Publications by authors named "Cristina Santoro"

80 Publications

Eltrombopag second-line therapy in adult patients with primary immune thrombocytopenia in an attempt to achieve sustained remission off-treatment: results of a phase II, multicentre, prospective study.

Br J Haematol 2021 Feb 22. Epub 2021 Feb 22.

Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.

Up to 30% immune thrombocytopenia (ITP) patients achieve a sustained remission off-treatment (SROT) after discontinuation of thrombopoietin receptor agonists (TPO-RAs). Factors predictive of response are lacking. Patients aged ≥18 years with newly diagnosed or persistent ITP were treated with eltrombopag for 24 weeks. Primary end-point was SROT: the proportion of responders that were able to taper and discontinue eltrombopag maintaining the response during a period of observation (PO) of six months. Secondary end-points included the association between some immunological parameters (TPO serum levels, cytokines and lymphocyte subsets) and response. Fifty-one patients were evaluable. Primary end-point was achieved in 13/51 (25%) treated patients and 13/34 (38%) patients who started the tapering. Baseline TPO levels were not associated with response at week 24 nor with SROT. Higher baseline levels of IL-10, IL-4, TNF-α and osteopontin were negative factors predictive of response (P = 0·001, 0·008, 0·02 and 0·03 respectively). This study confirms that SROT is feasible for a proportion of ITP patients treated with eltrombopag. Some biological parameters were predictive of response.
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http://dx.doi.org/10.1111/bjh.17334DOI Listing
February 2021

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

Semin Thromb Hemost 2021 Feb 1;47(1):84-89. Epub 2021 Feb 1.

Regional Reference Center for Inherited Bleeding Disorders, University Hospital, Parma, Italy.

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%;  < 0.001). Among the other variables analyzed (age, mutation, type and intensity of treatment and treatment regimen), 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 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.
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http://dx.doi.org/10.1055/s-0040-1718870DOI Listing
February 2021

Clinical phenotype, fibrinogen supplementation and health-related quality of life in patients with afibrinogenemia.

Blood 2021 Jan 27. Epub 2021 Jan 27.

University Hospital of Geneva, Geneva, Switzerland.

Due to its low prevalence, epidemiologic data on afibrinogenemia are limited and none are available on health-related quality of life (HRQoL). We conducted a cross-sectional international study to characterize the clinical features, the fibrinogen supplementation modalities and their impact on HRQoL in patients with afibrinogenemia. A total of 204 patients (119 adults and 85 children) from 25 countries were included. The bleeding phenotype was severe: 68 (33.3%) patients having at least one bleed per month and 48 (23%) a history of cerebral bleeding. About 35% (n=72) of patients were treated with fibrinogen concentrates or cryoprecipitates as prophylaxis, 18.1% (n=37) received more than one injection per week and 16.6% (n=34) were on home treatment. A thrombotic event was reported in venous and/or arterial territories by 37 (18.1%) patients. Thrombosis occurred even in young patients and recurrence was frequent (7.4%). The total HRQoL was lower in children than in adults. Discomfort linked to treatment and limitations to sports and leisure were the main concerns. Women and children were particularly affected in family relationships. In multivariate analyses, younger age, residence in Asia or Africa and a previous thrombotic event were statistically correlated with a worse HRQoL. In conclusion, our study underlines the severe bleeding and thrombotic phenotype and their impact on HRQoL in afibrinogenemia. The optimal strategy for fibrinogen supplementation needs to be determined.
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http://dx.doi.org/10.1182/blood.2020009472DOI Listing
January 2021

Von Willebrand factor with increased binding capacity is associated with reduced platelet aggregation but enhanced agglutination in COVID-19 patients: another COVID-19 paradox?

J Thromb Thrombolysis 2021 Jan 2. Epub 2021 Jan 2.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Patients with Coronavirus-associated disease-2019 (COVID-19) display alterations of the hemostatic system and the presence of a prothrombotic status frequently leading to vascular complications. However, the impact of COVID-19 on platelet activity, aggregation and agglutination still needs to be clarified. We measured total levels of von Willebrand factor (vWF) and vWF binding to the platelet glycoprotein (Gp) complex (GPIb-IX-V), in a cohort of COVID-19 patients admitted to the intensive care unit of our Institution. Moreover, we evaluated platelet aggregation in response to agonists (ADP, collagen, arachidonic acid) and platelet agglutination in response to ristocetin. We found that levels of vWF antigen and the active form of vWF binding to platelets (vWF:RCo), were markedly increased in these patients. These results were associated with higher agglutination rates induced by ristocetin, thereby indirectly indicating an increased capability of vWF to bind to platelets. Conversely, we found that platelet aggregation in response to both ADP and collagen was lower in COVID-19 patients compared to healthy volunteers. This study shows that COVID-19 is associated with increased vWF-induced platelet agglutination but reduced platelet responsivity to aggregation stimuli. Our findings have translational relevance since platelet adhesion to vWF may represent a marker to predict possible complications and better delineate therapeutic strategies in COVID-19 patients.
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http://dx.doi.org/10.1007/s11239-020-02339-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7778414PMC
January 2021

