Immune thrombocytopenia (ITP) is one of the most common causes of thrombocytopenia. The diagnosis is established when platelet counts are consistently below 100 × 109/L, after excluding alternative etiologies through a targeted laboratory workup. However, the initial evaluation should always be adapted to the clinical context, taking rare causes into consideration. Establishing an accurate diagnosis is essential, as it allows for the prompt initiation of appropriate treatment tailored to the individual situation and facilitates long-term management. In this article, the diagnostic workup and the initial therapeutic management of ITP are discussed.

Heme toxicity plays a central role in the pathophysiology of Sickle Cell Disease (SCD), contributing to severe complications such as vaso-occlusion and acute chest syndrome. The continuous release of hemoglobin and heme from increased intravascular hemolysis can exceed the capacity of protective scavenger proteins, leading to heme accumulation in plasma. Interactions with various binding partners result in the formation of different plasma heme species and the compartmentalization of the plasma heme pool. In an observational biomarker study, we used novel bioanalytical assays to quantify plasma heme species in 36 stable-state SCD patients and 36 age, sex, and ethnicity-matched controls. Our results revealed substantially different compartmentalization of plasma heme, despite similar levels of total plasma heme in SCD patients (50 µmol/L) and controls (43 µmol/L). Using a correlation analysis across 85 biomarkers, we examined the association of specific heme species with SCD pathophysiology. Hemopexin-accessible heme (HAH) emerged as a refined indicator of heme burden linked to pathways driving severe SCD complications. A strong inverse correlation was observed between HAH and hemopexin (R = -0.73, p < 0.001), suggesting that hemopexin deficiency contributes to elevated HAH levels. Accurate characterization of clinically relevant plasma heme species and understanding their effects on SCD pathophysiology is essential for the development of new targeted therapies.

The most recent somatic gene therapies strategies for β-hemoglobinopathies - sickle cell disease and β-thalassemia – aim at stable re-expression of high level of fetal hemoglobin (HbF) are transforming the contemporary therapeutic landscape. HbF, expressed during in utero life and physiologically silenced after birth, has a higher affinity for oxygen allowing for transplacental exchange of oxygen. Its persistence at significant levels in the maternal circulation could impair fetal oxygenation during subsequent pregnancies. To anticipate the obstetric risks in this emerging population, we synthesize existing evidence on pregnancy outcomes in women with hereditary persistence of fetal hemoglobin (HPFH)—a naturally occurring model of elevated HbF—to apprehend potential maternal and fetal impacts in individuals having undergone gene therapy for β-hemoglobinopathies. Evidence is very limited. It strongly suggests that moderate HbF levels (10–30%) reduce both maternal and fetal complications in sickle cell disease. However, levels exceeding 50%, as observed after gene editing in β-thalassemia, might blunt the maternal-fetal oxygen affinity gradient and contribute to placental insufficiency and fetal growth restriction. Based on these elements this viewpoint outlines pragmatic adaptation of the current recommendations for antenatal monitoring in pregnancies with supraphysiological level of maternal HbF. As gene-therapies are offered to teenagers and young adults and includes fertility preservation prior to conditioning, obstetricians and hematologists will be requested to manage post-therapy pregnancies in this population. Multidisciplinary guidelines and dedicated registries will be essential to ensure maternal safety and optimize perinatal outcomes within this evolving therapeutic landscape.

