RARE DISEASE
Hereditary spherocytosis
Hereditary spherocytosis
Hereditary spherocytosis
Synonyms: Minkowski-Chauffard disease
Synonyms: Minkowski-Chauffard disease
Synonyms: Minkowski-Chauffard disease
Drug discovery
419
papers
On emerging therapies
Overview
Hereditary spherocytosis (HS) is an autosomal dominant* congenital hemolytic anemia caused by defects in erythrocyte membrane proteins (spectrin, ankyrin, band 3), leading to spherical RBCs with reduced deformability and splenic sequestration [1][4][13]. Clinical presentation varies from asymptomatic carriers to severe anemia with jaundice, splenomegaly, and pigment gallstones [1][10]. Diagnosis relies on spherocytes on blood smear, elevated reticulocytes, negative DAT, and osmotic fragility testing [1][8]. Management includes folate supplementation, transfusions for crises, and splenectomy for severe cases ≥6 years [5][12].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
419 drug discovery papers about Hereditary spherocytosis, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
419 drug discovery papers about Hereditary spherocytosis, with 1 first-in-class emerging drug candidate forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-29 | Pharmacological readthrough and base editing for ANK1 nonsense mutations in an erythroid model of hereditary spherocytosis.
Hereditary spherocytosis (HS) is the most common inherited chronic hemolytic anemia and results from defects in proteins of the erythrocyte membrane skeleton. Nonsense mutations in ANK1 are a common cause of HS, yet current treatments remain largely supportive without addressing genetic defects. In this study, we identified two ANK1 nonsense mutations (p.R281X and p.Q744X) in unrelated HS pedigrees and generated K562 erythroid differentiation models using cytosine base editor-mediated knockin to evaluate potential targeted therapies. Functional analyses confirmed that both mutations markedly reduced ankyrin-1 expression and disrupted membrane-skeletal integrity. We then assessed two targeted therapeutic strategies: translational readthrough-inducing drugs (TRIDs) and adenine base editors (ABEs). Gentamicin promoted translational readthrough at both mutant sites, whereas CC-90009 showed activity primarily at p.Q744X. Both agents partially restored full-length ankyrin-1 expression, accompanied by restored membrane stability. In parallel, ABE8e-mediated correction achieved efficient (>85%) and precise genomic repair in bulk-edited K562 populations, leading to near-complete recovery of ankyrin-1 expression and membrane-skeletal integrity with minimal off-target effects. Together, these findings provide exploratory proof-of-concept for targeted molecular intervention in ANK1 nonsense mutation-associated HS, highlighting TRIDs and ABEs as mechanistically distinct strategies with complementary strengths and limitations and suggesting their relative utility may depend on mutation-specific and clinical contexts.
2026-07-12 | Heparin combined with urokinase therapy for the treatment of acute portal vein thrombosis in children.
Acute portal vein thrombosis (PVT) poses a significant threat to life, with mortality rates ranging from 20% to 50%. However, a clear consensus on the management of acute PVT in children is lacking, and treatment strategies often rely on protocols established for adults. This study summarizes our experience and results in treating acute PVT with heparin combined with urokinase, providing reference data for the diagnosis and treatment of pediatric acute PVT. From November 2017 to February 2026, 5 children (2 males and 3 females) experienced acute PVT after surgery in our hospital. The ages of these children ranged from 2 to 14 years (median: 13 years). Among the 5 patients, one had hereditary spherocytosis (HS), one had total splenic infarction caused by myeloproliferative neoplasms (MPNs), and three had Abernethy malformation. Splenectomy was performed in two patients with HS and MPN, and ligation of the portosystemic shunt was performed in the other three patients with Abernethy malformation. Abdominal ultrasound (US) and enhanced computed tomography (CT) were routinely performed at postoperative days 1-7 to detect PVT. An anticoagulant and thrombolytic treatment protocol involving the combined use of heparin and urokinase is implemented in cases of PVT involving the main portal vein and/or superior mesenteric vein (SMV); in this, intravenous heparin is administered continuously at an initial dosage of 20 U/kg per hour with an increased infusion rate to achieve APTT of 60-85 s, and intravenous urokinase is continuously administered at a dosage of 4400 U/kg per hour for 2-6 h every day. After the stabilization or disappearance of the PVT, oral medications, including aspirin and dipyridamole or rivaroxaban, were used for 6 months. The routine follow-up was performed after 1, 3, and 6 months, and every 6 months thereafter. The acute PVT was detected by US and CT in all patients at postoperative days 1-7 (median: 3 days). The thrombus was located in the main portal vein in 3 patients, in the SMV in 4 patients, in the IMV in 3 patients, and in the splenic vein in 4 patients. PVT occurred simultaneously in three or more branches of the portal vein system in 4 patients. One patient experienced severe abdominal pain caused by PVT, and there were no symptoms, including abdominal pain, hematochezia, nausea, or vomiting in the other 4 patients. When portal vein thrombosis is detected, there is a notable elevation in D-dimer levels. The level of D-dimer was gradually reduced, followed by the reduction of PVT after the anti-coagulation and thrombolysis therapy. The usage of heparin combined with urokinase therapy was successful in all patients; one patient developed CTPV but exhibited no symptoms of portal hypertension, whereas the PVT completely resolved in the remaining four patients between after 19 days to 6 months. There was no bleeding caused by anticoagulation or thrombolysis during therapy. The duration of hospitalization after surgery ranged from 15 to 34 days (median: 20 days). The duration of follow-up ranged from 2 months to 4 years (median: 1 year). There was no recurrence of PVT in all patients. The use of heparin combined with urokinase for the treatment of pediatric PVT is feasible and effective under the premise of ensuring safety. Nevertheless, further verification of its safety and effectiveness is still needed through increased sample size.
2026-07-10 | Role of Next-Generation Sequencing in Deciphering Congenital Hemolytic Anemia: A Case of Multiple Mutations Leading to Dual Congenital Hemolytic Anemia
Before the widespread availability of next-generation sequencing (NGS), the diagnosis of hereditary spherocytosis (HS) and dehydrated hereditary stomatocytosis (DHS) was predominantly clinical. Here, we describe a patient with both HS and DHS who was initially treated for HS until NGS revealed that she had concomitant HS and DHS, leading to a pivot in clinical management. A 21-year-old female patient presented for evaluation of hemolytic anemia during pregnancy. The patient was clinically diagnosed with HS and treated with as-needed transfusions, with a plan for splenectomy. NGS revealed both HS and DHS. Thus, splenectomy was canceled, and aspirin was started. While treatments for HS and DHS differ greatly, in this case, where the patient has both, it is critical that treatment for DHS is prioritized because of the high risk of thromboembolic events following splenectomy. Early genetic evaluation is critical to provide an accurate diagnosis and to guide appropriate management.
2026-07-01 | Pyruvate kinase activators in the context of erythropoiesis defects
Pyruvate kinase activators are a promising class of small molecules that boost glycolytic flux and influence cellular energy metabolism. This review covers the development of pyruvate kinase activation as a therapeutic strategy, its impact on conditions such as pyruvate kinase deficiency, thalassemia, sickle cell disease, myelodysplastic syndrome, and hereditary spherocytosis. The review focuses on the role of pyruvate kinase activity dysregulation in various metabolic and hematologic disorders, the pharmacologic activators that modulate these disease-related metabolic pathways, as well as the clinical evidence supporting its application in these diseases.
