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Relapsing or occurring de novo autoimmune hemolytic anemia (AIHA) during pregnancy or puerperium is a poorly described condition. Here we report 45 pregnancies occurring in 33 women evaluated at 12 centers from 1997 to 2022. Among the 20 women with AIHA diagnosis before pregnancy, 10 had a relapse. Additional 13 patients developed de novo AIHA during gestation/puerperium (two patients had AIHA relapse during a second pregnancy). Among 24 hemolytic events, anemia was uniformly severe (median Hb 6.4 g/dL, range 3.1-8.7) and required treatment in all cases (96% steroids +/- intravenous immunoglobulin, IVIG, 58% transfusions). The response was achieved in all cases and was complete in 65% of cases. Antithrombotic prophylaxis was administered in eight patients (33%). Rituximab was administered in four patients, and cyclosporine was added in one after delivery. The rate of maternal complications was 15%, including premature rupture of membranes, placental detachment, and preeclampsia. Early miscarriages occurred in 13% of pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and two perinatal deaths. In conclusion, the occurrence of AIHA does not preclude the ability to carry a healthy pregnancy, provided close monitoring, prompt therapy, and awareness of potential maternal and fetal complications.

Background: Mild haemophilia (MH) is mainly characterized by haemorrhages secondary to surgery/invasive procedures or trauma. Haemostatic treatment in MH ranges from on demand to short prophylaxis according to the type of bleeding events and the basal clotting factor level. Oral surgery and dental extractions can represent a frequent haemostatic challenge in MH requiring appropriate treatment. However, only few studies on limited numbers of patients are available in the literature regarding the implications of dental management in patients with MH. Objectives: The purpose of the study was to evaluate the impact of dental care on the burden of haemostatic treatment in patients affected by MH. Methods: We conducted a retrospective multicentre study evaluating adult patients with MH regularly examined at the Haemophilia Treatment Centres (HTCs) of the Saint-Luc University Hospital, Brussels (Belgium) and of Paolo Giaccone Hospital, Palermo (Italy). The population consisted of 107 male patients with MH, with a mean age of 39 years (range 18–81 years). Results: The majority of patients (86/107, 79%) needed at least one treatment within the study period, and 44% (38/86) of them received haemostatic therapy for dental care. Haemostatic therapy in our study varied from antifibrinolytic therapy alone and perioperative factor replacement to the absence of treatment at all. The great majority of oral interventions (27/42, 64%) were managed with clotting factor concentrate. Conclusion: This study demonstrates that dental care currently represents a major reason for haemostatic treatments in patients with MH. Maintaining good oral health appears as a priority to minimize avoidable replacement therapy and optimize resources.

The primary aim of this study was to describe the use of primary anti-infective prophylaxis (AP) in common clinical practice in patients affected by immune thrombocytopenia (ITP) and treated with RTX. Population studied consisted of patients affected by ITP (age ≥ 18 years) who had received at least one dose of RTX from January 2008 to June 2018. Five Italian haematology centres participated in the current study. Data were retrospectively collected: demographic data (age, gender), concomitant comorbidities and previous therapies for ITP, characteristics of AP, the occurrence of infections and their management. The ITP cohort consisted of 67 patients sub-grouped into two categories according to the administration of AP: (1) treated with AP (N= 34; 51%) and (2) not treated with AP (N=33, 49%). AP consisted of combined trimethoprim/sulfamethoxazole (TMP/SMX) and acyclovir (AC) in half of patients. TPM/SMX as a single agent was adopted in 32% patients and one patient received only AC. Overall, infections were experienced in 15% of patients during follow-up with a similar proportion in the 2 groups (treated and not treated) of patients (14.7% vs 15%). Clinical course of infections was however, less severe in patients treated with AP, where all infections were grade 2 and did not require hospitalization. In neither group of patients was reported Pneumocystis pneumonia. In conclusion, despite the absence of clear evidence, our analysis shows that AP in patients with ITP receiving RTX is frequently adopted, even if in the absence of well-defined criteria. Prophylaxis administration is quite consistent within the same haematological Center; thus, it seems related to clinicians' experience.

