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Biomedical subjects

J Batlle

Publications and source records attributed to J Batlle.

At least 19 recordsLinked to original sources
PubMed2006

Linkage analysis in families diagnosed with type 1 von Willebrand disease in the European study, molecular and clinical markers for the diagnosis and management of type 1 VWD.

BACKGROUND: von Willebrand disease (VWD) type 1 is a congenital bleeding disorder caused by genetic defects in the von Willebrand factor (VWF) gene and characterized by a reduction of structurally normal VWF. The diagnosis of type 1 VWD is difficult because of clinical and laboratory variability. Furthermore, inconsistency of linkage between type 1 VWD and the VWF locus has been reported. OBJECTIVES: To estimate the proportion of type 1 VWD that is linked to the VWF gene. PATIENTS AND METHODS: Type 1 VWD families and healthy control individuals were recruited. An extensive questionnaire on bleeding symptoms was completed and phenotypic tests were performed. Linkage between VWF gene haplotypes and the diagnosis of type 1 VWD, the plasma levels of VWF and the severity of bleeding symptoms was analyzed. RESULTS: Segregation analysis in 143 families diagnosed with type 1 VWD fitted a model of autosomal dominant inheritance. Linkage analysis under heterogeneity resulted in a summed lod score of 23.2 with an estimated proportion of linkage of 0.70. After exclusion of families with abnormal multimer patterns the linkage proportion was 0.46. LOD scores and linkage proportions were higher in families with more severe phenotypes and with phenotypes suggestive of qualitative VWF defects. About 40% of the total variation of VWF antigen could be attributed to the VWF gene. CONCLUSIONS: We conclude that the diagnosis of type 1 VWD is linked to the VWF gene in about 70% of families, however after exclusion of qualitative defects this is about 50%.

Adolescent↗
PubMed2006

A quantitative analysis of bleeding symptoms in type 1 von Willebrand disease: results from a multicenter European study (MCMDM-1 VWD).

BACKGROUND: A quantitative description of bleeding symptoms in type 1 von Willebrand disease (VWD) has never been reported. OBJECTIVES: The aim was to quantitatively evaluate the severity of bleeding symptoms in type 1 VWD and its correlation with clinical and laboratory features. PATIENTS AND METHODS: Bleeding symptoms were retrospectively recorded in a European cohort of VWD type 1 families, and for each subject a quantitative bleeding score (BS) was obtained together with phenotypic tests. RESULTS: A total of 712 subjects belonging to 144 families and 195 controls were available for analysis. The BS was higher in index cases than in affected family members (BS 9 vs. 5, P < 0.0001) and in unaffected family members than in controls (BS 0 vs. -1, P < 0.0001). There was no effect of ABO blood group. BS showed a strong significant inverse relation with either von Willebrand ristocetin cofactor (VWF:RCo), von Willebrand antigen (VWF:Ag) or factor VIII procoagulant activity (FVIII:C) measured at time of enrollment, even after adjustment for age, sex and blood group (P < 0.001 for all the four upper quintiles of BS vs. the first quintile, for either VWF:RCo, VWF:Ag or FVIII:C). Higher BS was related with increasing likelihood of VWD, and a mucocutaneous BS (computed from spontaneous, mucocutaneous symptoms) was strongly associated with bleeding after surgery or tooth extraction. CONCLUSIONS: Quantitative analysis of bleeding symptoms is potentially useful for a more accurate diagnosis of type 1 VWD and to develop guidelines for its optimal treatment.

ABO Blood-Group System↗
PubMed2005

The discriminant power of bleeding history for the diagnosis of type 1 von Willebrand disease: an international, multicenter study.

