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The risk of venous thromboembolism (VTE) is increased during pregnancy and it is further increased together with pregnancy complications in women with personal history of VTE and thrombophilia abnormalities. It is unclear how the use of low-molecular-weight heparin (LMWH) may prevent such complications.To evaluate the potential benefits and risks of the use of LMWH for prevention of pregnancy-related VTE and obstetrical complications in the first pregnancy after a previous VTE.This retrospective cohort study includes fertile women referred to the Thrombosis Center from January 2000 to September 2018 for a thrombophilia work-up, after having had at least one previous VTE and one pregnancy thereafter. Data on pregnancy-related recurrent VTE, pregnancy outcomes and the use of LMWH were collected.Among 208 women, no thrombosis or major bleeding was recorded in 138 pregnancies conducted with LMWH, whereas 10 VTE (14%) were recorded in 70 pregnancies conducted without. Nine women (90%) with recurrent VTE had had a previous hormone-related event. The incidence of miscarriage was lower in pregnancies with LMWH than in those without (11% vs. 26%, relative risk 0.4, 95% confidence interval: 0.2-0.8), whereas late obstetrical complications and terminations were similar in the two groups. The prevalence of terminations was doubled in women with thrombophilia (12%) than in those without (6%).LMWH prophylaxis during pregnancy appears to be effective and safe for the prevention of recurrent VTE and may reduce the incidence of miscarriage.

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by the persistent positivity of antiphospholipid antibodies (aPLA) together with thrombosis or obstetrical complications. Despite their recognized predominant role, aPLA are not sufficient to induce the development of thrombosis and a second hit has been proposed to be necessary. The mainstay of treatment of APS is anticoagulant therapy. However, its optimal intensity in different presentations of the disease remains undefined. Moreover, decision on which patients with aPLA would benefit from an antithrombotic prophylaxis and its optimal intensity are challenging because of the lack of stratification tools for the risk of thrombosis. Finally, decision on the optimal type of anticoagulant drug is also complex because the central pathway responsible for the development of thrombosis is so far unknown and should be carried out on an individual basis after a careful evaluation of the clinical and laboratory features of the patient. This review addresses the epidemiology, physiopathology, diagnosis and management of thrombosis and obstetrical complications in APS, with a special focus on the role of direct oral anticoagulants.

Primary brain tumors are associated with an increased risk of pulmonary embolism (PE), particularly in the early post-operative period. The pathophysiological mechanisms of PE are poorly understood. This study aims to describe prospectively extracellular vesicles (EVs) levels and investigate whether or not their variations allow to identify patients at increased risk of post-operative PE. Consecutive meningioma or glioma patients candidate to tumor resection were included in the study if a pulmonary perfusion scan (Q-scan) performed before surgery ruled out PE. EVs derived from platelets (CD41+) or endothelial cells (CD144+), tissue factor-bearing EVs (CD142+) and their procoagulant subtype (annexin V+) were analyzed by flow cytometry before surgery (T0), within 24 h (T1), two (T2) and seven days (T7) after surgery. Q-scan was repeated at T2. Ninety-three patients with meningioma, 59 with glioma and 76 healthy controls were included in the study. CD142+ and annexin V+/CD142+ EVs were increased at T0 in meningioma and glioma patients compared to healthy controls. Twenty-nine meningioma (32%) and 16 glioma patients (27%) developed PE at T2. EVs levels were similar in meningioma patients with or without PE, whereas annexin V+ and annexin V+/CD142+ EVs were significantly higher at T1 and T2 in glioma patients with PE than in those without. Procoagulant EVs, particularly annexin V+/CD142+, increase after surgery and are more prevalent in glioma patients who developed PE after surgery than in those who did not.

It is unknown whether moderate thrombocytopenia represents a risk factor for post-partum haemorrhage (PPH). We assessed PPH risk among women with a platelet count of between 100 and 50 × 10

