Real-world use of thrombopoietin receptor agonists in older patients with primary immune thrombocytopenia.

The efficacy and safety of thrombopoietin receptor agonists (TRAs) in older patients with primary immune thrombocytopenia (ITP) are unknown. We investigated TRA response and switch, thrombotic/hemorrhagic risk, and sustained responses off-treatment (SROTs) in 384 patients with ITP aged ≥60 years. After 3 months, 82.5% and 74.3% of eltrombopag- and romiplostim-treated patients, respectively, achieved a response; 66.7% maintained the response (median follow-up, 2.7 years). Eighty-five (22.2%) patients switched to the alternative TRA; although no cross-toxicity was observed, 83.3% of resistant patients had a response after the switch. Thirty-four major thromboses (3 fatal) and 14 major hemorrhages (none fatal) occurred in 18 and 10 patients, respectively, while on TRAs and were associated with thrombosis history (subdistribution hazard ratio, 2.04, P = .05) and platelet count <20 × 109/L (subdistribution hazard ratio, 1.69; P = .04), respectively, at TRA start. A recurrent event occurred in 15.6% of patients surviving thrombosis, in all cases but 1 during persisting TRA treatment (incidence rate, 7.7 per 100 patient-years). All recurrences occurred in the absence of adequate antithrombotic secondary prophylaxis. Sixty-two (16.5%) responding patients discontinued TRAs; 53 (13.8%) patients maintained SROTs, which were associated with TRA discontinuation in complete response (P < .001). Very old age (≥75 years; 41.1%) was associated with the more frequent start of TRAs in the persistent/acute phase but not with response or thrombotic/hemorrhagic risk. TRAs are effective in older patients with ITP, with no fatal hemorrhages and with SROTs in a significant portion of patients. Caution is warranted in patients with a history of thrombosis, and a careful risk/benefit balance should be considered.

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.

Italian experience with rVIII-single chain: a survey of patients with haemophilia A and their physicians.

rVIII-SingleChain is indicated for treatment and prophylaxis of bleeding in patients with haemophilia A (HA). The safety and efficacy of rVIII-SingleChain have previously been shown in the AFFINITY clinical trial programme. This survey evaluated clinical experience following a switch to rVIII-SingleChain from the perspective of both physicians and patients. A web-based survey (July-September 2019) involving 14 Haemophilia Treatment Centres (HTCs) collected data about HA patients who were under treatment with rVIII-SingleChain for ≥ 12 months, as reported by their physicians. In addition, about half of these patients were separately interviewed. Out of 91 patients receiving rVIII-SingleChain in the 14 participating HTCs, 48 had been treated for ≥ 12 months; among those 48, 38% were ≤ 18 years, 37% 19-40 years and 25 % ≥ 41 years; 73% of them had severe HA and 85% were being treated with prophylactic therapy. Twenty-six patients accepted to be separately interviewed: mean age was 30 years; 62% had severe HA and 85% were receiving prophylaxis. Focusing on those patients who were already in prophylaxis with prior FVIII (all but one with recombinant factors), infusion frequency was significantly reduced from 3-2 per week following the switch to rVIII-SingleChain (mean, 2.74 vs. 2.44, respectively; p=0.013), as reported by physicians; the rate of patients needing 3 infusions per week dropped from 74% with previous products to 44% with rFVIII-SingleChain. The annual mean factor consumption was 4740 IU/Kg (median, 4500 IU/Kg; min, 2.215 IU/Kg; max, 7.200 IU/Kg) with prior product and 4320 IU/Kg (median, 4320 IU/Kg; min, 2.215 IU/Kg; max, 6.646 IU/Kg) with rVIII-SingleChain. Both physicians and patients reported a significant reduction in annual total bleeding rates with rVIII-SingleChain compared with prior product (mean 2.15-0.96 and 2.46-0.71 events/year, p = 0.031 and p = 0.018, respectively). Mean satisfaction ratings (from 1; dissatisfied, to 5; very satisfied) for rVIII-SingleChain were quite high for both physicians (4.14, 86% satisfied/very satisfied) and patients (4.18, 86% satisfied/very satisfied). This survey suggested that switching to rVIII-SingleChain allowed patients to reduce their injection frequency without increasing factor consumption or compromising clinical results. Both physicians and patients reported a positive experience with rVIII-SingleChain after 1 year of treatment.

