First described 100 years ago, von Willebrand disease (VWD) is the most common inherited bleeding disorder, characterized by a quantitative or qualitative deficiency of von Willebrand factor (VWF), a large multimeric glycoprotein central to hemostasis. Despite its prevalence, VWD remains globally underdiagnosed. Accurate diagnosis requires thorough clinical assessment and specialized laboratory evaluation. Although international evidence-based guidelines have advanced care, significant diagnostic and management challenges remain. Management focuses on treating and preventing bleeding, ensuring periprocedural safety, and improving quality of life through individualized strategies and the use of various hemostatic agents and therapeutic strategies. Optimal management approaches in complex clinical scenarios remain challenging. In this comprehensive illustrated review, we cover the biology and physiology of VWF, along with the pathophysiology, diagnosis, and management of VWD. We review current clinical practice recommendations and provide practical guidance for challenging scenarios such as surgery, pregnancy, cardiovascular disease, aging, and acquired von Willebrand syndrome. We also highlight emerging therapeutics and models of care in VWD.

With the widespread adoption of genomic testing, germline predisposition syndromes such as RUNX1-familial platelet disorder with associated myeloid malignancy (FPD-MM) are increasingly encountered in routine hematological practice. FPD-MM is driven by RUNX1 haploinsufficiency, which initially manifests as quantitative and qualitative platelet abnormalities. Over time, this constitutional defect promotes the formation of an inflammation-dominant bone marrow microenvironment, facilitating clonal hematopoiesis, clonal expansion, and the stepwise accumulation of secondary somatic alterations, ultimately leading to myeloid or lymphoid malignancies. Accurate diagnosis requires careful interpretation of tumor-based sequencing results, followed by confirmatory testing using appropriate germline specimens in conjunction with standardized variant classification frameworks. Clinical management encompasses bleeding risk mitigation and disease-specific therapy for overt hematologic neoplasms, including allogeneic hematopoietic stem cell transplantation. Genetic counseling is an essential component of donor coordination in FPD-MM, given the documented risk of donor-derived leukemia when related donors harbor the same pathogenic germline variant as the proband. Beyond the management of affected individuals, surveillance for asymptomatic variant carriers is also essential for early intervention before disease progression. This review summarizes the pathobiology, diagnostic strategy, and practical clinical management of FPD-MM, emphasizing family management as a central medical and ethical challenge at the intersection of hematology and clinical genetics.

Endometrial injury-related disorders, including intrauterine adhesions, thin endometrium, and chronic endometritis, are a major cause of female infertility. Conventional therapeutic approaches, primarily hormone therapy and surgical interventions, show limited effectiveness in patients with moderate to severe endometrial damage. In this context, regenerative medicine has emerged as a promising direction to overcome current therapeutic limitations and promote functional reconstruction of the endometrium. A comprehensive literature search was conducted across PubMed, Web of Science, Embase, and Scopus to identify relevant studies on endometrial repair and regenerative medicine. The search covered publications from January 2000 to August 2025. The following keyword combinations and MeSH terms were used: ("endometrial repair" OR "endometrial regeneration" OR "intrauterine adhesion" OR "Asherman syndrome" OR "thin endometrium" OR "chronic endometritis") AND ("mesenchymal stem cells" OR "platelet-rich plasma" OR "exosomes" OR "extracellular vesicles" OR "biomaterials" OR "hydrogel" OR "scaffold" OR "regenerative medicine"). Both basic science investigations and clinical studies were included to provide a comprehensive overview of current developments in the field. To minimize the risk of omission, the reference lists of included articles and relevant reviews were manually screened, and potentially pertinent studies were further evaluated. Inclusion criteria: (1) Original research articles or meta-analyses; (2) Focus on therapeutic interventions for endometrial regeneration; (3) Human clinical studies or mammalian animal models. Exclusion criteria: (1) Non-English articles, letters, conference proceedings, etc.; (2) Purely descriptive studies of endometrial physiology without therapeutic intervention, articles lacking quantitative data or sufficient methodological details. The screening process followed the PRISMA 2020 guidelines (Fig. 1). After removing duplicates, 1936 records were screened by title and abstract, and 605 full-text articles were assessed for eligibility. Finally, 102 studies were included in this qualitative synthesis. This review provides a systematic synthesis of recent advances in cell-based therapies, cell-free approaches, and bioengineering strategies for endometrial repair. Evidence derived from different sources of mesenchymal stem cells, including bone marrow, umbilical cord, and endometrium, is comparatively evaluated alongside platelet-rich plasma and extracellular vesicles, with an emphasis on hierarchical assessment of evidence levels. Several critical issues are further examined. Current stem cell-based interventions are largely characterized by a broad reparative profile, yet precise targeting of key molecular mechanisms remains insufficient. To date, no studies have demonstrated the capacity to directly reverse suppression of signaling pathways such as the GZMA-PARD3 axis or to restore depleted regenerative stromal subpopulations, including IGFBP3[+] cells. Clinical investigations of platelet-rich plasma exhibit substantial heterogeneity, which appears to stem mainly from the absence of standardized preparation protocols and the frequent reliance on surrogate endpoints, particularly endometrial thickness. However, the predictive value of endometrial thickness for live birth is limited, and its use as a primary endpoint may overestimate clinical benefit. Therefore, emphasis should shift toward patient-centered outcomes such as live birth rate. Concerns also arise regarding the degradation kinetics of biomaterials, as mismatches between material resorption and the cyclical regenerative dynamics of the endometrium may increase the risk of secondary adhesions. In addition, the actual delivery efficiency of microneedle-based systems within the enclosed and humid uterine environment has not yet been fully clarified. Based on this critical appraisal, we propose a translational framework that links mechanistic discovery with precision intervention. The importance of long-term follow-up is emphasized, with live birth rate regarded as a more clinically meaningful primary endpoint for evaluating therapeutic efficacy in endometrial regenerative medicine. Endometrial regenerative medicine is transitioning from empirical repair toward mechanism-informed reconstruction. Current evidence is dominated by short-term (< 12 months), small-sample (n < 50) exploratory studies with high interventional heterogeneity. Clinical translation will require unified preparation standards, individualized treatment strategies, and well-designed multicenter randomized controlled trials with live birth rate as the primary endpoint and minimum 2-year follow-up.