2026-05-18 | Targeting pyruvate kinase in rare anemias: a novel therapeutic strategy
Red blood cells (RBCs) are responsible for oxygen transport throughout the human body, which is necessary for the cellular processes in different tissues. For proper functionality and survival of RBCs, they are dependent on glycolysis, the process that generates energy within RBCs. A key enzyme in glycolysis is pyruvate kinase (PK). The aim of this thesis was to shed light on PK in RBCs of patients with different rare (RBC) disorders. These disorders are hereditary spherocytosis (HS), hereditary xerocytosis (HX), and the myelodysplastic syndromes (MDS). HS and HX are congenital diseases of the RBC, where RBCs are broken down more rapidly in the spleen, leading to anemia. MDS are a group of acquired bone marrow diseases, occurring more frequently in late adulthood. Patients with MDS suffer from impaired production of RBCs due to bone marrow dysplasia, resulting in anemia. We observe that in all three of these diseases, the enzyme PK is affected in the RBCs. Therefore, we investigated the ex vivo effects of PK activators on the RBCs of these patients. Our results show that the RBCs of all three patient groups respond to PK activation. PK activity increases, resulting in increased energy levels. This also has a beneficial effect on the functionality of the RBCs. This forms the basis for future research into whether these patients may also benefit from taking PK activators as therapeutic drugs. Additionally, the role of a diagnostic test, namely osmotic gradient ektacytometry, is further explored: this laboratory test may also be of value for understanding the disease mechanism and assessing the disease severity in patients with HS. This is important, as it may allow physicians to extract even more information from a standard diagnostic test.
cell therapies
2024-03-20 | Artificial cells for in vivo biomedical applications through red blood cell biomimicry
Abstract Recent research in artificial cell production holds promise for the development of delivery agents with therapeutic effects akin to real cells. To succeed in these applications, these systems need to survive the circulatory conditions. In this review we present strategies that, inspired by the endurance of red blood cells, have enhanced the viability of large, cell-like vehicles for in vivo therapeutic use, particularly focusing on giant unilamellar vesicles. Insights from red blood cells can guide modifications that could transform these platforms into advanced drug delivery vehicles, showcasing biomimicry’s potential in shaping the future of therapeutic applications.
2021-07-07 | Case Report: Signal Transducer and Activator of Transcription 3 Gain-of-Function and Spectrin Deficiency: A Life-Threatening Case of Severe Hemolytic Anemia.
STAT3 gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of STAT3 GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a de novo STAT3 gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of STAT3 GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention.
2016-10-06 | Erythrocytes as Carriers for Drug Delivery in Blood Transfusion and Beyond
Red blood cells (RBCs) are innate carriers that can also be engineered to improve the pharmacokinetics and pharmacodynamics of many drugs, particularly biotherapeutics. Successful loading of drugs, both internally and on the external surface of RBCs, has been demonstrated for many drugs including anti-inflammatory, antimicrobial, and antithrombotic agents. Methods for internal loading of drugs within RBCs are now entering clinical use. Although internal loading can result in membrane disruption that may compromise biocompatibility, surface loading using either affinity or chemical ligands offers a diverse set of approaches for the production of RBC drug carriers. A wide range of surface determinants is potentially available for this approach, although there remains a need to characterize the effects of coupling agents to these surface proteins. Somewhat surprisingly, recent data also suggest that red cell-mediated delivery may confer tolerogenic immune effects. Questions remaining before widespread application of these technologies include determining the optimal loading protocol, source of RBCs, and production logistics, as well as addressing regulatory hurdles. Red blood cell drug carriers, after many decades of progress, are now poised to enter the clinic and broaden the potential application of RBCs in blood transfusion.
2006-07-12 | Iron overload and prolonged ingestion of iron supplements: Clinical features and mutation analysis of hemochromatosis‐associated genes in four cases
Abstract We evaluated and treated four white adults (one man, three women) who had iron overload associated with daily ingestion of iron supplements for 7, 15, 35, and 61 years, respectively. We performed HFE mutation analysis to detect C282Y, H63D, and S65C in each patient; in two patients, HFE exons were sequenced. In two patients, direct sequencing was performed to detect coding region mutations of TFR 2 , HAMP , FPN 1 , HJV , and ALAS 2 . Patients 1–4 ingested ˜153, 547, 1,341, and 4,898 g of inorganic iron as supplements. Patient 1 had hemochromatosis, HFE C282Y homozygosity, and β‐thalassemia minor. Patient 2 had spherocytosis and no HFE coding region mutations. Patient 3 had no anemia, a normal HFE genotype, and no coding region mutations in HAMP , FPN 1 , HJV , or ALAS 2 ; she was heterozygous for the TFR 2 coding region mutation V583I (nt 1,747 G→A, exon 15). Patient 4 had no anemia and no coding region mutations in HFE , TFR 2 , HAMP , FPN 1 , HJV , or ALAS 2. Iron removed by phlebotomy was 32.4, 10.4, 15.2, and 4.0 g, respectively. There was a positive correlation of log 10 serum ferritin and the quantity of iron removed by phlebotomy ( P = 0.0371). Estimated absorption of iron from supplements in patients 1–4 was 20.9%, 1.9%, 1.1%, and 0.08%. We conclude that the clinical phenotypes and hemochromatosis genotypes of adults who develop iron overload after ingesting iron supplements over long periods are heterogeneous. Therapeutic phlebotomy is feasible and effective, and would prevent complications of iron overload. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
2003-04-01 | Allogeneic bone marrow transplantation for severe post‐splenectomy thrombophilic state in leaky red cell membrane haemolytic anaemia of the stomatocytosis class
Summary. The tendency for thrombosis to occur if haemolysis persists after splenectomy is especially marked in ‘hereditary stomatocytosis’, in which the red cell membrane ‘leaks’ Na and K. A 21‐year‐old woman, who was splenectomized in childhood for a congenital haemolytic state, presented with major pulmonary embolism that recurred despite anticoagulation. Tests showed a significant cation leak with a ‘shallow‐slope’ abnormality in temperature dependence. Allogeneic bone marrow transplantation caused the thrombophilic state to cease and subsequently anticoagulation was stopped without recurrence of thromboembolism. However, she died 9 months after transplantation: iron overload, intensified by the transfusion demands of the transplant, was a major factor.
proteins
2024-10-25 | Biomechanics of phagocytosis of red blood cells by macrophages in the human spleen.
The clearance of senescent and altered red blood cells (RBCs) in the red pulp of the human spleen involves sequential processes of prefiltration, filtration, and postfiltration. While prior work has elucidated the mechanisms underlying the first two processes, biomechanical processes driving the postfiltration phagocytosis of RBCs retained at interendothelial slits (IES) are still poorly understood. We present here a unique computational model of macrophages to study the role of cell biomechanics in modulating the kinetics of phagocytosis of aged and diseased RBCs retained in the spleen. After validating the macrophage model using in vitro phagocytosis experiments, we employ it to probe the mechanisms underlying the kinetics of phagocytosis of mechanically altered RBCs, such as heated RBCs and abnormal RBCs in hereditary spherocytosis (HS) and sickle cell disease (SCD). Our simulations show pronounced deformation of the flexible and healthy RBCs in contrast to minimal shape changes in altered RBCs. Simulations also show that less deformable RBCs are engulfed faster and at lower adhesive strength than flexible RBCs, consistent with our experimental measurements. This efficient sensing and engulfment by macrophages of stiff RBCs retained at IES are expected to temper splenic congestion, a common pathogenic process in malaria, HS, and SCD. Altogether, our combined computational and in vitro experimental studies suggest that mechanical alterations of retained RBCs may suffice to enhance their phagocytosis, thereby adapting the kinetics of their elimination to the kinetics of their mechanical retention, an equilibrium essential for adequately cleaning the splenic filter to preserve its function.
