Moving towards Normalization of haemostasis and health equity: Evolving treatment goals for haemophilia A.

BACKGROUND: Treatment options for people with haemophilia are evolving at a rapid pace and a range of prophylactic treatment options using various technologies are currently available, each with their own distinct safety and efficacy profile. TREATMENT GOALS: The access to replacement therapy and prophylaxis has driven a dramatic reduction in mortality and resultant increase in life expectancy. Beyond this, the abolition of bleeds and preservation of joint health represent the expected, but rarely attained, goals of haemophilia treatment and care. These outcomes also do not address the complexity of health-related quality of life impacted by haemophilia and its treatment. CONCLUSION: Capitalizing on the major potential of therapeutic innovations, 'Normalization' of haemostasis, as a concept, should include the aspiration of enabling individuals to live as normal a life as possible, free from haemophilia-imposed limitations. To achieve this-being supported by the data reviewed in this manuscript-the concept of haemostatic and life Normalization needs to be explored and debated within the wider multidisciplinary teams and haemophilia community.

Patient Perspective on Disease Burden and Gene Therapy for Hemophilia A and B: The "Haemvolution for Patients" Italian Survey.

Hemophilia is a rare X-linked congenital bleeding disorder due to a deficiency of factor VIII (hemophilia A [HA]) or factor IX (hemophilia B [HB]). Replacement and nonreplacement treatments are available but have limitations. Gene therapy (GT) provides an effective, long-term, single-dose treatment option, now approaching clinical practice. This study aimed to understand patient perspectives on GT for HA and HB in Italy using a qualitative questionnaire distributed through Italian patient associations, addressing patient views on daily life, treatments, unmet needs, quality of life (QoL), and GT for hemophilia. In total, 141 participants had HA, and 14 had HB (severe 78.6%). Daily life was most affected by pain and/or joint function limitations (57.5% of participants), high infusion frequency (42.5%), management of breakthrough bleeding episodes (40.3%), and anxiety/fear of severe or sudden bleeding (38.8%). Despite current treatments, about half of the participants experienced three or more annual bleeding episodes. Most participants knew of GT (87.2%) and expected improvements in QoL (60.5%), reduced frequency of current treatments (53.5%), and a permanent cure (49.1%); 46.4% were unaware of its once-off dosage and 46.4% were not concerned about the costs they anticipated to be associated with GT. Although several fears were reported, 25.0% of participants were willing to undergo GT with the support of a multidisciplinary team. This survey provided valuable insight into patient perspectives on hemophilia and GT in Italy. Overall, relevant proportions of patients still experience limitations affecting their daily life. Most were positive about GT and anticipated improvements in their clinical outcomes and QoL.

Development and Application of an IoT-Based System for Soil Water Status Monitoring in a Soil Profile.

Soil water content (θ), matric potential (h) and hydraulic conductivity (K) are key parameters for hydrological and environmental processes. Several sensors have been developed for measuring soil θ-h-K relationships. The cost of such commercially available sensors may vary over several orders of magnitude. In recent years, some sensors have been designed in the framework of Internet of Things (i.e., IoT) systems to make remote real-time soil data acquisition more straightforward, enabling low-cost field-scale monitoring at high spatio-temporal scales. In this paper, we introduce a new multi-parameter sensor designed for the simultaneous estimation of θ and h at different soil depths and, due to the sensor's specific layout, the soil hydraulic conductivity function via the instantaneous profile method (IPM). Our findings indicate that a second-order polynomial function is the most suitable model (R2 = 0.99) for capturing the behavior of the capacitive-based sensor in estimating θ in the examined soil, which has a silty-loam texture. The effectiveness of low-cost capacitive sensors, coupled with the IPM method, was confirmed as a viable alternative to time domain reflectometry (TDR) probes. Notably, the layout of the sensor makes the IPM method less labor-intensive to implement. The proposed monitoring system consistently demonstrated robust performance throughout extended periods of data acquisition and is highly suitable for ongoing monitoring of soil water status.

Six-Year, Real-World Use of Prophylaxis with Recombinant Factor IX-Albumin Fusion Protein (rIX-FP) in Persons with Hemophilia B: A Single-Center Retrospective-Prospective Study.

