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.

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.

Risk factors and one-year mortality in patients with direct oral anticoagulant-associated gastrointestinal bleeding.

BACKGROUND AND AIM: Risk factors and mortality in patients with DOACs-associated gastrointestinal bleeding (GIB) are not completely defined. Aims of this study were to identify risk factors for bleeding and evaluate one-year mortality in patients with DOACs-associated GIB. METHODS: We conducted a case-control study. Cases were patients with DOACs-associated GIB admitted to the Perugia Hospital, Italy between 2013 and 2019. Controls were derived from the prospective database of patients with DOACs referred to the ambulatory service. Cases and controls were matched by a 1:2 ratio for type and dose of DOAC, indication for anticoagulation and gender. Univariate and multivariable analyses were performed to identify risk factors. Hazard Ratio with 95% confidence interval was used to calculate mortality. RESULTS: We included 324 patients, of which 108 with DOACs-associated GIB. Mean age was 81.9 ± 7.2 years and 78.9 ± 8.7 years, respectively. The most frequent indication for anticoagulation was atrial fibrillation. Reduced doses of DOACs were prescribed in 186 patients (56.4%). At multivariable analysis, active cancer (OR:7.26; 95%CI 3.10-16.96), renal impairment (OR:4.26; 95%CI 1.98-9.17), bleeding predisposition (OR:3.66; 95%CI 2.00-6.68), COPD (OR:2.12; 95%CI 1.08-4.16) and uncontrolled hypertension (OR:1.86; 95%CI 1.07-3.23) were found to be predictors for DOACs-associated GIB. Adjusted one-year mortality was significantly higher in patients who experienced GIB compared with those who did not experience GIB (OR: 7.04; 95%CI 3.82-14.31). CONCLUSIONS: Predictors of DOACs-associated GIB included active cancer, renal impairment, bleeding predisposition, COPD and uncontrolled hypertension. The adjusted one-year-mortality was significantly increased in patients with DOACs-associated GIB in comparison to DOACs patients without GIB.

Recent Advances in the Treatment of Hemophilia: A Review.

Progress in hemophilia therapy has been remarkable in the first 20 years of the third millennium, but the innovation began with the description the fractionation of plasma in 1946. The first concentrates followed the discovery of FVIII in the cryoprecipitate of frozen plasma and FIX in the supernatant in the early 1960s, which led to the initial attempts at replacement therapy. Unfortunately, the lack of screening methods for viral pathogens resulted in people with hemophilia (PWH) receiving concentrates contaminated by hepatitis A virus, hepatitis C virus, and human immunodeficiency virus, as these concentrates were made from large industrial pools of plasma derived from thousands of donors. Fortunately, by 1985, viral screening methods and proper virucidal techniques were developed that made concentrates safe. Increasingly pure products followed the introduction of chromatography steps with monoclonal antibodies in the production process. The problem of immunogenicity of exogenously administered concentrates has not yet had a complete solution. The development of alloantibodies against FVIII in about 25-35% of PWH is the most serious adverse effect of replacement therapy. The next major advance followed the cloning of the F8 gene and later the F9 genes, which paved the way to produce concentrates of factors obtained by the recombinant DNA technology. The injected FVIII and FIX molecules had a relatively short circulating half-life in the plasma of people with hemophilia A and B, approximately 12 and 18 hours, respectively. The ability to prolong the plasma half-life and extend the interval between injections followed the application of methods to conjugate the factor molecule with the fragment crystallizable of IgG1 or albumin or by adding polyethylene glycol, which has led to an increase in the half-life of concentrates, especially for rFIX. The next frontier in hemophilia therapy is the application of durable and potentially curative therapies such as with gene addition therapy. Experiments in hemophilia B have demonstrated durable responses. Unfortunately, the results with gene therapy for hemophilia A have not been as remarkable and the durability must still be demonstrated. Nonetheless, the long-term safety, predictability, durability, and efficacy of gene therapy for hemophilia A and B remain an open question. At present, only healthy adult PWH have been enrolled in gene therapy clinical trials. The application of gene therapy to children and those with pre-existing antibodies against the delivery vector must also be studied before this therapy becomes widespread.

The availability of new drugs for hemophilia treatment.

