Diagnosis and management of Evans syndrome in adults: first consensus recommendations.

Evans syndrome is a rare disease marked by a severe clinical course, high relapse rate, infectious and thrombotic complications, and sometimes fatal outcome. Management is highly heterogeneous. There are several case reports but few large retrospective studies and no prospective or randomised trials. Here, we report the results of the first consensus-based expert recommendations aimed at harmonising the diagnosis and management of Evans syndrome in adults. After reviewing the literature, we used a fuzzy Delphi consensus method, with two rounds of a 42-item questionnaire that were scored by a panel of 13 international experts from five countries using a 7-point Likert scale. Panellists were selected by the core panel on the basis of their personal experience and previous publications on Evans syndrome and immune cytopenias; they met virtually throughout 2023. The panellists recommended extensive clinical and laboratory diagnostic tests, including bone marrow evaluation and CT scan, and an aggressive front-line therapy with prednisone (with or without intravenous immunoglobulins), with different treatment durations and tapering for immune thrombocytopenia and autoimmune haemolytic anaemias (AIHAs). Rituximab was strongly recommended as first-line treatment in cold-type AIHA and as second-line treatment in warm-type AIHA and patients with immune thrombocytopenia and antiphospholipid antibodies, previous thrombotic events, or associated lymphoproliferative diseases. However, rituximab was discouraged for patients with immunodeficiency or severe infections, with the same applying to splenectomy. Thrombopoietin receptor agonists were recommended for chronic immune thrombocytopenia and in the case of previous grade 4 infection. Fostamatinib was recommended as third-line or further-line treatment and suggested as second-line therapy for patients with previous thrombotic events. Immunosuppressive agents have been moved to third-line or further-line treatment. The panellists recommended the use of recombinant erythropoietin in AIHA in the case of inadequate reticulocyte counts, use of the complement inhibitor sutimlimab for relapsed cold AIHA, and the combination of rituximab plus bendamustine in Evans syndrome secondary to lymphoproliferative disorders. Finally, recommendations were given for supportive therapy, platelet or red blood cell transfusions, and thrombotic and antibiotic prophylaxis. These consensus-based recommendations should facilitate best practice for diagnosis and management of Evans syndrome in clinical practice.

Global hemostasis assays in acute myeloid leukemia: results of an observational prospective study.

BACKGROUND: Acute myeloid leukemia (AML) is characterized by a complex spectrum of coagulopathy ranging from hemorrhagic to thrombotic symptoms. To date, platelet count (PLT) and conventional coagulation tests (CCTs) cannot predict hemorrhagic events and thrombotic risk. Thromboelastography (TEG) measures the viscoelastic properties of the clot, thus providing information on the entire process of blood coagulation. The primary aim of the study was to assess the hemostatic balance from AML diagnosis to the end of chemotherapy (CHT) by TEG. MATERIAL AND METHODS: Here we present the results of a prospective study enrolling newly diagnosed AML patients treated with chemotherapy. Patients had complete blood counts (CBCs), TEG and CCTs performed at three time points: 1) diagnosis (T0); 2) during the first cycle of CHT (T1); and 3) at the end of CHT (T2). An algorithm of TEG indirectly calculated thrombin generation (TG). Patients underwent daily follow-up for bleeding and thrombotic episodes up to the time of hospital discharge or death. RESULTS: Eighty consecutive patients were evaluated; forty were eligible for the study, and 21 completed the entire study. At T1, maximum amplitude (MA), TG and K-time were significantly shifted toward a hypocoagulability state compared to T0 (p<0.05), while a hypercoagulable state at T2 was shown by changes in α-angle, MA and TG values. Otherwise, there were no statistically significant differences in CCTs between the evaluated time points. DISCUSSION: Overall, TEG revealed complex and dynamic coagulation abnormalities in patients with AML according to both the course of disease and therapy. Further studies are needed to investigate more fully the role of TEG in defining the hemostatic profile in patients with AML.

Autoimmune hemolytic anemia during pregnancy and puerperium: an international multicenter experience.

