Introduction: The factor VIII (FVIII)-mimetic bispecific monoclonal antibody, emicizumab, previously approved for prophylaxis in haemophilia A with inhibitors, has been recently licensed in several countries also in patients with severe haemophilia A (PWSHA) without inhibitors. The introduction of this innovative agent requires the development of specific pathways at Haemophilia Treatment Centres (HTC), particularly regarding laboratory testing and treatment of breakthrough bleeds and invasive procedures/surgeries, even more critical when patients are managed by non-specialist professionals. Limited literature data and clinical experience in PWSHA without inhibitors on emicizumab are currently available. Aim: To promote awareness and overcome these challenges, the Italian Association of Haemophilia Centres (AICE) issued a guidance on the management of PWSHA without inhibitors on emicizumab prophylaxis, focused on emergency and shared with other National Scientific Societies in the field. Methods: The document, drafted by an AICE expert panel and approved through online consultation, was further revised by a multidisciplinary working group, including members of 5 haemostasis, laboratory and emergency scientific societies. The final version was approved by the Council of each society. Results: General recommendations about use of FVIII concentrates for the treatment of bleeding or haemostatic coverage of invasive procedures/surgeries and laboratory monitoring in PWSHA without inhibitors on emicizumab are provided. Specific issues of the management in the emergency room are focused, highlighting the need for direct involvement or formalized supervision by specialist HTC physicians.

Background: Impaired glucose tolerance (IGT) is associated with increased cardiovascular morbidity and mortality. Enhanced thromboxane (TX)-dependent platelet activation plays a pivotal role in atherothrombosis and characterizes type 2 diabetes mellitus (DM). Whether this also pertains to IGT is currently unknown.We investigated whether TXA 2 -dependent platelet activation, as reflected by 11-dehydro-TXB 2 (TXM) urinary excretion, is comparably abnormal in IGT as in DM, is persistent over long-term follow-up, changes as a function of metabolic disease progression, and is influenced by food intake. Methods:We prospectively investigated subjects with IGT (n = 48) and two control groups with DM diagnosed either less than 12 months (n = 60) or 12 months or more (n = 58).Results: Baseline TXM excretion was comparable between subjects with IGT and DM, with no evidence of a circadian variation. During a 36-month follow-up, urinary TXM excretion was stable over time in the DM groups, while tended to increase in subjects with IGT. Increasing urinary TXM excretion over time was observed in the subjects who progressed to diabetes vs nonprogressors. Conclusions:We conclude that TXA 2 -dependent platelet activation was at least as high in IGT as in patients with DM and further increased over time, especially in those who progressed to overt diabetes. K E Y W O R D Scardiovascular morbidity, impaired glucose tolerance, platelet activation, thromboxane, type 2 diabetes mellitus This paper is dedicated to the memory of the late Professors Giovanni Davì and Giovanni Ciabattoni.Francesca Santilli and Francesco Zaccardi contributed equally to this study.

Platelet surface receptors for von Willebrand factor and for fibrinogen (glycoproteins GPIb and GPIIb/IIIa) were studied with monoclonal antibodies CD42 and CD41 and cytofluorometry in 31 healthy subjects, 10 hemodialysis patients with no A-V fistula obstruction (patent original fistula), 10 hemodialysis patients with frequent A-V fistula obstruction (more than twice), 12 patients with mild chronic renal failure (creatinine 1.75 +/- 0.40 mg/100 ml), 11 patients with advanced chronic renal failure (creatinine 5.62 +/- 1.22 mg/100 ml), and 10 patients with end-stage renal disease (ESRD) treated with peritoneal dialysis. There was a significant increase of platelet surface glycoproteins GPIb and GPIIb/IIIa in the population of hemodialysis patients with frequent A-V fistula obstruction. The expression of these platelet receptors might be related to the prothrombotic tendency of a group of patients with ESRD, who suffer more occlusive and thrombotic events of the A-V fistula. This group of patients may also have a higher frequency of systemic thrombotic and atherosclerotic complications.

Dear Sir, In a recent article by Nomura et al.[1] a reduction of platelet glycoprotein GPIb ex pression in the uremic patient was con firmed. just as reported by Sloand ct al. [2], We agree with these data, that clarify the important role of a defect in primary hemo stasis in the pathogenesis of uremic bleeding. We investigated the abnormalities of platelet surface glycoproteins GPIb, the receptor for von Willebrand factor, and GPIIb/llla. the receptor for fibrinogen, since the early stages of renal failure and we correlated them with the degree of uremia and plasma creatinine. We studied four groups of patients: group A (n = 18 healthy controls) creatinine = 0.8 ± 0.3 mg%; group B (n = 10) creatinine = 1.8 ± 0.5 mg%; group C (n = 8) creatinine = 5.4 ± 2.1 mg%; group D (n = 10) creatinine = 9.6 ± 3. In all the patients we investigated platelet glycoproteins GPIb and GPIIb/llla with monoclonal antibodies CD42b and CD41 (Biorad, Italy) and flow cytometric analysis (Bryte cytometer: Biorad). Mean values of GPIb glycoproteins (mean flow ± SD): group A = 43.09 ± 11.19; group B = 37.84 ± 5.57: group C = 34.82 ± 9.54 (p < 0.05); group D = 33.02 ± 7.6 (p < 0.05). Mean values of GPIIb/llla: group A = 312.40 ± 108.3: group B = 410.63 ± 34.65 (p < 0.05); group C = 434.89 ± 50.86 (p < 0.025); group D = 415.31 ± 70.5 (p< 0.05). Our data suggest: (1) that platelet surface gly coprotein abnormalities are present since the early stages of renal failure and are well cor related with the degree of uremia; (2) that also glycoprotein GPIIb/llla is altered in uremia (these further data are different from the data reported by other authors), and (3) that the defect is not corrected by dialytic procedure. Finally, we want to stress in ure mic patients the main importance of platelet glycoprotein abnormalities that also have an important role in the abnormal procoagulant response to treatment with recombinant hu man erythropoietin, as just reported [3].