Mariasanta Napolitano,1 Arne Agerlin Olsen,2 Anne Mette Nøhr,2 Hermann Eichler3 1Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), University of Palermo Reference Regional Center for Thrombosis and Hemostasis, Hematology Unit, Palermo, Italy; 2Novo Nordisk A/S, Biopharm Manufacturing Development, Gentofte, Denmark; 3Saarland University and Saarland University Hospital, Institute of Clinical Haemostaseology and Transfusion Medicine, Homburg (Saar), GermanyCorrespondence: Anne Mette NøhrBiopharm Manufacturing Development, Novo Nordisk A/S, Nybrovej 80, Gentofte 2820, DenmarkTel +45 3075 1619Email amnq@novonordisk.comPurpose: The stability under high-temperature conditions of factor VIII (FVIII) concentrates for replacement therapy is of critical importance to patients, particularly those who reside in, or travel to, regions with high ambient temperatures. Concerns about product stability may limit or prevent access to treatment for patients and may limit their ability to live a close-to-normal life. This study evaluated the effect of hot and humid storage conditions on the long-term stability of the recombinant FVIII products, turoctocog alfa and turoctocog alfa pegol.Methods: Turoctocog alfa samples were assessed for stability at 30°C for 9 months or 40°C for 3 months following storage at 5°C for 21 or 27 months, respectively, while turoctocog alfa pegol samples were assessed at 30°C for 12 months or 40°C for 3 months following storage at 5°C for 18 or 27 months, respectively. In addition, turoctocog alfa and turoctocog alfa pegol dry powders were evaluated for stability at 5°C/ambient humidity (AH) for 30 months, 30°C/75% relative humidity (RH) for 12 months and 40°C/75% RH for 6 months. Both studies utilized a range of product strengths. Key stability assessments included oxidized forms, potency, water content and high molecular weight protein (HMWP).Results: Both turoctocog alfa and turoctocog alfa pegol remained stable following storage at 40°C/75% RH for 3 months, and at single temperatures (5°C/AH, 30 and 40°C/75% RH), without any major increase in HMWP or any impairment of potency or water content.Conclusion: Turoctocog alfa and turoctocog alfa pegol offer stability at 40°C for up to 3 months without jeopardizing the quality of each product. These stability characteristics may offer patients flexibility with product storage and daily use.Keywords: factor VIII, hemophilia A, storage flexibility, temperature stability, turoctocog alfa, turoctocog alfa pegol

Circulating endothelial cells (CECs) are viable, apoptotic or necrotic cells, identified by CD 146 surface antigen expression, considered a biomarker of thrombotic risk, given their active role in inflammatory, procoagulant and immune processes of the vascular compartment. Growing evidence establishes that CECs are also involved in the pathogenesis of several hematological and solid malignancies. The primary aim of this study was to verify if CEC levels could predict both the course and treatment responses of splanchnic vein thrombosis (SVT), either in patients affected by myeloproliferative neoplasms (MPNs) or liver disease. Thus, a retrospective multicenter study was performed; fifteen patients receiving anticoagulant oral treatment with vitamin k antagonists (VKA) for SVT were evaluated. Nine patients were affected by MPN, and all of them received cytoreduction in addition to anticoagulant therapy; four of these patients had primary myelofibrosis (PMF) and were treated with ruxolitinib (RUX), and one patient with primary myelofibrosis, two patients with essential thrombocythemia (ET), and two patients with polycythemia vera (PV) were treated with hydroxyurea (HU). Six patients affected by liver diseases (three with liver cirrhosis and three with hepatocellular carcinoma) were included as the control group. CECs were assayed by flow cytometry on peripheral blood at specific time points, for up to six months after enrollment. The CEC levels were related to C-reactive protein (CRP) levels, splenic volume reduction, and thrombus recanalization, mainly in MPN patients. In patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC), for which the mechanism of SVT development is quite different, the relationship between CEC and SV reduction was absent. In conclusion, the CEC levels showed a significant correlation with the extent of venous thrombosis and endothelial cell damage in myeloproliferative neoplasm patients with splanchnic vein thrombosis. Although preliminary, these results show how monitoring CEC levels during cytoreductive and anticoagulant treatments may be useful to improve SVT outcome in MPN patients.