Clinical and Prognostic Features of Essential Thrombocythemia: Comparison of 2001 WHO Versus 2008/2016 WHO Criteria in a Large Single-center Cohort.

Clin Lymphoma Myeloma Leuk 2020 Nov 6. Epub 2020 Nov 6.

Department of Translational and Precision Medicine, University "Sapienza" of Rome, Rome, Italy. Electronic address:

Background: According to 2008/2016 classification of the World Health Organization (WHO), a platelet (PLT) count ≥ 450 × 10/L, reduced from the previously published WHO 2001 indicated level ≥ 600 × 10/L, was considered the new PLT threshold for the diagnosis of essential thrombocythemia (ET).

Patients And Methods: To validate this important diagnostic change in a setting of current clinical practice, we retrospectively analyzed clinical and hematologic features at diagnosis and during follow-up of 162 patients with ET, diagnosed in our center from January 2008 to December 2017. We subdivided patients according to PLT value at baseline into Group A (PLT ≥ 600 × 10/L) (124 patients; 76.5%) and Group B (PLT ≥ 450 × 10/L < 600 × 10/L) (38 patients; 23.5%).

Results: Among clinical features, only the median value of leukocytes (P < .001) was significantly higher in Group A. Cytostatic treatment was administered in 103 patients, with a significantly higher rate in patients of group A (P < .001). After a median follow-up of 42.4 months (interquartile range, 22.1-70.6 months), 8 thrombotic events were recorded in the entire cohort, without differences between the 2 groups (P = .336). The 5-year overall survival (OS) of the entire cohort was 96.9% (95% confidence interval, 92.6%-100%), without differences between the 2 groups (P = .255).

Conclusions: Our data indicate a substantial homogeneity among patients with ET regardless of the PLT count at diagnosis, thus confirming the usefulness of the 2008/2016 WHO diagnostic criteria.
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http://dx.doi.org/10.1016/j.clml.2020.11.003DOI Listing
November 2020

Pain assessment and management in Italian Haemophilia Centres.

Blood Transfus 2020 Nov 27. Epub 2020 Nov 27.

Policlinico Universitario di Padova, Padua, Italy.

Background: Although the widespread use of factor VIII/IX replacement therapy has significantly reduced the severity of arthropathy in persons with haemophilia (PWH), some develop degenerative joint changes, associated with significant pain. The aim of this survey was to investigate the management and perception of pain among Italian physicians who treat PWH.

Materials And Methods: Between September and October 2017, a questionnaire was distributed to 35 Italian haemophilia treatment centres (60 physicians).

Results: Fifty-three haemophilia specialists completed the survey. We found that there was good agreement (98.1%) on the need to investigate pain at each clinical visit, but there was heterogeneity in the opinions of haemophilia specialists with regards to the availability of validated guidelines (35.8%) and whether pain specialists should be a part of the comprehensive care team in daily clinical practice (58.5%). Haemophilia specialists also agreed pain should be evaluated using a rating scale validated in PWH (88.7%). Pain was mainly managed by the haemophilia specialists themselves, supported by a physiatrist and physiotherapist, while a pain specialist was only involved in 26.4% of cases. The combination of paracetamol with tramadol or codeine was the most common first-line treatment, while cyclo-oxygenase-2 inhibitors, non-steroidal anti-inflammatory drugs, and opioids were less commonly used.

Discussion: There are some unmet needs in Italy regarding pain management for PWH and the management of pain in these patients by haemophilia specialists. There is a lack of evidence-based guidelines for these specialists to use, as well as a reluctance to involve pain specialists. The lack of spontaneous reporting of pain by PWH, despite using pain relief, highlights the need for clinicians to actively ask patients about any pain they may be experiencing.
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http://dx.doi.org/10.2450/2020.0085-20DOI Listing
November 2020

Immune thrombocytopenia (ITP) World Impact Survey (iWISh): Patient and physician perceptions of diagnosis, signs and symptoms, and treatment.