Eltrombopag for immune thrombocytopenia secondary to chronic lymphoproliferative disorders: a phase 2 multicenter study.

Immune thrombocytopenia (ITP) secondary to chronic lymphoproliferative disorders (LPDs) is poorly responsive to conventional treatments. We conducted a multicenter phase 2 prospective 24-week study in 18 patients with ITP secondary to LPDs to assess the safety and efficacy of eltrombopag. Responsive patients entered an extension study for up to 5 years. For inclusion, patients should not require cytotoxic treatment and should have a platelet count <30 × 109/L or have symptoms of bleeding. Eltrombopag was initiated at 50 mg/day, with a maximum of 150 mg/day. The primary end point was platelet response after 4 weeks. Median age was 70 years (range, 43-83 years), and 14 patients had chronic lymphocytic leukemia, 2 had classic Hodgkin lymphoma, and 2 had Waldenström macroglobulinemia. All patients had received previous ITP treatments. Response rate at week 4 was 78% (95% confidence interval [CI], 58%-97%), with 50% of patients having a complete response (CR) (95% CI, 43%-57%); respective results at week 24 were 59% (95% CI, 36%-82%) with 30% reaching a CR (95% CI, 8%-52%). Median exposure to eltrombopag was 16 months; median dose at week 4 was 50 mg/day (range, 25-100 mg/day), and at week 24, it was 50 mg/day (range, 25-150 mg/day). No grade >2 adverse events were reported. Eltrombopag is active and well tolerated in ITP secondary to LPDs. This trial was registered at www.clinicaltrials.gov as #NCT01610180.

Immune tolerance induction with moroctocog-alpha (Refacto/Refacto AF) in a population of Italian haemophilia A patients with high-titre inhibitors: Data from REF.IT Registry.

BACKGROUND: The appearance of inhibitors is the most serious complication in haemophilia A (HA) patients. The primary objective is their eradication. Up to date, immune tolerance induction (ITI) was the only therapeutic option to achieve this. AIM: To assess the efficacy of moroctocog-alpha as an ITI regimen in a population of HA patients with high-titre inhibitors. METHODS: The REF.IT Registry is a retrospective-prospective study that collected data on all patients with HA and high-titre inhibitors treated with moroctocog-alpha as an ITI regimen at twelve Italian Haemophilia Centres. RESULTS: We enrolled 27 patients, 85.2% were children. All patients were high responders, 88.9% had severe HA. We found 69.3% of them had one or more risk factors for poor ITI prognosis, 14.8% were ITI rescue. Overall 59.3% achieved a complete/partial success (complete in 51.9%). ITI failed in 11 patients, 63.6% of them with poor-prognosis risk factors. Inhibitors appeared after a mean of 27 exposure days. Mean historical peak was 78.8 BU/mL. The primary ITIs started on average 20.2 months after the diagnosis. A partial or complete success after a mean of 15 months of treatment was achieved in 56.6% of the children while the same result was obtained by 75.0% adults after 22 months from ITI onset. Patients who were treated with high-dose moroctocog-alpha (200 UI/kg/day) were 63.0%. CONCLUSION: Our Registry showed that the use of moroctocog-alpha in the setting of ITI was effective and safe also in a population of patients with high-titre inhibitors, presenting one or more risk factors for poor ITI prognosis.

Thrombopoietin receptor agonists in patients with persistent or chronic immune thrombocytopenia.

OBJECTIVES: To assess long-term treatment patterns and outcomes in patients with persistent or chronic immune thrombocytopenia (ITP), also considering the impact of the treatment with thrombopoietin receptor agonists (TPO-RAs) prior to splenectomy. METHODS: Medical records of all patients with persistent or chronic ITP seen at our institution between January 1985 and December 2016 were reviewed. Data on demographic and clinical characteristics were analyzed using descriptive statistics. Wilcoxon rank-sum test was used to compare medians between groups of patients. RESULTS: Among 80 patients with persistent or chronic ITP, 34 underwent splenectomy and 59 were treated with TPO-RAs. Twenty patients were both splenectomized and treated with TPO-RAs; among them, 9 received TPO-RAs before splenectomy. Median time to splenectomy from diagnosis of ITP was 25 months in the group of patients pretreated with TPO-RAs vs 14.5 months in the group of splenectomized patients. These differences were not statistically significant. CONCLUSIONS: Our study provides some initial data on the potential benefits of the treatment with TPO-RAs that may allow splenectomy to be safely deferred for prolonged periods. More research is needed to evaluate the impact of the treatment with TPO-RAs prior to splenectomy.