BackgroundValproate is a broad-spectrum anticonvulsant that is effective in the treatment of tonic-clonic, myoclonic and absence seizures as well as in partial seizures as a second-line drug. It has been widely demonstrated in the literature that the effect of valproate on type-A γ-aminobutyric acid (GABA-A) receptors may reduce relapse to ethanol abuse. This retrospective study evaluated a 3-year period in which 42 patients from the Department of Alcoholism and Substance Abuse (DASA) were treated with valproate.ObjectivesWe compared different serum total valproic acid (VPA) concentrations, and the effectiveness of this drug in maintaining alcohol abstinence was evaluated by percentage of carbohydrate deficient transferrin (%CDT) values.MethodCDT is a biochemical marker used for identifying regular high alcohol consumption and monitoring abstinence in outpatients during treatment. Serum concentrations of valproate were divided into four groups: <10, 10–30, 31–50, and >50 µg/mL.ResultsThis study shows that a mean serum total VPA concentration >30 µg/mL is more effective in maintaining alcohol abstinence than a lower one (p < 0.05). In this study, mean serum total VPA concentrations between 31 and 50 µg/mL showed the same effectiveness as higher ones (>50 µg/mL); in fact, there was no significant difference in mean %CDT values between these two groups (p > 0.05). After at least 12 months’ treatment with valproate, mean platelet counts increased by 12 × 103/μL compared with baseline (254 ± 63 vs 242 × 103/μL, p > 0.05, respectively) in patients with mean serum total VPA levels <10 μg/mL; increased by 8 × 103/μL from baseline (253 ± 59 vs 245 × 103/μL, p > 0.05, respectively) in patients with levels between 10 and 30 μg/mL; decreased by 2 × 103/μL from baseline (265 ± 63 vs 267 × 103/μL, p > 0.05, respectively) in patients with levels between 31 and 50 μg/mL, and decreased by 48 × 103/μL from baseline (215 ± 56 vs 263 × 103/μL, p < 0.05, respectively) in patients with levels >50 μg/mL.ConclusionA mean serum total concentration lower than the currently accepted therapeutic level (50–100 µg/mL) may have the same effectiveness in maintaining alcohol abstinence with a lower risk of presenting side effects.

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BackgroundThe instant, single-sampling rule-out of acute myocardial infarction (AMI) is still an unmet clinical need. We aimed at testing and comparing diagnostic performance and prognostic value of two different single-sampling biomarker strategies for the instant rule-out of AMI.MethodsFrom the Biomarkers in Acute Cardiac Care (BACC) cohort, we recruited consecutive patients with acute chest pain and suspected AMI presenting to the Emergency Department of the University Medical Center Hamburg-Eppendorf, Hamburg, Germany. We compared safety, effectiveness and 12-month incidence of the composite endpoint of all-cause death and myocardial infarction between (i) a single-sampling, dual-marker pathway combining high-sensitivity cardiac troponin I (hs-cTnI) and ultra-sensitive copeptin (us-Cop) at presentation (hs-cTnI ≤ 27 ng/L, us-Cop &lt; 10 pmol/L and low-risk ECG) and (ii) a single-sampling pathway based on one-off hs-cTnI determination at presentation (hs-cTnI &lt; 5 ng/L and low-risk ECG). As a comparator, we used the European Society of Cardiology (ESC) 0/1-h dual-sampling algorithm.ResultsWe enrolled 1,136 patients (male gender 65%) with median age of 64 years (interquartile range, 51–75). Overall, 228 (20%) patients received a final diagnosis of AMI. The two single-sampling instant rule-out pathways yielded similar negative predictive value (NPV): 97.4% (95%CI: 95.4–98.7) and 98.7% (95%CI: 96.9–99.6) for dual-marker and single hs-cTnI algorithms, respectively (P = 0.11). Both strategies were comparably safe as the ESC 0/1-h dual-sampling algorithm and this was consistent across subgroups of early-comers, low-intermediate risk (GRACE-score &lt; 140) and renal dysfunction. Despite a numerically higher rate of false-negative results, the dual-marker strategy ruled-out a slightly but significantly higher percentage of patients compared with single hs-cTnI determination (37.4% versus 32.9%; P &lt; 0.001). There were no significant between-group differences in 12-month composite outcome.ConclusionsInstant rule-out pathways based on one-off determination of hs-cTnI alone or in combination with us-Cop are comparably safe as the ESC 0/1 h algorithm for the instant rule-out of AMI, yielding similar prognostic information. Instant rule-out strategies are safe alternatives to the ESC 0/1 h algorithm and allow the rapid and effective triage of suspected AMI in patients with low-risk ECG. However, adding copeptin to hs-cTn does not improve the safety of instant rule-out compared with the single rule-out hs-cTn at very low cut-off concentrations.

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