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.

von Willebrand disease (vWD) is the most common inherited bleeding disorder. Various subtypes of vWD exist as either quantitative deficiencies or qualitative defects of the von Willebrand factor (vWF) protein and lead to an array of bleeding manifestations. Individuals with vWD typically have increased mucocutaneous bleeding including oral mucosal bleeding, epistaxis, and heavy menstrual bleeding. Other common bleeding manifestations including petechiae, easy bruising, surgical-related bleeding, postpartum hemorrhage, and trauma-induced bleeding. In more severe subtypes gastrointestinal bleeding, hemarthrosis, and intramuscular bleeding can occur. Given the spectrum of bleeding phenotypes, management can differ greatly from one individual to the next with the majority of individuals receiving on-demand treatment while more severely affected individuals may receive long-term prophylaxis. Common on-demand therapeutics include oral, intravenous, topical, and/or intranasal antifibrinolytics, intravenous, subcutaneous and/or intranasal desmopressin, and intravenous plasma-derived and recombinant-vWF replacement therapy. Long-term prophylactic regimens include hormonal therapies and regularly scheduled infusions of plasma-derived and recombinant-vWF concentrates. Over the past 100 years the therapeutic landscape for individuals with vWD has changed significantly and continues to evolve. There are numerous studies currently underway to evaluate new treatments including several drugs administered via subcutaneous injection, and vagal nerve stimulation. Historically individuals with vWD have poorer health-related quality of life and higher healthcare resource utilization compared to the general population, emphasizing the ongoing need for improved therapeutics.

Glanzmann thrombasthenia (GT) is a rare, autosomal recessive platelet aggregation disorder caused by mutations in the ITGA2B and ITGB3 genes. These mutations result in quantitative or qualitative deficiencies in the alpha IIb beta 3 integrin complex, impairing platelet aggregation and leading to recurrent mucocutaneous bleeding. The key findings include absent or severely reduced platelet aggregation with adenosine diphosphate (ADP), epinephrine, and collagen, while aggregation with ristocetin remains normal. While hundreds of pathogenic variants have been identified, the genetic landscape of GT continues to expand with the discovery of novel mutations. GT treatment focuses on controlling bleeding. Hemopoietic stem cell transplantation (HSCT) offers a curative option for severe cases, while gene therapy is a promising future approach. Here, we report the case of a four-year-old female presenting with recurrent bilateral epistaxis and a significant family history of bleeding diathesis. Whole-exome sequencing (WES) revealed a novel homozygous missense variant in ITGA2B (c.655G>T; p.Gly219Cys). This variant, which is absent from public genomic databases, was predicted to be deleterious by multiple in-silico computational tools, supporting a diagnosis of GT. This case identifies a previously unreported pathogenic variant and underscores the critical role of genetic testing in diagnosing unexplained mucocutaneous bleeding, particularly in cases involving consanguinity.