Relapsing or occurring de novo autoimmune hemolytic anemia (AIHA) during pregnancy or puerperium is a poorly described condition. Here, we report 45 pregnancies in 33 women evaluated at 12 centers from 1997 to 2022. Among the 20 women diagnosed with AIHA before pregnancy, 10 had a relapse. An additional 13 patients developed de novo AIHA during gestation/puerperium (2 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). Response was achieved in all patients and was complete in 65% of the cases. Antithrombotic prophylaxis was administered to 8 patients (33%). After delivery, rituximab was administered to 4 patients, and cyclosporine was added to 1 patient. The rate of maternal complications, including premature rupture of membranes, placental detachment, and preeclampsia, was 15%. Early miscarriages occurred in 13% of the pregnancies. Fetal adverse events (22% of cases) included respiratory distress, fetal growth restriction, preterm birth, AIHA of the newborn, and 2 perinatal deaths. In conclusion, the occurrence of AIHA does not preclude the ability to carry out a healthy pregnancy, provided close monitoring, prompt therapy, and awareness of potential maternal and fetal complications.

The important impact of dental care on haemostatic treatment burden in patients with mild haemophilia.

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.

Lentiviral globin gene therapy with reduced-intensity conditioning in adults with ß-thalassemia: a phase 1 trial.

ß-Thalassemias are inherited anemias that are caused by the absent or insufficient production of the ß chain of hemoglobin. Here we report 6-8-year follow-up of four adult patients with transfusion-dependent ß-thalassemia who were infused with autologous CD34+ cells transduced with the TNS9.3.55 lentiviral globin vector after reduced-intensity conditioning (RIC) in a phase 1 clinical trial ( NCT01639690) . Patients were monitored for insertional mutagenesis and the generation of a replication-competent lentivirus (safety and tolerability of the infusion product after RIC-primary endpoint) and engraftment of genetically modified autologous CD34+ cells, expression of the transduced ß-globin gene and post-transplant transfusion requirements (efficacy-secondary endpoint). No unexpected safety issues occurred during conditioning and cell product infusion. Hematopoietic gene marking was very stable but low, reducing transfusion requirements in two patients, albeit not achieving transfusion independence. Our findings suggest that non-myeloablative conditioning can achieve durable stem cell engraftment but underscore a minimum CD34+ cell transduction requirement for effective therapy. Moderate clonal expansions were associated with integrations near cancer-related genes, suggestive of non-erythroid activity of globin vectors in stem/progenitor cells. These correlative findings highlight the necessity of cautiously monitoring patients harboring globin vectors.

Antimicrobial prophylaxis in patients with immune thrombocytopenia treated with rituximab: a retrospective multicenter analysis.

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.

Clinical Phenotype and Response to Different Lines of Therapy in Elderly with Immune Thrombocytopenia: A Retrospective Study.

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<0.0001), presence of three comorbidities (36% of patients, p<0.0001), World Health Organization grade 0 bleeding (46%, p=0.0001), and World Health Organization grade 1 bleeding (42%, p=0.0009). For bleeding sites, the most frequent were skin or mucosa (40%, p=0.0477). A decrease in platelet count was correlated with moderate or severe bleeding (ρ=-0.52, p=0.0001) and viscera or skin/mucosa + viscera site (ρ=-0.50, p=0.0002). Finally, a decreasing number of patients required treatment from first-line therapy to sixth (p<0.0001). Relapse was most frequent before second-line therapy (54%, p<0.0001) and less frequent before fivth and sixth (4%, p=0.0072; 2%, p=0.0027). CONCLUSION: ITP in older age poses considerable challenges, so specific management strategies should be considered to optimize outcomes. Our findings provide evidence of an inverse relationship between lines of therapy and timing of relapses. This study does not exclude the possibility that agents used after first-line therapy may have an impact on the response and modify the unfavorable course of ITP.

Cardiovascular Risk in Polycythemia Vera: Thrombotic Risk and Survival: Can Cytoreductive Therapy Be Useful in Patients with Low-Risk Polycythemia Vera with Cardiovascular Risk Factors?