Background: Extended half-life (EHL) factor IX (FIX) concentrates allow for prophylaxis with prolonged dosing intervals and high bleeding protection in persons with hemophilia B. Long-term real-world studies are lacking. Methods: In a retrospective-prospective study, the six-year use of prophylaxis with the EHL recombinant FIX-albumin fusion protein (rIX-FP) was analyzed, comparing outcomes with previous standard half-life (SHL) FIX in patients already on prophylaxis. Results: Prophylaxis with rIX-FP was prescribed in 15 patients (10 severe, 5 moderate; follow-up: 57 ± 17 months). Based on a pharmacokinetic assessment and clinical needs, the first regimen was 47 ± 7 IU/Kg every 9 ± 2 days. All but one patient remained on rIX-FP prophylaxis, adjusting infusion frequency and/or dose; the last prescribed frequency was ≥10 days in 10/13 patients, being reduced in seven and increased in four vs. the first regimen. The weekly FIX dose was unchanged; FIX trough levels were >5% in all patients. The annual infusion number and FIX IU/Kg significantly decreased (~60%) in eight patients previously on SHL FIX prophylaxis, with similar concentrate costs. Very low bleeding rates (most traumatic bleeds and the last quartile of the infusion interval), improved orthopedic and pain scores, unchanged HEAD-US scores and problem joints, and high treatment adherence (>90%) and satisfaction were registered. Conclusions: Personalized, carefully adjusted rIX-FP regimens contribute to the diffusion and optimization of prophylaxis in persons with severe and moderate hemophilia B, with long-term favorable bleeding, joint, and patient-reported outcomes.

The value-based healthcare approach to haemophilia: Development of outcome measures for the evaluation of care of people with haemophilia.

INTRODUCTION: Considering the advances in haemophilia management and treatment observed in the last decades, a new set of value-based outcome indicators is needed to assess the quality of care and the impact of these medical innovations. AIM: The Value-Based Healthcare in Haemophilia project aimed to define a set of clinical outcome indicators (COIs) and patient-reported outcome indicators (PROIs) to assess quality of care in haemophilia in high-income countries with a value-based approach to inform and guide the decision-making process. METHODS: A Value-based healthcare approach based on the available literature, current guidelines and the involvement of a multidisciplinary group of experts was applied to generate a set of indicators to assess the quality of care of haemophilia. RESULTS: A final list of three COIs and five PROIs was created and validated. The identified COIs focus on two domains: musculoskeletal health and function, and safety. The identified PROIs cover five domains: bleeding frequency, pain, mobility and physical activities, Health-Related Quality of Life and satisfaction. Finally, two composite outcomes, one based on COIs, and one based on PROIs, were proposed as synthetic outcome indicators of quality of care. CONCLUSION: The presented standard set of health outcome indicators provides the basis for harmonised longitudinal and cross-sectional monitoring and comparison. The implementation of this value-based approach would enable a more robust assessment of quality of care in haemophilia, within a framework of continuous treatment improvements with potential added value for patients. Moreover, proposed COIs and PROIs should be reviewed and updated routinely.

The psychosocial impact of haemophilia from patients' and caregivers' point of view: The results of an Italian survey.

BACKGROUD: A huge amount of data about psychosocial issues of people with haemophilia (PwH) are available; however, these materials are fragmentary and largely outdated, failing to reflect the impact of current treatment strategies. AIM: Describing the influence of illness on psychosocial aspects of adult PwH (≥18 years) and caregivers of children with haemophilia (CPwH) without inhibitors, in Italy. METHODS: Surveys (for adult PwH, CPwH and haemophilia specialists) were developed by a multidisciplinary working group and conducted from November 2019 to June 2020. RESULTS: A total of 120 PwH without inhibitors and 79 CPwH completed the survey. Adult patients reported a significant impairment in many psychosocial aspects, including working activities, relations with family members and social relations. Caregivers generally reported better scores in all aspects of the survey. Mobility, Pain and Mental health domains of EQ-5D were the most frequently impaired in both patients and caregivers, reducing the perceived quality of life. Genetic counselling was an important issue, 53% of CPwH declaring unawareness of their carrier status, as well as the psychological support offered by the reference center, 67.0% of respondents reporting that no psychological support was provided at the time of diagnosis communication. CONCLUSION: This study provides information about PwH's and CPwH's point of view in the current scenario of continuous innovations in haemophilia treatment and management furthermore, updated insights on psychosocial problems faced by patients and caregivers are reported.