INTRODUCTION: A number of new FVIII/IX concentrates enriched the portfolio of products available for the treatment of hemophilia A/B patients. Due to the large inter-patient variability, accurate tailoring of the therapy became essential to improve patients' adherence, clinical outcomes, and cost/effectiveness ratio. Recently, non-replacement therapies have taken the limelight and succeeded in decreasing the bleedings of patients. AREAS COVERED: The PK characteristics, efficacy, and safety of the new rFVIII and rFIX concentrates and of non-replacement therapy, are reported in detail in the published clinical trials. EXPERT OPINION: Outstanding improvements of rFIX concentrates' pharmacokinetics and pharmacodynamics have allowed to reduce the bleedings in hemophilia B patients, in order to increase their adherence to prophylaxis and quality of life. Less significant are the effects of pegylation or Fc fusion on the pharmacokinetics of the new rFVIII concentrates. The new non-replacement therapy is achieving the favor of many treaters and patients, in particular those with Factor VIII inhibitors. Great attention must be paid to the dangerous synergy of APCC and emicizumab, responsible for some fatal events during the clinical trials and compassionate use of this drug. So far, replacement therapy should be the standard of care for hemophilia patients without inhibitors or difficulties in venous access.

Emergency management in patients with haemophilia A and inhibitors on prophylaxis with emicizumab: AICE practical guidance in collaboration with SIBioC, SIMEU, SIMEUP, SIPMeL and SISET.

Emicizumab has been approved in several countries for regular prophylaxis in patients with congenital haemophilia A and FVIII inhibitors because it substantially reduces their bleeding risk and improves quality of life. However, although significantly less frequent, some breakthrough bleeds may still occur while on emicizumab, requiring treatment with bypassing or other haemostatic agents. Thrombotic complications have been reported with the associated use of activated prothrombin complex concentrates. In addition, when surgery/invasive procedures are needed while on emicizumab, their management requires multidisciplinary competences and direct supervision by experts in the use of this agent. Given this, and in order to expand the current knowledge on the use of emicizumab and concomitant haemostatic agents, and reduce the risk of complications in this setting, the Italian Association of Haemophilia Centres (AICE) here provides guidance on the management of breakthrough bleeds and surgery in emergency situations in patients with haemophilia A and inhibitors on emicizumab prophylaxis. This paper has been shared with other National Scientific Societies involved in the field.

Rate and appropriateness of polypharmacy in older patients with hemophilia compared with age-matched controls.

BACKGROUND: In older people, multiple chronic ailments lead to the intake of multiple medications (polypharmacy) that carry a number of negative consequences (adverse events, prescription and intake errors, poor adherence, higher mortality). Because ageing patients with haemophilia (PWHs) may be particularly at risk due to their pre-existing multiple comorbidities (arthropathy, liver disease), we chose to analyse the pattern of chronic drug intake in a cohort of PWHs aged 60 years or more. PATIENTS AND METHODS: S + PHERA is a multicentre observational study, with the broad goal to evaluate prospectively the health status and medication intake in 102 older patients with severe haemophilia A or B compared with 204 age- and residence-matched controls chosen randomly from the same general practices of PWHs. The rate of potential drug-drug interactions (PDDI) was evaluated as a proxy of prescription appropriateness. RESULTS: After excluding replacement therapies and antiviral drugs, PWHs took in average less daily drugs than controls (2.4 ± 2.5 vs 3.0 ± 2.4) and had a lower rate of polypharmacy. Moreover, their prevalence of PDDI was lower (16.7% vs 27%). CONCLUSIONS: The rate of polypharmacy and the appropriateness of medications other than those for haemophilia and related comorbidities are acceptable in Italian PWHs, and better than those in their age peers without haemophilia, perhaps owing to drug tailoring and deprescribing by the specialized haemophilia centres at the time of regular visits. However, the PWHs investigated herewith were relatively young and the rate of polypharmacy and related PDDIs may become more prominent and crucial when older ages are reached, suggesting the need of continuous surveillance on prescribed drugs and the risk of drug-drug interactions.

Patients with cancer and atrial fibrillation treated with doacs: A prospective cohort study.

