Impact of Bethesda assay titration of FVIII inhibitors. Haemophilia 2014, Vol.20, 905-911, DOI: 10.1111/hae.12494 [9] M. Müller et al: Evaluation of two, commercial, multi-dye, nucleic acid amplification technology tests, for HBV/HCV/HIV-1/HIV-2 and B19V/HAV, for screening blood and plasma for further manufacture. VoxSanguinis 2013, Vol.104, 19-29, DOI: 10.1111/j.1423-0410.2012.01635.x vorgelegt von: Patricia Hierzenhofer Masterarbeit Wien, FH Campus Wien 2016
- Published
- 2016
40. Poster Presentations.
- Subjects
BLOOD coagulation factor VIII ,POSTER presentations ,MEDICAL personnel - Published
- 2019
- Full Text
- View/download PDF
41. Neutralizing capacity of inhibitors on FVIII is lower for natural FVIII/ VWF complex than for isolated FVIII: in vitro comparative study in eleven different therapeutic FVIII concentrates.
- Author
-
Bravo, M. I., Ortiz, A. M., Costa, M., Grancha, S., and Jorquera, J. I.
- Subjects
BLOOD coagulation factor VIII antibodies ,VON Willebrand factor ,COMPARATIVE studies - Abstract
A letter to the editor is presented regarding an in vitro comparative study which revealed the lower capacity of inhibitors on factors (FVIII) for natural FVIII/von Willebrand factor (VWF) complex compared with isolated FVIII.
- Published
- 2016
- Full Text
- View/download PDF
42. Native plasma-derived FVIII/VWF complex has lower sensitivity to FVIII inhibitors than the combination of isolated FVIII and VWF proteins. Impact on Bethesda assay titration of FVIII inhibitors.
- Author
-
BRAVO, M. I ., DA ROCHA-SOUTO, B., GRANCHA, S., and JORQUERA, J. I .
- Abstract
Sensitivity to FVIII inhibitors of the native plasma‐derived (pd) FVIII/VWF complex vs. the complexes formed after exogenous FVIII infusion in the haemophilic patient has not been thoroughly studied. The role of VWF in the interaction of FVIII with inhibitors was studied in vitro using different combinations of VWF and FVIII concentrates. Normal plasma, pdFVIII/VWF and isolated FVIII (recombinant FVIII, B‐domain deleted and pdFVIII) were used. Titre (BU) was kinetically determined (up to 2h) in serial dilutions of inhibitor IgG (purified from a pool of plasmas with inhibitors) mixed with VWF and then incubated with the different FVIII. Inhibitor was also added to previously mixed VWF+FVIII. Residual FVIII:C was determined. TGA assays were performed with FVIII‐deficient plasma spiked with the FVIII‐VWF mixtures with/without an ESH‐8 antibody. Inhibitor titres for plasma and pdFVIII/VWF were comparable at all time points. Titres for all concentrates of isolated FVIII were significantly higher than those for plasma or pdFVIII/VWF (1.4–1.9 fold) even after preincubation with VWF. At t=0h, titres for plasma or pdFVIII/VWF were unquantifiable, but were detectable for isolated FVIII (0.6–1.6 BU). In contrast to pdFVIII/VWF, the decrease in thrombin generation parameters by isolated FVIII in the presence of ESH‐8 was significant (P<0.01) even when previously combined with VWF. In conclusion, VWF protection against FVIII inhibitor activity might be higher with native pdFVIII/VWF complex than with the corresponding compound formed from the isolated proteins. Bethesda assay titration using different FVIII concentrates would be advisable to guide the treatment of inhibitor patients. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
43. Kinetics of the interaction between anti-FVIII antibodies and FVIII from therapeutic concentrates, with and without von Willebrand factor, assessed by surface plasmon resonance.
- Author
-
Grancha, S., Ortiz, A. M., Marañón, C., Hampel, K., Moret, A., Zimmermann, B., Jorquera, J. I., and Aznar, J. A.
- Subjects
DRUG interactions ,IMMUNOGLOBULINS ,PHARMACOKINETICS ,SURFACE plasmon resonance ,HEMOPHILIA treatment ,G proteins - Abstract
The presence of VWF in plasma-derived FVIII (pdFVIII/VWF) products has been pointed out as a key difference with recombinant FVIII ( rFVIII) products with regard to immunogenicity. A Surface Plasmon Resonance (SPR) study was designed to characterize in detail the interaction between anti-FVIII (IgGs) from a severe haemophilia A patient, and FVIII from concentrates of different sources. Full-length rFVIII (preincubated or not with purified VWF), B domain-deleted (BDD)- rFVIII and pdFVIII/VWF were analysed. To ensure reproducible conditions for accurate determination of kinetic constants, a capture-based assay format was developed using protein G surfaces for specific and reversible coupling of endogenous anti-FVIII antibodies. Concentration ranges (n m) of FVIII products tested were 9-0.03 ( rFVIII) and 6-0.024 (pdFVIII/VWF). The association with antibodies was monitored for 3-5 min, whereas dissociation of the complex was followed for 5-20-240 min. A strong interaction of rFVIII and BDD- rFVIII with patient's IgG was detected with the K
D values in the low picomolar range (5.9 ± 3.0 and 12.7 ± 6.9 p m, respectively) and very slow dissociation rates, while pdFVIII/VWF showed only marginal binding signals. The VWF complexed rFVIII displayed reduced binding signals compared with uncomplexed rFVIII, but the KD was still in the picomolar range (4.1 ± 1.9 p m) indicating insufficient complex formation. rFVIII, alone or bound to exogenously added VWF, showed high affinity for anti-FVIII IgGs from a severe haemophilia A patient whereas pdFVIII/VWF did not. These results are in agreement with those studies that point towards rFVIII concentrates to be more immunogenic than pdFVIII concentrates. [ABSTRACT FROM AUTHOR]- Published