BACKGROUND:While neutropenic enterocolitis (NEC) is a well-known life-threatening complication during intensive chemotherapy, its incidence, impact, and outcome on specific at-risk populations remain ill defined. METHODS:We report 178 NEC episodes during 1963 myeloablative chemotherapy courses among 1259 adult patients with acute myeloid (AML) or lymphoblastic (ALL) leukemia or receiving autologous hematopoietic stem cell transplantation (auto-HCT) for lymphoma or multiple myeloma. Risk factors were assessed by multivariate logistic regression models. RESULTS:Most NEC cases (93.3%) occurred during AML induction (n = 92; 13.8% of chemotherapy course) and auto-HCT (n = 74; 9.5%). Independent risk factors for NEC during AML induction included high-dose corticosteroids (OR = 2.07; 95% CI: 1.29-3.30; P = .002), elevated circulating blasts at the time of diagnosis (>50 Giga/L; OR = 2.02; 95% CI: 1.15-3.56; P = .02), and use of azacitidine (OR = 2.45; 95% CI: 1.01-5.90; P = .05); purine-based regimens (eg, FLAG-Ida) were an independent protective factor (OR = .27; 95% CI: .15-.47; P < .001). Independent risk factors after auto-HCT included BEAM (carmustine, etoposide, cytarabine, and melphalan) versus another conditioning protocol (OR = 3.28; 95% CI: 1.98-5.43; P < .001) and age (OR = 1.03/year; 95% CI: 1.01-1.06; P = .007). For both AML induction and auto-HCT, NEC was associated with longer hospitalization (P = .03 and <.001), sepsis (quick SOFA ≥2; P = .03 and <.001), fungemia (P < .001 and P = .01), and intensive care admission (P = .03 and <.001, respectively). NEC was associated with increased in-hospital mortality during AML induction (6.5% vs 2.4%; P = .04) but not during auto-HCT (P = .3). CONCLUSIONS:The incidence of NEC depended on chemotherapeutic regimens, with higher occurrence during standard "7 + 3" AML induction and BEAM conditioning for auto-HCT. NEC was associated with longer hospitalization and increased morbidity, but 30-day mortality was lower than previously reported.

Introduction: Hemolytic disease of the fetus and newborn (HDFN) is a potentially life-threatening condition caused by maternal alloimmunization against fetal red blood cell (RBC) antigens. While most cases involve well-characterized antibodies such as anti-D, anti-c, or anti-K, antibodies against low-prevalence antigens (LPAs) — particularly those within the MNS blood group system — remain underrecognized and underreported. Case Presentation: We report a case of maternal alloimmunization against the paternally inherited low-prevalence antigen MUT (MNS35), carried on a hybrid glycophorin (GYPA*19, GP.Hut), across three pregnancies. The first pregnancy ended in fetal demise due to severe anemia at 33 weeks of gestation (WG). In a subsequent twin pregnancy, both neonates presented with severe HDFN after emergency cesarean section at 31 WG. Anti-MUT antibodies were identified in maternal plasma and neonatal eluates, with a high monocyte index observed in functional testing using paternal and GP.Mur-positive RBCs. Sequencing demonstrated the presence of the GYPA*19 (GYPA*Hut) allele in both infants. The two neonates had favorable outcome after exchange transfusion and intensive phototherapy. A third pregnancy was closely monitored. Anti-MUT antibodies remained stable at 1/32 between 20 and 36 WG. The patient delivered a healthy newborn without anemia. After birth, the child was tested GP.Hut negative. Conclusion: This case supports the pathogenicity of anti-MUT as a cause of severe HDFN. It underscores the diagnostic challenges posed by antibodies against LPAs and highlights the importance of extended serological, molecular, and functional testing. Crossmatching maternal plasma with paternal RBCs and systematic evaluation of serological discrepancies can reveal otherwise undetectable alloantibodies. Early identification, functional assessment, and multidisciplinary management are key to optimizing outcomes in pregnancies complicated by rare RBC alloimmunization. Anti-MUT should be considered a clinically significant antibody with the potential to cause severe HDFN, warranting proactive perinatal surveillance.

Hyperferritinaemia is a common laboratory finding, but true iron overload is present in only about 10 % of cases. A thorough clinical history and laboratory evaluation are essential for diagnosis. In about 90 % of cases, hyperferritinaemia is associated with acute infections, inflammatory conditions, or autoimmune diseases, and does not indicate iron overload. The remaining 10 % of cases of true iron overload arise from either excessive parenteral iron administration or increased intestinal absorption, often linked to hepcidin deficiency. Prompt recognition of these cases is critical, as timely intervention can prevent organ damage. To facilitate early treatment-particularly initiation of phlebotomy-the classification of haemochromatosis has recently been simplified.