Health-related quality of life and burden of fatigue in patients with primary immune thrombocytopenia by phase of disease.

The main objective of this study was to compare health-related quality of life (HRQOL) of primary immune thrombocytopenia (pITP) patients with that of general population, overall, and by patient group (i.e., newly diagnosed, persistent, and chronic patients). Fatigue was also investigated as a secondary objective. Overall, 424 adult patients were enrolled in a multicenter observational study and the control group consisted of a representative sample from the general population. Propensity score matching plus further multivariate linear regression adjustment was used to compare HRQOL outcomes between pITP patients and general population. Mean age of patients was 54 years. Of those with HRQOL assessment, 99 patients (23.6%) were newly diagnosed, 53 (12.6%) were persistent, and 268 (63.8%) were chronic pITP patients. Comparison by patient group versus their respective peers in the general population revealed greater impairments in persistent pITP patients. Persistent pITP patients reported clinically meaningful impairments in physical functioning (-15; 95% CI -24.1 to -5.8; P = 0.002), social functioning (-15.3; 95% CI -25.5 to -5.1; P = 0.004), role physical (-28.4; 95% CI -43.1 to -13.7; P < 0.001), role emotional (-23.9; 95% CI -40.1 to -7.7; P = 0.004), and mental health scales (-11.3; 95% CI -21.2 to -1.4; P = 0.026) of the SF-36 questionnaire. Higher fatigue severity was associated with lower physical and mental HRQOL outcomes. Our findings suggest that the burden of the disease and treatment might depend on the disease phase and that persistent pITP patients are the most vulnerable subgroup. Am. J. Hematol. 91:995-1001, 2016. © 2016 Wiley Periodicals, Inc.

Real-World Efficacy and Safety of Plasma-Derived Von Willebrand Factor-Containing Factor VIII Concentrates in Patients With Von Willebrand Disease in Italy.

Plasma-derived von Willebrand factor-containing factor VIII concentrates (pd-VWF/FVIII-C) are the mainstay of treatment in von Willebrand disease (VWD). Real-world data on efficacy and safety of these pd-VWF/FVIII-C are required. To retrospectively evaluate the efficacy and safety of pd-VWF/FVIII-C (Fanhdi® and Alphanate®, Grifols) in clinical practice in Italy. A multicentric, observational, retrospective study at 10 Italian centers was conducted. Eligible patients diagnosed with inherited VWD (ISTH criteria) were treated with either Fanhdi® or Alphanate® for bleeding episodes, prevention of surgical bleeding and secondary long-term prophylaxis (SLTP) according to clinical practice with medical records collected from January 2007 to December 2019. Efficacy/safety of pd-VWF/FVIII-C was assessed according to FDA-agreed objective criteria following regulatory procedures. Fifty-seven patients (M/F: 21/36) were enrolled in the study with the following VWD types: VWD1 (n = 29, 52%), VWD2A (n = 10, 18%), VWD2B (n = 7, 12%), VWD2M (n = 2, 4%), VWD2N (n = 1, 2%), VWD2 unclassified (n = 1, 2%), and VWD3 (n = 7, 12%). These pd-VWF/FVIII-C were used to manage 58 bleeding episodes (n = 24 patients), 100 surgeries (n = 47 patients), and 7 SLTP (n = 6 patients). Global clinical efficacy with these pd-VWF/FVIII-C was reported to be excellent/good in 85% of bleeding episodes, 98% of surgeries, and 100% of SLTP. As far as safety, no adverse-drug-related episodes, immunogenic or thrombotic events were reported. This study confirmed that Fanhdi® and Alphanate® were effective and safe in the management of bleeding episodes, the prevention of bleeding during surgeries and for SLTP in Italian patients with inherited VWD.

Anti-ADAMTS13 Autoantibodies: From Pathophysiology to Prognostic Impact-A Review for Clinicians.