Key Points Adult ES is a rare, often severe, and potentially fatal condition.ES is marked by frequent relapses, high therapy burden, and increased risk of infection/thrombosis, significantly affecting survival., Visual Abstract, Evans syndrome (ES) is a rare condition, defined as the presence of 2 autoimmune cytopenias, most frequently autoimmune hemolytic anemia and immune thrombocytopenia (ITP) and rarely autoimmune neutropenia. ES can be classified as primary or secondary to various conditions, including lymphoproliferative disorders, other systemic autoimmune diseases, and primary immunodeficiencies, particularly in children. In adult ES, little is known about clinical features, disease associations, and outcomes. In this retrospective international study, we analyzed 116 adult patients followed at 13 European tertiary centers, focusing on treatment requirements, occurrence of complications, and death. ES was secondary to or associated with underlying conditions in 24 cases (21%), mainly other autoimmune diseases and hematologic neoplasms. Bleeding occurred in 42% of patients, mainly low grade and at ITP onset. Almost all patients received first-line treatment (steroids with or without intravenous immunoglobulin), and 23% needed early additional therapy for primary refractoriness. Additional therapy lines included rituximab, splenectomy, immunosuppressants, thrombopoietin receptor agonists, and others, with response rates >80%. However, a remarkable number of relapses occurred, requiring ≥3 therapy lines in 54% of cases. Infections and thrombotic complications occurred in 33% and 21% of patients, respectively, mainly grade ≥3, and correlated with the number of therapy lines. In addition to age, other factors negatively affecting survival were severe anemia at onset and occurrence of relapse, infection, and thrombosis. These data show that adult ES is often severe and marked by a relapsing clinical course and potentially fatal complications, pinpointing the need for high clinical awareness, prompt therapy, and anti-infectious/anti-thrombotic prophylaxis.

Background: Evans syndrome (ES) is a rare condition, defined as the presence of two autoimmune cytopenias (AIC), more frequently autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP), and rarely autoimmune neutropenia (AIN). ES can be classified as primary or secondary to various conditions, including lymphoproliferative disease (LPD), primary immune deficiencies (PID) or other systemic autoimmune diseases (AID). ES onset may be acute and life-threatening, whilst its clinical course is usually chronic and marked by several relapses of AIHA, ITP or both. First line therapy is based on steroids +/- intravenous immunoglobulins (IVIG), followed by rituximab and splenectomy in refractory/relapsing cases. Concerning ITP, splenectomy is not always feasible, and rituximab is poorly effective on the long term. Thrombopoietin receptors agonists (TPO-RA), such as romiplostim (ROMI) and eltrombopag (EPAG), are commonly used in primary ITP with high efficacy; however, their use in ES has never been systematically studied. Aim: to evaluate the efficacy and safety of TPO-RA in a multicentric cohort of patients with ES. Methods: all ES patients treated with TPO-RA at 8 European hematologic hospitals (3 Italian, 2 Danish, 1 United Kingdom and 2 Spanish) were retrospectively evaluated. Baseline hematologic parameters, associated conditions, previous treatments and those administered concomitantly to TPO-RA were registered. The time from diagnosis to first TPO-RA was collected. Response rates were evaluated at 1, 3, 6, and 12 months, and classified as partial (PR) or complete (CR), for platelets >30x10^9/L or >100x10^9/L, respectively. Treatment emergent adverse events (TAEs) were registered and graded according to CTCAE. R esults: As shown in Figure 1, 22 ES patients have been evaluated, 9 of whom secondary (40%). Almost all patients had received steroids +/- IVIG, and the majority at least one further line. The median time from diagnosis to TPO-RA start was 25,74 months (1-1390). Response rates to the first TPO-RA (16 EPAG and 6 ROMI) were: 82% at month 1, 84% at month 3, 83% at month 6 and 93% at month12. Eight patients started TPO-RA within 1 year from ES diagnosis. These patients displayed significantly lower platelets (p=0.01) as compared to others, however response rates were comparable. Of note, 73% of patients required concurrent therapies, including steroids +/- IVIG (N=13), danazol (N=2), rituximab (N=3), and immunosuppressants (N=3). Moreover, 7 patients required the addition of a rescue therapy to control ITP (steroids +/- IVIG N=4, rituximab N=1, danazol N=1, daratumumab N=1, immunosuppressants N=2, parsaclisib N=1), particularly in secondary ES (63% vs 33%). The latters less frequently showed increased bone marrow megakaryocytes (67% vs 92%) but had higher dysplasia (50% of patients vs 33% in primary ES). Interestingly, 5 subjects switched to the alternative TPO-RA (3 ROMI to EPAG and 2 vice versa) 2 because of no response (NR), and 3 for relapses. Three subjects responded but required additional therapies, including splenectomy, steroids +/- IVIG, or platelet transfusions. Ten out of 22 patients developed at least one TEAE: G1 thrombocytosis (N=1), G2 bone marrow fibrosis (N=1), G3/4 thrombosis (3 venous and 2 arterial: 1 pulmonary embolism, 1 cerebral vein thrombosis CVT, and 1 splanchnic thrombosis, 1 atrial thrombus and 1 acute myocardial infarction in the same APS patient experiencing CVT). Thrombosis was associated with the presence of secondary ES (p=0.03). Five patients are still receiving TPO-RA, whilst the other stopped because of persistent CR (N=12), thrombosis (N=3), increase in bone marrow reticulin fibrosis (N=1), or death for infectious complication. Conclusions: TPO-RAs were effective in more than 80% of ES patients, even heavily pre-treated. However, TPO-RA use was complicated by a high occurrence of thrombotic events that may be also favored by the underlying conditions. Additionally, TPO-RA required a concomitant therapy in the majority of patients, suggesting that in ES autoimmune platelet destruction cannot be completely overcome by bone marrow stimulation. Figure 1 Figure 1. Disclosures Patriarca: Incyte: Honoraria; Argenix: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Glenthøj: Sanofi: Research Funding; Bristol Myers Squibb: Consultancy; Saniona: Research Funding; Agios: Consultancy; Novo Nordisk: Honoraria; Novartis: Consultancy; Alexion: Research Funding; Bluebird Bio: Consultancy. Lund Hansen: Alexion: Research Funding; Novartis: Research Funding. Frederiksen: Gilead: Research Funding; Alexion: Research Funding; Novartis: Research Funding; Janssen Pharmaceuticals: Research Funding; Abbvie: Research Funding. Gonzalez-Lopez: Sobi: Other: Advisory board honoraria; Amgen: Other: Advisory board and speakers honoraria, Research Funding; Novartis: Other: Advisoryboard and speakers honoraria, Research Funding; Grifols: Other: Advisory board honoraria. Barcellini: Novartis: Honoraria; Agios: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; Bioverativ: Membership on an entity's Board of Directors or advisory committees. Fattizzo: Kira: Speakers Bureau; Alexion: Speakers Bureau; Novartis: Speakers Bureau; Momenta: Honoraria, Speakers Bureau; Apellis: Speakers Bureau; Annexon: Consultancy; Amgen: Honoraria, Speakers Bureau. OffLabel Disclosure: Thrombopoietin receptor agonists in patients suffered from Evans syndrome when ITP is refractory/relapsing to standard therapies