Purpose Insufficient knowledge of primary immune thrombocytopenia purpura (ITP) in the elderly, together with a lack of clinical trial data, has resulted in wide variation in treatments. Here, we present a study focused on clinical characteristics of ITP in older subjects at diagnosis integrated with the subsequent course of the disease and treatment history. Methods In a retrospective monoinstitutional study, we evaluated >65-year-old patients with primary ITP. Clinical characteristics at the time of diagnosis were described and analyzed. We aimed to delineate whether subsequent lines of therapy influenced the number of relapses. In addition to initial regimens, we reported subsequent treatments and the impact on relapse trends. Results A total of 50 patients (56% males, mean age 78 years) were included. With regard to clinical variables at diagnosis, statistical significance was found for Eastern Cooperative Oncology Group performance status 1 (46% of patients, p

Although the inherited quantitative and qualitative disorders of fibrinogen are rare, in the course of time patients may develop complications including episodes of arterial and venous thrombosis. It can be useful to complete the laboratory assessment of these clinical conditions with the evaluation of the haemorheological profile. The data obtained from this study showed that congenital afibrinogenemia was characterized by a primary plasma hypoviscosity, whereas congenital dysfibrinogenemia by a primary plasma hyperviscosity. Both these haemorheological alterations may concur, with different mechanisms, to the pathogenesis of thrombotic vascular complications.

Background Circulating dysfunctional factor IX (FIX) might modulate distribution of infused FIX in hemophilia B (HB) patients. Recurrent substitutions at FIX activation sites (R191-R226, >300 patients) are associated with variable FIX activity and antigen (FIXag) levels. Objectives To investigate the (1) expression of a complete panel of missense mutations at FIX activation sites and (2) contribution of F9 genotypes on the FIX pharmacokinetics (PK). Methods We checked FIX activity and antigen and activity assays in plasma and after recombinant expression of FIX variants and performed an analysis of infused FIX PK parameters in patients (n = 30), mostly enrolled in the F9 Genotype and PK HB Italian Study (GePKHIS; EudraCT ID2017-003902-42). Results The variable FIXag amounts and good relation between biosynthesis and activity of multiple R191 variants results in graded moderate-to-mild severity of the R191C>L>P>H substitutions. Recombinant expression may predict the absence in the HB mutation database of the benign R191Q/W/K and R226K substitutions. Equivalent changes at R191/R226 produced higher FIXag levels for R226Q/W/P substitutions, as also observed in p.R226W female carrier plasma. Pharmacokinetics analysis in patients suggested that infused FIX Alpha distribution and Beta elimination phases positively correlated with endogenous FIXag levels. Mean residence time was particularly prolonged (79.4 h, 95% confidence interval 44.3-114.5) in patients (n = 7) with the R191/R226 substitutions, which in regression analysis were independent predictors (β coefficient 0.699, P = .004) of Beta half-life, potentially prolonged by the increasing over time ratio between endogenous and infused FIX. Conclusions FIX activity and antigen levels and specific features of the dysfunctional R191/R226 variants may exert pleiotropic effects both on HB patients' phenotypes and substitutive treatment.

Current cytoreductive and antithrombotic strategies in MPNs are mostly based on cell counts and on patient’s demographic and clinical history. Despite the numerous studies conducted on platelet function and on the role of plasma factors, an accurate and reliable method to dynamically quantify the hypercoagulability states of these conditions is not yet part of clinical practice. Starting from our experience, and after having sifted through the literature, we propose an in-depth narrative report on the contribution of the clonal platelets of MPNs—rich in tissue factor (TF)—in promoting a perpetual procoagulant mechanism. The whole process results in an unbalanced generation of thrombin and is self-maintained by Protease Activated Receptors (PARs). We chose to define this model as a “circulating wound”, as it indisputably links the coagulation, inflammation, and fibrotic progression of the disease, in analogy with what happens in some solid tumours. The platelet contribution to thrombin generation results in triggering a vicious circle supported by the PARs/TGF-beta axis. PAR antagonists could therefore be a good option for target therapy, both to contain the risk of vascular events and to slow the progression of the disease towards end-stage forms. Both the new and old strategies, however, will require tools capable of measuring procoagulant or prohaemorrhagic states in a more extensive and dynamic way to favour a less empirical management of MPNs and their potential clinical complications.

