Irena Preložnik Zupan

Background and Clinical Relevance: C5 inhibitors effectively control intravascular haemolysis (IVH) in paroxysmal nocturnal haemoglobinuria (PNH), but persistent extravascular haemolysis (EVH) may result in ongoing anaemia and transfusion dependence. Iptacopan, an oral complement factor B inhibitor, targets both mechanisms of haemolysis. Case Presentation: We report the 26-year clinical course of a female patient who developed PNH following severe aplastic anaemia. Despite long-term treatment with eculizumab and subsequently ravulizumab, she remained transfusion-dependent due to persistent EVH. The clinical course included three pregnancies, with successful delivery during the third following intensified eculizumab treatment and multidisciplinary management. Switching to iptacopan in 2024 resulted in normalization of haemoglobin, reticulocyte counts and lactate dehydrogenase levels, and complete transfusion independence. Conclusions: This case illustrates the evolving clinical and therapeutic challenges of aplastic anaemia-associated PNH over 26 years. It highlights the limitations of long-term C5 inhibition in controlling EVH and the potential of proximal complement inhibition to achieve sustained haematological recovery and transfusion independence.

Objective: To compare the effects of intravenous (IV) ferric carboxymaltose (FCM), IV ferric derisomaltose (FDI), and oral ferrous sulfate on hypophosphatemia in women with postpartum anemia. Methods: Single-centre, open-label, randomized trial. Women were randomly allocated to receive IV FCM, IV FDI, or oral ferrous sulfate. IV iron was infused in one or two doses (on days 0 and 7 postpartum), while ferrous sulfate once daily. Serum phosphate level was measured at enrollment and 6 weeks postpartum. Serum phosphate level and the proportion of women with hypophosphatemia were analyzed. The Kruskal–Wallis test was used for comparison of phosphate levels and the Chi-squared test for comparison of proportions (p < 0.05). Results: Three-hundred women with postpartum anemia (Hb < 100 g/L within 48 h postpartum) were included. Phosphate levels at six weeks postpartum did not differ between groups: 1.24 mmol/L (inter-quartile range (IQR) 1.10–1.35; equivalent to 3.84 mg/dL, IQR 3.41–4.19) in the FCM group, 1.23 mmol/L (IQR 1.09–1.35; equivalent to 3.81 mg/dL, IQR 3.38–4.19) in the FDI group, and 1.25 mmol/L (IQR 1.15–1.34; equivalent to 3.88 mg/dL, IQR 3.57–4.15) in the ferrous sulfate group (p = 0.86). The proportion of women with hypophosphatemia was similarly low in all three groups (3 (3.1%) vs. 2 (2.2%) vs. 2 (2.2%); p = 0.89). At six weeks postpartum, hemoglobin levels were slightly higher in both IV iron groups compared with oral iron, but the differences were small and unlikely to be clinically meaningful. Conclusions: Treatment of postpartum anemia with IV FCM, IV FDI, and oral ferrous sulfate had similar impact on phosphate levels and incidence of hypophosphatemia at six weeks postpartum.