Am J Hematol 2021 02 19;96(2):188-198. Epub 2020 Dec 19.

Division of Hematology/Oncology, Weill Cornell Medicine, New York, New York, USA.

Immune thrombocytopenia (ITP) is now well-known to reduce patients' health-related quality of life. However, data describing which signs and symptoms patients and physicians perceive as having the greatest impact are limited, as is understanding the full effects of ITP treatments. I-WISh (ITP World Impact Survey) was an exploratory, cross-sectional survey designed to establish the multifaceted impact of ITP, and its treatments, on patients' lives. It focused on perceptions of 1507 patients and 472 physicians from 13 countries regarding diagnostic pathway, frequency and severity of signs and symptoms, and treatment use. Twenty-two percent of patients experienced delayed diagnosis (caused by several factors), 73% of whom felt anxious as a result. Patients rated fatigue among the most frequent, severe symptom associated with ITP at diagnosis (58% most frequent; 73% most severe), although physicians assigned it lower priority (30%). Fatigue was one of the few symptoms persisting at survey completion (50% and 65%, respectively) and was the top symptom patients wanted resolved (46%). Participating physicians were experienced at treating ITP, thereby recognizing the need to limit corticosteroid use to newly-diagnosed or first-relapse patients and espoused increased use of thrombopoietin receptor agonists and anti-CD20 after relapse in patients with persistent/chronic disease. Patient and physicians were largely aligned on diagnosis, symptoms, and treatment use. I-WISh demonstrated that patients and physicians largely align on overall ITP symptom burden, with certain differences, for example, fatigue. Understanding the emotional and clinical toll of ITP on the patient will facilitate shared decision-management, setting and establishment of treatment goals and disease stage-appropriate treatment selection.
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http://dx.doi.org/10.1002/ajh.26045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898610PMC
February 2021

Immune thrombocytopenia (ITP) World Impact Survey (I-WISh): Impact of ITP on health-related quality of life.

Am J Hematol 2021 02 19;96(2):199-207. Epub 2020 Dec 19.

Division of Hematology/Oncology, Weill Cornell Medicine, New York, New York, USA.

Immune thrombocytopenia (ITP) has a substantial, multifaceted impact on patients' health-related quality of life (HRQoL). Data describing which aspects of ITP physicians and patients perceive as having the greatest impact are limited. The ITP World Impact Survey (I-WISh) was a cross-sectional survey, including 1507 patients and 472 physicians, to establish the impact of ITP on HRQoL and productivity from patient and physician perspectives. Patients reported that ITP reduced their energy levels (85% of patients), capacity to exercise (77%), and limited their ability to perform daily tasks (75%). Eighty percent of physicians reported that ITP symptoms reduced patient HRQoL, with 66% reporting ITP-related fatigue substantially reduced patient HRQoL. Patients believed ITP had a substantial impact on emotional well-being (49%) and 63% worried their condition would worsen. Because of ITP, 49% of patients had already reduced, or seriously considered reducing their working hours, and 29% had considered terminating their employment. Thirty-six percent of patients employed at the time of the survey felt ITP decreased their work productivity, while 51% of patients with high/very high symptom burden reported that ITP affected their productivity. Note, I-WISh demonstrated substantive impact of ITP on patients' HRQoL both directly for patients and from the viewpoint of their physicians. Patients reported reduced energy levels, expressed fears their condition might worsen, and those who worked experienced reduced productivity. Physicians should be aware not only of platelet counts and bleeding but also the multi-dimensional impact of ITP on patients' lives as an integral component of disease management.
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http://dx.doi.org/10.1002/ajh.26036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898815PMC
February 2021

Management of patients with severe haemophilia a without inhibitors on prophylaxis with emicizumab: AICE recommendations with focus on emergency in collaboration with SIBioC, SIMEU, SIMEUP, SIPMeL and SISET.

Haemophilia 2020 Nov 23;26(6):937-945. Epub 2020 Oct 23.

President of AICE; Haemophilia and Thrombosis Centre, Haematology, Ospedale del Mare, ASL Napoli 1 Centro, Naples, Italy.

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.

Conclusions: This guidance provides a reference pathway to be implemented in the different healthcare organizations, especially for the challenging emergency management in this setting.
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http://dx.doi.org/10.1111/hae.14172DOI Listing
November 2020

The factor VIII treatment history of non-severe hemophilia A.

