Secondary Prophylaxis of Venous Thromboembolism (VTE) with Low Dose Apixaban or Rivaroxaban: Results from a Patient Population with More than 2 Years of Median Follow-up.

Background: Direct oral anticoagulants (DOACs) are widely used for the treatment and secondary prophylaxis of venous thromboembolism (VTE). Nowadays, DOACs represent the gold standard for long-term anticoagulation, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit low-intensity apixaban and rivaroxaban are approved for clinical usage as secondary VTE prophylaxis, there are few literature data regarding their efficacy and safety with a long follow-up. Objectives: The aim of our study was to evaluate the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis in patients at high risk of VTE recurrence. Methods: We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5 mg BID or rivaroxaban 10 mg daily with a follow-up ≥ 12 months. Results: The examined patients were 323. The median low-dose DOAC administration time was 25.40 months (IQR 13.93-45.90). Twelve (3.7%) VTE recurrences were observed; 21 bleeding events were registered (6.5%), including one episode of Major bleeding (MB) (0.3%), 8 Clinically relevant nonmajor bleeding (CRNMB) (2.5%) and 12 minor bleeding (3.7%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between the rivaroxaban and apixaban groups. Patients included in the study for multiple episodes of VTE presented a significantly higher risk of a new VTE recurrence during low-intensity DOAC. Conclusions: Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis in patients at high risk of VTE recurrence; however, attention might be needed in their choice in such a scenario for patients who experienced multiple episodes of VTE.

Prednisone vs high-dose dexamethasone in newly diagnosed adult primary immune thrombocytopenia: a randomized trial.

ABSTRACT: A debate exists regarding which type of corticosteroids (standard-dose prednisone [PDN] or high-dose dexamethasone [HD-DXM]) is the best first-line treatment for adult patients with newly diagnosed untreated primary immune thrombocytopenia (pITP). An ad hoc study compared PDN with HD-DXM in newly diagnosed untreated patients with pITP (aged ≥18 but ≤80 years, platelet count of ≤20 or >20 but <50 × 109/L, and bleeding score of ≥8). Patients were randomised to receive PDN 1 mg/kg per day from days 0 to 28 (Arm A) or HD-DXM 40 mg per day for 4 days, every 14 days, for 3 consecutive courses (Arm B). Fifty-nine of 113 patients (52.2%) were randomized to Arm A and 54 of 113 (47.8%) to Arm B. In evaluable patients, total initial responses (complete response [CR], partial response [PR], minimal response [MR]) were 44 of 56 (78.57%) in Arm A and 46 of 49 (93.88%) in Arm B at days 42 and 46, respectively (P = 0.0284). Total final responses (at day 180 from initial response) were 26 of 43 (60.47%) in Arm A and 23 of 39 (58.97%) in Arm B (P = 0.8907). Total persistent responses (at 12 months from initial response) were 25 of 31 (80.65%) in Arm A and 20 of 36 (55.56%) in Arm B (P = 0.0292). Seven relapses occurred. Median follow-up was 44.4 months. Overall survival was 100% at 48 months, overall disease-free survival was 81.11% at 48 months from day 180. PDN and pulsed HD-DXM were well tolerated; HD-DXM allows effective initial responses but less long lasting than PDN. This trial was registered at www.clinicaltrials.gov as #NCT00657410.

Managing Relevant Clinical Conditions of Hemophilia A/B Patients.

The Medical Directors of nine Italian Hemophilia Centers reviewed and discussed the key issues concerning the replacement therapy of hemophilia patients during a one-day consensus conference held in Rome one year ago. Particular attention was paid to the replacement therapy needed for surgery using continuous infusion (CI) versus bolus injection (BI) of standard and extended half-life Factor VIII (FVIII) concentrates in severe hemophilia A patients. Among the side effects, the risk of development of neutralizing antibodies (inhibitors) and thromboembolic complications was addressed. The specific needs of mild hemophilia A patients were described, as well as the usage of bypassing agents to treat patients with high-responding inhibitors. Young hemophilia A patients may take significant advantages from primary prophylaxis three times or twice weekly, even with standard half-life (SHL) rFVIII concentrates. Patients affected by severe hemophilia B probably have a less severe clinical phenotype than severe hemophilia A patients, and in about 30% of cases may undergo weekly prophylaxis with an rFIX SHL concentrate. The prevalence of missense mutations in 55% of severe hemophilia B patients allows the synthesis of a partially changed FIX molecule that can play some hemostatic role at the level of endothelial cells or the subendothelial matrix. The flow back of infused rFIX from the extravascular to the plasma compartment allows a very long half-life of about 30 h in some hemophilia B patients. Once weekly, prophylaxis can assure a superior quality of life in a large severe or moderate hemophilia B population. According to the Italian registry of surgery, hemophilia B patients undergo joint replacement by arthroplasty less frequently than hemophilia A patients. Finally, the relationships between FVIII/IX genotypes and the pharmacokinetics of clotting factor concentrates have been investigated.