BACKGROUND/AIMS: Cardiovascular risk factors are not considered in the current scores for evaluation of the thrombotic risk in myeloproliferative neoplasms, and in polycythemia vera (PV) in particular. Cytoreduction is currently not indicated in low-risk patients with PV, despite the absence or presence of cardiovascular risk factors. Our purpose is to highlight how cardiovascular risk factors in patients with PV increase the thrombotic risk both in low- and high-risk patients. METHODS: We collected and analyzed data from 165 consecutive patients with a diagnosis of PV followed at our institution and compared the frequency of thrombosis in subgroups of patients distinguished by the presence or absence of cardiovascular risk factors. The statistic tools used to obtain the results were the χ2 and the Kruskal-Wallis test for frequencies, and the Kaplan-Meyer method as well as the log-rank test for analysis of survival data. RESULTS: The major result obtained is that the frequency of thrombotic events in our population is strictly linked with the cardiovascular risk, and it increases with the number of risk factors. Moreover, survival significantly worsens with the number of cardiovascular risk factors, despite the classical PV risk stratification. CONCLUSION: It should be useful to design perspective studies to determine the real influence of cardiovascular risk factors on the thrombotic risk for patients with PV and on survival in order to evaluate the opportunity to develop new specific therapeutic recommendations.

Coexistence of Von Willebrand disease and gastrointestinal stromal tumor (G.I.S.T): Case report of a rare and challenge association.

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.

The Essential Thrombocythemia, Thrombotic Risk Stratification, and Cardiovascular Risk Factors.

Essential thrombocythemia is a rare hematological malignancy with good overall survival, but moderate to high risk of developing arterial or venous thrombosis lifelong. Different thrombotic risk scores for patients with essential thrombocythemia have been proposed, but only one of them (the IPSET-t scoring system) takes into account the classical cardiovascular risk factors as one of the scoring items. Currently, in clinical practice, the presence of cardiovascular risk factors in patients with diagnosis of ET rarely determines the decision to initiate cytoreductive therapies. In our study, we compared different risk models to estimate the thrombotic risk of 233 ET patients and the role of specific driver mutations and evaluated the impact that conventional cardiovascular risk factors (hypertension, cigarette smoking, diabetes, obesity, and dyslipidaemia) have on thrombotic risk in patients with ET. Perspective studies conducted on a polycentric large cohort of patients should be conducted to estimate the impact of cardiovascular risk factors in determining thrombosis in ET patients, evaluating the opportunity of initiating a cytoreductive therapy in patients with cardiovascular risk factors, even if classified into low to moderate risk groups according to other scoring systems.

Quality of Life in Patients With Cancer Under Prolonged Anticoagulation for High-Risk Deep Vein Thrombosis: a Long-Term Follow-Up.

Current guidelines recommend to prolong anticoagulant treatment in patients with cancer with venous thromboembolism (VTE); only few studies evaluated other parameters than cancer itself for selecting patients at higher risk of recurrent VTE. Long-term management of VTE is thus challenged by several controversies mainly for patients compliance. We here report results of a long-term follow-up in patients with deep vein thrombosis under anticoagulant treatment with low-molecular-weight heparin (LMWH) for residual vein thrombosis (RVT) detected at compression ultrasonography (CUS), 6 months after standard anticoagulant treatment. Patients with RVT were deemed at high risk of recurrences and included in the current observational study. They continued LMWH (reduced at 75% standard dose) for further additional 2 years after enrolment or until death. Patients were followed up every 3 months or earlier, if needed. Among ancillary study end points, there was the assessment of patients' quality of life during daily treatment with subcutaneous injections. Quality of life was determined by the EORTC-C30 questionnaire, administered by a skilled psychologist at enrolment and every 6 months follow-up visits. Overall, 128 patients were evaluated during follow-up. Mean global EORTC-C30 score at enrollment and at 6, 12 and 24 months follow-up were 52.1, 51.4, 50.8 and 50.1, respectively. There were no statistically significant differences between scores at enrolment and at the last available follow-up (P = .1). Long-term treatment with LMWH resulted, effective and safe, it was globally well tolerated and exempt of negative impact on quality of life of the enrolled patients. Reported results support long-term anticoagulant treatment with LMWH in cancer patients at risk of recurrent VTE.

Plasma viscosity pattern and erythrocyte aggregation in two patients with congenital afibrinogenemia.

: 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.

Cardiovascular Risk in Essential Thrombocythemia and Polycythemia Vera: Thrombotic Risk and Survival.

Thromboembolic and bleeding events pose a severe risk for patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET). Many factors can contribute to promoting the thrombotic event due to the interaction between platelets, leukocytes, and endothelium alterations. Moreover, a significant role can be played by cardiovascular risk factors (CV.R) such as cigarette smoking habits, hypertension, diabetes, obesity and dyslipidemia. In this study, we evaluated the impact that CV.R plays on thrombotic risk and survival in patients with PV and ET.