J Thromb Haemost 2020 12 28;18(12):3203-3210. Epub 2020 Sep 28.

The Royal London Haemophilia Centre, QMUL, Barts and the London School of Medicine and Dentistry, London, UK.

Background: In patients with non-severe hemophilia A, we lack detailed knowledge on the timing of treatment with factor VIII (FVIII) concentrates. This knowledge could provide information about the expected treatment timing in patients with severe hemophilia A treated with non-replacement therapies.

Objective: To assess the FVIII treatment history in patients with non-severe hemophilia A.

Methods: Patients with non-severe hemophilia (baseline FVIII activity [FVIII:C] 2-40 IU/dL) were included from the INSIGHT study. The primary outcome was median age at first FVIII exposure (ED1). In a subgroup of patients for whom more detailed information was available, we analyzed the secondary outcomes: median age at first 20 EDs, annualized bleeding rate for all bleeds (ABR), joint bleeds (AJBR), and major spontaneous bleeds (ASmBR).

Results: In the total cohort (n = 1013), median baseline FVIII activity was 8 IU/dL (interquartile range [IQR] 4-15) and the median age at ED1 was 3.7 years (IQR 1.4-7.7). Median age at ED1 rose from 2.5 years (IQR 1.2-5.7) in patients with FVIII:C 2-5 IU/dL to 9.7 years (IQR 4.8-16.0) in patients with FVIII:C 25-40 IU/dL. In the subgroup (n = 104), median age at ED1, ED5, ED10, and ED20 was 4.0 years (IQR 1.4-7.6), 5.6 years (IQR 2.9-9.3), 7.5 years (IQR 4.4-11.3), and 10.2 years (IQR 6.5-14.2), respectively. Median ABR, AJBR, and ASmBR were 1.1 (IQR 0.5-2.6), 0.3 (IQR 0.1-0.7), and 0 (IQR 0-0), respectively.

Conclusion: This study demonstrates that in non-severe hemophilia A, the age at first FVIII exposure increases with baseline FVIII:C and that major spontaneous bleeds rarely occur.
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http://dx.doi.org/10.1111/jth.15076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756346PMC
December 2020

Rituximab for treating inhibitors in people with inherited severe hemophilia.

Cochrane Database Syst Rev 2020 08 3;8:CD010810. Epub 2020 Aug 3.

Association for the Promotion of Multimedia Education, Zagreb, Croatia.

Background: Hemophilia A and B are inherited coagulation disorders characterized by a reduced or absent level of factor VIII or factor IX respectively. The severe form is characterized by a factor level less than 0.01 international units (IU) per milliliter. The development of inhibitors in hemophilia is the main complication of treatment, because the presence of these antibodies, reduces or even nullifies the efficacy of replacement therapy, making it very difficult to control the bleeding. People with inhibitors continue to have significantly higher risks of morbidity and mortality, with considerable treatment costs. Given the wide 'off-label' use of rituximab for treating people with hemophilia and inhibitors, its efficacy and safety need to be evaluated. This is an update of a previously published Cochrane Review.

Objectives: To assess the efficacy and safety of rituximab for treating inhibitors in people with inherited severe hemophilia A or B.

Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register, complied from electronic database searches and handsearching of journals and conference abstract books. We searched the reference lists of relevant articles and reviews and also searched for ongoing or unpublished studies. We also undertook further searches of other bibliographic databases and trial registries. Date of last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Coagulopathies Trials Register: 19 March 2020.

Selection Criteria: Randomized controlled trials and controlled clinical trials investigating the efficacy and safety of rituximab for treating inhibitors in people with hemophilia.

Data Collection And Analysis: No randomized controlled trials matching the selection criteria were eligible for inclusion.

Main Results: No randomized controlled trials on rituximab for treating inhibitors in people with hemophilia were identified.

Authors' Conclusions: We were unable to identify any relevant trials on the efficacy and safety of rituximab for treating inhibitors in people with hemophilia. The research evidence available is from case reports and case series. Randomized controlled trials are needed to evaluate the efficacy and safety of rituximab for this condition. However, prior to the publication of any possible future randomized controlled trials, meta-analysis of case reports and case series may provide some evidence.
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http://dx.doi.org/10.1002/14651858.CD010810.pub4DOI Listing
August 2020

Acquired Haemophilia A: An Intriguing Disease.