(1) Background: Postpartum anemia is a common maternal complication and is recognized as a cause of impaired quality of life, reduced cognitive abilities, and fatigue. Efficient iron supplementation for the treatment of postpartum anemia is an essential component of high-quality maternal care. The optimal mode of iron supplementation has not been determined yet, whether oral or intravenous. The objective of this study was to compare postpartum anemia treatment with intravenous ferric carboxymaltose, intravenous ferric derisomaltose, and oral ferrous sulfate. (2) Methods: A single-center, open-label, randomized controlled trial. Women with hemoglobin < 100 g/L within 48 h postpartum were randomly allocated to receive intravenous ferric carboxymaltose, intravenous ferric derisomaltose, or oral ferrous sulfate. Intravenous iron was given in one or two doses, while ferrous sulfate was given as two 80 mg tablets once daily. The primary outcome was maternal fatigue measured by the Multidimensional Fatigue Inventory (MFI) six weeks postpartum. Hemoglobin, ferritin, and transferrin saturation levels were analyzed as secondary outcomes. A Kruskal–Wallis test was used for group comparison (p < 0.05 significant). (3) Results: Three hundred women were included. The MFI score at six weeks postpartum did not differ between groups (median 38 (inter-quartile range (IQR) 29–47) in the ferric carboxymaltose group, median 34 (IQR 26–42) in the ferric derisomaltose group, and median 36 (IQR 25–47) in the ferrous sulfate group; p = 0.26). Participants receiving oral iron had lower levels of hemoglobin (135 (131–139) vs. 134 (129–139) vs. 131 (125–137) g/L; p = 0.008), ferritin (273 (198–377) vs. 187 (155–246) vs. 24 (17–37) µg/L; p < 0.001) and transferrin saturation (34 (28–38) vs. 30 (23–37) vs. 24 (17–37) %; p < 0.001) than those receiving ferric carboxymaltose or ferric derisomaltose. (4) Conclusions: Intravenous ferric carboxymaltose, intravenous ferric derisomaltose, and oral ferrous sulfate had similar impacts on maternal fatigue at six weeks postpartum despite improved laboratory parameters in the intravenous groups.

Prophylactic treatment with emicizumab has become an important and effective bleeding prevention for people with hemophilia A (PwHA). Perioperative management of PwHA using emicizumab prophylaxis is still challenging due to a lack of experience. Medical records of perioperative management and outcomes were reviewed, and data were collected for adult PwHA receiving emicizumab and undergoing surgical procedures between August 2019 and July 2022 at the University Medical Center Ljubljana. Twelve surgical procedures were performed in eight PwHA (one with FVIII inhibitors) while on emicizumab prophylaxis. Three minor procedures included cataract surgery, cystoscopic lithotripsy, and percutaneous coronary intervention. Nine major surgeries included four osteosyntheses, necrectomy of chronic osteomyelitis with new ankle arthrodesis, two below-knee amputations, total knee replacement, and placement of ventriculostomy after a spontaneous intraventricular hemorrhage. No major bleeds, thrombotic events or deaths, or new inhibitors appeared. Our real-world experience demonstrates that minor and major surgeries can be performed safely in PwHA on emicizumab prophylaxis. Additional data are needed to optimize dosing/duration of additional hemostatic agents in diverse invasive procedures and complex clinical situations.

Introduction Hemolysis in paroxysmal nocturnal hemoglobinuria (PNH) is complement-mediated due to the lack of complement inhibitors in the hemopoietic cell membranes, making complement inhibition the best approach to manage PNH. Three complement inhibitors are approved by the European Medicines Agency as targeted therapy for PNH: eculizumab and ravulizumab, two humanized monoclonal antibodies targeting the same complement 5 (C5) epitope, approved in 2007 and 2019, respectively, and the more recently approved cyclic peptide, the complement 3 (C3) inhibitor pegcetacoplan. Although national and international PNH treatment guidelines exist, they do not take into consideration the latest clinical trial evidence. Given the lack of evidence-based data for some clinical situations encountered in real life, we identified specific populations of patients who may benefit from switching to proximal C3 from terminal C5 inhibition. Methods The expert recommendations presented here were created using a Delphi-like process by a group of expert PNH specialists across Central Europe. Based on an initial advisory board meeting discussion, recommendations were prepared and reviewed as part of a Delphi survey to test agreement. Results Using a systematic approach, literature databases were searched for relevant studies, and 50 articles were reviewed by the experts and included as supporting evidence. Conclusion Implementation of these recommendations uniformly across healthcare institutions will promote the best use of complement inhibition in managing PNH, and has the potential to positively impact patient outcomes in Central Europe and worldwide.

