RARE DISEASE
Bernard-Soulier syndrome
Bernard-Soulier syndrome
Bernard-Soulier syndrome
Synonyms: Giant platelet syndrome, Hemorrhagiparous thrombocytic dystrophy
Synonyms: Giant platelet syndrome, Hemorrhagiparous thrombocytic dystrophy
Synonyms: Giant platelet syndrome, Hemorrhagiparous thrombocytic dystrophy
Drug discovery
3
drugs
With orphan designations
Overview
Bernard-Soulier syndrome (BSS) is a rare autosomal recessive platelet disorder caused by mutations in GP1BA, GP1BB, or GP9 genes, leading to defective glycoprotein Ib-IX-V complex formation. This results in macrothrombocytopenia, impaired platelet adhesion, and bleeding manifestations such as epistaxis, menorrhagia, and prolonged post-traumatic hemorrhage. Diagnosis involves platelet aggregation studies (absent ristocetin response) and flow cytometry.
Burden
Lifelong bleeding risk requiring tailored interventions; 20–30% develop platelet transfusion refractoriness [3][8][12].
Frequent misdiagnosis as ITP, leading to inappropriate therapies (e.g., steroids, splenectomy) [5][15].
Quality-of-life impacts: activity restrictions (e.g., contact sports), iron deficiency anemia, and obstetric challenges [6][14].
Categories: rare genetic diseases, rare hematological diseases
Research Papers
138 drug discovery papers about Bernard-Soulier syndrome, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
138 drug discovery papers about Bernard-Soulier syndrome, with 4 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-07 | Genetic depletion in zebrafish uncovers requirement for septins in haematopoiesis
Abstract Haematopoiesis and differentiation of immune cells from haematopoietic stem and progenitor cells (HSPCs) are essential to core aspects of health and disease. A key player in haematopoiesis and HSPC differentiation is the cytoskeleton, which governs cell division and lineage bias. Despite insights using mouse models, regulation of haematopoiesis by the septin cytoskeleton is mostly unknown. Septins are unconventional filament forming proteins best known for roles in cell division and host defence. To investigate septin-mediated host defence in vivo , we generated septin-deficient zebrafish models for infection with Mycobacterium marinum . Unexpectedly, septin-deficient larvae were protected from mycobacterial infection due to significantly increased macrophage numbers, reduced cell death, and enhanced inflammatory responses. Underlying this, we found that septin-deficient larvae produce significantly more HSPCs and show myeloid lineage bias, establishing a requirement for septins in haematopoiesis. In agreement with classical HSPC hierarchy, increased myeloid production in septin-deficient larvae is at the expense of erythroid lineage production. Our findings that septins play a role in haematopoiesis is consistent with hallmarks of haematological disorders in which septin dysfunction has been implicated, including acute myeloid leukaemia, myelodysplastic syndrome, and platelet disorder Bernard-Soulier syndrome. These results highlight zebrafish as a new model to investigate septin-mediated haematopoiesis and application of septin-based medicines to treat blood disorders.
2025-09-11 | An Infectious Accelerant: Dual Hemostatic and Antimicrobial Therapy for Catastrophic Hemoptysis in Bernard–Soulier Syndrome
IntroductionBernard-Soulier syndrome (BSS), or hemorrhagiparous thrombocytic dystrophy, is a rare autosomal recessive bleeding disorder caused by genetic mutations affecting the platelet glycoprotein Ib-IX-V complex [1]. This defect impairs platelet a
2025-05-19 | Anesthesia Management Using Remimazolam in A Patient With Bernard-Soulier Syndrome: A Case Report.
Bernard-Soulier syndrome (BSS) is a platelet dysfunction disorder characterized by massive thrombocytopenia and a lack of platelet aggregation. Remimazolam, a short-acting benzodiazepine sedative, is believed to have minimal effects on platelets. Here, we report the safe use of remimazolam for anesthesia management in a patient with BSS.
2025-03-06 | Increased RhoA pathway activation downstream of αIIbβ3/SRC contributes to heterozygous Bernard Soulier syndrome.