2021-09-28 | Tangential flow filtration of haptoglobin.
Haptoglobin (Hp) is a plasma glycoprotein that scavenges cell-free hemoglobin (Hb). Hp has various potential therapeutic applications, but it has been mainly studied for treatment of acute hemolytic conditions that can arise from situations such as massive blood transfusion, infusion of stored red blood cells, severe burns, trauma, sepsis, radiation injury, and others. Therefore, Hp may also be beneficial during chronic hemolytic disease states such as hereditary spherocytosis, nocturnal hemoglobinuria, sickle-cell anemia, and malaria. Various methods have been developed to purify Hp from plasma or plasma fractions. However, none of these methods have exploited the large molecular weight (MW) range distribution of Hp polymers to easily isolate Hp from other plasma proteins. The present study used tangential flow filtration (TFF) to isolate polymeric Hp from plasma proteins using human Fraction IV (FIV) as the starting material. After removal of insoluble material from a suspension of FIV paste, the protein mixture was clarified on a 0.2 μm hollow fiber (HF) TFF filter. The clarified protein solution was then bracketed based on protein MW using HF filters with MW cut-offs (MWCOs) of 750, 500, and 100 kDa. Using untreated FIV, the Hp purity of the main bracket was ~75% with a total Hb binding capacity (HbBC) yield of 1.2 g starting from 500 g of FIV paste. However, pretreatment of FIV with fumed silica to remove lipoproteins increased Hp purity to >95% with a HbBC yield of 1.7 g per 500 g of FIV. Taken together this study provides a novel and scalable method to purify Hp from plasma or plasma fractions.
2021-04-06 | Successful Splenectomy Management in a Patient With Moderate Factor VII Deficiency and Concomitant Severe Hereditary Spherocytosis.
By the advent of the effective therapies for many coagulation diseases and hereditary spherocytosis (HS), patient's survival has been improved significantly; however, if patients are diagnosed late or left untreated, both diseases could ominously be life threatening. Concurrent occurring of factor VII (FVII) deficiency and HS is extremely rare and there is no literature report that explain this condition, thus far. In this study, we confronted a 9-year-old female patient diagnosed with HS and enlarged spleen as a result of this blood disorder. Given to her sever signs and symptoms of splenomegaly, she was candidate for emergent splenectomy. However, assessment of coagulation tests revealed a prolonged prothrombin time, suggesting the moderate FVII deficiency. With a multidisciplinary consultation, we decided to performed total splenectomy with prophylaxis administration of totally 6 doses of active recombinant FVII, initiated 1 hour before surgery and followed until 30 hours postoperation. As a result of cautious undertaken in Mofid Children's Hospital, the patient did not experience any hemostatic defect. Patient is now 14-year-old, generally well-being under regular surveillance of FVII deficiency.
2020-03-01 | Linkage of typically cytosolic peroxidases to erythrocyte membrane – A possible mechanism of protection in Hereditary Spherocytosis
Hereditary Spherocytosis (HS) is a non-immune hemolytic anemia associated to oxidative stress (OS), namely to the linkage of cytosolic antioxidant enzymes to the erythrocyte membrane.Our aims were to evaluate erythrocyte OS changes and the membrane linkage of peroxiredoxin 2 (Prx2), glutathione peroxidase (GPx) and catalase (CAT) in unsplenectomized (unspl) and splenectomized (spl) HS patients and to search for associations with clinical severity (in unspl HS patients).We studied 114 HS patients (74 unspl and 40 spl) and 30 healthy individuals and we evaluated membrane bound hemoglobin (MBH), membrane lipid-peroxidation (LPO), enzymatic activities of GPx and CAT and the amounts of membrane bound Prx2, GPx and CAT, as well as, clinical and analytical parameters for characterization of HS.We found that unspl HS patients showed clear signs of anemia and in spl HS, a correction to this anemia was observed; the latter patients presented higher levels of OS biomarkers, namely, MBH and LPO.CAT was detected in the membrane of all individuals (control and HS groups), while GPx and Prx2 were only present in HS patients; moreover, their linkage to the membrane (in HS) appears to be cumulative since membrane bound peroxidases amount was higher as the number of peroxidases detected increased.MBH increased with the number/amount of membrane bound peroxidases, however LPO levels remained similar.In conclusion, our data suggest that the binding of these typically cytosolic peroxidases to erythrocyte membrane may be part of a mechanism of membrane protection to maintain its integrity by possibly regulating LPO.
2019-09-10 | Treatment of a Child With Submassive Pulmonary Embolism Associated With Hereditary Spherocytosis Using Ultrasound-Assisted Catheter-Directed Thrombolysis
Background: The clinical presentation of hereditary spherocytosis varies from no symptoms to severe hemolytic anemia requiring splenectomy. Splenectomy imposes the risk of hypercoagulability and acute pulmonary embolism. Catheter-directed thrombolysis is an established treatment for submassive pulmonary embolism in adults. However, the literature regarding its use in children is limited. Case Report: We present the case of a 12-year-old male with hereditary spherocytosis who was diagnosed with pulmonary embolism and successfully treated with catheter-directed thrombolysis. The patient was initially treated with 10.5 mg of recombinant tissue plasminogen activator (r-tPA) delivered over 8 hours. However, because of minimal clinical and hemodynamic improvement, a second course of thrombolytic was administered for an additional 24 hours (25 mg of r-tPA), and the treatment resulted in marked clinical and hemodynamic improvement. Clot resolution was confirmed via angiography. The patient was discharged on enoxaparin and with regular follow-up. One year later, the patient was asymptomatic on enoxaparin. Conclusion: This case demonstrates that catheter-based treatment of submassive pulmonary embolism restores hemodynamic stability and thus is an alternative to surgery or systemic thrombolysis, even in the pediatric setting. While catheter-directed thrombolysis is a safe and effective alternative to systemic thrombolysis, further research is needed to establish appropriate dosing and indications in the adolescent population.
gene therapies
2026-08-20 | A Pathogenic ANK1 c.5096G>A Mutation Disrupting the Ankyrin-1/β-Spectrin Interaction in Hereditary Spherocytosis.