von Willebrand disease (VWD) and hemophilia A (HA) are the most common inherited bleeding disorders, caused by quantitative or qualitative defects of von Willebrand factor (VWF) and coagulation factor VIII (FVIII). Over the past decades, both diseases have undergone a profound therapeutic transformation, evolving from supportive care to highly effective replacement, pharmacological, and prophylactic strategies. This perspective article compares the parallel but distinct trajectories of therapeutic developments in HA and VWD, highlighting shared milestones and disease-specific limitations. In HA, advances in recombinant technology, extended half-life factor concentrates, nonfactor therapies such as FVIII mimetics and emerging gene therapy approaches have established prophylaxis as the standard of care. VWD therapy has evolved more slowly, largely owing to the marked clinical and molecular heterogeneity of this disease, that often causes difficult and delayed diagnosis. Current management is based on desmopressin, plasma-derived products, and recombinant VWF, with limited prophylaxis implementation. Nevertheless, a rapidly expanding pipeline of novel therapies -- including VWF half-life extension strategies, VWF-independent coagulation rebalancing agents, antifibrinolytics, platelet-mimetic technologies, and gene-based approaches -- suggests an imminent shift in VWD management. Collectively, these developments indicate a transition toward more individualized and mechanism-driven therapy, with the potential to fill the therapeutic gap between VWD and HA and improve long-term outcomes and quality of life in patients with these inherited bleeding disorders.

Bleeding disorders represent a broad spectrum of conditions that disrupt normal clot formation through abnormalities in platelet function or the coagulation cascade. Disorders affecting primary hemostasis typically manifest as mucosal bleeding, whereas abnormalities in secondary hemostasis more often lead to deep tissue hemorrhage. However, certain conditions, such as von Willebrand disease, may involve features of both pathways, complicating clinical evaluation. This report describes two adolescent patients who presented with mucocutaneous bleeding but were ultimately diagnosed with different underlying conditions: Glanzmann thrombasthenia and type 2 von Willebrand disease. The first patient exhibited recurrent gingival bleeding with normal platelet counts and near-normal coagulation studies. Further evaluation using platelet aggregation testing revealed impaired responses to multiple agonists, consistent with a defect in platelet aggregation. The second patient presented with gingival bleeding and severe menorrhagia and was initially treated as a case of hemophilia due to reduced factor VIII levels. Lack of therapeutic response prompted further testing, which demonstrated abnormal von Willebrand factor activity, confirming a qualitative defect. These cases highlight the importance of correlating clinical presentation with specialized laboratory investigations. Reliance on routine tests alone may lead to misdiagnosis, whereas a systematic diagnostic approach allows accurate identification and appropriate management of bleeding disorders.