Bioequivalence of recombinant factor VIII products: a position paper from the Italian Association of Hemophilia Centers.

Over the last three decades, the continuous evolution of recombinant factor VIII (rFVIII) concentrates for replacement treatment of hemophilia A, including recent extended half-life products, implies that patients may switch from one product to another, technologically more advanced, with the aim of improving treatment efficacy, safety, management and, ultimately, quality of life. In this scenario, the issues of bioequivalence of rFVIII products and the clinical implications of their interchangeability are keenly debated, in particular when economic reasons or purchasing systems influence product availability and choices. Although sharing the same Anatomical Therapeutic Chemical (ATC) level, rFVIII concentrates, as other biological products, show relevant differences in terms of molecular structure, source and manufacturing process, which make them unique products, recognized as new active substances by regulatory agencies. Moreover, data from clinical trials with both standard and extended half-life products clearly document the large inter-patient variability of pharmacokinetic profiles after administering the same dose of the same product; in cross-over evaluations, even when mean values are comparable, some patients show better patterns with one product or with the comparator one. Pharmacokinetic assessment thus reflects the response to a specific product in the individual patient, with his genetic determinants, only partially identified, affecting the behavior of exogenous FVIII. These concepts, consistent with the currently recommended approach of personalization of prophylaxis, are discussed in this position paper endorsed by the Italian Association of Hemophilia Centers (AICE), highlighting that ATC or other available classifications do not completely consider differences between drugs and innovations and that substitutions of rFVIII products will not invariably ensure the previously achieved clinical outcomes or generate benefits for all patients.

IDEAL study: A real-world assessment of pattern of use and clinical outcomes with recombinant coagulation factor IX albumin fusion protein (rIX-FP) in patients with haemophilia B in Italy.

INTRODUCTION: Factor IX replacement therapy is used for treatment and prophylaxis of bleeding in haemophilia B. rIX-FP is an extended half-life albumin-fusion protein, which, in clinical studies, has demonstrated prolonged dosing intervals up to 21 days for routine prophylaxis, providing therapeutic benefit. AIMS: To describe dosing frequency and consumption (primary endpoint), efficacy and safety of rIX-FP treatment during routine clinical practice in Italy. METHODS: Patients with moderate/severe haemophilia B on prophylaxis with rIX-FP for ≥6 months, were enrolled in this observational study from October 2017 to February 2019 and followed-up for 2 years. Descriptive analysis included prospective and retrospective data (12 months prior to switching to rIX-FP). RESULTS: Data were collected from 59 male patients (median age 30.1 years) enrolled by 23 Italian centres. Of them, 50 were on prophylaxis during the entire observation period and completed the study. The infusion frequency changed from 2-3 times/week in 86.0% of patients with previous treatment, to less than once a week in 84.0% of patients treated with rIX-FP at the 2nd-year follow-up. The annual number of infusions decreased by about 70%, whereas the mean FIX activity trough level increased from 3.8% to 14.4% (mean > 10% in all the infusion regimens). Median Annualised Bleeding Rate of .0 was achieved across all prophylaxis regimens. Subjects with zero bleedings increased from 66.0% to 78.0% with rIX-FP. CONCLUSION: Treatment with rIX-FP reduced infusion frequency, while providing higher FIX trough levels with substantial benefit in terms of annualised bleeding rate and a good safety profile.

Analytical Performance of Different Laboratory Methods for Measuring Susoctocog-Alfa.

Recombinant porcine factor VIII (rpFVIII) is indicated for treating bleeding episodes in acquired haemophilia A, but there are few data regarding laboratory methods to adequately monitor treatment. This study involving three Italian laboratories aimed to evaluate the analytical performance of different assays for measuring rpFVIII. Five spiked rpFVIII samples (0.5-1.5 IU/mL) were analysed on three days, in triplicate, with eleven combinations of reagents (Werfen, Boston, MA, USA: SynthasIL and SynthaFax for one-stage assay, Chromogenix Coamatic FVIII for chromogenic assay), FVIII depleted plasmas (with or without von Willebrand factor-VWF) and calibrators (HemosIL human calibrator plasma, porcine calibrator diluted in FVIII deficient plasma with or without VWF). The assays were performed on ACL TOP analysers (Werfen, Boston, MA, USA). Intra- and inter-assay and inter-laboratory Coefficient of Variation (CV%) were calculated together with percentage of recovery (% recovery) on the expected value. The results showed that the reagent combinations reaching satisfactory analytical performance are: SynthasIL/human calibrator/deficient plasma+VWF (total recovery 99.4%, inter-laboratory CV 4.04%), SynthasIL/porcine calibrator/deficient plasma+VWF (total recovery 111%, inter-laboratory CV 2.75%) and Chromogenic/ porcine calibrator/deficient plasma+VWF (total recovery 96.6%, inter-laboratory CV 8.32%). This study highlights that the use of porcine standard (when available) and FVIII deficient plasma with VWF should be recommended.