Immune thrombocytopenia management during COVID-19 pandemic: An Italian monocentric experience.

Over the last 2 years, different cases of immune thrombocytopenia (ITP) in patients affected by SARS-CoV2 have been reported. The management of SARS-CoV2 in subjects with simultaneous or previous ITP can be challenging because of the great involvement of the haemostatic system in this viral infection. In this report, we describe the management and outcome of patients with newly diagnosed (ND), chronic and previous ITP, infected by COVID-19, referred to the Haematology Institute of University Hospital Policlinico Umberto I in Rome. Steroids + immunoglobulins for ND or relapsed ITP and continuation of home therapy for chronic ITP are advised, although further knowledge is required.

Refractory primary immune thrombocytopenia (ITP): current clinical challenges and therapeutic perspectives.

Chronic primary immune thrombocytopenia (ITP) can today benefit from multiple therapeutic approaches with proven clinical efficacy, including rituximab, thrombopoietin receptor agonists (TPO-RA), and splenectomy. However, some ITP patients are unresponsive to multiple lines of therapy with prolonged and severe thrombocytopenia. The diagnosis of refractory ITP is mainly performed by exclusion of other disorders and is based on the clinician's expertise. However, it significantly increases the risk of drug-related toxicity and of bleedings, including life-threatening events. The management of refractory ITP remains a major clinical challenge. Here, we provide an overview of the currently available treatment options, and we discuss the emerging rationale of new therapeutic approaches and their strategic combination. Particularly, combination strategies may target multiple pathogenetic mechanisms and trigger additive or synergistic effects. A series of best practices arising both from published studies and from real-life clinical experience is also included, aiming to optimize the management of refractory ITP.

Diagnosis and treatment of chronic synovitis in patients with haemophilia: consensus statements from the Italian Association of Haemophilia Centres.

Although synovitis is recognized as a marker of joint disease activity, its periodic assessment is not included in routine clinical surveillance of patients with haemophilia (PwH). In order to evaluate the current knowledge and to identify controversial issues, a preliminary literature search by the Musculoskeletal Committee of the Italian Association of Haemophilia Centres (AICE) has been conducted. Statements have been established and sent to the Italian AICE members to collect their level of agreement or disagreement by a Delphi process. Thirty-seven consensus recommendations have been drafted. We found a general agreement on the indication to consider the presence of synovitis as a marker of joint disease activity in PwH. Accordingly, there was agreement on the indication to search for synovitis both in patients reporting joint pain and in asymptomatic ones, recognizing ultrasound as the most practical imaging technique to perform periodic joint screening. Interestingly, after detection of synovitis, there was agreement on the indication to modify the therapeutic approach, suggesting prophylaxis in patients treated on demand and tailoring treatment in patients already under prophylaxis. Whereas the need of an early consultation with a physiotherapist is recommended for PwH affected by chronic synovitis, the exact timing for an orthopaedic surgeon consultation is currently unknown.

Promoting physical activity in people with haemophilia: the MEMO (Movement for persons with haEMOphilia) expert consensus project.

Regular physical activity can increase joint stability and function, reduce the risk of injury, and improve quality of life of people with haemophilia (PwH). However, a recent review of the literature shows that appropriate physical activity and sport are not always promoted enough in the overall management of PwH. A group of Italian experts in haemophilia care undertook a consensus procedure to provide practical guidance on when and how to recommend physical exercise programmes to PwH in clinical practice. Three main topics were identified -haemophilia and its impact on movement, physical activity recommendations for PwH, and choice and management of sports activity in PwH- and ten statements were formulated. A modified Delphi approach was used to reach a consensus. The group also created practical tools proposing different physical activities and frequencies for different age groups, the Movement Pyramids, to be shared and discussed with patients and caregivers. In conclusion, in the opinion of the working group, physical activity can be considered as a low-price intervention that can prevent/reduce the occurrence of chronic diseases and should be further encouraged in PwH to obtain multiple physical and psychological benefits. Future research should include prospective studies focusing on participation in sports, specific risk exposure and clinical outcomes.