BACKGROUND: Limited data are available on the use of direct oral anticoagulants (DOACs) in patients with cancer and atrial fibrillation (AF). METHODS: Consecutive patients with non-valvular AF treated with DOACs were enrolled in a prospective cohort with the aim of evaluating thromboembolic (ischemic stroke or transient ischemic attack or systemic embolism) and major bleeding (MB) events according to presence and type of cancer. The risk of study outcomes over time was compared using Kaplan-Meier method and log-rank test or Cox proportional hazards regression. RESULTS: 2304 patients with non-valvular AF receiving DOACs were enrolled and 16 excluded: 2288 analysed of whom 289 (12.6%) had cancer. Gastrointestinal (21%), genitourinary (15%), prostate (15%), haematological (14%), breast (13%), and lung (8%) were the more frequent sites of cancer. After a mean follow-up of 451 days, thromboembolic events occurred in 2.1% and 0.8% patient-year of cancer and non-cancer patients (adjusted-HR 2.58, 95% CI 1.08-6.16, p = 0.033). The rate of MB was 6.6% and 3.0% patient-year in cancer and non-cancer patients (adjusted-HR 2.02, 95% CI 1.25-3.27, p = 0.004). The differences in bleeding were mainly accounted for by bleeding at gastrointestinal and genitourinary sites. No significant differences were found concerning the rates of non-cancer-related mortality, fatal bleeding or fatal thrombotic events. CONCLUSIONS: In this study, the higher bleeding risk found in cancer compared to non-cancer patients was mainly due to an excess of bleeding at gastrointestinal and at genitourinary sites. Larger studies on the optimal management of cancer patients with AF are needed.

Current challenges in the diagnosis and management of patients with inherited von Willebrand's disease in Italy: an Expert Meeting Report on the diagnosis and surgical and secondary long-term prophylaxis.

Recent advances in the care of von Willebrand's disease (vWD) have allowed the majority of patients to be managed adequately. Even in the more severe forms, it is now possible to control recurrent bleeding through secondary long-term prophylaxis with von Willebrand factor-containing concentrates. Moreover, in the setting of surgical prophylaxis, the combination of interdisciplinary management and close patient monitoring yields a positive outcome in nearly all cases, although safety concerns remain. In clinical practice, the effectiveness of therapy is hindered by the difficulties in making a rapid, yet accurate diagnosis, in identifying the subgroup of bleeders who may benefit most from a specific strategy, and in selecting the optimal product and regimen.Since specific guidelines for heavy bleeders requiring short- and long-term prophylaxis are still lacking, sharing the experience of experts dealing with vWD patients on a daily basis is crucial to fill gaps in information relating to patient management. To address this important issue, 13 Italian haematologists met in Milan on April, 2, 2016 and in Florence on July, 9, 2016. A 30-question survey constituted the input to discuss (i) optimisation of the diagnostic workflow for vWD, (ii) the characteristics of patients who may benefit from secondary long-term prophylaxis (in particular with the purified von Willebrand factor concentrate with a low content of factor VIII), (iii) the key elements to consider when selecting a concentrate and (iv) the pre-operative and post-operative management of vWD patients. A summary of the main points covered is provided in this report.

Vitamin K and non-vitamin K antagonist oral anticoagulants for non-valvular atrial fibrillation in real-life.

BACKGROUND: Current guidelines recommend vitamin K antagonists (VKAs) or non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in patients with non-valvular atrial fibrillation (AF). METHODS: We compared the clinical features of consecutive in- and out-patients with non-valvular AF newly-treated with NOACs or on treatment with VKAs. RESULTS: Overall, 1314 patients newly-treated with NOACs and 1024 on treatment with VKAs were included in the study. The mean CHA2DS2-VASc score was 4.3±1.5 and 4.0±1.5 and the mean HAS-BLED score was 2.8±1.2 and 2.2±1.1 in the two groups, respectively (both p<0.001). Hypertension, previous stroke, female gender, vascular diseases and previous bleeding were more prevalent in NOACs patients. Renal failure, age ≥75years and congestive heart failure were more prevalent in VKAs patients. Among NOACs patients, 438 were given dabigatran, 463 rivaroxaban and 413 apixaban (33%, 35% and 31%, respectively). The mean CHA2DS2-VASc and HAS-BLED scores were higher in rivaroxaban or apixaban patients compared with dabigatran (both p<0.001) and VKAs patients (both p<0.001). A lower mean age was observed in patients newly-treated with dabigatran. Patients newly-treated with reduced doses of NOACs (599 patients, 45.5%) had a higher CHA2DS2-VASc (4.8±1.4 vs. 3.9±1.5 vs. 4.0±1.5) and HAS-BLED (2.9±1.1 vs. 2.8±1.2 vs. 2.2±1.1) scores compared with those treated with regular doses of NOACs or VKAs. CONCLUSION: Patients given rivaroxaban and apixaban in clinical practice have a higher thrombotic and hemorrhagic risk in comparison with patients given dabigatran or VKAs. A considerable proportion of patients receive reduced doses of NOACs.