OBJECTIVE: The aim of this study was the validation of the criteria defining a significant mucocutaneous-bleeding history in type 1 von Willebrand disease (VWD). SUBJECTS AND METHODS: To avoid selection bias, 42 obligatory carriers (OC) of type 1 VWD were identified from a panel of 42 families with type 1 VWD enrolled by 10 expert centers. OC were identified by the presence of an offspring and another first degree relative with type 1 VWD (affected subjects, AFF). A standardized questionnaire was administered to evaluate hemorrhagic symptoms at the time of first examination, using a bleeding score ranging from 0 (no symptom) to 3 (hospitalization, replacement therapy, blood transfusion). Sensitivity, specificity, diagnostic likelihood ratios, positive and negative predictive values for the diagnosis of type 1 VWD were calculated from the data collected in OC and in 215 controls. RESULTS: Having at least three hemorrhagic symptoms or a bleeding score of 3 in males and 5 in females was very specific (98.6%) for the bleeding history of type 1 VWD, although less sensitive (69.1%). None of the misclassified OC had life-threatening bleeding episodes after diagnosis. CONCLUSIONS: We suggest that the use of a standardized questionnaire and bleeding score may be useful for the identification of subjects requiring laboratory evaluation for VWD.

Adult↗
PubMed2002

Advances in the therapy of von Willebrand disease.

von Willebrand disease (vWD) is a very common autosomal inherited bleeding disorder, caused by a quantitative deficiency or a qualitative structural defect of von Willebrand factor (vWF). Two main therapeutic options are available for the treatment of spontaneous bleeding episodes and for prevention of bleeding: desmopressin (DDAVP) and replacement therapy with plasma products. DDAVP is the treatment of choice for most patients with type 1 vWD. In patients with the type 3 disease and in most subjects with type 2 disease, DDAVP alone is ineffective or contraindicated, and it is usually necessary to switch to plasma concentrates containing both factor VIII (FVIII) and vWF. Concentrates subjected to virucidal treatment (e.g. solvent/detergent treatment) during manufacture should always be used in preference to cryoprecipitate. A recombinant vWF concentrate is now undergoing preclinical development and preliminary data suggest it possesses good haemostatic function and may correct the bleeding in vWD after its administration in several animal models. Although treatment of vWD is relatively simple (assuming access to even basic laboratory facilities), actual diagnosis is often far from straightforward, and the patients should be well characterized phenotypically to tailor the treatment to the different types and subtypes of the disease. It is probably wise to refer samples for the characterization to expert laboratories.

Chemotherapy, Adjuvant↗
PubMed2002

Single-dose ciprofloxacin versus 3 days of norfloxacin in uncomplicated urinary tract infections in women.

A double-blind, randomized controlled study to evaluate the efficacy and safety of a single dose of 500 mg of ciprofloxacin versus 3 days 400 mg twice-daily of norfloxacin in uncomplicated urinary tract infection in women was designed. Patients underwent four visits: baseline, and at 3, 7 and 28 days. The main efficacy variables were clinical and microbiological outcome at day 7. Analyses on both valid patients and intention-to-treat populations were performed. Two hundred and twenty-six patients (114 receiving ciprofloxacin and 112 receiving norfloxacin) were considered valid for efficacy evaluation. Bacteriologic cure was 91.2% in the ciprofloxacin group and 91.9% in the norfloxacin group. Clinical resolution was 91.2 and 93.8%, respectively. Both treatments were equally efficacious (P = 0.016).

Adolescent↗
PubMed2001

Type 2B von Willebrand's disease due to Val1316Met mutation. Heterogeneity in the same sibship.

An analysis was conducted in four members of the same family, two of whom had a history of severe bleeding associated with type 2B von Willebrand's disease (VWD) which, although found to be due to the same mutation, nevertheless exhibited different phenotype patterns in the two subjects involved. Von Willebrand's factor (VWF) multimers were assayed with high- and low-resolution sodium dodecyl sulfate (SDS) agarose gels. The patients were studied before and after intravenous administration of desmopressin (DDAVP) at doses of 0.4 microg/kg body weight. Automatic sequencing techniques were used to analyze VWF gene exon 28. The propositus presented with mild basal thrombocytopenia with ristocetin-induced platelet aggregation (RIPA) at low concentrations of ristocetin. He had a very prolonged bleeding time (BT), and his plasma VWF was found to be lacking in large and intermediate multimers. Thrombocytopenia was observed to intensify transiently after the administration of DDAVP. The propositus' mother, in contrast, presented reduced RIPA while in a basal state, with only partial loss of the high molecular weight VWF multimers. Although she had a very prolonged BT, her platelet count was borderline. Transient correction of BT and a decrease in the platelet count were observed after administration of DDAVP and RIPA was observed at low concentrations of ristocetin. Exon 28 sequencing revealed a G4196A-->Val1316Met mutation in both patients. No other abnormality was detected within this exon. Val1316Met has been reported in type 2B VWD. In conclusion, in the family presented here, the phenotype pattern in one patient was typical of type 2B VWD, whereas the pattern in his mother was closer to type 2A VWD. After administration of DDAVP, however, a type 2B phenotype could be clearly attributed to both, indicating that this drug can be a useful tool for elucidating ambiguous phenotypes.