Mediterr J Hematol Infect Dis 2020 1;12(1):e2020045. Epub 2020 Jul 1.

Ematologia, Azienda Ospedaliera Universitaria Policlinico Umberto I, Roma, Italia.

. 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.
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http://dx.doi.org/10.4084/MJHID.2020.045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340240PMC
July 2020

Direct oral anticoagulants in patients with hematologic malignancies.

Hematol Oncol 2020 Oct 29;38(4):589-596. Epub 2020 Jul 29.

Hematology, Departement of Translational and Precision Medicine, "Sapienza", University of Rome, Rome, Italy.

The anticoagulant treatment for patients with hematologic malignancies is low molecular weight heparin (LMWH), which is considered the safest in this particular patients setting. Although direct oral anticoagulants (DOACs) have proven their efficacy and safety in patients with cancer, their use can be challenging in patients with hematologic malignancies due to the peculiarity of these neoplasms: high thrombotic risk, possible onset of thrombocytopenia and concomitant anticancer therapies. The aim of our study was to evaluate the efficacy and safety of DOACs for venous thromboembolism or atrial fibrillation in patients with hematologic malignancies and plasmatic DOACs level during anticancer therapy and at time of bleeding or thrombotic complications. We evaluated patients with hematologic malignancies treated with DOACs for venous thromboembolism or atrial fibrillation-therapy was maintained until the platelet count was ≥50 × 10 /L. In case of concomitant anticancer treatment and haemorrhagic or thrombotic events, we checked DOACs plasma levels (trough and peak). The patients evaluated were 135: 104/135 were on anticancer therapy. We did not observe either thrombotic or major haemorrhagic adverse events. Minor bleedings occurred in 10 patients and clinical relevant non-major (CRNM) in two patients. There was a statistically significant correlation between bleedings and myelodysplastic syndrome. DOACs resulted effective and safe in patients with hematologic malignancies. DOACs plasma level can be helpful in suggesting an early dose adjustment to prevent haemorrhagic adverse event in patients on concomitant anticancer therapy. Larger prospective studies including hematologic patients are warranted to confirm the safety and efficacy of DOACs.
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http://dx.doi.org/10.1002/hon.2770DOI Listing
October 2020

Anagrelide in Essential Thrombocythemia (ET): Results from 150 patients over 25 years by the "Ph1-negative Myeloproliferative Neoplasms Latium Group".

Eur J Haematol 2020 Sep 16;105(3):335-343. Epub 2020 Jun 16.

Ematologia, Azienda Ospedaliera Universitaria Policlinico Umberto I, Roma, Italia.

Background And Aims: Anagrelide is a drug effective in reducing platelet counts in essential thrombocythemia (ET) and Ph1-negative myeloproliferative neoplasms. The aim of this study was to evaluate the real-life use of anagrelide in patients with ET followed over 25 years at the Haematological Institutes belonging to "Ph1-negative Myeloproliferative Neoplasms Latium Group."

Patients And Methods: Eligibility criteria were diagnosis of ET and treatment with anagrelide. Data were collected through an ad hoc case report form.

Results: One hundred and fifty patients received anagrelide for a median time of 7.4 years (0.1-23.2). Anagrelide was administered as first-line therapy in 34.7% of patients, as second-line in 52% and as third-line in 13.3%: 85.4% responded to therapy. Sixty-eight/136 evaluable patients reported side effects: palpitations, peripheral vasodilation, anaemia, diarrhoea and gastric distress. Fourteen thrombotic (arterial 10, venous 4) and 51 bleeding events (minor 48, major 3) occurred. Sixteen/150 (10.6%) patients developed secondary myelofibrosis and 3/150 (2%) an acute myeloid leukaemia.

Conclusions: In our experience, anagrelide is an effective drug in reducing platelet levels in a high percentage of patients with ET. It is especially addressed to younger people. A careful assessment of the thrombotic risk and monitoring of cardiac function, at diagnosis and during follow-up, is mandatory.
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http://dx.doi.org/10.1111/ejh.13454DOI Listing
September 2020

Right elbow arthropathy in a patient with severe haemophilia A.

Br J Haematol 2020 08 7;190(4):484. Epub 2020 May 7.

Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1111/bjh.16707DOI Listing
August 2020

BAY 81-8973 prophylaxis and pharmacokinetics in haemophilia A: Interim results from the TAURUS study.

Eur J Haematol 2020 Aug 23;105(2):164-172. Epub 2020 Apr 23.

University of Colorado, Aurora, CO, USA.