IDO1 suppresses inhibitor development in hemophilia A treated with factor VIII.

The development of inhibitory antibodies to factor VIII (FVIII) is a major obstacle in using this clotting factor to treat individuals with hemophilia A. Patients with a congenital absence of FVIII do not develop central tolerance to FVIII, and therefore, any control of their FVIII-reactive lymphocytes relies upon peripheral tolerance mechanisms. Indoleamine 2,3-dioxygenase 1 (IDO1) is a key regulatory enzyme that supports Treg function and peripheral tolerance in adult life. Here, we investigated the association between IDO1 competence and inhibitor status by evaluating hemophilia A patients harboring F8-null mutations that were either inhibitor negative (n = 50) or positive (n = 50). We analyzed IDO1 induction, expression, and function for any relationship with inhibitor occurrence by multivariable logistic regression and determined that defective TLR9-mediated activation of IDO1 induction is associated with an inhibitor-positive status. Evaluation of experimental hemophilic mouse models with or without functional IDO1 revealed that tryptophan metabolites, which result from IDO1 activity, prevent generation of anti-FVIII antibodies. Moreover, treatment of hemophilic animals with a TLR9 agonist suppressed FVIII-specific B cells by a mechanism that involves IDO1-dependent induction of Tregs. Together, these findings indicate that strategies aimed at improving IDO1 function should be further explored for preventing or eradicating inhibitors to therapeutically administered FVIII protein.

Clotting factor concentrates given to prevent bleeding and bleeding-related complications in people with hemophilia A or B.

BACKGROUND: The hallmark of severe hemophilia is recurrent bleeding into joints and soft tissues with progressive joint damage, notwithstanding on-demand treatment. Prophylaxis has long been used but not universally adopted because of medical, psychosocial, and cost controversies. OBJECTIVES: To determine the effectiveness of clotting factor concentrate prophylaxis in the management of people with hemophilia A or B. SEARCH STRATEGY: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register. In addition, we searched major electronic databases (MEDLINE, EMBASE, CENTRAL), handsearched relevant journals and abstract books and reference lists of relevant articles.Last search of Group's Coagulopathies Trials Register: 07 April 2011. SELECTION CRITERIA: Randomised controlled trials and quasi-randomised controlled trials evaluating people with severe hemophilia A or hemophilia B receiving prophylactic clotting factor concentrates. DATA COLLECTION AND ANALYSIS: Two authors independently reviewed studies for eligibility, assessed risk of bias and extracted data. MAIN RESULTS: Six studies (including 142 participants) were eligible for inclusion. Two compared three-times-a-week prophylactic administration with on-demand treatment in children with hemophilia. Pooled results from these two studies showed a rate ratio of 0.30 (95% confidence interval; 0.12 to 0.76) for all bleedings and 0.22 (95% confidence interval 0.08 to 0.63) for joint bleedings favouring prophylaxis. Results on the number of patients with preserved joints after three to seven years of follow-up were not pooled due to significant heterogeneity. Three of the remaining four studies evaluated hemophilia A; one showed a statistically significant decrease in frequency of joint bleeds with prophylaxis compared to placebo, with a rate difference of -10.73 (95% confidence interval -16.55 to -4.91) bleeds per year. Two studies compared two prophylaxis regimens, failing to demonstrate an advantage of one regimen over the other in terms of bleeding frequency. The fourth study evaluated hemophilia B and showed fewer joint bleeds with weekly (15 IU/kg) versus bi-weekly (7.5 IU/kg) prophylaxis, rate difference -3.30 (95% confidence interval -5.50 to -1.10) bleeds per year. Non-significant increases in both inhibitor and infectious complications were observed in patients on prophylaxis, which occurred more often when using long-term venous access. AUTHORS' CONCLUSIONS: There is strong evidence from randomised controlled trials and observational trials that prophylaxis preserves joint function in children with hemophilia as compared to on-demand treatment. There is insufficient evidence from randomised controlled trials to confirm the observational evidence that prophylaxis decreases bleeding and related complications in patients with existing joint damage. Well-designed randomised controlled trials and prospective observational controlled studies are needed to establish the best prophylactic regimen and to assess the effectiveness of prophylactic clotting factor concentrates in adult patients.

