Recombinant ADAMTS13 in Congenital Thrombotic Thrombocytopenic Purpura.

BACKGROUND: Congenital thrombotic thrombocytopenic purpura (TTP) results from severe hereditary deficiency of ADAMTS13. The efficacy and safety of recombinant ADAMTS13 and standard therapy (plasma-derived products) administered as routine prophylaxis or on-demand treatment in patients with congenital TTP is not known. METHODS: In this phase 3, open-label, crossover trial, we randomly assigned patients in a 1:1 ratio to two 6-month periods of prophylaxis with recombinant ADAMTS13 (40 IU per kilogram of body weight, administered intravenously) or standard therapy, followed by the alternate treatment; thereafter, all the patients received recombinant ADAMTS13 for an additional 6 months. The trigger for this interim analysis was trial completion by at least 30 patients. The primary outcome was acute TTP events. Manifestations of TTP, safety, and pharmacokinetics were assessed. Patients who had an acute TTP event could receive on-demand treatment. RESULTS: A total of 48 patients underwent randomization; 32 completed the trial. No acute TTP event occurred during prophylaxis with recombinant ADAMTS13, whereas 1 patient had an acute TTP event during prophylaxis with standard therapy (mean annualized event rate, 0.05). Thrombocytopenia was the most frequent TTP manifestation (annualized event rate, 0.74 with recombinant ADAMTS13 and 1.73 with standard therapy). Adverse events occurred in 71% of the patients with recombinant ADAMTS13 and in 84% with standard therapy. Adverse events that were considered by investigators to be related to the trial drug occurred in 9% of the patients with recombinant ADAMTS13 and in 48% with standard therapy. Trial-drug interruption or discontinuation due to adverse events occurred in no patients with recombinant ADAMTS13 and in 8 patients with standard therapy. No neutralizing antibodies developed during recombinant ADAMTS13 treatment. The mean maximum ADAMTS13 activity after recombinant ADAMTS13 treatment was 101%, as compared with 19% after standard therapy. CONCLUSIONS: During prophylaxis with recombinant ADAMTS13 in patients with congenital TTP, ADAMTS13 activity reached approximately 100% of normal levels, adverse events were generally mild or moderate in severity, and TTP events and manifestations were rare. (Funded by Takeda Development Center Americas and Baxalta Innovations; ClinicalTrials.gov number, NCT03393975.).

Validación de la escala Short FES-I en población española mayor de 70 años / Validation of the short FES-I scale in Spanish population over 70 years

Introducción Las caídas deterioran la calidad de vida de los ancianos y el miedo a estas ha demostrado ser un factor de riesgo independiente para fragilidad, por lo que es prioritario disponer de herramientas para su evaluación. La escala ShortFalls Efficacy Scale-International (FES)-I, versión corta (siete ítems) de la escala FES-I (16 ítems), evalúa el miedo a caer (MC). El objetivo de este estudio es validar la escala Short FES-I en población española mayor de 70 años y analizar la relación entre el miedo a las caídas, el riesgo de las mismas y la fragilidad. Material y métodos Se trata de un estudio observacional transversal. La muestra consistió en 227 sujetos (50,7% varones; edad media 75,8 años). La ubicación fue en el norte de España. Las variables empleadas fueron sociodemográficas, clínicas, pruebas de ejecución Short Physical Performance Battery (SPPB) y Timed Up and Go Test (TUG), FES-I y Short FES-I. Se analizaron las propiedades psicométricas: validez y fiabilidad. Resultados La escala Short FES-I muestra excelentes consistencia interna (alfa de Cronbach = 0,90, coeficiente correlación intraclase = 0,89) y reproducibilidad test-retest (Rho Spearman = 0,76). Tiene una elevada validez de criterio concomitante analizada por su correlación con FES-I (Rho Spearman = 0,90). La validez de constructo discriminante ha sido confirmada tanto para SPPB como TUG. Short FES-I presenta buena capacidad de clasificación de fragilidad (definida por SPPB) con área bajo la curva [AUC] = 0,715; como punto de corte se propone un valor Short FES-I>8 para miedo moderado/alto de caídas. Conclusiones La escala Short FES-I es un buen instrumento para estudiar el miedo a las caídas en población española mayor de 70 años y es válida para su uso clínico y en investigación. (AU)