Objectives: To report interim data from TAURUS, a study assessing real-world prophylactic treatment with unmodified, full-length recombinant FVIII BAY 81-8973 (Kovaltry ; Bayer) indicated for haemophilia A.

Methods: TAURUS (NCT02830477) is an international, open-label, prospective, non-interventional, single-arm study with a one-year observation period (target N = 350). Patients have moderate or severe haemophilia A (FVIII ≤5% or ≤1%) and ≥50 exposure days to any FVIII product. Clinician- and patient-reported outcomes are captured on previous product use, changes in prophylaxis dose and dosing frequency, FVIII consumption, reported bleeding rates, treatment satisfaction and adherence, pharmacokinetic (PK) data (if available) and safety data.

Results: At cut-off, baseline data were available from 160 patients (89 had ≥6 months of follow-up data). Most patients had severe haemophilia A (85%), infused BAY 81-8973 ≥ 3×/wk (59%) and experienced a median number of total bleeds of 2.0 (non-annualised; 246 days median documentation period). Good levels of treatment satisfaction (Hemo-SAT ) and adherence (VERITAS-Pro) were maintained. TAURUS demonstrated a favourable PK profile of BAY 81-8973 in comparison with other standard half-life rFVIIIs and supported the WAPPS PopPK model. No patients developed inhibitors.

Conclusions: TAURUS data demonstrate effective prophylaxis with BAY 81-8973 in the real world without compromising patient satisfaction or adherence.
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http://dx.doi.org/10.1111/ejh.13420DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7497079PMC
August 2020

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

Heliyon 2020 Feb 25;6(2):e03426. Epub 2020 Feb 25.

Department Head-Neck, Sapienza University, Rome, Italy.

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.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044789PMC
February 2020

Perceived well-being and mental health in haemophilia.

Psychol Health Med 2020 10 26;25(9):1062-1072. Epub 2020 Jan 26.

Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti, Università degli Studi di Milano , Milano, Italy.

The investigation of mental health among persons with haemophilia is mostly focused on negative and disease-related indicators. Literature however shows that psychosocial resources and optimal daily functioning can co-exist with chronic disease. The Dual Continua Model operationalizes positive mental health as 'flourishing', a condition comprising emotional, psychological, and social well-being dimensions. In the present study physical and mental health were comparatively assessed through positive and negative indicators in adults with haemophilia and a control group. Participants included 84 Italian persons with severe haemophilia (M = 43.44; SD = 13.04) and 164 adults without history of chronic illness (M = 40.98; SD = 12.26), who completed the Short Form Health Survey, the Positive and Negative Affect Schedule, and the Mental Health Continuum Short Form. MANOVA and post-hoc t-tests provided evidence of worse general health, lower negative affect and higher psychological well-being among participants with haemophilia compared with the control group. Moreover, the percentage of flourishing individuals was higher among participants with haemophilia. Results support previous evidence suggesting that a chronic disease does not prevent mental well-being attainment. The identification of assets and strengths allowing people with haemophilia to flourish can be fruitfully used to design resource-centered interventions.
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http://dx.doi.org/10.1080/13548506.2020.1717556DOI Listing
October 2020

PICC-related upper deep venous thrombosis in patients with hematological malignancies. Management of anticoagulant therapy according to the platelet count.

J Thromb Thrombolysis 2020 Apr;49(3):426-430

Hematology, Department of Translational and Precision Medicine, Sapienza University, Via Benevento 6, 00161, Rome, Italy.

Peripherally inserted central catheters (PICCs) for central venous access are frequently used in patients with hematological malignancies. Their use may be complicated by upper extremity deep venous thrombosis (UEDVT). Additionally, hematological patients are frequently thrombocytopenic and the optimal management of UEDVT in patients with thrombocytopenia is challenging and poorly standardized. We retrospectively analyzed 50 adult patients affected by hematological malignancies who presented a PICC-associated UEDVT. UEDVT treatment was compared in 3 groups: patients with a platelet count ≥ 50 × 10/l (group1) who underwent a therapeutic dose of low molecular weight heparin (LMWH) or fondaparinux 7.5 mg; patients with a platelet count < 50 × 10/l and ≥ 30 × 10/l (group 2) who were treated with a 50% reduced dose of LMWH or fondaparinux 5 mg; patients with platelets < 30 × 10/l (group 3) were observed and treated with anticoagulants when the count was > 30 × 10//l. At the onset of thrombosis, 36 patients were in group 1, 8 in group 2 and 6 in group 3. We observed no hemorrhagic or thrombotic complications related to the anticoagulant therapy; length of treatment was comparable between groups 1 and 2 (51 days group 1 vs 50 days group 2). Reduced doses of LMWH or fondaparinux may represent a safe and effective therapeutic approach in patients with moderate thrombocytopenia (< 50 × 10/l and ≥ 30 × 10/l) and a PICC-associated UEDVT.
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http://dx.doi.org/10.1007/s11239-020-02040-8DOI Listing
April 2020

Management of elderly patients with immune thrombocytopenia: Real-world evidence from 451 patients older than 60 years.