Adult↗
PubMed2001

Immune tolerance treatment in haemophilia patients with inhibitors: the Spanish Registry.

We present a retrospective study of immune tolerance treatment (ITT) carried out in 42 Spanish haemophiliac patients. Most of the patients were high responders (39/42), with a median maximum titre of 67 Bethesda units (BU) (range 6-2984). The median inhibitor titre at the start the ITT was 11 BU (range 1-256 BU) and the median age of the patients was 7 years (range 0-57). The mean factor dosage was 140 IU kg bodyweight(-1) day(-1) (range 25-500). In most of the ITTs, plasma-derived factor concentrate of intermediate and high purity was used. The inhibitor was eradicated in 26/38 (68%) of the patients who completed the treatment and two patients changed their status from high to low responders. Multivariate logistic regression analysis showed that three significant variables were associated with the highest probability of success: (i) the use of low factor doses for ITT (< or = 100 IU kg(-1) day(-1); P = 0.0106; 95% CI 0.000289-0.342); (ii) a titre of < 10 BU at start of ITT (P = 0.0286; 95% CI 0.00253-0.7189) and (iii) a lower maximum titre (P = 0.0214; 95% CI 0.98-0.9994).

Actuarial Analysis↗
PubMed2000

A transcriptional insulator at the imprinted H19/Igf2 locus.

Igf2 and H19 exhibit parent-of-origin-specific monoallelic expression. H19 is expressed from the maternal chromosome and Igf2 from the paternal. The two genes share enhancer elements and monoallelic expression of both genes is dependent on cis-acting sequences upstream of the H19 promoter. In this work we examine the mechanisms by which this region silences the maternal Igf2 allele and we demonstrate that deletion of this region can result in high levels of activation of both H19 and Igf2 from a single chromosome. Moreover, by inserting this cis element between a promoter and its enhancer at a heterologous position, we demonstrate that the sequences carry both insulator activity and the ability to be stably imprinted. We also characterize the insulator in vitro and show that it is neither enhancer nor promoter specific.

Animals↗
PubMed1999

Induction of immune tolerance with recombinant factor VIII in haemophilia A patients with inhibitors.

We report on 11 patients (nine unrelated and a brother pair) with severe haemophilia A and factor VIII (FVIII) inhibitor, in whom immune tolerance (IIT) was induced with recombinant FVIII (r-FVIII). Their age ranged from 11 months to 47 years. The number of exposure days (ED) at inhibitor detection varied from 11 to 130. Nine of the 11 patients were high responders ¿>10 Bethesda units (BU) with peak inhibitor levels ranging from 10 to 566 BU. The other two were low responders with peak levels between 0.7 and 2 BU. Before inhibitor detection, the patients had been receiving products of various purities. The IIT regimens were very heterogeneous, and the treatment schedule varied from a short period with 50 IU kg-1 every 2 days, followed by 100 IU kg-1 every 2 days and then 220 IU kg-1 daily. The outcome was considered successful when the inhibitor level fell to 0.6 BU or lower after IIT treatment. The outcome overall was successful in nine out of 11 patients (81.8%), with the nine successful cases comprising seven of the nine high responders (77.8%) and the two low responders. Definite failure of IIT was observed in one high responder after two different IIT regimens. A second high responder is still on IIT treatment. All patients in whom IIT was successful are currently receiving r-FVIII on demand or prophylactically at various dosages. Despite the variability of the patient characteristics and the IIT schedules, this study demonstrates that r-FVIII represents an effective alternative for the eradication of inhibitors through IIT.