Introduction Falls deteriorate the quality of life of the elderly and the fear of falling has been shown to be an independent risk factor for frailty, so having tools for its evaluation is a priority. The short FES-I scale, short version (7 items) of the FES-I scale (16 items), assesses fear of falling. The objective of this study is to validate the short FES-I scale in the Spanish population over 70 years and to analyze the relationship between fear of falling, risk of falls and frailty. Material and methods Cross-sectional observational study. Sample: 227 subjects (50.7% male; mean age 75.8 years). Setting: northern Spain. Variables: sociodemographic, clinical, short physical performance battery (SPPB) and timed up and go test (TUG) execution tests, FES-I and short FES-I. Analysis of psychometric properties: validity and reliability. Results The short FES-I scale shows excellent internal consistency (Cronbach's alpha = 0.90, intraclass correlation coefficient = 0.89) and test–retest reliability (rho Spearman = 0.76). It has a high concomitant criterion validity analyzed by its correlation with FES-I (rho Spearman = 0.90). The discriminant construct validity has been confirmed for both SPPB and TUG. Short FES-I presents good capacity for frailty classification (defined by SPPB) with AUC = 0.715. As a cut-off point, a short FES-I value > 8 is proposed for moderate/high fear of falling. Conclusions The short FES-I scale is a good instrument to study fear of falling in the Spanish population over 70 years and is valid for clinical and research use. (AU)

Validación de la escala Short FES-I en población española mayor de 70 años / Validation of the short FES-I scale in Spanish population over 70 years

Introducción Las caídas deterioran la calidad de vida de los ancianos y el miedo a estas ha demostrado ser un factor de riesgo independiente para fragilidad, por lo que es prioritario disponer de herramientas para su evaluación. La escala ShortFalls Efficacy Scale-International (FES)-I, versión corta (siete ítems) de la escala FES-I (16 ítems), evalúa el miedo a caer (MC). El objetivo de este estudio es validar la escala Short FES-I en población española mayor de 70 años y analizar la relación entre el miedo a las caídas, el riesgo de las mismas y la fragilidad. Material y métodos Se trata de un estudio observacional transversal. La muestra consistió en 227 sujetos (50,7% varones; edad media 75,8 años). La ubicación fue en el norte de España. Las variables empleadas fueron sociodemográficas, clínicas, pruebas de ejecución Short Physical Performance Battery (SPPB) y Timed Up and Go Test (TUG), FES-I y Short FES-I. Se analizaron las propiedades psicométricas: validez y fiabilidad. Resultados La escala Short FES-I muestra excelentes consistencia interna (alfa de Cronbach = 0,90, coeficiente correlación intraclase = 0,89) y reproducibilidad test-retest (Rho Spearman = 0,76). Tiene una elevada validez de criterio concomitante analizada por su correlación con FES-I (Rho Spearman = 0,90). La validez de constructo discriminante ha sido confirmada tanto para SPPB como TUG. Short FES-I presenta buena capacidad de clasificación de fragilidad (definida por SPPB) con área bajo la curva [AUC] = 0,715; como punto de corte se propone un valor Short FES-I>8 para miedo moderado/alto de caídas. Conclusiones La escala Short FES-I es un buen instrumento para estudiar el miedo a las caídas en población española mayor de 70 años y es válida para su uso clínico y en investigación. (AU)

Introduction Falls deteriorate the quality of life of the elderly and the fear of falling has been shown to be an independent risk factor for frailty, so having tools for its evaluation is a priority. The short FES-I scale, short version (7 items) of the FES-I scale (16 items), assesses fear of falling. The objective of this study is to validate the short FES-I scale in the Spanish population over 70 years and to analyze the relationship between fear of falling, risk of falls and frailty. Material and methods Cross-sectional observational study. Sample: 227 subjects (50.7% male; mean age 75.8 years). Setting: northern Spain. Variables: sociodemographic, clinical, short physical performance battery (SPPB) and timed up and go test (TUG) execution tests, FES-I and short FES-I. Analysis of psychometric properties: validity and reliability. Results The short FES-I scale shows excellent internal consistency (Cronbach's alpha = 0.90, intraclass correlation coefficient = 0.89) and test–retest reliability (rho Spearman = 0.76). It has a high concomitant criterion validity analyzed by its correlation with FES-I (rho Spearman = 0.90). The discriminant construct validity has been confirmed for both SPPB and TUG. Short FES-I presents good capacity for frailty classification (defined by SPPB) with AUC = 0.715. As a cut-off point, a short FES-I value > 8 is proposed for moderate/high fear of falling. Conclusions The short FES-I scale is a good instrument to study fear of falling in the Spanish population over 70 years and is valid for clinical and research use. (AU)

[Validation of the short FES-I scale in Spanish population over 70 years]. / Validación de la escala Short FES-I en población española mayor de 70 años.