Thromb Res 2020 01 21;185:88-95. Epub 2019 Nov 21.

Institute of Hematology "L. and A. Seràgnoli", Sant'Orsola-Malpighi University Hospital, Bologna, Italy.

Introduction: Primary Immune thrombocytopenia (ITP) in the elderly is a major clinical challenge which is increasingly frequent due to global ageing population.

Materials And Methods: To describe baseline ITP features, management, and outcome, a centralized electronic database was established, including data of 451 patients aged ≥60 years that were treated from 2000 onwards and were observed for ≥1 year (total observation of 2704 patient-years).

Results: At ITP diagnosis, median age was 71.1 years (age ≥ 75: 42.8%); 237 (53.9%) patients presented with haemorrhages (grade ≥ 3: 7.5%). First-line therapy included prednisone (82.9%), dexamethasone (14.6%), thrombopoietin-receptor agonists (TRAs, 1.3%), and oral immunosuppressive agents (1.1%). Prednisone starting dose ≥1 mg/kg/d (p = .01) and dexamethasone 40 mg/d (p < .001) were mainly reserved to patients aged 60-74, who were more treated with rituximab (RTX, p = .02) and splenectomy (p = .03) second-line. Overall response rates to first and second-line therapies were 83.8% and 84.5%, respectively, regardless of age and treatment type/dose. A total of 178 haemorrhages in 101 patients (grade ≥ 3: n. 52, 29.2%; intracranial in 6 patients), 49 thromboses in 43 patients (grade ≥ 3: n. 26, 53.1%) and 115 infections in 94 patients (grade ≥ 3: n. 23, 20%) were observed during follow-up. Incidence rates of complications per 100 patient-years were: 4.5 (haemorrhages, grade ≥ 3: 1.7), 1.7 (thromboses, grade ≥ 3: 0.9), and 3.9 (infections, grade ≥ 3: 0.7). TRAs use were associated with reduced risk of bleeding and infections, while cardiovascular risk factors (particularly, diabetes) significantly predicted thromboses and infections.

Conclusions: Age-adapted treatment strategies are required in elderly and very elderly patients.
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http://dx.doi.org/10.1016/j.thromres.2019.11.026DOI Listing
January 2020

Validation of the ISTH/SSC bleeding assessment tool for inherited platelet disorders: A communication from the Platelet Physiology SSC.

J Thromb Haemost 2020 03 16;18(3):732-739. Epub 2019 Dec 16.

Department of Internal Medicine, IRCCS Policlinico S. Matteo Foundation, University of Pavia, Pavia, Italy.

Background: Careful assessment of bleeding history is the first step in the evaluation of patients with mild/moderate bleeding disorders, and the use of a bleeding assessment tool (BAT) is strongly encouraged. Although a few studies have assessed the utility of the ISTH-BAT in patients with inherited platelet function disorders (IPFD) none of them was sufficiently large to draw conclusions and/or included appropriate control groups.

Objectives: The aim of the present study was to test the utility of the ISTH-BAT in a large cohort of patients with a well-defined diagnosis of inherited platelets disorder in comparison with two parallel cohorts, one of patients with type-1 von Willebrand disease (VWD-1) and one of healthy controls (HC).

Patients/methods: We enrolled 1098 subjects, 482 of whom had inherited platelet disorders (196 IPFD and 286 inherited platelet number disorders [IT]) from 17 countries.

Results: IPFD patients had significantly higher bleeding score (BS; median 9) than VWD-1 patients (median 5), a higher number of hemorrhagic symptoms (4 versus 3), and higher percentage of patients with clinically relevant symptoms (score > 2). The ISTH-BAT showed excellent discrimination power between IPFD and HC (0.9 < area under the curve [AUC] < 1), moderate (0.7 < AUC < 0.9) between IPFD and VWD-1 and between IPFD and inherited thrombocytopenia (IT), while it was inaccurate (AUC ≤ 0.7) in discriminating IT from HC.