Hereditary spherocytosis (HS) is a common inherited hemolytic anemia characterized by spherical erythrocytes, splenomegaly, and increased osmotic fragility, with ANK1 mutations being the most frequent cause. We identified a novel ANK1 mutation (c.5096G>A, p.R1699K) in a patient with classic HS phenotypes and a family history of hemolytic anemia. To explore its pathogenicity, we performed a series of hematological and morphological analyses. Compared with wild-type mice, the Ank1 c.5198G>A knock-in mice displayed typical HS features. Hematologically, they showed reduced MCV, MCH, and MCHC. The EMA fluorescence intensity was significantly decreased, and RBCs exhibited increased osmotic fragility. Morphologically, peripheral smears revealed abundant spherocytes, and electron microscopy showed a transformation from normal biconcave discs to spherical erythrocytes. Additionally, the Ank1 c.5198G>A knock-in mice presented with significant splenomegaly. Mechanistically, coimmunoprecipitation analysis indicated a significantly weakened association between ankyrin-1 and β-spectrin in the Ank1 c.5198G>A knock-in mice. This study provides in vivo evidence that the Ank1 R1733K mutation impairs erythrocyte membrane stability and cytoskeletal integrity, recapitulating the HS phenotype in mice. Our findings support the pathogenicity of the ANK1 c.5096G>A mutation and offer a useful model for further investigating the molecular mechanisms of HS.
2026-08-19 | The molecular genetic spectrum of hereditary spherocytosis in the Russian population
Introduction. Hereditary spherocytosis (HS) is a hereditary hemolytic anemia caused by defects in erythrocyte membrane and cytoskeleton due to mutations mainly in five genes: ANK1, SPTB, SPTA1, SLC4A1, and EPB42. The genetic landscape of HS is characterized by considerable interpopulation variability. Aim – to investigate the molecular genetic spectrum of HS in the Russian population. Materials and methods. The study included 240 patients under 21 years of age with genetically confirmed HS. We analyzed the distribution of pathogenic variants by gene, mutation type, frequency of recurrent and previously undescribed variants, and also assessed the genotype–phenotype correlation with disease severity. Results. Pathogenic variants in the SPTB gene were identified in 45.8% of the patients, in the ANK1 gene in 34.6%, in the SLC4A1 gene in 11.3%, and in the SPTA1 gene in 8.3%. In the SPTB and ANK1 genes, loss-of-function mutations, such as nonsense, frameshift, and splice-site mutations, predominated. In the SLC4A1 gene, missense mutations were the most common, whereas in the SPTA1 gene there was a heterogeneous mutation spectrum, including the frequent intronic mutation with low aLEPRA expression. Novel mutations accounted for 54.2% of all variants. In SPTA1-associated HS, complex genotypes were frequently observed: compound heterozygous variants and digenic variants were found in 35% and in 20% of the patients, respectively. Our clinical severity analysis showed that patients with SPTB- and ANK1-associated HS had mostly moderate disease, patients with SLC4A1-associated HS had a mild course with no severe cases, while SPTA1-associated HS was characterized by a relatively high proportion of severe cases. Conclusion. The Russian cohort belongs to populations with an SPTB-dominant mutation pattern and represents one of the largest national cohorts of patients with genetically confirmed HS worldwide.
2026-07-23 | Hereditary Spherocytosis in a Child due to a Deletion in β‐Spectrin Detected by Low‐Input DNA Long‐Read Whole‐Genome Sequencing
The authors declare no conflicts of interest. Relevant data are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2026-07-10 | Erythroid-derived extracellular vesicles and interplay with soluble transferrin receptor in hereditary hemolytic anemias
In hereditary hemolytic anemia (HHA), soluble transferrin receptor (sTfR) reflects erythropoietic activity, whereas in iron deficiency anemia, it indicates iron-restricted hematopoiesis. Improving our understanding of sTfR biology, including its relationship with extracellular vesicles (EVs), could help improve the management of disorders involving abnormal iron metabolism and chronic hemolysis. We investigated the role of sTfR and EVs in HHA with respect to disease severity, iron biology, and splenectomy status. This cross-sectional observational study included 95 adult patients with HHA, including hemoglobinopathies (n = 33), red cell enzyme disorders (n = 31), and red cell membrane disorders (n = 31). Hematological parameters and biochemical markers of hemolysis and iron homeostasis were measured, and EVs were characterized by flow cytometry using cell-specific markers. We observed HHA-specific patterns of plasma EV levels and composition, reflecting anemia severity and modes of red blood cell clearance in patients with hereditary spherocytosis (HS) and pyruvate kinase deficiency. In patients with HS, sTfR levels correlated with erythropoietin ( r = 0.826) and reticulocyte count ( r = 0.688) in those with moderately severe anemia, suggesting a high erythroid output, which is not seen in splenectomized patients. Across HHA subtypes, circulating sTfR levels closely paralleled CD71 + EV concentrations ( r = 0.779), suggesting a fraction of sTfR is EV-associated. Overall, EV and sTfR levels in HHA represented disease severity and erythropoietic drive, whereas sTfR was not suitable as a marker of iron metabolism or ineffective erythropoiesis in HHA. Longitudinal studies measuring EV and sTfR levels before and after splenectomy, combined with analyses of EV content in HHA, are required to assess their predictive value and clinical potential in HHA.
2026-03-19 | Symptomatic Recurrent Splenomegaly Following Partial Splenectomy in Patients With Hereditary Spherocytosis.
Hereditary spherocytosis (HS) is an inherited hematologic disorder characterized by spherical erythrocytes that are prematurely destroyed in the spleen. Total splenectomy (TS) and partial splenectomy (PS) are surgical interventions used to manage HS, but long-term outcomes, including recurrence of splenomegaly and splenomegaly-related symptoms, remain poorly understood. This study aims to evaluate the long-term recurrence of splenomegaly and splenomegaly-related symptoms in children with HS who underwent PS versus TS at a single institution between 2008 and 2020. A retrospective chart review of children with HS who underwent TS or PS was performed. The primary end point was the long-term recurrence of splenomegaly and splenomegaly-related symptoms. Variables collected included age, sex, surgical method (PS vs. TS), postoperative hematologic markers, splenic volume, postoperative complications, length of hospital stay, recurrence of splenomegaly, and need for completion splenectomy. Symptomatic recurrent splenomegaly is defined as splenic volume > 450 mL and the presence of symptoms directly attributable to the spleen and its effects on adjacent organs or hemolysis. Statistical analysis included comparisons of continuous variables using a Kruskal-Wallis test and categorical variables using a Fisher's exact test. Forty-four patients with HS met the inclusion criteria for the study. Of these, 31 (71%) patients underwent laparoscopic PS and 13 (30%) patients underwent laparoscopic TS. TS was associated with significantly less intraoperative blood loss (p = 0.003), shorter hospital stays (p = 0.01), and greater reduction in hemolysis compared to PS, as evidenced by lower postoperative bilirubin levels and reticulocyte counts (both p < 0.001). Eighteen (58%) PS patients experienced recurrent splenomegaly, and six (19%) PS patients experienced splenomegaly-related symptoms leading to completion splenectomy. Among the six patients who required completion splenectomy, intraoperative hemorrhage requiring conversion to open procedure occurred in half. The median time to need completion splenectomy was 10.5 years (range, 3-15 years). TS offers more significant long-term hematologic improvements but comes with the loss of immune function and increased risk of overwhelming post-splenectomy infection (OPSI). PS, while preserving some splenic function and theoretically reducing OPSI risk, carries a higher risk of recurrent symptomatic splenomegaly and may require additional surgeries. These findings highlight the importance of long-term follow-up for HS patients who undergo PS and the need to balance the advantages and risks of both surgical approaches.
small molecules
2026-08-29 | Pharmacological readthrough and base editing for ANK1 nonsense mutations in an erythroid model of hereditary spherocytosis.