It is well established that immune thrombocytopenia (ITP) results from increased immune mediated platelet destruction (anti-platelets antibodies, autoreactive T cells, and reduction of regulatory T cells) along with impaired production in the bone marrow.1 The latter has been attributed to both cellular and humoral mediators that cause suppression of megakaryocyte production and maturation.2 Current standard first line therapy consists of corticosteroids, with or without intravenous Ig, achieving about 70-80% response rate. However, a consistent proportion of patients would relapse after corticosteroid discontinuation or tapering, and requires further therapy. ...

The last decade has been very important for the quantity of preclinical information obtained regarding chronic myeloproliferative neoplasms (MPNs) and the following will be dedicated to the translational implications of the new biological acquisitions. The overcoming of the mechanistic model of clonal evolution and the entry of chronic inflammation and dysimmunity into the new model are the elements on which to base a part of future therapeutic strategies. The innate immune system plays a major role in this context. Protagonists of the initiation and regulation of many pathological aspects, from cytokine storms to fibrosis, the NLRP3 and AIM2 inflammasomes guide and condition the natural history of the disease. For this reason, MPNs share many biological and clinical aspects with non-neoplastic diseases, such as autoimmune disorders. Finally, cardiovascular risk and disturbances in iron metabolism and myelopoiesis are also closely linked to the role of inflammasomes. Although targeted therapies are already being tested, an increase in knowledge on the subject is desirable and potentially translates into better care for patients with MPNs.

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

Iron deficiency anemia is among the most frequent causes of disability. Intravenous iron is the quickest way to correct iron deficiency, bypassing the bottleneck of iron intestinal absorption, the only true mechanism of iron balance regulation in human body. Intravenous iron administration is suggested in patients who are refractory/intolerant to oral iron sulfate. However, the intravenous way of iron administration requires several precautions; as the in-hospital administration requires a resuscitation service, as imposed in Europe by the European Medicine Agency, it is very expensive and negatively affects patient’s perceived quality of life. A new oral iron formulation, Sucrosomial iron, bypassing the normal way of absorption, seems to be cost-effective in correcting iron deficiency anemia at doses higher than those usually effective with other oral iron formulations. In this multicentric randomized study, we analyze the cost-effectiveness of intravenous sodium ferrigluconate vs oral Sucrosomial iron in patients with iron deficiency anemia refractory/intolerant to oral iron sulfate without other interfering factors on iron absorption.

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

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Mariasanta Napolitano, 1 Maria Francesca Mansueto, 1 Davide Sirocchi, 1 Angelo Davide Contrino, 1 Simona Raso, 2 Sergio Siragusa 1 1Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), Haematology Unit, Reference Regional Centre for Thrombosis and Haemostasis, University of Palermo, Palermo, Italy; 2Division of Haematology, Department of Surgical, Oncological and Stomatological Disciplines (Di.Chir.On.S.), AOUP Paolo Giaccone, Palermo, ItalyCorrespondence: Mariasanta NapolitanoDepartment of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties (PROMISE), Haematology Unit, Reference Regional Centre for Thrombosis and Haemostasis, via del Vespro 127, Palermo 90127, ItalyTel +39 0916554519Fax +39 0916554403Email marysanta@libero.it The ongoing pandemic calls on doctors to cope with new specific patient needs,associated with the isolation and need to avoid face to face contacts if not strictlynecessary. Following some calls by haemophilia patients followed by ourReference Regional Centre for questions related to regular replacement therapywith factor VIII and IX concentrate supply and availability, and also for reassurancerelated to safety of plasma-derived concentrates from Coronavirus potentialinfections, we have sent by email or mobile apps a short survey to our patients with severe haemophilia and asked them to reply within 24 hours. The survey waselaborated by our psychologist with the following questions: How much are you concerned about the regular replacement treatment supply and safe drug productionprocess during the COVID-19 pandemic? The only available option to avoidfurther widespread infection is isolation, do you feel the weight of this? Do youagree that anxiety and worry do not help in the management of this emergency?How important for you are the support and availability of the haemophiliacentre personnel? For each of the above reported questions, according to a Likertscale, patients may select one of the following four options: not at all, a little, wellenough, very much. Further, the following open question was reported: How areyou personally coping with the COVID-19 pandemic? The survey was sent to 30patients, 23 of them replied within 24 hours. We report here the survey results. &nbsp