Use of the von Willebrand factor concentrate with low factor VIII content to manage patients with inherited von Willebrand disease requiring surgical or secondary long-term prophylaxis: An expert opinion paper from an Italian panel.

OBJECTIVES: The present review aims to summarize the state-of-the-art von Willebrand disease (VWD) treatment focusing on specific clinical settings (obstetrics, surgery, long-term prophylaxis and comorbidities) as well as on the use of a Von Willebrand factor (VWF) concentrate with low FVIII content. METHODS: Literature research and case reports. RESULTS AND CONCLUSIONS: Considering that patients affected by VWD have an intact ability to synthesize FVIII, in order to avoid excessive levels of FVIII, a highly purified plasma VWF concentrate with low FVIII content could be particularly useful in those patients and clinical circumstances at high thrombotic risk as well as for long-term prophylaxis. When deciding the optimal therapeutic strategy, physicians should take into account both the patient's history and the differences among available concentrates according to the clinical situations requiring treatment.

Intracranial Haemorrhage in Haemophilia Patients Is Still an Open Issue: The Final Results of the Italian EMO.REC Registry.

Background: Intracranial hemorrhage (ICH) is a highly serious event in patients with haemophilia (PWH) which leads to disability and in some cases to death. ICH occurs among all ages but is particularly frequent in newborns. Aim: The primary aim was to assess the incidence and mortality due to ICH in an Italian population of PWH. Secondary aims were to evaluate the risk factors for ICH, the role of prophylaxis, and the clinical management of patients presenting ICH. Methods: A retrospective-prospective registry was established in the network of the Italian Association of Haemophilia Centers to collect all ICHs in PWH from 2009 to 2019 reporting clinical features, treatments, and outcomes. Results: Forty-six ICHs were collected from 13 Centers. The ICHs occurred in 15 children (10 < 2 years), and in 31 adults, 45.2% of them with mild hemophilia. Overall, 60.9% patients had severe haemophilia (15/15 children). Overall ICH incidence (×1000 person/year) was 0.360 (0.270−0.480 95% CI), higher in children <2 years, 1.995 (1.110−3.442 95% CI). Only 7/46 patients, all with severe haemophilia, had received a prophylactic regimen before the ICH, none with mild. Inhibitors were present in 10.9% of patients. In adult PWHs 17/31 suffered from hypertension; 85.7% of the mild subjects and 29.4% of the moderate/severe ones (p < 0.05). ICH was spontaneous in the 69.6% with lower rate in children (46.7%). Surgery was required in 21/46 patients for cerebral hematoma evacuation. Treatment with coagulation factor concentrates for at least three weeks was needed in 76.7% of cases. ICH was fatal in 30.4% of the cases. Of the survivors, 50.0% became permanently disabled. Only one-third of adult patients received long term prophylaxis after the acute treatment. Conclusion: The results from our Registry confirm the still high incidence of ICH in infants <2 years and in adults, particularly in mild PWHs presenting hypertension and its unfavorable outcomes. The majority of PWHs were treated on-demand before ICH occurred, suggesting the important role of prophylaxis in preventing such life-threatening bleeding.

Global cognitive function correlates with P-wave dispersion in frail hypertensive older adults.

P-Wave Dispersion (PWD) is an ECG parameter defined as the difference between the longest and the shortest P-Wave duration. PWD has been associated with hypertension, a leading cause of age-related cognitive decline. Moreover, hypertension is associated with vascular dementia and Alzheimer's Disease. Based on these considerations, we evaluated PWD and global cognitive function in frail hypertensive older adults with a previous diagnosis of cognitive decline. We evaluated consecutive frail hypertensive patients ≥65-year-old with a Mini-Mental State Examination (MMSE) score <26. Patients with evidence of secondary hypertension, history of stroke, myocardial infarction, or therapy with beta-blockers or acetylcholinesterase inhibitors were excluded. Beta-blocker therapy causes a significant decrease in PWD; patients treated with acetylcholinesterase inhibitors were not included to avoid confounding effects on cognitive function. By examining 180 patients, we found that PWD significantly correlated with MMSE score. Strikingly, these effects were confirmed in a linear multivariate analysis with a regression model. To our knowledge, this is the first study showing that PWD correlates with global cognitive function in frail hypertensive older adults.