INTRODUCTION: Falls deteriorate the quality of life of the elderly and the fear of falling has been shown to be an independent risk factor for frailty, so having tools for its evaluation is a priority. The short FES-I scale, short version (7 items) of the FES-I scale (16 items), assesses fear of falling. The objective of this study is to validate the short FES-I scale in the Spanish population over 70 years and to analyze the relationship between fear of falling, risk of falls and frailty. MATERIAL AND METHODS: Cross-sectional observational study. SAMPLE: 227 subjects (50.7% male; mean age 75.8 years). SETTING: northern Spain. VARIABLES: sociodemographic, clinical, short physical performance battery (SPPB) and timed up and go test (TUG) execution tests, FES-I and short FES-I. Analysis of psychometric properties: validity and reliability. RESULTS: The short FES-I scale shows excellent internal consistency (Cronbach's alpha = 0.90, intraclass correlation coefficient = 0.89) and test-retest reliability (rho Spearman = 0.76). It has a high concomitant criterion validity analyzed by its correlation with FES-I (rho Spearman = 0.90). The discriminant construct validity has been confirmed for both SPPB and TUG. Short FES-I presents good capacity for frailty classification (defined by SPPB) with AUC = 0.715. As a cut-off point, a short FES-I value > 8 is proposed for moderate/high fear of falling. CONCLUSIONS: The short FES-I scale is a good instrument to study fear of falling in the Spanish population over 70 years and is valid for clinical and research use.

Vitrification of Iberian wolf (Canis lupus signatus) sperm: A possible alternative to conventional cryopreservation.

Sperm vitrification is a simple, inexpensive method that allows the cryopreservation of sperm in the field and for endangered species is a useful alternative to conventional freezing. The study, therefore, is focused on the suitability of vitrification for cryopreserving Iberian wolf sperm and utilizing plasma testosterone concentration as a marker for procedure efficacy. Sperm and blood samples were collected from 17 wolves. There were 14 samples suitable for cryopreservation (12 ejaculated and two epididymal). Immediately after collection, these samples were proportioned into two aliquots for conventional freezing using a Tris-citric acid-glucose based extender (TCG) or vitrification utilizing an animal protein free extender (HTF®). Vitrification occurred by directly plunging a sperm suspension into liquid nitrogen. Sperm were assessed for motility, membrane integrity, acrosomal status and DNA integrity before and after cryopreservation. With both techniques, there were similar post-thaw/warming results (P > 0.05) with respect to progressive motility, kinetic variables VCL, VSL, VAP and BCF, DNA fragmentation, sperm membrane functionality and morphological abnormalities. Total motile sperm, progression ratios LIN, STR, and WOB, the ALH, sperm viability and sperm with intact membrane and acrosome were greater (P < 0.05) in the conventional frozen-thawed sperm than vitrified-warmed sperm. Plasma testosterone concentrations varied from 0.0 ng/mL to 7.7 ng/mL. For epididymal sperm, sperm motility and viability following thawing were greater in vitrified-warmed samples than conventionally-frozen samples; however, small sample numbers precluded statistical analysis. When considered together, these results indicate vitrification may be a possible alternative for wolf sperm cryopreservation.

Multisystem combined uranium resistance mechanisms and bioremediation potential of Stenotrophomonas bentonitica BII-R7: Transcriptomics and microscopic study.

The potential use of microorganisms in the bioremediation of U pollution has been extensively described. However, a lack of knowledge on molecular resistance mechanisms has become a challenge for the use of these technologies. We reported on the transcriptomic and microscopic response of Stenotrophomonas bentonitica BII-R7 exposed to 100 and 250 µM of U. Results showed that exposure to 100 µM displayed up-regulation of 185 and 148 genes during the lag and exponential phases, respectively, whereas 143 and 194 were down-regulated, out of 3786 genes (>1.5-fold change). Exposure to 250 µM of U showed up-regulation of 68 genes and down-regulation of 290 during the lag phase. Genes involved in cell wall and membrane protein synthesis, efflux systems and phosphatases were up-regulated under all conditions tested. Microscopic observations evidenced the formation of U-phosphate minerals at membrane and extracellular levels. Thus, a biphasic process is likely to occur: the increased cell wall would promote the biosorption of U to the cell surface and its precipitation as U-phosphate minerals enhanced by phosphatases. Transport systems would prevent U accumulation in the cytoplasm. These findings contribute to an understanding of how microbes cope with U toxicity, thus allowing for the development of efficient bioremediation strategies.