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, potentially fatal disorder of haematopoietic stem cells caused by mutations in an X-linked gene called phosphatidylinositol glycan class A, characterised by intravascular haemolysis, bone marrow failure and thrombotic events. The disease can occur at any age, although preferentially it affects young adults; its estimated prevalence is about 1/500,000 [1]. Clinical symptoms are variable and can include haemolytic anaemia, moderate to severe impairment of haematopoiesis and, in approximately 40% of patients, thrombosis of the vessels of the abdomen, brain and skin [2]. Rare, atypical site thrombosis of the splanchnic veins or cerebral sinuses are recognized as suggestive of the presence of a PNH clone [3]. To date, however, the prevalence of PNH clones in unselected patients with cerebral venous thrombosis is not yet known. The primary objective of this study was to determine the prevalence of PNH clones in patients with a recent history of cerebral sinus venous thrombosis (CSVT) and up to twenty-four months follow-up. In this multicentre cross-sectional study, patients with an objective diagnosis of CSVT of new onset or occurring in the previous three years were investigated for the presence of PNH clones. Known or clinically suspected PNH and active treatments able to interfere

In this case report, we examine the behavior of plasma viscosity, explored at high and low shear rates, and erythrocyte aggregation in two patients with congenital afibrinogenemia, a clinical disorder firstly described in 1920 and that has an estimated incidence of 1 : 1-200 0000. The two hemorheological parameters examined by us showed a marked decrease in both patients, in one of whom erythrocyte aggregation was even undetectable. Keeping in mind that spontaneous thrombosis (venous and arterial) has been often described in congenital afibrinogenemia, it can be hypothesized that the decrease in plasma viscosity and erythrocyte aggregation might cause a reduction of the endothelial synthesis and release of nitric oxide through the fall of the wall shear stress.

Von Willebrand disease (VWD) is the most common inherited bleeding disorder and is caused by a quantitative (type 1 and 3) or qualitative (type 2) defect of Von Willebrand factor (VWF). Bleeding from the gastrointestinal (GI) tract is not uncommon in VWD and is usually associated with angiodysplasia. We report herein on the management of a patient affected by VWD2B with severe GI bleeding secondary to gastrointestinal stromal tumor (GIST) complicated by deep vein thrombosis (DVT). The current case demonstrated that the hemostatic balance, in RBDs under specific circumstances, can range from a tendency toward a hemorrhagic to normal or prothrombotic state. In these patients, a close collaboration between hematologists and surgeons can guarantee appropriate management in high-risk clinical scenarios.

BAY 81-8973 is an unmodified, full-length third generation recombinant factor VIII (rFVIII) which offers a more favorable pharmacokinetic (PK) profile, compared to its predecessor sucrose-formulated rFVIII (rFVIII-FS). We here report on a retrospective case series of nine patients affected by hemophilia A (HA), with variable disease severity, bleeding phenotype and comorbidities, to underline our clinical practice on prophylaxis with a recently introduced standard hall-life recombinant Factor VIII. The current case series highlights how the current clinical management of hemophilia is able to personalize treatment in several specific conditions like concomitant illnesses with thrombotic risk and allergic reactions.

The use of hydroxychloroquine (HCL) has been very common in countries with a rapid spread of coronavirus disease 2019 (COVID-19), although controversial and the subject of heated scientific discussions with implications for the whole society. This article is protected by copyright. All rights reserved.

The Essential Thrombocythemia is a Chronic Philadelphia-negative Myeloproliferative Neoplasm characterized by a survival curve that is only slightly worse than that of age- and sex-adjusted healthy population. The criteria for diagnosis were reviewed in 2016 by WHO. The incidence varies from 0.2 to 2.5:100 000 people per year, with a prevalence of 38 to 57 cases per 100 000 people. The main characteristics of ET are the marked thrombocytosis and the high frequency of thrombosis. The spectrum of symptoms is quite wide, but fatigue results to be the most frequent. Thrombosis is frequently observed, often occurring before or at the time of diagnosis. The classification of thrombotic risk has undergone several revisions. Recently, the revised-IPSET-t has distinguished 4 risk classes, from very low risk to high risk. Driver mutations seem to influence thrombotic risk and prognosis, while the role of sub-driver mutations still remains uncertain. Antiplatelet therapy is recommended in all patients aged ⩾ 60 years and in those with a positive history of thrombosis or with cardiovascular risk factors, while cytoreductive therapy with hydroxyurea or interferon is reserved for high-risk patients.