Heritable platelet function disorders (HPFD) are a diverse group of bleeding disorders characterised by a primary qualitative defect in platelet function rather than platelet number. HPFD may be broadly categorised according to the severity of bleeding, with Glanzmann thrombasthenia and Bernard Soulier syndrome classically considered severe HPFD, with well-described clinical and laboratory phenotypes. The remaining non-severe HPFD are less completely characterised and provide additional challenges in diagnosis despite advances in standardising diagnostic approaches for HPFD. Distinguishing patients with non-severe HPFD from patients who do not have a bleeding disorder may be aided by employing bleeding assessment tools early in patient assessment, although there may be limitations according to patient factors. Distinguishing patients with non-severe HPFD from those with acquired platelet function disorders and from those with other heritable disorders of haemostasis (including bleeding disorder of unknown cause) requires more sophisticated clinical and laboratory tools, including platelet light transmission aggregometry, secretion and flow cytometry assays, which can categorise many HPFD to the level of the defective platelet pathway and some to the level of an individual protein. The increasing availability of high-throughput genetic sequencing has made genetic diagnosis possible for some patients with non-severe HPFD; however, this is limited by difficulties with standardisation of laboratory phenotyping and the challenges of distinguishing pathogenic from benign genetic variation. This review will focus on updates in diagnostic approaches for patients with non-severe HPFD since the last IJLH education article on this topic in 2014.

Mild bleeding disorders (MBDs) comprise a heterogeneous group of inherited conditions characterized by clinically relevant bleeding symptoms despite largely normal or inconclusive results in routine hemostatic testing. These disorders account for a substantial proportion of referrals to specialized hemostasis clinics and include von Willebrand disease (VWD), inherited platelet function disorders, and mild coagulation factor deficiencies. Despite systematic diagnostic algorithms, many patients with MBDs remain without a definitive diagnosis and are classified as having bleeding disorder of unknown cause (BDUC), complicating clinical management and counseling. Conventional diagnostic approaches rely on structured bleeding assessment tools, detailed family history, and stepwise laboratory testing. Biological variability, assay limitations, and phenotypic overlap often result in inconclusive findings.

Acquired von Willebrand Syndrome (AVWS) is a rare bleeding disorder characterized by quantitative or qualitative defects of von Willebrand factor (VWF) in patients without a personal or family history of bleeding. It is frequently associated with systemic diseases, particularly lymphoproliferative disorders (LPDs) and myeloproliferative neoplasms (MPNs). In this single-center, retrospective cross-sectional study, we included patients diagnosed with AVWS at the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center between April 2014 and March 2025. Bleeding severity was assessed using the ISTH-BAT score. Laboratory tests included FVIII:C, VWF:Ag, VWF:GPIbR, VWF:RCo, VWF:CB, VWFpp, and multimer analysis. Among 140 patients, 106 (76%) had MPNs and 26 (19%) LPDs. At least one bleeding symptom was observed in 70% of patients, with clinically significant bleeding occurring in 24% of the cohort. Clinically relevant bleeding (mainly mucocutaneous and gastrointestinal) was more frequent and severe in LPDs (58%) than in MPNs (13%). LPDs showed severe VWF functional defects, marked HMWM loss, and elevated VWFpp/VWF:Ag ratios (median 6.7), consistent with accelerated clearance. MPNs displayed mild HMWM reduction, normal clearance (median VWFpp/VWF:Ag ratio 1.0), and an inverse correlation between platelet count and the degree of HMWM depletion (ρ = -0.48, p < 0.001). Bleeding severity correlated inversely with VWF:GPIbR in LPDs (ρ = -0.50, p = 0.02) and with VWF:RCo in MPNs. Anti-VWF antibodies were found in 30% of tested LPDs or autoimmune cases. The two main phenotypes presented in AVWS were immune-mediated in LPDs and platelet-mediated in MPNs. Understanding the underlying mechanism is crucial for accurate diagnosis and targeted treatment to reduce bleeding risk and improve outcomes.

Platelets are small anucleate blood cells derived from megakaryocytes, essential for hemostasis and involved in thrombosis, inflammation, immunity, and tissue repair. Their production depends on tightly regulated processes of megakaryopoiesis and thrombopoiesis. Inherited platelet disorders (IPDs) are a heterogeneous group of rare diseases caused by germline variants affecting megakaryocyte development and maturation, platelet production, structure, or function. These include inherited thrombocytopenias, characterized by reduced platelet counts, and inherited platelet function disorders, caused by qualitative platelet defects. Depending on the underlying genetic alteration, patients may present with bleeding, syndromic manifestations, or predisposition to hematologic malignancies. Recent advances in platelet biology and molecular genetics have improved diagnosis, personalized management, and genetic counseling. In parallel, IPDs have emerged as valuable human models for understanding the molecular mechanisms regulating platelet biogenesis and function in health and disease.

von Willebrand Disease (VWD) is the most common heritable bleeding disorder worldwide and arises from quantitative or qualitative deficiencies of von Willebrand Factor (VWF). VWF is a multimeric protein essential for primary hemostasis and factor VIII stabilization. Diagnosis of VWD requires integration of bleeding history and laboratory testing. Traditional laboratory assays, such as ristocetin cofactor activity (VWF:RCo) are increasingly being replaced by newer methods with improved analytical performance, including VWF:GPIbM and VWF:GPIbR. Advances in multimer analysis, Collagen Binding, and genetic testing are further refining the approach to VWD subtype classification. This review summarizes recent diagnostic innovations.