Recurrent miscarriage is a distressing condition with limited therapeutic options. Chronic histiocytic intervillositis of unknown etiology (CIUE) is a rare inflammatory placental disorder characterized by maternal immune cell infiltration of the intervillous space, fibrin deposition, and ischemic tissue damage, leading to pregnancy loss. The condition likely reflects an immune response against paternal alloantigens, with histopathological features resembling antibody-mediated rejection in solid organ transplantation. We investigated two women with recurrent CIUE-related pregnancy losses. Detailed immunological profiling included anti-human leukocyte antigen (HLA) antibody characterization, compatibility testing, and histopathological examination of previous placentas, as well as screening for other causes of recurrent pregnancy losses. Based on evidence of antibody-mediated alloimmune injury, we implemented a targeted immunosuppressive regimen derived from transplantation medicine, combining intravenous immunoglobulins (IVIG), tacrolimus, corticosteroids, and hydroxychloroquine, with close pregnancy monitoring. The first patient, after six consecutive CIUE-related pregnancy losses, underwent preconception desensitization and continued treatment throughout pregnancy. Early signs of placental dysfunction prompted therapy intensification, leading to delivery of a viable infant at 33 + 2 weeks. Placental histology showed only minor residual CIUE lesions. The second patient, with two pregnancy losses and a fetal demise from CIUE, began treatment at 6 weeks’ gestation and delivered a healthy infant at 36 weeks. In both cases, therapy was generally well tolerated, with gestational diabetes as the main complication, and no major maternal or neonatal adverse events. These cases support the concept that CIUE represents a breakdown of maternal immune tolerance toward paternal antigens, mediated by fetal-specific anti-HLA antibodies—akin to solid organ graft rejection. An immunosuppressive protocol adapted from transplantation medicine achieved two successful live births after multiple CIUE-related pregnancy losses. Targeting antibody-mediated alloimmunity may represent a promising therapeutic strategy for selected patients with recurrent miscarriages due to CIUE. Further studies are warranted to define optimal regimens and identify predictors of response.

ABSTRACT Introduction 5‐Azacitidine (AZA) is a major treatment option for myelodysplastic neoplasms (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). Here we evaluate the efficacy and toxicity of an alternative AZA regimen (100 mg/m2/day for 5 days/28 days) in 68 patients (51 MDS, 17 MDS/MPN) treated between 2008 and 2018. Results Median patient age was 66 years, with most patients (98%) having intermediate or high‐risk disease. Overall response rate (ORR) was 62% with 22% complete responses (CR). Median OS and median PFS were 22.5 and 18.2 months, respectively. Inferior response rates were calculated in therapy‐related MDS (t‐MDS) and MDS with excess blast II, with t‐MDS having also statistically worse OS and PFS. MDS/MPN patients showed 73.6% ORR with 31.5% CR. Transfusion independence (TI) for red blood cells (RBC) was achieved in 45.9% of transfusion‐dependent patients and in 30% for platelets. CR patients showed longer mOS and mPFS (70.6 and 64.7 months, respectively). Longer mOS was also correlated with allogeneic transplantation (48.8 vs. 16.9 months, p = 0.01) and RBC TI (25.4 vs. 13.3 months, p = 0.01). Grade 3/4 cytopenias occurred in 41.1% (neutropenia in 33.8%), and treatment‐related mortality was 7.4%. Conclusion This study demonstrates that this alternative AZA regimen has comparable efficacy and safety to the standard regimen, compared with historical data. Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder characterized by the absence of complement regulatory proteins on the surface of erythrocytes, leading to intravascular hemolysis and thrombosis. Managing PNH during pregnancy poses significant challenges due to increased risks of morbidity and mortality. This case report describes the detailed obstetric course of a 44-year-old woman with PNH and additional hereditary protein C deficiency who had previously experienced multiple thrombotic events and adverse pregnancy outcomes (two early miscarriages and one stillbirth at 25 weeks gestation [WG]), treated with eculizumab (terminal C5 inhibitor) and optimal anticoagulation management. Close monitoring of hemolysis and hemostasis parameters was conducted throughout the gestation period together with increased obstetrical surveillance. The pregnancy progressed without thrombotic complications or breakthrough hemolysis, and the patient delivered a healthy newborn at 36 WG after induction of labor due to restricted fetal growth. To the best of our knowledge, this is the first reported case of a positive pregnancy outcome despite PNH in conjunction with hereditary thrombophilia. This case report highlights the importance of a multidisciplinary approach involving hematologists and obstetricians in the management of pregnant women with PNH. Tailored therapy, close monitoring, and comprehensive care are crucial to minimize risks and optimize outcomes.