Evidence on the discrimination of quinoa grains with a combination of FT-MIR and FT-NIR spectroscopy.

Quinoa is considered as a valuable re-emergent crop due to its nutritional composition. In this study, five quinoa grains from different geographical origin (Real, CHEN 252, Regalona, BO25 and UDc9) were discriminated using a combination of FT-MIR and FT-NIR spectra as input for principal component analysis (PCA), cluster analysis (CA) and soft independent modelling class analogy (SIMCA). The results obtained from PCA and CA show a great power of discrimination, with an average silhouette width value of 0.96. Moreover, SIMCA showed an error rate and accuracy values of 0 and 1 respectively with only 4% misclassified samples. A relationship between each principal component and the most important variables for the discrimination were mainly due to vibrations of several oleofins groups (C-H, C-H2, C-H3), alkene group (-CH=CH-), hydroxyl group (O-H) and Amides I and II vibrational modes.

Management of Adult Patients with Primary Immune Thrombocytopenia (ITP) in Clinical Practice: A Consensus Approach of the Spanish ITP Expert Group.

BACKGROUND AND OBJECTIVE: Diagnosis and management of primary immune thrombocytopenia (ITP) have changed dramatically in the last decade. The aim of the study was to obtain information about the opinion of the Spanish ITP Group (GEPTI) members regarding the best clinical practices for diagnosis and management of adult patients with ITP. MATERIALS AND METHODS: A two-round Delphi method was carried out by sending to 129 experts a 90-item questionnaire developed by 11 specialists, with a 4-point Likert scale ("never," "sometimes," "frequently," and "always") for the assessment of responses. RESULTS: Forty out of the 129 experts participated in the survey (participation rate 30.2%) and 39 completed the questionnaire (response rate 97.5%). Salient consensus points included the following: the need to indicate workup studies from a sustained platelet count < 100 x 109/L in the absence of a clear etiology; bone marrow aspiration in elderly patients with suspected ITP; beginning treatment in asymptomatic patients with a platelet count < 20 x 109/L; not exceeding 6-7 weeks of corticosteroid therapy; switching from corticosteroids to one thrombopoietin receptor agonist (TRA); switching to other TRA or other options as combinations of them with immunosuppressive drugs in case of failure; how to reduce tapering TRA; treating patients with symptomatic persistent ITP and platelet count > 20 x 109/L; and considering mucosal or severe bleeding as a basic criterion for hospital admission. CONCLUSIONS: The present consensus document provides a reference framework for the management of patients with ITP in clinical practice.

Effectiveness of ultra-rapid cryopreservation of sperm from endangered species, examined by morphometric means.

This study compares the effectiveness of the ultra-rapid and conventional freezing of sperm from captive bovids, giraffids, cervids, ursids, a cercopithecid, a delphinid and a phascolarctid. The relationship between sperm head dimensions and cryosurvival was also examined. Compared to conventional freezing, the ultra-rapid freezing of epididymal sperm from the dama gazelle, giraffe and brown bear returned higher cryoresistance ratios (CR, the ratio, in percentage, between the value of the variable after thawing/value before thawing) for sperm viability and motility. In the remaining species, the conventional freezing of epididymal sperm returned better CR values. The conventional freezing method also returned better CR values for ejaculated samples from all species. The head dimensions of both fresh epididymal and ejaculated sperm differed widely among species: for epididymal sperm, dolphin sperm heads were the smallest (7.189 ±â€¯0.049 µm2) and dama gazelle sperm heads the largest (43.746 ±â€¯0.291 µm2), while for ejaculated sperm, giant panda sperm heads were the smallest (15.926 ±â€¯0.150 µm2) and mouflon sperm heads the largest (38.258 ±â€¯0.104 µm2). However, no significant correlations were detected between the CR for motility, viability, membrane functional integrity or acrosome integrity and the sperm head area, either for epididymal or ejaculated sperm. In conclusion, ultra-rapid freezing is especially recommended for the cryopreservation of dama gazelle, giraffe and brown bear epididymal sperm. Sperm head dimensions appear not to be useful predictors of how well sperm might survive freezing.