Conclusions: The ISTH-BAT allows to efficiently discriminate IPFD from HC, while it has lower accuracy in distinguishing IPFD from VWD-1. Therefore, the ISTH-BAT appears useful for identifying subjects requiring laboratory evaluation for a suspected IPFD once VWD is preliminarily excluded.
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http://dx.doi.org/10.1111/jth.14683DOI Listing
March 2020

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.

Blood Transfus 2020 03 18;18(2):143-151. Epub 2019 Oct 18.

Haemophilia Centre, Department of Medicine, University Hospital of Padua, Padua, Italy.

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.
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http://dx.doi.org/10.2450/2019.0186-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141940PMC
March 2020

Use of edoxaban for the treatment of venous thromboembolism in HIV-infected patients.

HIV Med 2020 03 16;21(3):e7. Epub 2019 Oct 16.

Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy.

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http://dx.doi.org/10.1111/hiv.12803DOI Listing
March 2020

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.

Haemophilia 2019 Nov 11;25(6):1003-1010. Epub 2019 Oct 11.

Regional Reference Centre for Inherited Bleeding Disorders, University Hospital of Parma, Parma, Italy.

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.
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http://dx.doi.org/10.1111/hae.13859DOI Listing
November 2019

Antithrombotic prophylaxis for surgery-associated venous thromboembolism risk in patients with inherited platelet disorders. The SPATA-DVT Study.

Haematologica 2020 07 26;105(7):1948-1956. Epub 2019 Sep 26.

Department of Medicine, Section of Internal and Cardiovascular Medicine, University of Perugia, Italy

Major surgery is associated with an increased risk of venous thromboembolism (VTE), thus the application of mechanical or pharmacologic prophylaxis is recommended. The incidence of VTE in patients with inherited platelet disorders (IPD) undergoing surgical procedures is unknown and no information on the current use and safety of thromboprophylaxis, particularly of low-molecular-weight-heparin in these patients is available. Here we explored the approach to thromboprophylaxis and thrombotic outcomes in IPD patients undergoing surgery at VTE-risk participating in the multicenter SPATA study. We evaluated 210 surgical procedures carried out in 155 patients with well-defined forms of IPD (VTE-risk: 31% high, 28.6% intermediate, 25.2% low, 15.2% very low). The use of thromboprophylaxis was low (23.3% of procedures), with higher prevalence in orthopedic and gynecological surgeries, and was related to VTE-risk. The most frequently employed thromboprophylaxis was mechanical and appeared to be effective, as no patients developed thrombosis, including patients belonging to the highest VTE-risk classes. Low-molecular-weight-heparin use was low (10.5%) and it did not influence the incidence of post-surgical bleeding or of antihemorrhagic prohemostatic interventions use. Two thromboembolic events were registered, both occurring after high VTE-risk procedures in patients who did not receive thromboprophylaxis (4.7%). Our findings suggest that VTE incidence is low in patients with IPD undergoing surgery at VTE-risk and that it is predicted by the Caprini score. Mechanical thromboprophylaxis may be of benefit in patients with IPD undergoing invasive procedures at VTE-risk and low-molecular-weight-heparin should be considered for major surgery.
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http://dx.doi.org/10.3324/haematol.2019.227876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7327644PMC
July 2020

Antithrombin concentrate during pregnancy in congenital antithrombin deficiency: a single-center experience.

Blood Coagul Fibrinolysis 2019 Sep;30(6):304-307

Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome Italy.

: Pregnancy carries a high risk of thromboembolic complications, especially in the postpartum period. This risk is particularly high in women with inherited thrombophilias, among these antithrombin deficiency seems to carry the highest risk. In this case, the use of low molecular weight heparin (LMWH) is recommended, while the use of antithrombin concentrate is controversial. We report our experience of seven pregnancies occurred in five women: two, with a personal and familiar history negative for venous thromboembolism, were treated with LMWH during pregnancy and antithrombin concentrate immediately before and after the delivery. The other three women had a personal and familiar history positive for venous thromboembolism and were treated with LMWH and antithrombin concentrate during all the pregnancy and the postpartum period. No thromboembolic or hemorrhagic complications were observed in both groups, demonstrating that our strategy could be safe and effective.
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http://dx.doi.org/10.1097/MBC.0000000000000835DOI Listing
September 2019