Adolescent↗
PubMed1999

[Correction].

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Factor V↗
PubMed1997

Alloantibody from a patient with severe von Willebrand disease inhibits von Willebrand factor-FVIII interaction.

The aim of this study was to analyze the ability of an alloantibody from a patient with severe von Willebrand disease (vWD) to interfere with the vWF domain for FVIII, to inhibit factor VIII (FVIII), and to compare it with a rabbit polyclonal antibody. The vWF domain for binding to FVIII was assayed by a method previously described but using recombinant FVIII (r-FVIII, Kogenate), which contains no vWF, instead of Hemofil M (HM). Rabbit or human antibodies towards FVIII (FVIII-Ab) were analyzed using microtiter wells with immobilized r-FVIII through a monoclonal anti-FVIII antibody and an ELISA method. IgG from plasma of a patient with hemophilia A and FVIII inhibitor was used as a positive control. Normal human and rabbit IgGs were included as negative controls. Human vWD alloantibody IgG and the rabbit anti-vWF antibody IgG reacted with immobilized normal vWF, inhibiting its binding to r-FVIII in a dose-dependent manner, which suggests that it is specific. Normal human IgG fraction, as well as nonspecific rabbit IgG, did not interfere with this binding at all. The monoclonal antibody used in this assay to immobilize vWF did not alter this interaction at all. Human vWD alloantibody IgG and the rabbit antibody against vWF showed a partial inhibitory activity to plasma FVIII as well as r-FVIII. The inhibition reached a plateau with residual FVIII activity. FVIII-Ab were not detected in human alloantibody or in rabbit antibody preparations. In contrast, hemophiliac FVIII inhibitor showed FVIII-AB. This human vWD alloantibody behaves like polyclonal heterologous antibodies, and their inhibition of FVIII seems to be nonspecific due to a steric hindrance mechanism provided that both have no FVIII antibodies.

Animals↗
PubMed1997

The problem of diagnosing von Willebrand's disease.

Diagnosis of von Willebrand's disease (vWD), particularly vWD Type 1, remains a clinical problem for several aspects. Its definitive diagnosis requires documentation of three factors: bleeding, low levels of qualitatively normal von Willebrand factor (vWF), and inheritance. In the absence of any of these factors the diagnosis may be only merely 'possible', or even unacceptable. Laboratory diagnosis of vWD includes screening tests and confirmatory tests. vWD Types 2 and 3 are relatively easy to diagnose and appear to be genetic disease of a single locus, the vWF gene. As new genetic and possibly non-genetic factors are discovered, the diagnosis of vWD Type 1 may become easier.

Diagnosis, Differential↗
PubMed1996

Antibodies to factor VIII in plasma of patients with hemophilia A and normal subjects.