Bernard Soulier syndrome (BSS) is a severe bleeding disorder with moderate to severe thrombocytopenia, giant platelets, and platelet dysfunction, caused by biallelic mutations in GP1BA, GP1BB, or GP9 genes. We generated induced pluripotent stem cells (iPSC) from a BSS patient with a novel heterozygous GP1BA p.N103D mutation, resulting in moderate macrothrombocytopenia. The mutation does not affect megakaryocyte (MK) differentiation or GPIb-GPIX complex expression but reduces affinity to von Willebrand factor (VWF). It induces increased signaling independent of VWF and αIIbβ3-mediated outside-in signaling, causing a profound defect in proplatelet formation after adhesion on fibrinogen. Pre-activation of αIIbβ3 integrin and heightened stress fiber formation linked to RhoA pathway overactivation were observed, likely due to increased phosphorylation of SRC at Y419 downstream of GPIbα. Dasatinib, a SRC inhibitor, restored stress fiber formation. Using a 3D bone marrow model to mimic platelet release under flow, we demonstrated that the ROCK1/2 inhibitor Y27632 increased platelet number and restored platelet size in GPIbαN103D MK, as well as in MK from two other patients with heterozygous GP1BA mutations (p.L160P and p.N150S). However, Y27632 had no additional effect on platelet generation from MK of two patients with biallelic BSS, suggesting a distinct molecular mechanism in biallelic cases.
2024-12-19 | Roles of ROCK/Myosin Pathway in Macrothrombocytopenia in Bernard-Soulier Syndrome.
Megakaryocytes (MK) from Bernard-Soulier syndrome (BSS) induced pluripotent stem cells (iPSCs) yielded reduced numbers but increased sizes of platelets. The molecular mechanisms remain unclear. This study aims to determine roles of signaling molecules involved in this process.Wild-type (WT) iPSCs and iPSCs from BSS patients with GP1BA (BSS-A) or GP1BB (BSS-B) mutations were differentiated into MKs and platelets with or without myosin II inhibitor (blebbistatin), ROCK inhibitor (Y27632), and procaspase-3 activator (PAC-1). Proplatelet and platelet numbers and sizes were characterized. The iPSC lines containing tubulin-green fluorescent protein (GFP) reporters were constructed to observe proplatelet formation under time-lapse microscopy.BSS-derived MKs (BSS-MKs) yielded fewer but larger platelets compared with the WT. In the presence of blebbistatin, ROCK inhibitor, or PAC-1, WT, BSS-A, and BSS-B MKs could generate more platelets with decreased sizes, but PAC-1 caused CD42 loss on WT platelets. The proportions of proplatelet formation from MKs carrying tubulin-GFP were not different between WT and BSS-MKs, as well as among inhibitors. Notably, initially thick cytoplasmic processes were transformed into thin branching proplatelets over the observation time. The proplatelet shafts of BSS-MK became thinner in the presence of blebbistatin or ROCK inhibitor, but not of PAC-1, which displayed uneven F-actin distribution.Inhibition of the ROCK/myosin pathway, downstream of GpIb, could restore normal morphology of proplatelets in BSS-MKs. Procaspase-3 activation could increase platelet yields, but with abnormal proplatelet and platelet structures. Our model can be used for therapeutic drug screening and a disease model for platelet production in the future.
antibodies
2025-04-23 | Acquired Bernard-Soulier-like syndrome due to a plasma-based inhibitor treated successfully with rituximab.
Bernard-Soulier syndrome (BSS) is an autosomal recessive disorder caused by deficient platelet glycoprotein Ib-IX-V expression resulting in abnormal bleeding, thrombocytopenia, giant platelets, and reduced platelet aggregation response to ristocetin that manifests in childhood. Acquired BSS is a rare disorder characterized by Bernard-Soulier (BS)-like platelet dysfunction in a patient without a history consistent with a bleeding disorder. Can acquired BSS respond to immune-directed therapy? We describe a case of a 79-year-old man presenting with refractory epistaxis found to have an isolated BS-like platelet function defect due to a plasma-based inhibitor. He was treated with rituximab with immediate cessation of bleeding and normalization of platelet function studies. To our knowledge, this is the first case of acquired BS-like syndrome described in the absence of systemic illness due to a presumed autoantibody, and we report the successful use of rituximab for treatment of this rare disorder.