Thrombotic thrombocytopenic purpura (TTP) is a fatal disease in which platelet-rich microthrombi cause end-organ ischemia and damage. TTP is caused by markedly reduced ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity. ADAMTS13 autoantibodies (autoAbs) are the major cause of immune TTP (iTTP), determining ADAMTS13 deficiency. The pathophysiology of such autoAbs as well as their prognostic role are continuous objects of scientific studies in iTTP fields. This review aims to provide clinicians with the basic information and updates on autoAbs' structure and function, how they are typically detected in the laboratory and their prognostic implications. This information could be useful in clinical practice and contribute to future research implementations on this specific topic.

Surgery and Prophylaxis with Susoctocog-Alfa in Acquired Hemophilia: Case Series and Literature Review.

BACKGROUND: Acquired hemophilia A (AHA) is a rare bleeding disease due to autoantibodies directed against clotting factor VIII (FVIII). Treatment of AHA consists of inhibitor eradication with immunosuppressive therapy (IST) and prompt control of bleeding obtained with bypassing agents or recombinant porcine FVIII (rpFVIII). The latter has recently been licensed for management of acute bleeding in AHA. Unlike treatment with bypassing agents, rpFVIII can be monitored to provide a successful hemostatic effect and avoid overtreatment. Correlation between rpFVIII inhibitor titers and efficacy of rpFVIII treatment remains a matter of debate. METHODS: We report three cases of AHA in which rpFVIII was successfully used with an unconventional schedule despite the presence of medium-high titers of the rpFVIII. The modified Nijmegen-Bethesda inhibitor assay (NBA) was used to dose porcine FVIII inhibitors. RESULT: The presence of rpFVIII inhibitors prior to the exposition to susoctocog-alfa, that may suggest a cross-reactivity with human FVIII inhibitors, did not affect hemostasis. CONCLUSION: In our experience, rpFVIII demonstrates safety and efficacy in the presence of rpFVIII inhibitors and using an unconventional schedule in both the perioperative and outpatient settings. Laboratory measurement of inhibitors against rpFVIII during treatment is described for the first time.

Pediatric immune thrombocytopenia: a focus on eltrombopag as second-line therapy.

BACKGROUND: Immune thrombocytopenia (ITP) is the most common acquired bleeding disorder. In both children and adults, the primary goal of any therapeutic approach consists of cessation of bleeding and its prevention. Several options are currently available for first-line therapy in Europe, including corticosteroids and intravenous immunoglobulin (IVIg) infusion, which has a similar efficacy and safety profile in both the pediatric and adult populations. When second-line therapy is needed in the pediatric setting, current guidelines recommend eltrombopag as the drug of choice. PROCEDURE: The aim of this article is to summarize the available evidence and present real-life experience on eltrombopag as second-line therapy in pediatric patients with ITP, with a focus on dosing and response to therapy as well as its tapering and discontinuation. RESULTS: In our setting, eltrombopag is associated with good safety profile as well as promising efficacy; dose de-escalation was feasible in 94% of cases and often reached very low pro/kg dosage, with full discontinuation in 15% of cases. In daily practice, a standardized approach for discontinuation of eltrombopag in pediatric patients with ITP is still lacking. Herein, an easy-to-use scheme for tapering and discontinuation in candidate pediatric patients is proposed that proposes 25% dose reduction every four weeks. CONCLUSIONS: In future management of pediatric ITP patients, it will be crucial to assess if thrombopoietin receptor agonists might be more effective in earlier phases of the disease and can modify the course of the disease.

Management of patients with bleeding disorders and educational needs regarding hemophilia a in 23 italian emergency departments - Results from a survey conducted in Piedmont.

BACKGROUND: Haemophilia and von Willebrand disease are the bleeding disorders most frequently encountered in the emergency department (ED), that are often the first point of contact for patients. Evidence suggests that management in the ED is currently suboptimal, mainly because the physicians have few opportunities to deal with this kind of patients. OBJECTIVES: We carried out a survey to investigate the management of patients with haemophilia A in Emergency Departments (EDs), and to understand the training needs of the involved physicians. METHODS: Overall, in Piedmont Region there are 32 EDs, and considering that our survey was conducted on 21 physicians working in 23 Emergency Departments (EDs), this number is representative of the Region's reality. The interviews were conducted through face-to-face meetings, including general aspects regarding the clinical characteristics and the management of patients, and self-evaluation of knowledge and interest in receiving information about the disease. RESULTS: In 2019, 131 patients with haemophilia A were admitted (108 adults, 23 paediatric). The best-known and most widely available and used treatments were plasma derivatives, followed by first- and second-generation recombinant FVIII. More recent recombinant and bypassing agents were less known. Half of the interviewees considered their -knowledge of bleeding disorders in general and haemophilia in particular to be "basic", and only one third defined it as "good"; however, 86% expressed great interest in receiving information about the topic. CONCLUSIONS: The survey confirms the needs related to the clinical management of rare inherited clotting disorders in EDs. The physicians involved are keen to overcome this lack of knowledge, and proper initiatives should be implemented.