Haemophilia management and treatment: An Italian survey on patients', caregivers' and clinicians' point of view.

INTRODUCTION: Haemophilia management and patients' quality of life significantly improved. However, data on current patients', caregivers' and clinicians' satisfaction and limitations of treatments and haemophilia management are limited. AIM: Assessing the management satisfaction and unmet needs from the perspective of Italian patients with haemophilia (PWH) without inhibitors (or caregivers if children) and of specialist physicians. METHODS: Surveys (for patients≥18 years, caregivers of children and haemophilia specialists) were developed by a multidisciplinary working group and conducted from November 2019 to June 2020. RESULTS: Among 275 participants, 120 (43.6%) were PWH without inhibitors, 79 (28.7%) caregivers and 37 (13.4%) clinicians. Patients and caregivers perceived a higher control of the disease compared to clinicians. However, more than 40% of patients and caregivers reported to feel significantly conditioned by the risk of bleeding during their daily life. PWH reported a 6-month mean/median (range) of bleeds 2.3/.0 (0-24) and caregivers 1.3/.0 (0-16) in children. The treatment burden (frequency of administration) was not satisfactory for more than half adults and caregivers of children treated with prophylaxis. A good access to treatment, haemophilia centres and medical service was reported, with issues associated to the multidisciplinary approach and treatment at emergency department. CONCLUSIONS: This large national study provides an updated overview of haemophilia care in Italy from different points of views, highlighting positive aspects and unmet needs. This information can guide future interventions to improve haemophilia management and the assessment of impact of new treatment options.

Acquired haemophilia A: Italian Consensus Recommendations on diagnosis, general management and treatment of bleeding.

BACKGROUND: Acquired haemophilia A (AHA) is a rare bleeding disorder due to autoantibodies to coagulation factor VIII that may be secondary to autoimmune diseases, cancer, drugs, pregnancy, infections, or be idiopathic. Recurrent bleeding, often severe, mostly in muscles and soft tissues, and isolated prolonged activated partial thromboplastin time (aPTT), in the absence of personal and family history of bleeding, are typical features that should raise the suspicion of AHA. Poor awareness of the disease results in diagnostic delays and inappropriate treatment. MATERIALS AND METHODS: The Italian Association of Haemophilia Centres (AICE) developed consensus recommendations in cooperation with the Italian Society on Thrombosis and Haemostasis (SISET). The document was shared with scientific societies of specialist physicians, laboratory professionals and pharmacists to spread knowledge about AHA and promote appropriate diagnosis/treatment. RESULTS: Ready availability of the aPTT mixing test is crucial, although diagnostic confirmation and optimal management require prompt referral of patients to specialised centres with rapidly available diagnostic and therapeutic facilities. If immediate referral is unfeasible, treatment must be undertaken early, under guidance of specialised centres or based on shared protocols. Recommendations about diagnosis, general management and, in bleeding patients, haemostatic therapy using bypassing agents or replacement treatment, including the recently available recombinant porcine factor VIII, are provided, considering the different clinical settings and laboratory facilities. DISCUSSION: This consensus document aims to improve the overall healthcare pathways for AHA, harmonise the management and therapeutic approaches to newly diagnosed patients and reduce the still relevant complications and mortality in this setting.

Current Choices and Management of Treatment in Persons with Severe Hemophilia A without Inhibitors: A Mini-Delphi Consensus.