Since their license in 2008, studies on thrombopoietin receptor agonists (TPO-RAs) are proceeding at a fast pace. Their favorable efficacy and safety profile makes them good candidates for the management of thrombocytopenia in different settings, even beyond their current indications. In the last 10 years, we faced patients with refractory thrombocytopenia that required treatment with off-label TPO-RA, despite the paucity of data in the literature and the possible risks, particularly that of thrombosis. We hereby report our 10-year real-life single-center experience of TPO-RA used off-label. Fourteen patients were divided into three groups according to the etiology of thrombocytopenia: myelodysplastic syndromes, post-transplantation, and lymphoproliferative diseases. Clinical features and results are reported within each group. Overall, TPO-RA proved effective in all these conditions achieving responses also in heavily pretreated patients. The overall response rate (ORR) was 100% in patients with thrombocytopenia after transplantation and in those with lymphoproliferative diseases and 75% in patients with myelodysplastic syndromes. The median duration of therapy was 285 days (range 93–1,513 days). Four patients (29%) discontinued treatment because of lack of response (n=2) or a sustained response (n=2). No grade 3–4 adverse events occurred, particularly no thrombosis. In our real-life experience, TPO-RAs were effective and safe and proved of value in the challenging management of patients with refractory thrombocytopenia associated with different conditions.

Inherited platelet function defects are characterized by sub-acute and chronic mucocutaneous bleedings leading to iron deficiency anemia (IDA). Oral supplementation is the mainstay of treatment of IDA; however, it can be insufficient to compensate the losses and is often associated with gastrointestinal (GI) side effects. Intravenous (IV) iron is indicated for severe anemia or to overcome GI intolerance. Previous IV iron formulations were limited by the risk of free iron toxicity and immunogenicity, while currently available compounds (ferumoxytol, iron isomaltoside and ferric carboxymaltose (FCM)) allow the administration of high doses with low immunogenicity. There are neither any randomized studies nor case reports evaluating the efficacy of FCM in patients with inherited platelet disorders. We herein present three cases of patients with IDA related to Glanzmann thrombasthenia and Bernard-Soulier syndrome, who have been successfully treated with FCM with increase in hemoglobin levels, reduced hospital visits and improvement in quality of life.