Antiviral treatment for chronic hepatitis C in patients with human immunodeficiency virus.

BACKGROUND: Antiviral treatment for chronic hepatitis C may be less effective if patients are co-infected with human immunodeficiency virus (HIV). OBJECTIVES: To assess the benefits and harms of antiviral treatment for chronic hepatitis C in patients with HIV. SEARCH STRATEGY: Trials were identified through manual and electronic searches in The Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded. The last search was May 2009. SELECTION CRITERIA: Randomised trials comparing at least 12 weeks of any anti-HCV treatment versus another treatment regimen or no treatment. Included patients had chronic hepatitis C and stable HIV irrespective of previous antiviral therapy. DATA COLLECTION AND ANALYSIS: Data extraction and assessment of risk of bias were done in duplicate. Analysis was by intention-to-treat. MAIN RESULTS: Fourteen trials were included. None of the included 2269 patients were previously treated for chronic hepatitis C. Peginterferon (either 2a, 180 microgram, or 2b, 1.5 microgram/kg, once weekly) plus ribavirin was more effective in achieving end of treatment and sustained virological response compared with interferon plus ribavirin (5 trials, 1340 patients) or peginterferon (2 trials, 714 patients). The benefit of peginterferon plus ribavirin was seen irrespective of HCV genotype although patients with genotype 1 or 4 had lower response rates (27%) than patients with genotype 2 or 3 (56%). The remaining trials compared different treatment regimens in patients who were treatment naive or had no virological response after three months of treatment, but overall they had not enough power to show any effect of increasing the dose of interferon or adding both amantadine or ribavirin. The overall mortality was 23/2111 patients with no significant differences between treatment regimens. Treatment increased the risk of adverse events including anaemia and flu-like symptoms, and several serious adverse events occurred including fatal lactic acidosis, liver failure, and suicide due to depression. AUTHORS' CONCLUSIONS: Peginterferon plus ribavirin may be considered a treatment for patients with chronic hepatitis C and stable HIV who have not received treatment for hepatitis C as the intervention may clear the blood of HCV RNA. Supporting evidence comes mainly from the analysis of this non-validated surrogate outcome assessed in comparisons against other antiviral treatments. There is no evidence on treatment of patients who have relapsed or did not respond to previous therapy. Careful monitoring of adverse events is warranted.

Peginterferon plus ribavirin for chronic hepatitis C in patients with human immunodeficiency virus.

OBJECTIVES: The aim of this study was to assess the effects of peginterferon plus ribavirin for chronic hepatitis C in patients with human immunodeficiency virus (HIV). METHODS: Trials were identified through manual and electronic searches. Randomized trials comparing peginterferon plus ribavirin with other antiviral treatments for patients with chronic hepatitis C and HIV were included. The primary outcome measure was virological response at the end of treatment and after > or =6 months (sustained). Intention-to-treat meta-analyses including data on all patients who were randomized were carried out. RESULTS: Seven randomized trials were eligible for inclusion. The patients included had chronic hepatitis C and stable HIV and were not previously treated with interferon or ribavirin (treatment naive). The mean dosages were 180 or 1.5 microg/kg once weekly for peginterferon and 800 mg daily for ribavirin. The treatment duration ranged from 24 to 48 weeks. Peginterferon plus ribavirin increased the proportion of patients with an end-of-treatment or sustained virological response compared with interferon plus ribavirin or peginterferon alone. In subgroup analyses of trials comparing peginterferon plus ribavirin with interferon plus ribavirin, the proportion with a sustained virological response was 26% (109 of 423) for patients with genotype 1 or 4 and 57% (130 of 230) for genotype 2 or 3. Several adverse events occurred, including fatal lactic acidosis and liver failure, but there were no significant differences in mortality rates between treatment groups. CONCLUSIONS: Peginterferon plus ribavirin may be considered for treatment-naive patients with HIV and chronic hepatitis C. Adverse events should be monitored carefully.