Predictors of Mortality in Nondemented Patients With Parkinson Disease: Motor Symptoms Versus Nonmotor Symptoms.

BACKGROUND AND OBJECTIVE: The aim of this study is to identify risk factors for mortality in a community-based cohort of nondemented patients with Parkinson disease (PD) during prospective long-term follow-up, while also comparing the effect of motor complications to nonmotor symptoms (NMS) on risk of mortality. METHODS: One hundred forty seven nondemented patients with PD (57.1% males; 70.9 ± 8.6 years old) were included in this 48 month follow-up, longitudinal, single, evaluation study. Motor and therapy-related complications were assessed using the Unified Parkinson's Disease Rating Scale/part-IV (UPDRS-IV). Non-Motor Symptoms Scale (NMSS) total score was used to assess NMS burden. Cox proportional hazard models were applied to identify independent predictors of mortality during follow-up. RESULTS: Twenty-two patients of 146 (15.1%) died (1 case without information). Both UPDRS-IV and NMSS total scores were higher at baseline in patients with PD who died (3.5 ± 3.1 vs 2.4 ± 2.4, P = .049 and 96.9 ± 58.6 vs 61.9 ± 51.0, P = .004, respectively). Unadjusted hazard ratios (HRs) associated with UPDRS-IV and NMSS total scores among those who died during follow-up were 1.171 (95% confidence interval [CI]: 1.012-1.357; P = .035) and 1.008 (95% CI: 1.002-1.013; P = .006), respectively. Independent predictors of mortality during follow-up after adjusting for other covariates were UPDRS-IV (HR: 1.224; 95% CI: 1.002-1.494; P = .047), age (HR: 1.231; 95% CI: 1104-1.374; P < .0001), and comorbidity (Charlson Index; HR: 1.429; 95% CI: 1.023-1.994; P = .036), but not NMSS total score (HR: 1.005; 95% CI: 0.996-1.014; P = .263). CONCLUSIONS: Both motor complications (UPDRS-IV) and NMS (NMSS) were associated with mortality at 4 years, being motor complications an independent predictor of it.

Comorbid conditions associated with Parkinson's disease: A longitudinal and comparative study with Alzheimer disease and control subjects.

BACKGROUND AND OBJECTIVE: To study what comorbid conditions were present at baseline and 3years later in a cohort of Spanish Parkinson's disease (PD) patients, to compare comorbidity with both Alzheimer's disease (AD) and control groups and to analyze the role of comorbidity as predictor of mortality. METHODS: One hundred and forty-seven non-demented PD patients (57.1% males; 70.9±8.6years old) were included in this 36months follow-up (2012-2015), monocenter, evaluation study. The International Classification of Diseases, Tenth Revision (ICD-10), Charlson Index (CI), Comorbidity-Polypharmacy Score (CPS) and Elixhauser Comorbidity Measure (ECM) were used to assess comorbidity at baseline and at 3years. Forty-four AD patients and 44 control subjects were included as comparator groups. RESULTS: Total number of comorbidities (ICD-10) and polypharmacy at baseline were higher in PD and AD patients than controls (4.4±2.3 vs 5.2±2.4 vs 3.4±1.9 [p=0.001] and 81.6% vs 75% vs 56.8% [p=0.003], respectively). Diseases of the circulatory system (ICD-10/chapter-IX) and endocrine, nutritional and metabolic diseases (ICD-10/chapter-IV) were the most frequent in all groups. There was a significant increase in comorbidity (mean, +1.6±2.8) in all groups (p<0.0001) without differences between them. Seventeen patients died and 8 cases were did not follow-up. Comorbidity was a predictor of death in PD patients after adjust for other covariates (including age, sex, disease duration, disease stage, motor status and non-motor symptoms): ICD-10 (total number of comorbidities), hazard ratio 1.285 (95% confidence interval, 1.047-1.577; p=0.017); CI, hazard ratio 1.462 (95% confidence interval, 1.045-2.047; p=0.027). CONCLUSIONS: Comorbidity is frequent in PD patients, increases significantly over time and predicts mortality.

Espacios de Virchow-Robin: ¿una causa de parkinsonismo? / Virchow-Robin spaces: A cause of parkinsonism?

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Identification and characterization of contrasting sunflower genotypes to early leaf senescence process combining molecular and physiological studies (Helianthus annuus L.).