Second-line administration of thrombopoietin receptor agonists in immune thrombocytopenia: Italian Delphi-based consensus recommendations.

INTRODUCTION: In patients with primary immune thrombocytopenia (ITP), a short course of steroids is routinely given as first-line therapy. However, the response is often transient and additional therapy is usually needed. Thrombopoietin receptor agonists (TPO-RAs) are frequently used as second-line therapy, although there is little clinical guidance on the timing of their administration and on tapering/discontinuation of the drug. To provide clinical recommendations, we used the Delphi technique to obtain consensus for statements regarding administration and on tapering/discontinuation of second-line TPO-RAs among a group of Italian clinicians with expertise in management of ITP. METHODS: The Delphi process was used to obtain agreement on five statements regarding initiation and on tapering/discontinuation of second-line TPO-RAs. Agreement was considered when 75% of participants approved the statement. Eleven experts participated in the voting. RESULTS: Full consensus was reached for three of the five statements. The experts held that an early switch from corticosteroids to a TPO-RA has the dual advantage of sparing patients from corticosteroid abuse and improve long-term clinical outcomes. All felt that dose reduction of TPO-RAs can be considered in patients with a stable response and platelet count >100 × 109/L that is maintained for at least 6 months in the absence of concomitant treatments, although there was less agreement in patients with a platelet count >50 × 109/L. Near consensus was reached regarding the statement that early treatment with a TPO-RA is associated with an increase in clinically significant partial or complete response. The experts also agreed that optimization of tapering and discontinuation of TPO-RA therapy in selected patients can improve the quality of life. CONCLUSION: The present consensus can help to provide guidance on use of TPO-RAs in daily practice in patients with ITP. PLAIN LANGUAGE SUMMARY: Second-line administration of thrombopoietin receptor agonists in immune thrombocytopenia There is little guidance on the timing of administration and tapering/discontinuation of thrombopoietin receptor agonists (TPO-RAs) in patients with primary immune thrombocytopenia (ITP).The Delphi technique was used to obtain consensus for five statements.The present consensus among Italian clinicians aims to provide guidance on second-line use of TPO-RAs for patients with ITP in daily practice.

Eltrombopag treatment for severe immune thrombocytopenia during pregnancy: a case report.

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia (platelet count <100 × 109/l) in the absence of other causes or disorders associated. The incidence of ITP in pregnancy is one to two cases per 1000 gestations. ITP could be diagnosed before or during pregnancy; sometimes a relapse of a previously diagnosed ITP can occur. Intravenous immune globulins (IVIg) and corticosteroids are the standard frontline therapy because of their well known safety profile either for the mother or for the neonate. Treatments for refractory patients are limited by potential fetal risk. We report the case of a patient with ITP along pregnancy, refractory to corticosteroids and IVIg, successfully treated with, the thrombopoietin receptor agonist (TPO-RA) eltrombopag. Patient received this compound for almost the whole pregnancy and in particular for the whole first trimester, without any complication for the mother and the neonate. Although transient administration of TPO-RAs in pregnancy seems to be well tolerated, their use during the whole gestation is still controversial; this is the reason of the description of this case, which did not show any complications, and thus it could add useful information on this field.

Single centre experience on Acquired Haemophilia A patients: Diagnosis, clinical management and analysis of factors predictive of response and outcome.

BACKGROUND: Acquired Haemophilia A (AHA) patients show a high response rate to immunosuppressive therapy (IST) but few information about predictors of response and outcome are reported. AIMS: We describe a large single-centre AHA cohort, investigating prognostic variables for the 'best response' (BR), time to BR (TTBR) and overall survival (OS). METHODS: A total of 61 patients were included, collecting data from clinical charts. RESULTS: A progressive increase in diagnoses, from 1978 to 2019, was observed. Fifty/56 patients (89%) underwent haemostatic therapy (rFVIIa 46%, aPCC 34%) with no significant differences in the response (rFVIIa 92.3% vs aPCC 100%) and no thromboembolic events. Sixty/61 patients underwent first-line IST with an initial response rate of 58.4%. The 12-months OS was 85%, the bleeding associated mortality rate 3% (2/61). The response rates at last observation were: CR 64%, PR 8%. We evaluated the influence of age, gender, associated conditions, IST, haemoglobin levels, FVIII:C, inhibitor titre on BR, TTBR and OS: post-partum AHA achieved the BR after a longer time than AHA related to other aetiologies or idiopathic (p = .05); in univariate analysis female sex (p = .03) and the achievement of BR (p = .001) had a positive impact on the OS while AHA secondary to neoplasms showed a shorter survival (p = .04); only the BR achievement remained significant in multivariate analysis (p = .02). CONCLUSIONS: Our data on response and survival confirmed those from the main registries. Post-partum AHA and BR achievement were significantly associated to a longer TTBR and a longer OS, respectively. Other predictors of outcome deserve to be explored in prospective studies.