Audit of the clinical use of fresh-frozen plasma in Umbria: study design and results of the pilot phase.

BACKGROUND: Fresh-frozen plasma (FFP) is unanimously recognised by international guidelines as the blood component of choice for the management of acute haemorrhage when accompanied by disorders of haemostasis, for disseminated intravascular coagulation in the presence of haemorrhage, for rare bleeding disorders when specific clotting factor concentrates are not available and for thrombotic thrombocytopenic purpura. The literature, however, reports a high percentage of inappropriate requests for FFP. This article presents the results of a pilot study of clinical auditing of the use of FFP in the Region of Umbria (Italy). METHODS: This study was based on the examination of the requests for FFP made in April 2006 to four Immunotransfusion Services (ITS) in Umbria and of the clinical records of the patients receiving transfusions. The following indicators were identified and evaluated: completeness of the request, appropriateness of the indication and the dose, completeness of the records in the clinical charts, adverse events, in-hospital morbidity and mortality, efficacy of the treatment (evaluated by analysing the changes between pre- and post-transfusion coagulation test results) and, as an indicator of the process, the correspondence between data in the paper request form and in the computerised database. The data were extracted from the ITS databases, from the paper request forms and from the patients' clinical records. RESULTS: Two hundred and twenty-one requests (615 units of FFP) for 109 patients and 92.8% of the related clinical records were examined. The patients were admitted in medical (22.9%), surgical (51.4%) and critical care units (25.7%). In 50.7% of the cases, the completeness of the data in the individual requests was good (65-80% of the fields filled in). The indication was appropriate in 31.5% of the requests evaluated (56.1% of the total), with no difference related to different requesters. The dosage was appropriate in 62.7% of the requests evaluated (62% of the total). A comparison of pre- and posttransfusion laboratory data showed a significant correction of pathological values (p=0.02) only for the International Normalised Ratio (INR). CONCLUSIONS: Critical areas that should be targeted by interventions to improve plasma usage are those related to the appropriateness of the indication, the completeness of the data entered in the request forms and the data recorded in the clinical charts.

The good use of plasma. A critical analysis of five international guidelines.

BACKGROUND: The clinical use of fresh-frozen plasma (FFP) is progressively increasing both nationally and internationally, despite the fact that many studies have shown the weaknesses of the indications for its use. Guidelines on the good use of plasma have, therefore, been adopted in various countries. The aim of the present study was to analyse some of the existing guidelines on the good use of plasma, applying a scientifically validated method, as a preliminary step in the implementation of Regional guidelines. METHODS: Abibliographic search (1990-2006) was conducted in databases, websites, and the archives of scientific societies. Relevant articles were recovered in full. The selected guidelines were evaluated using theAGREE instrument, which assesses the completeness and structural quality of the guidelines and, in some aspects, the contents of the recommendations. The project, co-ordinated by the Regional Centre for Co-ordination and Compensation (CRCC) and carried out by four Services of Immunohaematology and Transfusion (SIT) in Umbria, was funded by the Region of Umbria and approved by the four health care institutions involved. RESULTS: The bibliographic search yielded 3067 abstracts of which 239 were considered relevant. The analysis of these led to the recovery of 11 guidelines, among which five were selected: those from the British Committee for Standards in Haematology, theAgence Française de Securité Sanitaire de Produits de Sante, the Canadian Members of the Expert Working Group, the American Society of Anesthesiologists Task Force on Blood Component Therapy and the National Health and Medical Research Council (NHMRC)/Australasian Society of Blood Transfusion. CONCLUSIONS: None of the guidelines analysed obtained a score higher than 50% in all the domains of the AGREE score. There was no evidence of a tendency to improvement over time in the guidelines analysed. Objective evaluation of the guidelines analysed could provide the starting point for the subsequent production of similar documents.