Leaf senescence is a complex mechanism ruled by multiple genetic and environmental variables that affect crop yields. It is the last stage in leaf development, is characterized by an active decline in photosynthetic rate, nutrients recycling and cell death. The aim of this work was to identify contrasting sunflower inbred lines differing in leaf senescence and to deepen the study of this process in sunflower. Ten sunflower genotypes, previously selected by physiological analysis from 150 inbred genotypes, were evaluated under field conditions through physiological, cytological and molecular analysis. The physiological measurement allowed the identification of two contrasting senescence inbred lines, R453 and B481-6, with an increase in yield in the senescence delayed genotype. These findings were confirmed by cytological and molecular analysis using TUNEL, genomic DNA gel electrophoresis, flow sorting and gene expression analysis by qPCR. These results allowed the selection of the two most promising contrasting genotypes, which enables future studies and the identification of new biomarkers associated to early senescence in sunflower. In addition, they allowed the tuning of cytological techniques for a non-model species and its integration with molecular variables.

Practical aspects of factor concentrate use in patients with von Willebrand disease undergoing invasive procedures: a European survey.

INTRODUCTION: The bleeding propensity in von Willebrand disease (VWD) is usually moderate or mild and patients with VWD do not need continuous treatment, but do require extra increased haemostatic cover when undergoing dental or surgical procedures. Desmopressin can be effective in certain patient groups and this has been considered in a previous publication. AIM: This paper now seeks to evaluate current knowledge and practice in the use of factor concentrate in the management of VWD patients undergoing invasive procedures. METHODS: A literature search was performed on the use of factor concentrates to cover invasive procedures and a survey of current practice in a number of specialist haematology centres across Europe represented by the European Haemophilia Strategy Board was conducted. RESULTS: Our review of the literature and the results of the survey showed considerable heterogeneity in treatment regimens, and a lack of consistency in reporting of the variables that determine factor concentrate dosing and monitoring. CONCLUSION: By analysing the literature, examining guidelines and using consensus deliberation, this survey allowed the group to develop recommendations for management of VWD patients undergoing invasive procedures.

Efficacy and safety of long-acting recombinant fusion protein linking factor IX with albumin in haemophilia B patients undergoing surgery.

INTRODUCTION: Recombinant factor IX fusion protein (rIX-FP) has been developed to improve the pharmacokinetic (PK) profile of factor IX (FIX), allowing maintenance of desired FIX activity between injections at extended intervals, ultimately optimizing haemophilia B treatment. AIM: To determine the efficacy and safety of rIX-FP in the perioperative setting. METHODS: Subjects were adult and paediatric patients with severe to moderately severe haemophilia B (FIX ≤ 2%) participating in three Phase III clinical trials and undergoing a surgical procedure. PK profiles were established prior to surgery for each patient. Haemostatic efficacy was assessed by the investigator for up to 72 h after surgery. Safety measurements during the study included adverse events and inhibitors to FIX. FIX activity was monitored during and after surgery to determine if repeat dosing was required. RESULTS: Twenty-one, both major and minor, surgeries were performed in 19 patients. Haemostatic efficacy was rated as excellent (n = 17) or good (n = 4) in all surgeries. A single preoperative dose maintained intraoperative haemostasis in 20 of 21 surgeries. Nine major orthopaedic surgeries were conducted in eight patients with a mean of 7 (range: 6-12) rIX-FP injections during surgery and the 14-day postoperative period. Median rIX-FP consumption for orthopaedic surgeries was 87 IU kg(-1) preoperatively and 375 IU kg(-1) overall. No subject developed inhibitors to FIX or antibodies to rIX-FP. CONCLUSION: Recombinant factor IX fusion protein was well tolerated and effectively maintained haemostasis during and after surgery. Stable FIX activity was achieved with a prolonged dosing interval and reduced consumption compared to conventional or currently available long-acting recombinant FIX.

Efficacy and safety of pegylated full-length recombinant factor VIII with extended half-life for perioperative haemostasis in haemophilia A patients.