BACKGROUND: Regular treatment to prevent bleeding and consequent joint deterioration (prophylaxis) is the standard of care for persons with severe hemophilia A, traditionally based on intravenous infusions of the deficient clotting FVIII concentrates (CFCs). In recent years, extended half-life (EHL) CFCs and the non-replacement agent emicizumab, subcutaneously administered, have reduced the treatment burden. METHODS: To compare and integrate the opinions on the different therapies available, eight hemophilia specialists were involved in drafting items of interest and relative statements through the Estimate-Talk-Estimate (ETE) method ("mini-Delphi"), in this way reaching consensus. RESULTS: Eighteen items were identified, then harmonized to 10, and a statement was generated for each. These statements highlight the importance of personalized prophylaxis regimens. CFCs, particularly EHL products, seem more suitable for this, despite the challenging intravenous (i.v.) administration. Limited real-world experience, particularly in some clinical settings, and the lack of evidence on long-term safety and efficacy of non-replacement agents, require careful individual risk/benefit assessment and multidisciplinary data collection. CONCLUSIONS: The increased treatment options extend the opportunities of personalized prophylaxis, the mainstay of modern management of hemophilia. Close, long-term clinical and laboratory follow-up of patients using newer therapeutic approaches by specialized hemophilia treatment centers is needed.

The effect of carriers' reproductive choices and pregnancy history on sporadic severe haemophilia: A 20-year retrospective study through a regional registry.

INTRODUCTION: Haemophilias are X-linked inherited bleeding disorders, due to de novo F8/F9 gene variants in 30-50% of cases. The identification of causative variant in index cases (IC) is crucial for genetic counselling in related women. Over the last 20 years the Emilia-Romagna Regional Haemophilia Registry documented high proportions of sporadic severe haemophilia. AIM: To clarify if carriers' reproductive choices influence the sporadic/familial ratio of severe haemophilia. METHODS: Genetic counselling and genotyping in 221 relatives of severe IC were retrospectively reviewed, retrieving reproductive choices and pregnancy history of childbearing-age carriers from familial and sporadic pedigrees and according to the IC degree of relationship (mothers, daughters, II/other). RESULTS: Carriers' identification rates were lower in sporadic women and in other-degree relatives. Among childbearing age women (n = 140), carriers were 37/48 (77%) and 57/92 (62%) of familial and sporadic relatives, respectively. Forty-five/57 sporadic carriers experienced 67 pregnancies, while 21/37 familial carriers had 39 pregnancies (four voluntary terminations), with a significantly higher number of affected sons in the former (40/67 vs. 12/35, P = .025). Prenatal diagnosis was chosen by 40% and 47% of sporadic and familial aware carriers, respectively. Sporadic mothers often avoided further pregnancies (17/38, 45%) after a firstborn affected child, while familial mothers tended to face pregnancies without prenatal approaches (6/10, 60%). CONCLUSION: In this cohort sporadic offspring account for more than 70% of severe haemophilia cases. This increasing proportion is likely to reflect the influence in reproductive choices of awareness of carriers' status, particularly in sporadic mothers, and of prenatal diagnosis options.

The pesticide fate tool for groundwater vulnerability assessment within the geospatial decision support system LandSupport.

The protection of groundwater resources from non-point-source pollutants, such as those coming from agricultural practices, is the focus of several European Directives, including the Water Framework Directive and the Pesticide Directive. Besides the environmental goals to be reached by the single EU member state, these directives clearly underline the role of experts in supporting planners and public authorities to fulfil these objectives. This work presents a new web-based, freely-available dynamical tool, named the pesticide fate tool, developed within the geospatial Decision Support system (DSS), LandSupport, for the assessment of groundwater vulnerability, specific for type of pollutant. The tool is based on the extended transfer function model, specifically expanded to consider the transport of reactive solutes, such as pesticides. The work describes the tool implementation for three case studies, with different spatial scales and pedo-climatic conditions: Valle Telesina, IT, Marchfeld, AT, and Zala County, HU. Principal inputs of the tool are: soil physical and hydrological properties, climate, groundwater table depth, type of crops and related pesticides. Results of the model are shown through the LandSupport GUI both as coloured maps, representing the relative concentration of pesticide at the arrival to the water table at the end of the simulation period, and as cumulative charts of the solute arrival at the depth of interest. The three case studies are shown as examples of application of the LandSupport DSS in supporting the Water and Pesticides directives, demonstrating that it represents a valuable instrument for public authorities, environmental planners, as well as agricultural extension services. For example, large differences are shown by soils in filtering the tetraconazole (99.9% vs 76%), a fungicide used in viticulture, or different percentage of arrival (0.32% and 0,01%) to the groundwater table are shown for two herbicides (Tribenuron and Florasulam) largely used to control annual dicotyledonous weeds.