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.

ABO Blood Group and Inhibitor Risk in Severe Hemophilia A Patients: A Study from the Italian Association of Hemophilia Centers.

Considering the profound influence exerted by the ABO blood group system on hemostasis, mainly through the von Willebrand factor and factor VIII (FVIII) complex, we have conducted a study evaluating the possible role of blood type on the risk of inhibitor development in hemophilia A. A total of 287 consecutive Caucasian patients with severe hemophilia A (202 without FVIII inhibitors and 85 with FVIII inhibitors) followed at seven Italian Hemophilia Treatment Centers belonging to the Italian Association of Hemophilia Centers (AICE) were included in the study. A higher prevalence of O blood group was detected in patients without inhibitors as compared in inhibitor patients (55 vs. 30.6%; p < 0.001). Among the other variables analyzed (age, F8 mutation, type and intensity of treatment and treatment regimen), F8 mutation class (high-risk vs. low-risk), and treatment regimen (on-demand vs. prophylaxis) were significantly correlated with inhibitor development. However, on a multivariate analysis, only the effects of F8 mutation and ABO blood type were independent of other covariates, being that non-O blood type is associated with a 2.89-fold increased risk of inhibitor development. In conclusion, our study supports the protective effect of O blood type on inhibitor risk in severely affected hemophilia A patients.

Early Palliative Home Care versus Hospital Care for Patients with Hematologic Malignancies: A Cost-Effectiveness Study.

Background: There is paucity of data on the potential value of early palliative home care for patients with hematologic malignancies. Objective: To compare costs, use of resources, and clinical outcomes between an early palliative home care program and standard hospital care for active-advanced or terminal phase patients. Patients and Methods: In this real-life, nonrandomized comparative study, the allocation of advanced/terminal phase patients to either home or hospital was based on pragmatic considerations. Analysis focused on resources use, events requiring blood unit transfusions or parenteral therapy, patient-reported symptom burden, mean weekly cost of care (MWC), cost-minimization difference, and incremental cost-effectiveness ratio (ICER). Results: Of 119 patients, 59 patients cared at home were more debilitated and had a shorter survival than the 60 in hospital group (p = 0.001). Nevertheless, symptom burden was similar in both groups. At home the mean weekly number of transfusions (1.45) was lower than that at hospital (2.77). Higher rate of infections occurred at hospital (54%) versus home (21%; <0.001). MWC for hospitalization was significantly higher in a 3:1 ratio versus home care. Compared with hospital, domiciliary assistance produced a weekly saving of € 2314.9 for the health provider, with a charge of € 85.9 for the family, and was cost-effective by an ICER of € -7013.9 of prevented days of care for avoided infections. Conclusions: Current findings suggest that costs of early palliative home care for patients with hematologic malignancies are lower than standard hospital care costs. Domiciliary assistance may also be cost-effective by reducing the number of days to treat infections.

COVID-19 in Patients with Hematologic Disorders Undergoing Therapy: Perspective of a Large Referral Hematology Center in Rome.