Introduction The association between hepatitis C virus (HCV) infection and B-cell non-Hodgkin’s Lymphomas (NHL) is well established. Antiviral therapy (AVT) is the first-line treatment for HCV-related indolent NHL whereas diffuse large B-cell lymphoma (DLBCL) requires immediate start of chemoimmunotherapy (CIT), usually deferring AVT. However, an early HCV elimination may reduce the risk of CIT-induced liver toxicity and consequent CIT interruption or withdrawal. To date few data are available on safety and efficacy of concomitant administration of direct-acting antivirals (DAA) and CIT in HCV-associated DLBCL. Methods 7 consecutive patients (5 males, median age 65 years) with HCV infection (four genotype 2a/2c, two genotype 1b, one genotype 4; one patient with compensated cirrhosis) and DLBCL received different DAA regimens concurrently with CIT. Results All patients completed the scheduled AVT and CIT with neither interruption nor withdrawal of the latter. One case of neutropenia was observed during concomitant therapy, no liver toxicity occurred. All patients achieved sustained virological response and complete DLBCL response (median follow-up of 12 months). Conclusions Concomitant administration of DAA and CIT for HCV-associated DLBCL is safe and may prevent CIT-induced liver toxicity. Large, prospective studies are needed to confirm these preliminary data and to assess prognostic implications.

Autoimmune hemolytic anemias are rare and heterogeneous disorders characterized by hemolysis, which is a well-recognized risk factor for thrombosis. The most common immune-mediated anemias are represented by autoimmune hemolytic anemia and paroxysmal nocturnal hemoglobinuria, both associated with a high rate of thrombosis. Multiple pathophysiological mechanisms for thrombosis have been proposed, involving hemolysis itself and additional effects of the immune system. Despite the increasing awareness of the thrombotic risk in these conditions, evidence-based guidance on prevention and management of thrombotic events is lacking. We herein report available evidence on epidemiological data on thrombosis and thrombophilia in immune-mediated hemolysis, together with possible underlying pathophysiological mechanisms. In addition, we summarize current recommendations for treatment of thrombosis in immune-mediated hemolysis. In particular, we address the issue of thrombotic complications treatment and prophylaxis by proposing a therapeutic algorithm, focusing on specific situations such as splenectomy and pregnancy.

Primary brain tumors are associated with an increased risk of pulmonary embolism (PE), particularly in the early post-operative period. The pathophysiological mechanisms of PE are poorly understood. This study aims to describe prospectively extracellular vesicles (EVs) levels and investigate whether or not their variations allow to identify patients at increased risk of post-operative PE. Consecutive meningioma or glioma patients candidate to tumor resection were included in the study if a pulmonary perfusion scan (Q-scan) performed before surgery ruled out PE. EVs derived from platelets (CD41

To the Editor, In this journal, risk factors for disease progression in hospitalized patients with COVID-19 were recently described in a study from Beijing, China [1]. Multivariate logistic analysi...

Summary Background Inherited quantitative (type I) deficiency of plasma antithrombin is associated with a high risk of venous thromboembolism, which further increases in pregnancy. Inherited thrombophilia also increases the risk of obstetrical complications, but data on maternal and fetal outcomes in women with antithrombin deficiency are scarce. The aim of this study was to evaluate the risk of pregnancy-associated venous thromboembolism and obstetrical complications in women with type I antithrombin deficiency. Methods In this single-centre, retrospective cohort study, women who had been referred to our Hemophilia and Thrombosis Centre, Milan, Italy for a thrombophilia work-up from Jan 1, 1980, to Jan 1, 2018, with type I antithrombin deficiency and who had had at least one pregnancy were included. Women with type II anthithrombin deficiency were excluded from the study. Data on pregnancy-associated venous thromboembolism, pregnancy outcomes, and the use of low-molecular-weight heparin (LMWH) were collected to evaluate the risk of pregnancy-associated venous thromboembolism and obstetrical complications with or without use of LMWH. Findings 126 women had been referred to the hospital, of whom 88 (70%) had had at least one pregnancy. Eight were excluded because of referral for venous thromboembolism during pregnancy or the puerperium, resulting in 80 (63%)women evaluated for the risk of venous thromboembolism. One woman was excluded because of referral for obstetrical complications, resulting in 87 (69%) evaluated for risk of obstetrical complications. We observed three events of venous thromboembolism in 43 pregnancies in women treated with LMWH (7·0%, 95% CI 1·8–17·8), and 17 events in 146 pregnancies in women who did not receive LMWH (11·6%, 7·2–17·6; relative risk [RR] 0·6, 95% CI 0·2–1·9; p=0·57). The risk of venous thromboembolism without LMWH was 5·4% (95% CI 0·9–16·7) in women with a negative family history of venous thromboembolism, and 11·8% (6·4–19·6) in those with a positive family history of venous thromboembolism. Of the 87 women evaluated for the risk of obstetrical complications, miscarriages occurred in 6 (13%) of 45 pregnant women treated with LMWH and 32 (20%) of 161 women who did not receive LMWH (terminations excluded). Late obstetrical complications occurred in 11 (24%) of women treated with LMWH and nine (6%) in those who did not receive LMWH (RR 4·4, 95% CI 1·9–9·9; p=0·0006). Interpretation Our results confirm that women with type I antithrombin deficiency have a high risk of first or recurrent venous thromboembolism during pregnancy. The risk of venous thromboembolism is highest in women with a positive family history of the condition, but still relevant in those with a negative family history, suggesting that LMWH prophylaxis should also be considered in these patients. Funding None.