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.

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.

Impact of COVID-19 Infection, Vaccination, and Serological Response in Immune Thrombocytopenic Purpura Patients: A Single-Center Global Analysis.

Both SARS-CoV-2 infection and vaccination have raised concern in immune-mediated diseases, including immune thrombocytopenic purpura (ITP) considering risk of de novo ITP development and ITP recurrence. Here, we report on data from a single-center retrospective-prospective collection aiming to evaluate platelet (plt) dynamics in patients (pts) with chronic ITP after COVID-19 infection (before and after vaccination) and after the first, second and third vaccine doses. Furthermore, we analyzed the serological response after the first two doses of COVID-19 vaccination. A total of 64 pts currently followed for chronic ITP who experienced COVD-19 infection and/or vaccination with an available plt count before and after such events were included in the analysis. A low incidence of ITP exacerbation following vaccine sessions (6-16%) was observed in comparison with a high frequency of exacerbation and rescue treatment necessity after COVID-19 infection in unvaccinated pts (83%). Moreover, the lower ITP exacerbation rate observed in infected pts previously vaccinated (18%) suggests further protective effects in this population. Finally, a high seroconversion rate was observed, confirming data reported in previously published studies on immune cytopenia and rheumatological diseases, but more evidence is awaited to establish the clinical impact of serological response.

ADAMTS13 Autoantibodies and Burden of Care in Immune Thrombotic Thrombocytopenic purpura: New Evidence and Future Implications.

The introduction Caplacizumab in the management of Immune thrombotic thrombocytopenic purpura (iTTP) has raised different questions, considering its cost-efficacy and the optimal immunosuppressive treatment (IST) to associate. A retrospective multicenter collection of 42 first iTTP cases was conducted to identify variables associated with a higher burden of care and necessity of an implemented IST with early Rituximab (RTX) rescue. A significant correlation resulted between ADAMTS13 inhibitors (ADAMTS13inh) at diagnosis with total plasma exchange (PEXtot) and PEX needed to achieve clinical response (PEXtoCR, r = 0.46; r = 0.48), along with age (r = - 0.31; r = -0.35), platelet count (r = -0.30; r = -0.30), LDH (r = 0.44; r = 0.41) and total bilirubin (r = 0.54; r = 0.35). ADAMTS13inh also correlated with number of days of hospitalization (DoH, r = 0.44). A significant difference was observed in terms of median ADAMTS13inh titer at diagnosis in patient treated with RTX rescue and those responding to only steroid treatment. Thus, ADAMTS13inh titer resulted a marker of iTTP burden of care, associated with higher number of PEXtot, PEXtoCR, DoH and higher probability of needing RTX rescue to achieve clinical response and could be a useful tool for management of new iTTP cases and an interesting variable to optimize iTTP cases stratification in future Caplacizumab cost-efficacy analysis.

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.

Simulation of the Impact on the Workload of the Enlargement of the Clinical Staff of a Specialistic Reference Center.

Quality of care and patient satisfaction are important aspects of high standard care. If clinical staff is subject to an elevated workload there is a possible decrease of both. This justifies the development of tools to quantify the workload and to find organizational changes that will normalize it. We have previously developed a simulation system to quantify the workload of the staff working in a regional reference center for the treatment of bleeding and hemorrhagic disorders. The goal of this new work is to simulate, through an agent-based model, the impact of adding a physician to the staff. Ten sets of initial parameters were defined to simulate ten typical weeks. Results show that the introduction of the new physician together with a second ambulatory room can reduce the workload of all the staff to the expected 8-hour. In this situation, in which the staff workload does not exceed the daily capacity, we may suppose that an increase in the quality of care and patient satisfaction will be possible.