Can we compare haemophilia carriers with clotting factor deficiency to male patients with mild haemophilia?

INTRODUCTION: Certain haemophilia carriers demonstrate an increased bleeding tendency, mainly related to clotting factor deficiency. No study has so far formally compared the bleeding phenotype of women and girls with mild FVIII or FIX deficiency and associated management with that of male patients affected by mild haemophilia A and B. MATERIAL AND METHODS: We retrospectively evaluated 44 women and girls with mild FVIII or FIX deficiency (FVIII or FIX 0.05-0.5 IU/mL) and 77 male patients with mild haemophilia A or B and compared them with respect to clotting factor level, age at and trigger for diagnosis, as well as treatment modalities. RESULTS: After excluding gender-related haemorrhagic symptoms, haemophilia carriers with plasma factor levels in the mild haemophilia range and male patients affected by mild haemophilia present a comparable haemorrhagic profile, mainly characterized by mucocutaneous and postinjury bleeding. Haemophilia carriers with clotting factor deficiency, however, distinguish themselves in terms of later age at diagnosis, higher mean factor levels and trigger for diagnosis. CONCLUSIONS: Women and girls with mild FVIII or FIX deficiency should be considered as mild haemophilia patients and have access to care and management inspired from male haemophilia patients while integrating differences and specificities. Larger international studies comparing the clinical presentation and treatment modalities of mild clotting FVIII and FIX deficiencies in both haemophilia males and females should be encouraged.

Splenomegaly impacts prognosis in essential thrombocythemia and polycythemia vera: A single center study.

Splenomegaly is one of the major clinical manifestations of primary myelofibrosis and is common also in other chronic Philadelphia-negative myeloproliferative neoplasms, causing symptoms and signs and affecting quality of life of patients diagnosed with these diseases. We aimed to study the impact that such alteration has on thrombotic risk and on the survival of patients with essential thrombocythemia and patients with Polycythemia Vera (PV). We studied the relationship between splenomegaly (and its grade), thrombosis and survival in 238 patients with et and 165 patients with PV followed at our center between January 1997 and May 2019.

Buffy coat-derived platelets cryopreserved using a new method: Results from a pivotal clinical trial on thrombocytopenic patients with acute leukaemia.

The administration of cryopreserved platelets (PLTs) may overcome the limits of platelet shortage and availability, especially during some seasons or in specific contexts like rural areas. After in vitro validation studies, ad hoc prepared buffy coat-derived pooled platelet concentrates (BC-PLTs), treated with dimethyl sulphoxide (DMSO) and cryopreserved (CRY BC-PLTs) at -80 °C with a modified Valeri method, were transfused in patients with severe thrombocytopenia secondary to chemotherapy for acute leukaemia (AL). Five inpatients were enrolled in the pivotal clinical trial NCT02032134: 4 males and 1 female with a mean age of 71 years (range: 65-80). Four patients were diagnosed with acute myeloid leukaemia and 1 had acute lymphoblastic leukaemia.Transfusion of one Unit of CRY BC-PLTs resulted effective in active bleeding control in two patients without any adverse reaction or concomitant antihaemorrhagic therapies. CRY BC-PLTs met the currently accepted criteria for cryopreserved PLTs, their transfusion in patients with AL was safe. (Clinical trial: NCT02032134).

Immunosenescence and lymphomagenesis.

One of the most important determinants of aging-related changes is a complex biological process emerged recently and called "immunosenescence". Immunosenescence refers to the inability of an aging immune system to produce an appropriate and effective response to challenge. This immune dysregulation may manifest as increased susceptibility to infection, cancer, autoimmune disease, and vaccine failure. At present, the relationship between immunosenescence and lymphoma in elderly patients is not defined in a satisfactory way. This review presents a brief overview of the interplay between aging, cancer and lymphoma, and the key topic of immunosenescence is addressed in the context of two main lymphoma groups, namely Non Hodgkin Lymphoma (NHL) and Hodgkin Lymphoma (HL). Epstein Barr Virus (EBV) plays a central role in the onset of neoplastic lymphoproliferation associated with immunological changes in aging, although the pathophysiology varies vastly among different disease entities. The interaction between immune dysfunction, immunosenescence and Epstein Barr Virus (EBV) infection appears to differ between NHL and HL, as well as between NHL subtypes.