Lateral periodontal cysts (LPCs) are rare odontogenic cysts of developmental origin. A 52-year-old man presented with an asymptomatic gingival swelling located between the mandibular left canine and first premolar, both of which were vital. Radiography showed a well-circumscribed radiolucent area and loss of the lamina dura around the tooth socket in contact with the lesion and of the interproximal buccal bone. The lesion was enucleated. The defect was immediately grafted with a 1:1 mixed autologous and heterologous bone graft covered with a collagen membrane. Histology confirmed the diagnosis of LPC. At 12- and 24-month clinical and radiologic follow-up, complete bone and periodontal healing was found, with no sign of recurrence.

Introduction Acquired immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening thrombotic microangiopathy caused by the development of anti-ADAMTS13 autoantibodies. Up to 50% of patients surviving an acute iTTP event experience one or more relapses. Recent guidelines suggest treatment with rituximab in clinical remission in iTTP patients with low ADAMTS13 activity to prevent acute iTTP relapses. A 10% of cases who do not respond to rituximab or develop allergic reactions requiring therapy discontinuation have been reported. In these patients, azathioprine might be an alternative treatment to prevent acute iTTP relapses. The aim of this study was to assess the efficacy and safety of azathioprine treatment in iTTP patients in clinical remission. Methods We designed a retrospective cohort study including all iTTP patients treated with azathioprine during clinical remission, enrolled in the Milan TTP Registry between May 2003 and October 2020 and followed for at least six months. The efficacy of azathioprine was assessed in patients with at least four weeks of treatment. The primary outcome was clinical relapse during azathioprine treatment. The secondary outcomes were the partial and complete responses of ADAMTS13 (an ADAMTS13 activity increase above 20% and 45%, respectively) in patients with ADAMTS13 activity below 20% before azathioprine start. ADAMTS13 relapse (an ADAMTS13 activity decrease below 20%) in patients with a prior ADAMTS13 response was also assessed. As for the safety analysis, adverse events (AEs), associated or not with treatment discontinuation, were retrieved from clinical charts of all patients. Lastly, we assessed the association between variables such as sex, age, and concomitant autoimmune diseases, and ADAMTS13 response, using logistic regression models. Results We enrolled 43 patients with iTTP treated with azathioprine during clinical remission (Table 1). Forty-two percent of the patients had at least one concomitant autoimmune disease. The median exposure to azathioprine was 16 months (interquartile range [IQR] 8-49 months), the median dosage 1.3 mg/kg/day (IQR 0.9-1.6 mg/kg/day). Thirty-five cases were available for the primary outcome analysis (Table 2). Seven patients relapsed after a median time of 14 months after azathioprine start (IQR 8-58 months). The cumulative incidence of clinical relapse during azathioprine treatment was 10% at 1 year (95% Confidence Interval [CI] 0-21%), 22% at 2 years (95% CI 6-38%). Twenty-one cases were available for the secondary outcomes analysis. An ADAMTS13 partial response occurred in 10 patients (48%), after a median time of 3 months (IQR 3-9 months) after azathioprine start and lasted for a median time of 40 months (IQR 16-56 months). An ADAMTS13 complete response was achieved in 33% of patients, after a median time of 8 months (IQR 3-16 months) after azathioprine start and lasted for a median time of 16 months (IQR 0-53 months). Of the 10 responders, 3 (30%) had a subsequent ADAMTS13 relapse at 22, 24 and 37 months after azathioprine start. Adverse events were observed in 30% of patients, after a median time of 50 days after azathioprine start (IQR 26-331 days). Liver and pancreas alterations with increased levels of ALT, AST, GGT, ALP and lipase were the most frequent, followed by nausea and leukopenia (Table 3). In one patient, acute myeloid leukemia was diagnosed 6 months after azathioprine start. Fifteen percent of the patients had to stop the treatment due to AEs. No demographic or anamnestic variables were associated with ADAMTS13 response to azathioprine. Conclusions Forty-eight percent of patients attained an ADAMTS13 activity above 20%, with a durable response lasting more than 3 years, while adverse events were generally mild in nature. Azathioprine could be a valid and safe alternative in case of ineligibility or failure to respond to rituximab. Figure 1 Figure 1. Disclosures Mancini: Instrumentation Laboratory, Sanofi: Honoraria. Peyvandi: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria. OffLabel Disclosure: Azathioprine. It is an immunosuppressive drug used for the prevention of rejection in renal homotransplantation and for treatment of active rheumatoid arthritis.