2022-04-01 | Activated Platelets Upregulate β2 Integrin Mac-1 (CD11b/CD18) on Dendritic Cells, Which Mediates Heterotypic Cell–Cell Interaction
Abstract Recent evidence suggests interaction of platelets with dendritic cells (DCs), while the molecular mechanisms mediating this heterotypic cell cross-talk are largely unknown. We evaluated the role of integrin Mac-1 (αMβ2, CD11b/CD18) on DCs as a counterreceptor for platelet glycoprotein (GP) Ibα. In a dynamic coincubation model, we observed interaction of human platelets with monocyte-derived DCs, but also that platelet activation induced a sharp increase in heterotypic cell binding. Inhibition of CD11b or GPIbα led to significant reduction of DC adhesion to platelets in vitro independent of GPIIbIIIa, which we confirmed using platelets from Glanzmann thrombasthenia patients and transgenic mouse lines on C57BL/6 background (GPIbα−/−, IL4R-GPIbα-tg, and muMac1 mice). In vivo, inhibition or genetic deletion of CD11b and GPIbα induced a significant reduction of platelet-mediated DC adhesion to the injured arterial wall. Interestingly, only intravascular antiCD11b inhibited DC recruitment, suggesting a dynamic DC–platelet interaction. Indeed, we could show that activated platelets induced CD11b upregulation on Mg2+-preactivated DCs, which was related to protein kinase B (Akt) and dependent on P-selectin and P-selectin glycoprotein ligand 1. Importantly, specific pharmacological targeting of the GPIbα–Mac-1 interaction site blocked DC–platelet interaction in vitro and in vivo. These results demonstrate that cross-talk of platelets with DCs is mediated by GPIbα and Mac-1, which is upregulated on DCs by activated platelets in a P-selectin glycoprotein ligand 1–dependent manner.
2018-02-21 | The search for new antithrombotic mechanisms and therapies that may spare hemostasis
Abstract Current antithrombotic drugs, including widely used antiplatelet agents and anticoagulants, are associated with significant bleeding risk. Emerging experimental evidence suggests that the molecular and cellular mechanisms of hemostasis and thrombosis can be separated, thereby increasing the possibility of new antithrombotic therapeutic targets with reduced bleeding risk. We review new coagulation and platelet targets and highlight the interaction between integrin αMβ2 (Mac-1, CD11b/CD18) on leukocytes and GPIbα on platelets that seems to distinguish thrombosis from hemostasis.
2016-10-01 | Platelets and platelet adhesion molecules: novel mechanisms of thrombosis and anti-thrombotic therapies
Platelets are central mediators of thrombosis and hemostasis. At the site of vascular injury, platelet accumulation (i.e. adhesion and aggregation) constitutes the first wave of hemostasis. Blood coagulation, initiated by the coagulation cascades, is the second wave of thrombin generation and enhance phosphatidylserine exposure, can markedly potentiate cell-based thrombin generation and enhance blood coagulation. Recently, deposition of plasma fibronectin and other proteins onto the injured vessel wall has been identified as a new "protein wave of hemostasis" that occurs prior to platelet accumulation (i.e. the classical first wave of hemostasis). These three waves of hemostasis, in the event of atherosclerotic plaque rupture, may turn pathogenic, and cause uncontrolled vessel occlusion and thrombotic disorders (e.g. heart attack and stroke). Current anti-platelet therapies have significantly reduced cardiovascular mortality, however, on-treatment thrombotic events, thrombocytopenia, and bleeding complications are still major concerns that continue to motivate innovation and drive therapeutic advances. Emerging evidence has brought platelet adhesion molecules back into the spotlight as targets for the development of novel anti-thrombotic agents. These potential antiplatelet targets mainly include the platelet receptors glycoprotein (GP) Ib-IX-V complex, β3 integrins (αIIb subunit and PSI domain of β3 subunit) and GPVI. Numerous efforts have been made aiming to balance the efficacy of inhibiting thrombosis without compromising hemostasis. This mini-review will update the mechanisms of thrombosis and the current state of antiplatelet therapies, and will focus on platelet adhesion molecules and the novel anti-thrombotic therapies that target them.
2013-04-05 | Targeting Platelet GPIbβ Reduces Platelet Adhesion, GPIb Signaling and Thrombin Generation and Prevents Arterial Thrombosis
Objective— The glycoprotein (GP) Ib-V-IX complex regulates the adhesion, activation, and procoagulant activity of platelets. We previously reported that RAM.1, a rat monoclonal antibody directed against the extracellular domain of mouse GPIbβ, diminished adhesion of platelets and chinese hamster ovary cells transfected with the human GPIb-IX complex to von Willebrand factor under flow conditions. Here, we further evaluated the functional importance of GPIbβ by studying the impact of RAM.1 on GPIb-mediated platelet responses and in vitro and in vivo thrombus formation. Approach and Results— We show that RAM.1 dramatically reduced GPIb-mediated filopodia extension of chinese hamster ovary GPIb-IX cells after adhesion to von Willebrand factor. RAM.1 also reduced filopodia extension and GPIb-mediated Ca 2+ signaling after adhesion of mouse platelets to von Willebrand factor. RAM.1 inhibited thrombin generation in platelet-rich plasma without impairing phosphatidylserine exposure. In addition, RAM.1 reduced thrombus formation after perfusion of mouse whole blood over collagen in a shear-dependent manner. This effect was confirmed in vivo, because injection of F(ab)′2 fragments of RAM.1 diminished thrombus formation induced by laser beam injury of mesenteric arterioles and forceps injury of the abdominal aorta. In contrast, RAM.1 F(ab)′2 did not prolong the tail-bleeding time or increase the volume of blood lost. Conclusions— These findings are the first evidence that targeting a subunit other than GPIbα can lead to an antithrombotic effect via the GPIb-V-IX complex. This could represent an alternative way to reduce thrombus formation with a minor impact on hemostasis.