- 2012
- Full Text
- View/download PDF
44. Management of bleeding disorders: basic science.
- Author
-
OFOSU, F. A., SANTAGOSTINO, E., GRANCHA, S., and MARCO, P.
- Subjects
BLOOD coagulation disorders ,HEMOPHILIA ,VON Willebrand factor ,CHRONIC diseases ,BLOOD coagulation factors - Abstract
. Development of factor VIII (FVIII) inhibitors is the most severe and challenging complication of haemophilia A treatment and represents the highest economic burden for a chronic disease. Therefore, major research efforts are ongoing to optimize the therapeutic approaches able to minimize this complication. FVIII inhibitors have variable immuno-reactivity against different FVIII concentrates and generally have a lower reactivity against von Willebrand factor (VWF)-containing FVIII concentrates than plasma-derived FVIII (pdFVIII) or recombinant FVIII (rFVIII) that are devoid of VWF, in particular when the inhibitors are directed against the light chain of FVIII. This paper provides an overview of several in vitro and in vivo studies that compared three clinically available clinical FVIII products (Kogenate®, Bayer AG, Leverkusen, Germany; Advate®, Baxter Healthcare, Zurich, Switzerland; and Fanhdi®, Grifols S.A., Barcelona, Spain) in order to evaluate the functional actvity of the FVIII fractions in rFVIII that cannot bind VWF; explore the use of the thrombin generation assay (TGA) as a potential tool for optimizing the choice of FVIII concentrate for use in haemophilia A patients with inhibitors; compare the kinetics of the interactions between anti-FVIII antibodies and FVIII both in the presence/absence of VWF, using surface plasmon resonance. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
45. Understanding FVIII/VWF complex - report from a symposium of XXIX WFH meeting 2010.
- Author
-
GRINGERI, A., OFOSU, F. A., GRANCHA, S., OLDENBURG, J., EWING, N. P., and FEDERICI, A. B.
- Subjects
VON Willebrand factor ,BLOOD coagulation factor VIII ,IMMUNOLOGICAL tolerance - Abstract
. von Willebrand factor (VWF) has the capacity to form a complex with factor VIII (FVIII) which may modulate the immunogenicity of FVIII. It has been proposed that a significant fraction of recombinant FVIII (rFVIII) is unable to bind VWF. In an experimental model studied at the McMaster University in Canada, this VWF-unbound rFVIII fraction showed no coagulant function. Sulphation of FVIII tyrosine (Tyr) 1680 has been reported as essential for the interaction with VWF. In a study performed at the Grifols and CNS-CSIC in Spain, Tyr1680 sulphation was observed to be incomplete in rFVIII and complete in plasma-derived FVIII (pdFVIII). This could explain the incapability of some rFVIII molecules to bind VWF. Experience with immune tolerance induction (ITI) at the Bonn Haemophilia Centre indicates that only eradication of FVIII inhibitors allows safe haemostasis control and the option of prophylactic treatment. Various clinical trials were planned to evaluate the clinical role VWF-containing FVIII concentrates (FVIII/VWF). RES.I.ST (an acronym for REScue Immunotolerance STudy) is an international, prospective study aimed at assessing whether FVIII/VWF can induce ITI in high-risk haemophilia patients (RES.I.ST naïve) and whether patients who previously failed ITI with FVIII alone can be rescued with FVIII/VWF (RES.I.ST experienced). Enrolment started in November 2009. In the FAIReSt.Will (Fanhdi and Alphanate Italian Retrospective Study in Willebrand disease) study, 120 von Willebrand disease (VWD) patients treated with Fanhdi
® or Alphanate® were retrospectively analysed. Efficacy was excellent and no side effects were reported. The ongoing PRO.Will study is a prospective, multicenter trial aimed at assessing the efficacy, safety and pharmacoeconomics of secondary long-term prophylaxis in patients with severe inherited VWD. [ABSTRACT FROM AUTHOR]- Published
- 2012
- Full Text
- View/download PDF
46. Thrombosis in Systemic Lupus Erythematosus: A Review Article.
- Author
-
Al-Homood, IbrahimA.