INTRODUCTION: Patients with cancer may be more susceptible to and have higher morbidity and mortality rates from COVID-19 than the general population, while epidemiologic data specifically addressed to hematologic patients are limited. To investigate whether patients with hematologic diseases undergoing therapy are at increased risk for acquiring SARS CoV-2 infection compared to the general population, a retrospective study was carried out at a referral hematologic center in Rome, Italy, during the period of the greatest epidemic spread (March 8 to May 14, 2020). METHODS: All adult and pediatric patients with a diagnosis of a neoplastic or a nonneoplastic hematologic disease who underwent treatment (chemotherapy or immunosuppressive or supportive therapy) during the study period or in the previous 6 months were considered. The prevalence of COVID-19 in the overall outpatient and inpatient population undergoing hematologic treatment compared to that of the general population was analyzed. The measures taken to manage patients during the epidemic period are described. RESULTS: Overall, 2,513 patients with hematological diseases were considered. Out of 243 (9.7%) patients who were screened for SARS CoV-2, three of 119 (2.5%) outpatients with fever or respiratory symptoms and none of 124 asymptomatic patients were diagnosed with COVID-19. Three further patients were diagnosed with COVID-19 and managed in other hospitals in Rome. As of May 14, 2020, the prevalence of COVID-19 in our hematologic population accounted for 0.24% (95% CI 0.23-0.25; 6 of 2,513 patients: 1 case in every 419 patients) as compared to 0.12% (7,280 of 5,879,082 residents; 1 case in every 807 residents) in the general population (p = 0.14). Three of 6 patients diagnosed with COVID-19 required critical care and 2 died while still positive for SARS CoV-2. Out of 225 healthcare providers on duty at our Institution during the study period, 2 (0.9%) symptomatic cases were diagnosed with COVID-19. CONCLUSION: In our experience, the prevalence of COVID-19 in hematologic patients, mainly affected by malignancies, was not significantly higher compared to that of the general population. Definition of adapted strategies for healthcare services, while continuing to administer the standard hematologic treatments, represents the crucial challenge for the management of hematologic diseases in the COVID-19 era.

Acquired Haemophilia A: An Intriguing Disease.

. Acquired Haemophilia A is a rare acquired bleeding disorder caused by Factor VIII autoantibodies, which neutralise FVIII activity. These inhibitors differ from alloantibodies against FVIII, which can occur in congenital Haemophilia A after repeated exposures to plasma-derived or recombinant FVIII products. In most cases, the disease occurs suddenly in subjects without a personal or familiar history of bleedings, with symptoms that may be mild, moderate, or severe. However, only laboratory alterations are present in ~ 30% of patients. The incidence varies from 1 to 4 cases per million/year; more than 80% of patients are elderly, males and females are similarly affected. There is a small peak of incidence related to pregnancy in young women aged 20-40 years. The disease may be underdiagnosed in the elderly. The diagnostic algorithm is based on an isolated prolonged activated partial thromboplastin time, normal thrombin time, absence of Lupus Anticoagulant, and a mixing test that reveals the presence of an inhibitor: the finding of reduced FVIII activity and the detection of neutralising autoantibodies against FVIII lead to the diagnosis. The disease is idiopathic in 44%-63% of cases, while in the others etiological factors are present. Bleeding prevention and treatment are based on therapeutic tools as by-passing agents, recombinant porcine FVIII concentrate or, in a limited number of cases, FVIII concentrates and desmopressin. As soon as the diagnosis has been made, immunosuppressive therapy must be started to eradicate the inhibitor. Better knowledge of the disease, optimal management of bleeding and eradication of the inhibitor have significantly reduced morbidity and mortality in most patients.

Direct oral anticoagulants for the treatment of Mondor's disease not responding to low-molecular weight heparin.

Mondor's disease is a rare condition and usually treated with low-molecular weight heparin and non-steroidal anti-inflammatory drugs. Because of paucity of cases and for the usually spontaneous resolution, there is not a standard treatment strategy and the use of oral anticoagulation in controversial. We reported the efficacy of direct oral anticoagulants in the recurrent Mondor's disease refractory to standard therapy.

Dental invasive procedures in von Willebrand disease outpatients treated with high purity FVIII/VWF complex concentrate (Fanhdi®): experience of a single center.

PURPOSE: To retrospectively assess the effectiveness and safety of customized hemostatic protocols using a plasma-derived, von Willebrand Factor (VWF)-containing Factor VIII concentrate (pdVWF/FVIII) in von Willebrand disease (VWD) patients undergoing dental invasive procedures. METHODS: Protocol for each patient was drawn up by the Blood Unit based on the VWD type, disease severity, and type of treatment. pdFVIII/VWF infusions and doses were registered at 30-60 min before intervention (t0) and at 12-24-36-48-72 h after intervention (t12-t72) and up to day 7. Any peri- or postoperative bleeding, complication or adverse event was registered. RESULTS: Forty-five dental procedures were performed on 20 VWD patients (six type-1, two type-2a, six type-2b, six type-3). Most pdFVIII/VWF infusions at t0 were 60 IU/kg (n = 7) and 50 IU/kg (n = 9). Subsequent infusions were mostly 30-50 IU/kg. No bleeding complications or adverse events were reported. CONCLUSION: This study supports the safety and efficacy of pdFVIII/VWF to prevent peri- and postoperative bleeding after invasive oral procedures.