INTRODUCTION: BAX 855 is a pegylated full-length recombinant factor VIII (rFVIII) with an extended half-life, built on a licensed rFVIII (ADVATE(®) ). BAX 855 demonstrated efficacy and safety in prophylaxis and the treatment of bleeding episodes in previously treated patients (PTPs) with severe haemophilia A. AIM: This phase 3 surgery study evaluates the haemostatic efficacy and safety of BAX 855 for perioperative haemostasis in PTPs with severe haemophilia A undergoing surgery. METHODS: Elective procedures were prospectively classified as major or minor. The dose and frequency of BAX 855 administered perioperatively were to be guided by each patient's pharmacokinetic profile for major procedures or BAX 855 incremental recovery for minor procedures. Haemostatic efficacy was evaluated using a predefined scale. Blood loss was compared to the expected average and maximum blood loss predicted preoperatively. RESULTS: A total of 15 male patients (aged 19-52 years) underwent 15 procedures (11 major and four minor). The overall intra- and perioperative haemostatic efficacy of BAX 855 was 'excellent' in all 15 subjects (100%). Postoperatively, evaluated at postoperative Day 1, all treatments were 'excellent' except for one minor (dental) procedure which was rated 'good'. No related adverse events, allergic reactions, thrombotic events, nor signs of immunogenicity in terms of induction of binding antibodies to FVIII, PEG or PEG-VIII, or FVIII inhibitors were observed. CONCLUSION: These results demonstrate that BAX 855 is safe and haemostatically effective in patients with severe haemophilia A undergoing surgery.

Practical aspects of DDAVP use in patients with von Willebrand Disease undergoing invasive procedures: a European survey.

INTRODUCTION: Desamino D-arginine vasopressin (DDAVP or desmopressin) is a useful and effective haemostatic treatment for patients with von Willebrand Disease (VWD). However, there are still issues regarding in which subtypes of VWD DDAVP is appropriate and little consensus on its use in different surgical settings. We also lack information concerning the appropriate laboratory parameters that should be monitored. AIM: The European Haemophilia Therapy Strategy Board (EHTSB) wished to investigate published information and clinical use of DDAVP in VWD patients. METHODS: We conducted a literature survey on management of VWD during surgical interventions and undertook a survey of specialist haematologist centres across Europe to assess current management of VWD patients. RESULTS: DDAVP is ineffective in type 3 VWD and its use in type 2B remains controversial due to the possibility of thrombocytopenia. It can, however, be used effectively to cover minor surgery and dental procedures in most other VWD patients. For major surgery there is wider use of factor concentrate in preference to DDAVP depending on the subtype of VWD. We give consensus recommendations on the use of DDAVP for surgical interventions in VWD including laboratory parameters that denote an adequate response and contraindications to its use. CONCLUSIONS: DDAVP can be recommended to cover invasive procedure in selected patients with VWD, however, we need more information and systematic recording of adverse events associated with DDAVP use in VWD. A companion paper will be published covering the use of factor concentrates in VWD patients.

Diagnosis of inherited von Willebrand disease: comparison of two methodologies and analysis of the discrepancies.

Diagnostics of von Willebrand disease (VWD) includes assessment of factor VIII (FVIII) coagulant activity, von Willebrand factor (VWF) antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo), and more specific tests as multimeric and genetic analyses are necessary for the correct VWD classification. The ACL AcuStar analyzer introduces chemiluminescence (CL) technology in detection of VWD with automated VWF:Ag and VWF:RCo assays. Compare VWF:Ag-ELISA and VWF:RCo by aggregometry conventional assays with new CL VWF:Ag-IL and VWF:RCo-IL assays, investigate the ability to make accurate VWD diagnosis and concordance with multimeric and genetic analyses. 146 patients with congenital VWD (51 Type 1; 34 Type 2A; 16 Type 2B; 31 Type 2M; 5 Type 2N; 9 Type 3) and 30 healthy normal subjects were included. A comparison was made between CL and conventional methods. Diagnostic evaluation included: VWF:RCo/VWF:Ag ratio, multimeric distribution (sodium dodecyl sulfate [SDS]-agarose gel) of VWF and genetic analysis in 110 of 146 patients. CL and conventional methods revealed good correlation. Kappa test agreement diagnosis was >0.8. CL diagnostic sensitivity was 100% and specificity 97%. Multimeric and genetic analysis were of help in clarifying 13 discrepancies of diagnosis between methods, of which six discrepancies were explained by lack of conventional methods' sensibility. CL methodology can detect VWD and discriminate between type 1, 3 and variant forms and offers an automated, faster, sensitive and less cumbersome method when compared to conventional assays, in particular VWF:RCo by aggregometry. In some cases, even with all phenotype and genetic analyses, discrepancies exist in the classification of VWD.