The next frontier in hemophilia A management has arrived. However, questions remain regarding the broader applicability of new and emerging hemophilia A therapies, such as the long-term safety and efficacy of non-factor therapies and optimal regimens for individual patients. With an ever-evolving clinical landscape, it is imperative for physicians to understand how available and future hemophilia A therapies could potentially be integrated into real-life clinical practice to improve patient outcomes. Against this background, nine hemophilia experts from Central European countries participated in a pre-advisory board meeting survey. The survey comprised 11 multiple-choice questions about current treatment practices and future factor and non-factor replacement therapies. The survey questions were developed to reflect current unmet needs in hemophilia management reflected in the literature. The experts also took part in a follow-up advisory board meeting to discuss the most important unmet needs for hemophilia management as well as the pre-meeting survey results. All experts highlighted the challenge of maintaining optimal trough levels with prophylaxis as their most pressing concern. Targeting trough levels of ≥30–50 IU/L or even higher to achieve less bleeding was highlighted as their preferred strategy. However, the experts had an equal opinion on how this could be achieved (i.e., more efficacious non-factor therapies or factor therapy offering broader personalization possibilities such as targeting trough levels to individual pharmacokinetic data). In summary, our study favors personalized prophylaxis to individual pharmacokinetic data rather than a "one-size-fits-all" approach to hemophilia A management to maintain optimal trough levels for individual patients.

Erythrocytosis has a diverse background. While polycythaemia vera has well defined criteria, the diagnostic approach and management of other types of erythrocytosis are more challenging. The aim of study was to retrospectively analyse the aetiology and management of non-clonal erythrocytosis patients referred to a haematology outpatient clinic in an 8-year period using a 3-step algorithm. The first step was inclusion of patients with Hb > 185 g/L and/or Hct > 0.52 in men and Hb > 165 g/L and/or Hct > 0.48 in women on two visits ≥ two months apart, thus confirming true erythrocytosis. Secondly, polycythaemia vera was excluded and secondary causes of erythrocytosis (SE) identified. Thirdly, idiopathic erythrocytosis patients (IE) were referred to next-generation sequencing for possible genetic background evaluation. Of the 116 patients, 75 (65%) are men and 41 (35%) women, with non-clonal erythrocytosis 34/116 (29%) had SE, 15/116 (13%) IE and 67/116 (58%) stayed incompletely characterized (ICE). Patients with SE were significantly older and had significantly higher Hb and Hct compared to patients with IE. Most frequently, SE was attributed to obstructive sleep apnoea and smoking. Phlebotomies were performed in 56, 53 and 40% of patients in the SE, IE, and ICE group, respectively. Approx. 70% of patients in each group received aspirin. Thrombotic events were registered in 12, 20 and 15% of SE, IE and ICE patients, respectively. Congenital erythrocytosis type 4 (ECYT4) was diagnosed in one patient. The study demonstrates real-life management of non-clonal erythrocytosis which could be optimized using a 3-step diagnostic algorithm.

Eritrocitoza je stanje s povečano maso eritrocitov v telesu. Odrazi se s povečanim hematokritom, zvečano koncentracijo hemoglobina in povečanim številom eritrocitov v krvi. Ločimo absolutno in relativno eritrocitozo. Absolutne oblike pa nato delimo na primarne in sekundarne ter obe skupini še na prirojene in pridobljene. Opredelitev diagnoze pri bolniku je mnogokrat težavna, zato pomemben delež bolnikov ostane diagnostično neopredeljen; govorimo o idiopatični eritrocitozi. Namen prispevka je izboljšati diagnosticiranje in vključiti nove genetske preiskave v klinično prakso v Sloveniji. Predlagamo razširjen in natančen algoritem za obravnavo eritrocitoz. Opisujemo razvrstitev različnih oblik eritrocitoz, klinično sliko, genetsko ozadje prirojenih eritrocitoz, diagnostične metode in možnosti zdravljenja. Pregledali smo tudi podatke o 5-letnem obdobju obravnave pridobljenih genetskih različic v JAK2 v Sloveniji. Gre za prvo laboratorijsko testiranje z namenom opredeliti vrsto eritrocitoz. S tem smo pridobili osnovni vpogled v razširjenost bolezni v Sloveniji.