Evans' syndrome is a rare condition (estimated prevalence of 1-9 per million), characterized by the association (concomitant or not) of immune thrombocytopenia (ITP), with autoimmune hemolytic anemia (AIHA), and/or autoimmune neutropenia (AIN). Here we investigated 106 adult patients (male to female ratio 0.89, median age 50 years) followed for a median of 7.5 years in 12 European tertiary centers. Hematological data and associated conditions at diagnosis, treatments, complications, and outcome were retrospectively collected. The vast majority of patients had the combination of ITP plus AIHA, whereas 6.6% had ITP plus AIN, 2.8% AIHA plus AIN, and 8.5% had triple lineage cytopenia. At presentation, thrombocytopenia, anemia, and concomitant cytopenias were equally frequent (about 1/3 each), whilst AIN was rarer. An associated condition was present in 29% of cases, and included: a) other autoimmune diseases (11.3%), namely Hashimoto thyroiditis (N=7), anti-phospholipid syndrome (N=3), systemic lupus erythematosus (N=1), rheumatoid arthritis (N=1); b) tumors/clonal disorders (12.2%), consisting of colorectal cancers (N=3), thymoma (N=1), Ewing sarcoma (N=1), lymphoproliferative disorders (N=3), multiple myeloma (N=1), MGUS (N=3), and paroxysmal nocturnal hemoglobinuria (N=1); and c) immunodeficiencies (5.6%), including common variable immunodeficiency (N=5), and Kabuki syndrome (N=1). Laboratory values are detailed in table 1, and show a great heterogeneity depending on the predominant cytopenia. Direct antiglobulin test was positive in 93/106 cases, diagnosing 82 warm AIHA (57 IgG, 23 IgG+complement, and 2 IgA), 4 cold and 7 mixed AIHA. Anti-platelets antibodies were positive in 41/48 patients (85%), and anti-neutrophil antibodies in 10/22 (45%). Immunoglobulin levels showed high variability consistently with the underlying conditions, with hypo-IgA present in 5/49 (10%), and hypo-IgG or IgM in 9 (18%) and 8 (16%), respectively. Additionally, anti-nuclear antibodies were positive in 33/88 (37.5%), ENA in 5/63 (8%), anti-DNA in 4/66 (6%), anti-cardiolipin antibodies in 12/64 (18.7%), anti-beta2 glycoprotein antibodies in 8/50 (16%), and lupus anticoagulant in 9/60 (15%). Regarding therapies, all patients received steroids as first-line and 84% intravenous immunoglobulins (mainly for ITP). Rituximab was administered in 51.8% (7 in first, 22 in second, and 26 in subsequent lines), immunosuppressors in 49% (mycophenolate mofetil N=15, azathioprine N=14, cyclophosphamide N=12, and cyclosporine N=11), and splenectomy was performed in 20% of patients. Notably, thrombopoietin receptor analogues (TPO-RA) were given in 38% of cases, namely eltrombopag (N=24), romiplostim (N=16) or both (N=4). Additional therapies included plasma exchange (N=4), recombinant erythropoietin (EPO, N=3), GCSF (N=2), bortezomib (N=2), fostamatinib (N=1), and parsaclisib (N=1). Response rate to first line steroids+/-IVIG was 85%, however, 21 patients required further concomitant treatment (including 2 splenectomies). Response rates beyond first line therapy are difficult to evaluate given that AIHA or ITP relapses required different treatments (i.e. EPO versus TPO-RA), and that many relapses were treated with multiple concomitant treatments. On the whole, relapses were very frequent with 81/106 (76.4%) experiencing at least one, 53.7% two, and 27.3% three or more relapses. Regarding complications, bleeding was observed in 45/106 (42.4%), thrombosis in 27 (25.4%), and CTCAE >3 infections in 46 (43.3%). Death occurred in 26% of cases. In conclusion, these data highlight the clinical severity and the unmet need for therapy in adult Evans' syndrome. Moreover, the great frequency of relapses and burden of complications underline the poor clinical outcome of this condition. Disclosures Michel: Bioverativ: Consultancy; Rigel: Consultancy; Alexion Pharmaceuticals: Consultancy. McDonald:Sobi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bianchi:Agios Pharmaceuticals: Other: Scientific Advisor. Barcellini:Bioverativ: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Other: invited speaker , Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: invited speaker , Research Funding.