- Abstract
Thrombosis is a well-known clinical entity in systemic lupus erythematosus (SLE), and it is multifactorial. The most important risk factor is the presence of antiphospholipid antibodies (APLAs). However, approximately 40% of adults with SLE who are negative for APL A are diagnosed with thrombosis, indicating the importance of other risk factors. Thus, the thrombosis risk factors should be evaluated extensively and regularly and treated aggressively in every patient with systemic lupus erythematosus. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
47. Emerging role of endothelial and inflammatory markers in preeclampsia.
- Author
-
Swellam, Menha, Samy, Nervana, Wahab, Susan Abdl, and Ibrahim, Mohamed Saeed
- Subjects
PREECLAMPSIA ,FIBRINOLYTIC agents ,BIOMARKERS ,C-reactive protein ,BLOOD coagulation factors - Abstract
Objectives: Endothelial disturbance and excess inflammatory response are pathogenic mechanisms in pre-eclampsia (PE). Authors determine the clinical diagnostic role for thrombomodulin (TM), plasminogen activator inhibitor-1 (PAI-1) as endothelial markers and C-reactive protein (CRP), and interlukin-6 (IL-6) as inflammatory markers when tested independently or in combinations. Materials and methods: We conducted a retrospective study in a cohort of 185 women grouped as 80 women with PE, 55 normotensive pregnant and 50 healthy non-pregnant. Plasma levels of TM, PAI-1, CRP and IL-6 were examined using enzyme linked immunosorbent assays. Results: Median levels and the positivity rates for the investigated markers were higher in PE as compared to the other groups (P < 0.0001). Using linear regression analysis, the investigated markers were significantly correlated regarding healthy non-pregnant vs PE or normotensive pregnant vs PE. The sensitivity of PAI-1 was the highest (98%) among the tested biomarkers. Combination between the investigated markers revealed absolute sensitivity (100%) and reliable specificity especially when PAI-1 was combined with CRP at 83% specificity. Conclusions: Investigated endothelial and inflammatory markers revealed sensitive diagnostic test for PE. However, coupled combination between PAI-1 with CRP showed superior both sensitivity and specificity which represent a promising new approach for detection of PE. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
48. Comparison of the plasminogen activator inhibitor-1 4G/5G gene polymorphism in females with venous thromboembolism during pregnancy or spontaneous abortion.
- Author
-
Schenk, J. F., Stephan, B., Zewinger, S., Speer, T., and Pindur, G.
- Subjects
PLASMINOGEN activators ,GENETIC polymorphisms ,THROMBOEMBOLISM ,PREGNANCY complications ,ABORTION complications ,GENOTYPE-environment interaction - Abstract
Genetic polymorphisms in plasminogen activator inhibitor-1 gene-675 4G/5G (PAI-1 4G/5G) are claimed to contribute to an increased risk of venous thromboembolism. Inherited thrombophilia, on the other hand, is associated with the occurrence of spontaneous abortions. The objective of this study was, to explore the significance of genetic polymorphisms of PAI-1 4G/5G with particular emphasis on 4G alleles in pregnant women suffering from venous thromboembolism or early spontaneous abortion, respectively. Therefore genetic PAI-1 4G/5G polymorphisms were studied in 108 pregnant females suffering from venous thromboembolism (n=69) or from spontaneous abortion (<20 week, n=39), respectively. Healthy volunteers (n=238) were taken as controls. The frequencies of 4G alleles (4G/4G or 4G/5G genotypes) of PAI-1 were significantly higher in venous thromboembolism (OR: 3.40, p=0.0088) and slightly higher, but not significantly, in abortions (RR: 2.33; p=0.1162) compared to controls. The incidence of 4G-carriers in females with abortion was 0.68 (-32%) compared to women suffering from venous thromboembolism alone. We conclude from these data, that the occurrence of PAI-1 4G/4G or 4G/5G genotypes, respectively, is clinically significant for the pathogenesis of venous thromboembolism in pregnancy but not for early abortion. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
49. CLOTTING FACTOR CONCENTRATES.
- Subjects
HEMOPHILIA ,BLOOD diseases ,BLOOD coagulation ,BLOOD coagulation disorders - Abstract
Provides overview of articles on clotting factor concentrates, published in the October 2, 2004 issue of "Haemophilia." "The Factor VIII Protein: Its Life Cycle and Structure Function Relationship," by E. Saenko and N. Ananyeva; "Mode of Action of Recombinant Factor VIIIA: Current and Future By-Passing Agents and Their Use in Acquired Hemophilia," by H. R. Roberts, C. Kempton and D. Monroe; "Assessment of Evidence for Preventive Treatment in Hemophilia: The Practicalities of Doing a Systematic Review," by K. Stobart.
- Published
- 2004
- Full Text
- View/download PDF
50. Clotting factor concentrates.
- Subjects
BLOOD coagulation ,HEMOPHILIA - Abstract
Presents abstracts related to the use of clotting factor concentrates in hemophilia patients. 'Continuous Infusion as Replacement Therapy,' by P. Mali, M. Dolniear; 'Continuous Intravascular Coagulation in Patients With Haemophilia,' by I. Bokarev, A. Safonov et al.
- Published
- 2000
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.