Hereditary spherocytosis (HS) is the most common inherited chronic hemolytic anemia and results from defects in proteins of the erythrocyte membrane skeleton. Nonsense mutations in ANK1 are a common cause of HS, yet current treatments remain largely supportive without addressing genetic defects. In this study, we identified two ANK1 nonsense mutations (p.R281X and p.Q744X) in unrelated HS pedigrees and generated K562 erythroid differentiation models using cytosine base editor-mediated knockin to evaluate potential targeted therapies. Functional analyses confirmed that both mutations markedly reduced ankyrin-1 expression and disrupted membrane-skeletal integrity. We then assessed two targeted therapeutic strategies: translational readthrough-inducing drugs (TRIDs) and adenine base editors (ABEs). Gentamicin promoted translational readthrough at both mutant sites, whereas CC-90009 showed activity primarily at p.Q744X. Both agents partially restored full-length ankyrin-1 expression, accompanied by restored membrane stability. In parallel, ABE8e-mediated correction achieved efficient (>85%) and precise genomic repair in bulk-edited K562 populations, leading to near-complete recovery of ankyrin-1 expression and membrane-skeletal integrity with minimal off-target effects. Together, these findings provide exploratory proof-of-concept for targeted molecular intervention in ANK1 nonsense mutation-associated HS, highlighting TRIDs and ABEs as mechanistically distinct strategies with complementary strengths and limitations and suggesting their relative utility may depend on mutation-specific and clinical contexts.
2026-07-12 | Heparin combined with urokinase therapy for the treatment of acute portal vein thrombosis in children.
Acute portal vein thrombosis (PVT) poses a significant threat to life, with mortality rates ranging from 20% to 50%. However, a clear consensus on the management of acute PVT in children is lacking, and treatment strategies often rely on protocols established for adults. This study summarizes our experience and results in treating acute PVT with heparin combined with urokinase, providing reference data for the diagnosis and treatment of pediatric acute PVT. From November 2017 to February 2026, 5 children (2 males and 3 females) experienced acute PVT after surgery in our hospital. The ages of these children ranged from 2 to 14 years (median: 13 years). Among the 5 patients, one had hereditary spherocytosis (HS), one had total splenic infarction caused by myeloproliferative neoplasms (MPNs), and three had Abernethy malformation. Splenectomy was performed in two patients with HS and MPN, and ligation of the portosystemic shunt was performed in the other three patients with Abernethy malformation. Abdominal ultrasound (US) and enhanced computed tomography (CT) were routinely performed at postoperative days 1-7 to detect PVT. An anticoagulant and thrombolytic treatment protocol involving the combined use of heparin and urokinase is implemented in cases of PVT involving the main portal vein and/or superior mesenteric vein (SMV); in this, intravenous heparin is administered continuously at an initial dosage of 20 U/kg per hour with an increased infusion rate to achieve APTT of 60-85 s, and intravenous urokinase is continuously administered at a dosage of 4400 U/kg per hour for 2-6 h every day. After the stabilization or disappearance of the PVT, oral medications, including aspirin and dipyridamole or rivaroxaban, were used for 6 months. The routine follow-up was performed after 1, 3, and 6 months, and every 6 months thereafter. The acute PVT was detected by US and CT in all patients at postoperative days 1-7 (median: 3 days). The thrombus was located in the main portal vein in 3 patients, in the SMV in 4 patients, in the IMV in 3 patients, and in the splenic vein in 4 patients. PVT occurred simultaneously in three or more branches of the portal vein system in 4 patients. One patient experienced severe abdominal pain caused by PVT, and there were no symptoms, including abdominal pain, hematochezia, nausea, or vomiting in the other 4 patients. When portal vein thrombosis is detected, there is a notable elevation in D-dimer levels. The level of D-dimer was gradually reduced, followed by the reduction of PVT after the anti-coagulation and thrombolysis therapy. The usage of heparin combined with urokinase therapy was successful in all patients; one patient developed CTPV but exhibited no symptoms of portal hypertension, whereas the PVT completely resolved in the remaining four patients between after 19 days to 6 months. There was no bleeding caused by anticoagulation or thrombolysis during therapy. The duration of hospitalization after surgery ranged from 15 to 34 days (median: 20 days). The duration of follow-up ranged from 2 months to 4 years (median: 1 year). There was no recurrence of PVT in all patients. The use of heparin combined with urokinase for the treatment of pediatric PVT is feasible and effective under the premise of ensuring safety. Nevertheless, further verification of its safety and effectiveness is still needed through increased sample size.
2026-07-10 | Role of Next-Generation Sequencing in Deciphering Congenital Hemolytic Anemia: A Case of Multiple Mutations Leading to Dual Congenital Hemolytic Anemia
Before the widespread availability of next-generation sequencing (NGS), the diagnosis of hereditary spherocytosis (HS) and dehydrated hereditary stomatocytosis (DHS) was predominantly clinical. Here, we describe a patient with both HS and DHS who was initially treated for HS until NGS revealed that she had concomitant HS and DHS, leading to a pivot in clinical management. A 21-year-old female patient presented for evaluation of hemolytic anemia during pregnancy. The patient was clinically diagnosed with HS and treated with as-needed transfusions, with a plan for splenectomy. NGS revealed both HS and DHS. Thus, splenectomy was canceled, and aspirin was started. While treatments for HS and DHS differ greatly, in this case, where the patient has both, it is critical that treatment for DHS is prioritized because of the high risk of thromboembolic events following splenectomy. Early genetic evaluation is critical to provide an accurate diagnosis and to guide appropriate management.
2026-07-01 | Pyruvate kinase activators in the context of erythropoiesis defects
Pyruvate kinase activators are a promising class of small molecules that boost glycolytic flux and influence cellular energy metabolism. This review covers the development of pyruvate kinase activation as a therapeutic strategy, its impact on conditions such as pyruvate kinase deficiency, thalassemia, sickle cell disease, myelodysplastic syndrome, and hereditary spherocytosis. The review focuses on the role of pyruvate kinase activity dysregulation in various metabolic and hematologic disorders, the pharmacologic activators that modulate these disease-related metabolic pathways, as well as the clinical evidence supporting its application in these diseases.