Venous thrombosis rarely occurs at unusual sites such as cerebral, splanchnic, upper-extremity, renal, ovarian, or retinal veins. Clinical features, symptoms, and risk factors of rare thrombotic manifestations are heterogeneous and in large part differ from those typical of the commonest manifestations of venous thrombosis at the lower extremities. The therapeutic approach also varies widely according to the affected site, whether cerebral, abdominal, or extraabdominal. To date, anticoagulant therapy for thrombosis at unusual sites is generally accepted, but the optimal therapeutic approach remains challenging. This review is focused on the treatment of unusual thrombotic manifestations as reported in the most recent guidelines and according to the updated scientific literature.

The cerebral venous system is an unusual site of thrombosis, with a particularly high incidence in young adults. This incidence has increased in past decades because of the improvement of neuroradiological techniques. Risk factors for cerebral venous sinus thrombosis overlap with those of other venous thromboembolism sites; however, some are specific for this particular anatomical district. Prognosis is favorable in most cases if diagnosis is made rapidly and treatment is promptly initiated, even if acute complications or chronic invalidity still occur in a quarter of patients. The mainstay of treatment is anticoagulation, which is necessary in order to block clot propagation and obtain recanalization. Intracranial bleeding does not contraindicate anticoagulation. Endovascular procedures are reserved for patients with a particularly severe presentation or rapidly declining neurological symptoms despite appropriate anticoagulation, although data from clinical trials are lacking. Specifically, this review addresses the epidemiology, clinical presentation and course, risk factors, and treatment of cerebral venous sinus thrombosis, with a special focus on the pediatric population.

Background Iron overload-related heart failure is the principal cause of death in transfusion dependent patients, including those with Thalassemia Major. Linking cardiac siderosis measured by T2* to therapy improves outcomes. T1 mapping can also measure iron; preliminary data suggests it may have higher sensitivity for iron, particularly for early overload (the conventional cut-point for no iron by T2* is 20ms, but this is believed insensitive). We compared T1 mapping to T2* in cardiac iron overload. Methods In a prospectively large single centre study of 138 Thalassemia Major patients and 32 healthy controls, we compared T1 mapping to dark blood and bright blood T2* acquired at 1.5T. Linear regression analysis was used to assess the association of T2* and T1. A “moving window” approach was taken to understand the strength of the association at different levels of iron overload. Results The relationship between T2* (here dark blood) and T1 is described by a log-log linear regression, which can be split in three different slopes: 1) T2* low, 30ms, weak relationship. All subjects with T2*20ms, 38% had low T1 with most of the subjects in the T2* range 20-30ms having a low T1. Conclusions In established cardiac iron overload, T1 and T2* are concordant. However, in the 20-30ms T2* range, T1 mapping appears to detect iron. These data support previous suggestions that T1 detects missed iron in 1 out of 3 subjects with normal T2*, and that T1 mapping is complementary to T2*. The clinical significance of a low T1 with normal T2* should be further investigated.

This work was inspired by a recent juridical development in Italy, whose purpose is to prevent rejection of damage claims whenever it is not possible to prove a causal link between iatrogenic illicit behavior and damage to the patient, despite the fact that the patient has clearly suffered physical or mental injury. In view of this, some European countries—e.g., France and Germany—have recently come up with a new damage interpretation called loss of chance, i.e., the missed opportunity to get a more favorable outcome through different or more timely and efficient therapies. Although the problem has been thoroughly discussed on several levels, no countries have conformed their legislation accordingly, leaving it up to the courts to settle issues of damage claims where loss of chance can be applied and to resolve doubts about the limits of applicability of this new type of damage interpretation. The concept of loss of chance seems to be applicable to many cases in ophthalmologic practice. For example, glaucoma and macular degeneration are common, serious, and potentially blinding diseases in which delayed diagnosis and therapy reduce the chances not only to limit injuries, but also to stop future progress of the disease. Hence, the authors emphasize that a good practice is the only way for ophthalmologists to avoid malpractice claims related to the new developments in tort law in Italy and in other European countries following the creation of new definitions of damage.