During pregnancy, the mother's IgG immunoglobulins cross the -placenta via the neonatal Fc receptor (FcRn), enabling the fetus to acquire passive immunity. In the presence of maternal allo- or auto-antibodies, placental transfer of these pathogenic antibodies mediated by FcRn can cause diseases in the fetus and/or the newborn. FcRn blockade therefore appears to be a therapeutic strategy in these high-risk pregnancies, firstly by reducing IgG recycling, -thereby reducing its concentration in the maternal circulation, and secondly by blocking placental transfer. The promising results of a recent trial testing nipocalimab, a monoclonal antibody targeting FcRn, in very severe erythrocyte alloimmunisation, has opened the way to new targeted therapeutic approaches for perinatal diseases mediated by maternal IgG.

Background and Aim Sickle cell disease (SCD) has significant pathophysiological complexity and phenotypic heterogeneity that need to be considered for therapeutic decision-making and the development of new treatments. Here we derived transcriptomic profiles from an unbiased whole-blood gene expression analysis to investigate their associations with SCD clinical phenotypes. Methods 36 patients aged ≥18 years diagnosed with SCD (HbSS and S/β-thalassemia) were included and compared to 36 age, sex, and ethnicity-matched healthy controls in a prospective cross-sectional observational study in two Swiss university hospitals between June 2020 and February 2023. Current and past (≤2 years) hematological parameters and clinical information were used to characterize SCD clinical phenotypes. Blood of SCD patients and healthy controls was collected and mRNA was sequenced on an Illumina system. Fragment counts were normalized as transcripts per million (TPM), and transcriptomic profiles were defined by dimensionality reduction using a Principal Coordinates Analysis (PCoA). Gene set enrichment analysis (GSEA) was performed against the GSEA Hallmark gene sets, based on the correlation of gene expression to PCoA dimensions. For the correlation of hematological and clinical variables with PCoA dimensions, Pearson correlation statistics are reported for continuous variables and one-way ANOVA statistics for factorial variables. Results Whole-blood transcriptomic profiles of SCD patients diverged from healthy controls in an unsupervised PCoA analysis, resulting in a clear separation of these two groups. Focusing on SCD profiles, we found substantial variability with increasing dissimilarity from controls captured by the first dimension of the PCoA solution (PCoA1). A strong correlation between PCoA1 and heme metabolism-related gene expression (GSEA adjusted p-value <0.001) indicated higher hemolytic activity with increasing distance from controls on PCoA1. In line with the expression of heme metabolism-related genes, blood values confirmed increased hemolysis in patients with more distant transcriptomic profiles. We found strong positive correlations between PCoA1 and increased LDH (R=0.52, adj.p=0.008), total bilirubin (R=0.47, adj.p=0.013), and reticulocyte counts (R=0.75, adj.p<0.001). Correspondingly, PCoA1 was negatively correlated with hemoglobin concentration (R=-0.42, adj.p=0.025) and erythrocyte counts (R=-0.61, adj.p<0.001). PCoA1 also correlated with blood values of the same patients from the 2 previous years (LDH R=0.46, adj.p=0.038; bilirubin R=0.50, adj.p=0.038; reticulocytes R=0.63, adj.p=0.007; erythrocytes R=-0.48, adj.p=0.035), providing longitudinal evidence for the association between transcriptomic profiles and the hemolytic phenotype. We investigated the correlation of transcriptomic profiles with other SCD-relevant demographic and clinical parameters. None of the examined characteristics (e.g., SCD genotypes, current hydroxyurea use, previous blood transfusions, hospitalizations, or complications such as vaso-occlusive crisis, acute chest syndrome, or pulmonary hypertension) were significantly associated with transcriptomic profiles. Conclusion Using an unbiased gene expression approach, our results confirm the fundamental role of hemolysis in the pathophysiology and phenotypic variability of SCD. While transcriptomic profiles strongly reflect hemolytic intensities in SCD patients, we did not find evidence for an association with specific complications related to the hemolytic phenotype, probably due to the limited size of the study population. However, there is great potential in further analyzing unbiased SCD gene expression profiles to better understand the transcriptomic basis of phenotypic heterogeneity in SCD.