2026-05-18 | Targeting pyruvate kinase in rare anemias: a novel therapeutic strategy
Red blood cells (RBCs) are responsible for oxygen transport throughout the human body, which is necessary for the cellular processes in different tissues. For proper functionality and survival of RBCs, they are dependent on glycolysis, the process that generates energy within RBCs. A key enzyme in glycolysis is pyruvate kinase (PK). The aim of this thesis was to shed light on PK in RBCs of patients with different rare (RBC) disorders. These disorders are hereditary spherocytosis (HS), hereditary xerocytosis (HX), and the myelodysplastic syndromes (MDS). HS and HX are congenital diseases of the RBC, where RBCs are broken down more rapidly in the spleen, leading to anemia. MDS are a group of acquired bone marrow diseases, occurring more frequently in late adulthood. Patients with MDS suffer from impaired production of RBCs due to bone marrow dysplasia, resulting in anemia. We observe that in all three of these diseases, the enzyme PK is affected in the RBCs. Therefore, we investigated the ex vivo effects of PK activators on the RBCs of these patients. Our results show that the RBCs of all three patient groups respond to PK activation. PK activity increases, resulting in increased energy levels. This also has a beneficial effect on the functionality of the RBCs. This forms the basis for future research into whether these patients may also benefit from taking PK activators as therapeutic drugs. Additionally, the role of a diagnostic test, namely osmotic gradient ektacytometry, is further explored: this laboratory test may also be of value for understanding the disease mechanism and assessing the disease severity in patients with HS. This is important, as it may allow physicians to extract even more information from a standard diagnostic test.
cell therapies
2024-03-20 | Artificial cells for in vivo biomedical applications through red blood cell biomimicry
Abstract Recent research in artificial cell production holds promise for the development of delivery agents with therapeutic effects akin to real cells. To succeed in these applications, these systems need to survive the circulatory conditions. In this review we present strategies that, inspired by the endurance of red blood cells, have enhanced the viability of large, cell-like vehicles for in vivo therapeutic use, particularly focusing on giant unilamellar vesicles. Insights from red blood cells can guide modifications that could transform these platforms into advanced drug delivery vehicles, showcasing biomimicry’s potential in shaping the future of therapeutic applications.
2021-07-07 | Case Report: Signal Transducer and Activator of Transcription 3 Gain-of-Function and Spectrin Deficiency: A Life-Threatening Case of Severe Hemolytic Anemia.
STAT3 gain-of-function (GOF) mutations can be responsible for an incomplete phenotype mainly characterized by hematological autoimmunity, even in the absence of other organ autoimmunity, growth impairment, or severe infections. We hereby report a case with an incomplete form of STAT3 GOF intensified by a concomitant hereditary hematological disease, which misleads the diagnosis. The patient presented with lymphadenopathy, splenomegaly, hypogammaglobulinemia, and severe autoimmune hemolytic anemia (AIHA) with critical complications, including stroke. A Primary Immune Regulatory Disorders (PIRD) was suspected, and molecular analysis revealed a de novo STAT3 gain-of-function mutation. The response to multiple immune suppressive treatments was ineffective, and further investigations revealed a spectrin deficiency. Ultimately, hematopoietic stem cell transplantation from a matched unrelated donor was able to cure the patient. Our case shows an atypical presentation of STAT3 GOF associated with hereditary spherocytosis, and how achievement of a good long-term outcome depends on a strict clinical and laboratory monitoring, as well as on prompt therapeutic intervention.
2016-10-06 | Erythrocytes as Carriers for Drug Delivery in Blood Transfusion and Beyond
Red blood cells (RBCs) are innate carriers that can also be engineered to improve the pharmacokinetics and pharmacodynamics of many drugs, particularly biotherapeutics. Successful loading of drugs, both internally and on the external surface of RBCs, has been demonstrated for many drugs including anti-inflammatory, antimicrobial, and antithrombotic agents. Methods for internal loading of drugs within RBCs are now entering clinical use. Although internal loading can result in membrane disruption that may compromise biocompatibility, surface loading using either affinity or chemical ligands offers a diverse set of approaches for the production of RBC drug carriers. A wide range of surface determinants is potentially available for this approach, although there remains a need to characterize the effects of coupling agents to these surface proteins. Somewhat surprisingly, recent data also suggest that red cell-mediated delivery may confer tolerogenic immune effects. Questions remaining before widespread application of these technologies include determining the optimal loading protocol, source of RBCs, and production logistics, as well as addressing regulatory hurdles. Red blood cell drug carriers, after many decades of progress, are now poised to enter the clinic and broaden the potential application of RBCs in blood transfusion.
2006-07-12 | Iron overload and prolonged ingestion of iron supplements: Clinical features and mutation analysis of hemochromatosis‐associated genes in four cases
Abstract We evaluated and treated four white adults (one man, three women) who had iron overload associated with daily ingestion of iron supplements for 7, 15, 35, and 61 years, respectively. We performed HFE mutation analysis to detect C282Y, H63D, and S65C in each patient; in two patients, HFE exons were sequenced. In two patients, direct sequencing was performed to detect coding region mutations of TFR 2 , HAMP , FPN 1 , HJV , and ALAS 2 . Patients 1–4 ingested ˜153, 547, 1,341, and 4,898 g of inorganic iron as supplements. Patient 1 had hemochromatosis, HFE C282Y homozygosity, and β‐thalassemia minor. Patient 2 had spherocytosis and no HFE coding region mutations. Patient 3 had no anemia, a normal HFE genotype, and no coding region mutations in HAMP , FPN 1 , HJV , or ALAS 2 ; she was heterozygous for the TFR 2 coding region mutation V583I (nt 1,747 G→A, exon 15). Patient 4 had no anemia and no coding region mutations in HFE , TFR 2 , HAMP , FPN 1 , HJV , or ALAS 2. Iron removed by phlebotomy was 32.4, 10.4, 15.2, and 4.0 g, respectively. There was a positive correlation of log 10 serum ferritin and the quantity of iron removed by phlebotomy ( P = 0.0371). Estimated absorption of iron from supplements in patients 1–4 was 20.9%, 1.9%, 1.1%, and 0.08%. We conclude that the clinical phenotypes and hemochromatosis genotypes of adults who develop iron overload after ingesting iron supplements over long periods are heterogeneous. Therapeutic phlebotomy is feasible and effective, and would prevent complications of iron overload. Am. J. Hematol., 2006. © 2006 Wiley‐Liss, Inc.
2003-04-01 | Allogeneic bone marrow transplantation for severe post‐splenectomy thrombophilic state in leaky red cell membrane haemolytic anaemia of the stomatocytosis class
Summary. The tendency for thrombosis to occur if haemolysis persists after splenectomy is especially marked in ‘hereditary stomatocytosis’, in which the red cell membrane ‘leaks’ Na and K. A 21‐year‐old woman, who was splenectomized in childhood for a congenital haemolytic state, presented with major pulmonary embolism that recurred despite anticoagulation. Tests showed a significant cation leak with a ‘shallow‐slope’ abnormality in temperature dependence. Allogeneic bone marrow transplantation caused the thrombophilic state to cease and subsequently anticoagulation was stopped without recurrence of thromboembolism. However, she died 9 months after transplantation: iron overload, intensified by the transfusion demands of the transplant, was a major factor.
proteins
2024-10-25 | Biomechanics of phagocytosis of red blood cells by macrophages in the human spleen.
The clearance of senescent and altered red blood cells (RBCs) in the red pulp of the human spleen involves sequential processes of prefiltration, filtration, and postfiltration. While prior work has elucidated the mechanisms underlying the first two processes, biomechanical processes driving the postfiltration phagocytosis of RBCs retained at interendothelial slits (IES) are still poorly understood. We present here a unique computational model of macrophages to study the role of cell biomechanics in modulating the kinetics of phagocytosis of aged and diseased RBCs retained in the spleen. After validating the macrophage model using in vitro phagocytosis experiments, we employ it to probe the mechanisms underlying the kinetics of phagocytosis of mechanically altered RBCs, such as heated RBCs and abnormal RBCs in hereditary spherocytosis (HS) and sickle cell disease (SCD). Our simulations show pronounced deformation of the flexible and healthy RBCs in contrast to minimal shape changes in altered RBCs. Simulations also show that less deformable RBCs are engulfed faster and at lower adhesive strength than flexible RBCs, consistent with our experimental measurements. This efficient sensing and engulfment by macrophages of stiff RBCs retained at IES are expected to temper splenic congestion, a common pathogenic process in malaria, HS, and SCD. Altogether, our combined computational and in vitro experimental studies suggest that mechanical alterations of retained RBCs may suffice to enhance their phagocytosis, thereby adapting the kinetics of their elimination to the kinetics of their mechanical retention, an equilibrium essential for adequately cleaning the splenic filter to preserve its function.