Non-neutralizing factor VIII (FVIII) antibodies (FVIII-Ab) in hemophilia A may be associated with an abnormal clinical response to FVIII concentrates. Patients with FVIII inhibitors may develop noncoagulation FVIII-Ab after the induction of immunotolerance. Natural FVIII-Ab may be detected in the plasma of some healthy subjects. The aim of this study was to analyze the presence of FVIII-Ab in the plasma of 53 normal blood donors and 124 patients with hemophilia A (18 patients had a previous history of FVIII inhibitor, but only 12 had inhibitor at the moment this study was performed). FVIIII inhibitor was measured using the Bethesda method. FVIII-Ab were analyzed by a specific ELISA assay using purified FVIII from a monoclonal concentrate and a standard plasma containing 26 Bethesda units (BU) of FVIII inhibitor. Purified FVIII was used to coat wells of a microtiter plate and was incubated with dilutions of plasma to be tested. Bound human IgG FVIII-Ab were detected by incubation with polyclonal sheep anti.human IgG alkaline phosphatase conjugate, and the OD405 was quantitated. A linear fit was obtained (by plotting FVIII-Ab positivity [OD 405nm] versus BU titer) when serial dilutions of this standard inhibitor plasma, containing titers of 0.5 BU or higher, were used. Four different levels of FVIII-Ab positivity [OD 405nm] were distinguished in this assay: Negative levels (-) were obtained with dilutions of the standard inhibitor containing < 0.5 BU. Mild levels (+) were obtained with dilutions of 0.5-5 BU. Moderate levels (+2) were obtained for dilutions ranging from 5-25 BU. Maximum positivity (+3) was obtained for dilutions of titers > 25 BU. FVIII-Ab positivity was detected in eight of the normal subjects (15%): three were found to be moderately positive (+2) and five mildly positive (+). No inhibitory activity was detectable when whole plasma was used. All the hemophilic patients with a presence of FVIII inhibitor at the time of the study were found to be positive for FVIII-Ab. In addition, the level of positivity correlated with the corresponding BU. Four of the six patients who had a history of inhibitory were negative and two positive. Twenty additional patients (16.12%) in whom no inhibitory activity was detected were found to be positive for FVIII-Ab: 16 + and four +2. The mean age of patients with FVII-Ab positivity was significantly higher than that of patients of the FVIII-Ab negative group (p < 0.005). In conclusion, FVIII-Ab positivity in patients with hemophilia A was 17.7% higher than the level of positivity detected by an inhibitory assay. We propose that this method for FVIII-Ab analysis could be used for patients with hemophilia A, at least to complement the functional inhibitor assay. FVIII recovery or half-life should be assessed in patients who test positive for FVIII-Ab and who show no evidence of inhibitor.

Adolescent↗
PubMed1994

Hemophilia A or von Willebrand disease?

Seven members of the same family were studied on several occasions due to a history of hemorrhages. The propositus, a 12-year-old boy, his sister, one brother, and their father all had a low plasma factor VIII (FVIII) level. Von Willebrand factor (vWF) activity, vWF multimeric analysis, and vWF factor domain for binding to FVIII were normal in all seven subjects. The sister had a normal 46XX karyotype. The study of two intragenic restriction fragment length polymorphisms (RFLPs) and two closely linked, highly polymorphic extragenic markers showed a phenotypic expression of mild hemophilia A, which suggests that the sister of the propositus is homozygous or compound heterozygous at the hemophilia A locus. She would have inherited two hemophilic genes: one from her carrier mother and the other from her father, a mild hemophiliac.

Binding Sites↗
PubMed1994

Proteolytic processing of von Willebrand factor subunit: heterogeneity in type-IIA von Willebrand disease.

Type IIA von Willebrand disease (vWD) is a heterogeneous disorder for which two different pathogenetic mechanisms have been proposed: increased proteolytic susceptibility of von Willebrand factor (vWF), and/or interference of its post-translational processing. Subunit analysis of vWF in type-IIA vWD has revealed an increased relative proportion of the 176- and 140-kDa subunit-derived fragments, suggesting an augmented fragmentation of vWF, even in the resting state. We analyzed the subunit pattern of vWF in plasma from five previously described patients with type-IIA vWD. All of them showed the above-mentioned pattern. In addition, the presence of a new band with an apparent molecular mass of 200 kDa, not described in normal individuals or in patients with vWD, was repeatedly observed in one of these patients. This patient also exhibited an abnormal vWF multimeric structure in platelets and in plasma, before and after desmopressin administration, when the blood was collected either in the presence or in the absence of proteinase inhibitors. We believe that an abnormal primary structure of vWF could be responsible for this abnormal proteolytic fragmentation pattern, as well as for the abnormal multimerization of vWF. Moreover, an abnormal susceptibility to proteolysis appears to be present, as suggested by the increase in the relative proportion of the 176-kDa fragment observed in the same patient. Future sequencing studies and genetic analysis may clarify whether there are one or two different defects related to the vWF of that patient. Our results indicate that the subunit analysis of vWF may reveal additional defects present in type-IIA vWD that may help our understanding of the pathogenesis of such disease.

Blood Platelets↗