INTRODUCTION In thalassemia patients transfusion therapy and inappropriately increased iron absorption due to ineffective erythropoiesis cause iron overload, which account for most morbidity in these patients, with involvement of liver, heart and endocrine glands. The most frequent endocrine defect is hypogonadotropic hypogonadism, followed by diabetes mellitus, hypothyroidism and hypoparathyroidism. The hypothalamic-pituitary-adrenal axis is rarely affected, but the identification of asymptomatic patients is crucial, as adrenal insufficiency is a potentially life-threatening condition. Hypoadrenalism can play a dramatic role in stressful situations like acute cardiac failure, sepsis or surgery. A better understanding of emerging complications, including adrenal insufficiency, is essential in the thalassemia population, considering their increased survival and life activities. We describe three cases of thalassemia major patients regularly monitored at our Rare disease Center. The annual endocrinological follow-up at our Clinic includes the evaluation of basal adrenal function (cortisol and corticotrophin serum levels), with completely normal results in the patients described. In all of them there were no symptoms nor clinical signs of hypoadrenalism, which dramatically emerged only on occasion of acute events and was confirmed by the finding of inappropriately low serum cortisol levels. CASE REPORT 1. A 52-year-old male was admitted to the Intensive Care Unit for severe sepsis due to bacterial pneumonia and heart failure associated with atrial fibrillation in November 2015. He was regularly transfused every three weeks, on oral iron chelation therapy with deferasirox with no liver nor cardiac iron overload. Conversely, endocrinopathy was present with type 2 diabetes, hypogonadotropic hypogonadism and hypoparathyroidism. Adrenal crisis was suspected because of persistent hypotension despite intensive treatment for septic shock, including intravenous norepinephrine. Intravenous replacement therapy with hydrocortisone rapidly reverted the hypotension. CASE REPORT 2. A 44-year-old male patient was admitted to the Intensive Care Unit in February 2015 for severe sepsis, hyponatremia, hypoglycemia and mental confusion. He was regularly transfused with two/three units of packed red cells every three weeks, on iron chelation therapy with deferasirox. He had not liver nor heart iron overload, and the only endocrine defect was hypogonadotropic hypogonadism. Hypoadrenalism was suspected as severe hypoglycemia did not respond to continuous ev glucose administration. Glucose blood levels normalized only after hydrocortisone ev. CASE REPORT 3. A 40-year-old male patient had a right abdominal mass known since 2002, and ascribed to extramedullary erythropoiesis. The mass volume had been progressively increasing up to 19 x 15 x 25 cm³. In 2015 a computed tomography scan of the abdomen showed a huge well circumscribed retroperitoneal mass in the right abdomen, originating from the right adrenal gland, displacing the liver medially and the right kidney caudally and anteriorly; moreover, it compressed the inferior vena cava and displaced the mesenteric vessels. In view of surgery, though adrenal basal function was normal an ACTH test was performed, disclosing adrenal insufficiency. Replacement therapy with hydrocortisone was set to make the patient able to cope with the stressful event. Laparotomy was performed and a 3.5 kg encapsulated tumour attached to the right adrenal gland was removed; histology revealed a giant myelolipoma. CONCLUSIONS The three cases presented show that adrenal insufficiency requires early detection, that it may be underdiagnosed and it can present dramatically in acute and even life-threatening conditions. Pituitary-adrenal axis should be screened in asymptomatic thalassemic patients, and once adrenal insufficiency has been identified, it should be treated to prevent potentially lethal consequences. Currently, our patients are asymptomatic on chronic oral replacement therapy with cortisone acetate. Increased awareness of the risks of hypoadrenocorticism in patients with iron overload is needed, because symptoms are usually not clinically evident and often neglected because of their mildness, especially in non-stressful situations. Disclosures Cappellini: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Genzyme-Sanofi: Membership on an entity's Board of Directors or advisory committees.

Background Congenital heart block (CHB) is a transplacentally acquired autoimmune disease associated with anti-Ro/SSA and anti-La/SSB maternal autoantibodies and is characterized primarily by atrioventricular (AV) block of the fetal heart. This study aims to investigate whether the T-type calcium channel subunit α1G may be a fetal target of maternal sera autoantibodies in CHB. Methodology/principal findings We demonstrate differential mRNA expression of the T-type calcium channel CACNA1G (α1G gene) in the AV junction of human fetal hearts compared to the apex (18-22.6 weeks gestation). Using human fetal hearts (20-22 wks gestation), our immunoprecipitation (IP), Western blot analysis and immunofluorescence (IF) staining results, taken together, demonstrate accessibility of the α1G epitope on the surfaces of cardiomyocytes as well as reactivity of maternal serum from CHB affected pregnancies to the α1G protein. By ELISA we demonstrated maternal sera reactivity to α1G was significantly higher in CHB maternal sera compared to controls, and reactivity was epitope mapped to a peptide designated as p305 (corresponding to aa305-319 of the extracellular loop linking transmembrane segments S5-S6 in α1G repeat I). Maternal sera from CHB affected pregnancies also reacted more weakly to the homologous region (7/15 amino acids conserved) of the α1H channel. Electrophysiology experiments with single-cell patch-clamp also demonstrated effects of CHB maternal sera on T-type current in mouse sinoatrial node (SAN) cells. Conclusions/significance Taken together, these results indicate that CHB maternal sera antibodies readily target an extracellular epitope of α1G T-type calcium channels in human fetal cardiomyocytes. CHB maternal sera also show reactivity for α1H suggesting that autoantibodies can target multiple fetal targets.