2021-09-28 | Tangential flow filtration of haptoglobin.
Haptoglobin (Hp) is a plasma glycoprotein that scavenges cell-free hemoglobin (Hb). Hp has various potential therapeutic applications, but it has been mainly studied for treatment of acute hemolytic conditions that can arise from situations such as massive blood transfusion, infusion of stored red blood cells, severe burns, trauma, sepsis, radiation injury, and others. Therefore, Hp may also be beneficial during chronic hemolytic disease states such as hereditary spherocytosis, nocturnal hemoglobinuria, sickle-cell anemia, and malaria. Various methods have been developed to purify Hp from plasma or plasma fractions. However, none of these methods have exploited the large molecular weight (MW) range distribution of Hp polymers to easily isolate Hp from other plasma proteins. The present study used tangential flow filtration (TFF) to isolate polymeric Hp from plasma proteins using human Fraction IV (FIV) as the starting material. After removal of insoluble material from a suspension of FIV paste, the protein mixture was clarified on a 0.2 μm hollow fiber (HF) TFF filter. The clarified protein solution was then bracketed based on protein MW using HF filters with MW cut-offs (MWCOs) of 750, 500, and 100 kDa. Using untreated FIV, the Hp purity of the main bracket was ~75% with a total Hb binding capacity (HbBC) yield of 1.2 g starting from 500 g of FIV paste. However, pretreatment of FIV with fumed silica to remove lipoproteins increased Hp purity to >95% with a HbBC yield of 1.7 g per 500 g of FIV. Taken together this study provides a novel and scalable method to purify Hp from plasma or plasma fractions.
2021-04-06 | Successful Splenectomy Management in a Patient With Moderate Factor VII Deficiency and Concomitant Severe Hereditary Spherocytosis.
By the advent of the effective therapies for many coagulation diseases and hereditary spherocytosis (HS), patient's survival has been improved significantly; however, if patients are diagnosed late or left untreated, both diseases could ominously be life threatening. Concurrent occurring of factor VII (FVII) deficiency and HS is extremely rare and there is no literature report that explain this condition, thus far. In this study, we confronted a 9-year-old female patient diagnosed with HS and enlarged spleen as a result of this blood disorder. Given to her sever signs and symptoms of splenomegaly, she was candidate for emergent splenectomy. However, assessment of coagulation tests revealed a prolonged prothrombin time, suggesting the moderate FVII deficiency. With a multidisciplinary consultation, we decided to performed total splenectomy with prophylaxis administration of totally 6 doses of active recombinant FVII, initiated 1 hour before surgery and followed until 30 hours postoperation. As a result of cautious undertaken in Mofid Children's Hospital, the patient did not experience any hemostatic defect. Patient is now 14-year-old, generally well-being under regular surveillance of FVII deficiency.
2020-03-01 | Linkage of typically cytosolic peroxidases to erythrocyte membrane – A possible mechanism of protection in Hereditary Spherocytosis
Hereditary Spherocytosis (HS) is a non-immune hemolytic anemia associated to oxidative stress (OS), namely to the linkage of cytosolic antioxidant enzymes to the erythrocyte membrane.Our aims were to evaluate erythrocyte OS changes and the membrane linkage of peroxiredoxin 2 (Prx2), glutathione peroxidase (GPx) and catalase (CAT) in unsplenectomized (unspl) and splenectomized (spl) HS patients and to search for associations with clinical severity (in unspl HS patients).We studied 114 HS patients (74 unspl and 40 spl) and 30 healthy individuals and we evaluated membrane bound hemoglobin (MBH), membrane lipid-peroxidation (LPO), enzymatic activities of GPx and CAT and the amounts of membrane bound Prx2, GPx and CAT, as well as, clinical and analytical parameters for characterization of HS.We found that unspl HS patients showed clear signs of anemia and in spl HS, a correction to this anemia was observed; the latter patients presented higher levels of OS biomarkers, namely, MBH and LPO.CAT was detected in the membrane of all individuals (control and HS groups), while GPx and Prx2 were only present in HS patients; moreover, their linkage to the membrane (in HS) appears to be cumulative since membrane bound peroxidases amount was higher as the number of peroxidases detected increased.MBH increased with the number/amount of membrane bound peroxidases, however LPO levels remained similar.In conclusion, our data suggest that the binding of these typically cytosolic peroxidases to erythrocyte membrane may be part of a mechanism of membrane protection to maintain its integrity by possibly regulating LPO.
2019-09-10 | Treatment of a Child With Submassive Pulmonary Embolism Associated With Hereditary Spherocytosis Using Ultrasound-Assisted Catheter-Directed Thrombolysis
Background: The clinical presentation of hereditary spherocytosis varies from no symptoms to severe hemolytic anemia requiring splenectomy. Splenectomy imposes the risk of hypercoagulability and acute pulmonary embolism. Catheter-directed thrombolysis is an established treatment for submassive pulmonary embolism in adults. However, the literature regarding its use in children is limited. Case Report: We present the case of a 12-year-old male with hereditary spherocytosis who was diagnosed with pulmonary embolism and successfully treated with catheter-directed thrombolysis. The patient was initially treated with 10.5 mg of recombinant tissue plasminogen activator (r-tPA) delivered over 8 hours. However, because of minimal clinical and hemodynamic improvement, a second course of thrombolytic was administered for an additional 24 hours (25 mg of r-tPA), and the treatment resulted in marked clinical and hemodynamic improvement. Clot resolution was confirmed via angiography. The patient was discharged on enoxaparin and with regular follow-up. One year later, the patient was asymptomatic on enoxaparin. Conclusion: This case demonstrates that catheter-based treatment of submassive pulmonary embolism restores hemodynamic stability and thus is an alternative to surgery or systemic thrombolysis, even in the pediatric setting. While catheter-directed thrombolysis is a safe and effective alternative to systemic thrombolysis, further research is needed to establish appropriate dosing and indications in the adolescent population.
gene therapies
2026-08-20 | A Pathogenic ANK1 c.5096G>A Mutation Disrupting the Ankyrin-1/β-Spectrin Interaction in Hereditary Spherocytosis.
Hereditary spherocytosis (HS) is a common inherited hemolytic anemia characterized by spherical erythrocytes, splenomegaly, and increased osmotic fragility, with ANK1 mutations being the most frequent cause. We identified a novel ANK1 mutation (c.5096G>A, p.R1699K) in a patient with classic HS phenotypes and a family history of hemolytic anemia. To explore its pathogenicity, we performed a series of hematological and morphological analyses. Compared with wild-type mice, the Ank1 c.5198G>A knock-in mice displayed typical HS features. Hematologically, they showed reduced MCV, MCH, and MCHC. The EMA fluorescence intensity was significantly decreased, and RBCs exhibited increased osmotic fragility. Morphologically, peripheral smears revealed abundant spherocytes, and electron microscopy showed a transformation from normal biconcave discs to spherical erythrocytes. Additionally, the Ank1 c.5198G>A knock-in mice presented with significant splenomegaly. Mechanistically, coimmunoprecipitation analysis indicated a significantly weakened association between ankyrin-1 and β-spectrin in the Ank1 c.5198G>A knock-in mice. This study provides in vivo evidence that the Ank1 R1733K mutation impairs erythrocyte membrane stability and cytoskeletal integrity, recapitulating the HS phenotype in mice. Our findings support the pathogenicity of the ANK1 c.5096G>A mutation and offer a useful model for further investigating the molecular mechanisms of HS.
2026-08-19 | The molecular genetic spectrum of hereditary spherocytosis in the Russian population
Introduction. Hereditary spherocytosis (HS) is a hereditary hemolytic anemia caused by defects in erythrocyte membrane and cytoskeleton due to mutations mainly in five genes: ANK1, SPTB, SPTA1, SLC4A1, and EPB42. The genetic landscape of HS is characterized by considerable interpopulation variability. Aim – to investigate the molecular genetic spectrum of HS in the Russian population. Materials and methods. The study included 240 patients under 21 years of age with genetically confirmed HS. We analyzed the distribution of pathogenic variants by gene, mutation type, frequency of recurrent and previously undescribed variants, and also assessed the genotype–phenotype correlation with disease severity. Results. Pathogenic variants in the SPTB gene were identified in 45.8% of the patients, in the ANK1 gene in 34.6%, in the SLC4A1 gene in 11.3%, and in the SPTA1 gene in 8.3%. In the SPTB and ANK1 genes, loss-of-function mutations, such as nonsense, frameshift, and splice-site mutations, predominated. In the SLC4A1 gene, missense mutations were the most common, whereas in the SPTA1 gene there was a heterogeneous mutation spectrum, including the frequent intronic mutation with low aLEPRA expression. Novel mutations accounted for 54.2% of all variants. In SPTA1-associated HS, complex genotypes were frequently observed: compound heterozygous variants and digenic variants were found in 35% and in 20% of the patients, respectively. Our clinical severity analysis showed that patients with SPTB- and ANK1-associated HS had mostly moderate disease, patients with SLC4A1-associated HS had a mild course with no severe cases, while SPTA1-associated HS was characterized by a relatively high proportion of severe cases. Conclusion. The Russian cohort belongs to populations with an SPTB-dominant mutation pattern and represents one of the largest national cohorts of patients with genetically confirmed HS worldwide.
2026-07-23 | Hereditary Spherocytosis in a Child due to a Deletion in β‐Spectrin Detected by Low‐Input DNA Long‐Read Whole‐Genome Sequencing
The authors declare no conflicts of interest. Relevant data are available from the corresponding author upon reasonable request. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
2026-07-10 | Erythroid-derived extracellular vesicles and interplay with soluble transferrin receptor in hereditary hemolytic anemias
In hereditary hemolytic anemia (HHA), soluble transferrin receptor (sTfR) reflects erythropoietic activity, whereas in iron deficiency anemia, it indicates iron-restricted hematopoiesis. Improving our understanding of sTfR biology, including its relationship with extracellular vesicles (EVs), could help improve the management of disorders involving abnormal iron metabolism and chronic hemolysis. We investigated the role of sTfR and EVs in HHA with respect to disease severity, iron biology, and splenectomy status. This cross-sectional observational study included 95 adult patients with HHA, including hemoglobinopathies (n = 33), red cell enzyme disorders (n = 31), and red cell membrane disorders (n = 31). Hematological parameters and biochemical markers of hemolysis and iron homeostasis were measured, and EVs were characterized by flow cytometry using cell-specific markers. We observed HHA-specific patterns of plasma EV levels and composition, reflecting anemia severity and modes of red blood cell clearance in patients with hereditary spherocytosis (HS) and pyruvate kinase deficiency. In patients with HS, sTfR levels correlated with erythropoietin ( r = 0.826) and reticulocyte count ( r = 0.688) in those with moderately severe anemia, suggesting a high erythroid output, which is not seen in splenectomized patients. Across HHA subtypes, circulating sTfR levels closely paralleled CD71 + EV concentrations ( r = 0.779), suggesting a fraction of sTfR is EV-associated. Overall, EV and sTfR levels in HHA represented disease severity and erythropoietic drive, whereas sTfR was not suitable as a marker of iron metabolism or ineffective erythropoiesis in HHA. Longitudinal studies measuring EV and sTfR levels before and after splenectomy, combined with analyses of EV content in HHA, are required to assess their predictive value and clinical potential in HHA.
2026-03-19 | Symptomatic Recurrent Splenomegaly Following Partial Splenectomy in Patients With Hereditary Spherocytosis.
Hereditary spherocytosis (HS) is an inherited hematologic disorder characterized by spherical erythrocytes that are prematurely destroyed in the spleen. Total splenectomy (TS) and partial splenectomy (PS) are surgical interventions used to manage HS, but long-term outcomes, including recurrence of splenomegaly and splenomegaly-related symptoms, remain poorly understood. This study aims to evaluate the long-term recurrence of splenomegaly and splenomegaly-related symptoms in children with HS who underwent PS versus TS at a single institution between 2008 and 2020. A retrospective chart review of children with HS who underwent TS or PS was performed. The primary end point was the long-term recurrence of splenomegaly and splenomegaly-related symptoms. Variables collected included age, sex, surgical method (PS vs. TS), postoperative hematologic markers, splenic volume, postoperative complications, length of hospital stay, recurrence of splenomegaly, and need for completion splenectomy. Symptomatic recurrent splenomegaly is defined as splenic volume > 450 mL and the presence of symptoms directly attributable to the spleen and its effects on adjacent organs or hemolysis. Statistical analysis included comparisons of continuous variables using a Kruskal-Wallis test and categorical variables using a Fisher's exact test. Forty-four patients with HS met the inclusion criteria for the study. Of these, 31 (71%) patients underwent laparoscopic PS and 13 (30%) patients underwent laparoscopic TS. TS was associated with significantly less intraoperative blood loss (p = 0.003), shorter hospital stays (p = 0.01), and greater reduction in hemolysis compared to PS, as evidenced by lower postoperative bilirubin levels and reticulocyte counts (both p < 0.001). Eighteen (58%) PS patients experienced recurrent splenomegaly, and six (19%) PS patients experienced splenomegaly-related symptoms leading to completion splenectomy. Among the six patients who required completion splenectomy, intraoperative hemorrhage requiring conversion to open procedure occurred in half. The median time to need completion splenectomy was 10.5 years (range, 3-15 years). TS offers more significant long-term hematologic improvements but comes with the loss of immune function and increased risk of overwhelming post-splenectomy infection (OPSI). PS, while preserving some splenic function and theoretically reducing OPSI risk, carries a higher risk of recurrent symptomatic splenomegaly and may require additional surgeries. These findings highlight the importance of long-term follow-up for HS patients who undergo PS and the need to balance the advantages and risks of both surgical approaches.
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