proteins
2026-02-26 | Hemostatic rescue with rFVIIa in Bernard-Soulier syndrome refractory to HLA-matched platelet transfusion.
We report the case of a man in his 50’s diagnosed with Bernard-Soulier syndrome (BSS) in childhood who developed refractory gluteal bleeding following a fall accident. The patient underwent four hematoma evacuation procedures and multiple platelet transfusions, including HLA (human leukocyte antigen) -matched platelet concentrates, without achieving sustained hemostatic control. Given the lack of response to platelet transfusion and ongoing bleeding risk, Eptacog Alfa (recombinant activated factor VII; rFVIIa) was administered for 4 days, following the dosing regimen recommended for Glanzmann thrombasthenia in surgical bleeding settings. Hemostasis was achieved shortly after rFVIIa administration, and no further surgical evacuation was necessary. Importantly, no thromboembolic complications occurred despite the use of rFVIIa. This case demonstrates that rFVIIa can serve as an effective adjunctive hemostatic therapy in patients with BSS who are refractory to platelet transfusions. We reviewed the existing literature on rFVIIa use in patients with BSS and summarized the clinical contexts, dosing strategies, efficacy, and safety outcomes. Our experience suggests that early consideration of rFVIIa may help prevent repeated surgical interventions and reduce bleeding-related morbidity in complex cases.
2026-02-01 | Immune-mediated platelet dysfunction with spontaneous formation of aggregates in pediatric end-stage liver disease: A case report
Introduction A 12-year-old girl with Alagille syndrome was admitted with progressive liver failure and subsequently listed for liver transplantation. Furthermore, the patient was born with tetralogy of Fallot, for which corrective surgery was performed. Eleven years after surgery, a stent was implanted in the pulmonary artery due to progressive pulmonary stenosis. As expected in advanced hepatic insufficiency, she developed thrombocytopenia (baseline 100-120 Tsd/µl) and reduced vitamin K-dependent clotting factors. In May, platelet counts suddenly became immeasurable due to pronounced spontaneous platelet aggregation, fluctuating over time. Pseudothrombocytopenia was excluded. Light transmission aggregometry revealed absent aggregation in response to arachidonic acid and ristocetin 1mg/ml, consistent with a Bernard–Soulier- and Aspirin-like phenotype. Since the glycoprotein profile was normal, it appeared to be an acquired disorder, even though there was no solid evidence of any specific antibodies. In order to demonstrate the presumed antibodies indirectly, mixing studies were performed. When donor platelets were combined with the patient’s plasma, aggregation responses to ristocetin 1M and arachidonic acid improved, followed by gradual desaggregation. However, donor plasma combined with the patient’s platelets did not improve aggregation, suggesting that antibodies were primarily platelet-bound. Peripheral blood smears showed fragmented erythrocytes and complement activity was elevated, indicating microangiopathy. During pre-transplant evaluation, acquired von Willebrand syndrome was also diagnosed, as expected following stent angioplasty. Method Light transmission aggregometry Glycoprotein-specific ELISA Results Subsequent to liver transplantation, the patient was treated with von-Willebrand-Factor-containing factor VIII concentrate and regular platelet transfusions regardless of the absolute count. Tranexamic acid was avoided because of possible microangiopathy. Standard anticoagulation with unfractionated heparin was administered perioperatively. The liver transplantation proceeded without bleeding or thrombotic complications. Within one week after the last platelet transfusion, platelet count had normalized completely, and light transmission aggregometry confirmed full recovery of platelet function. Conclusion This case illustrates the complex coagulation abnormalities observed in end-stage liver disease, where hemostatic impairment may extend beyond reduced clotting factors to include Bernard–Soulier-like phenotype, and microangiopathy. Despite severe preoperative coagulopathy, precise perioperative management with targeted replacement therapy and cautious avoidance of prothrombotic agents enabled successful transplantation without bleeding events. Liver transplantation not only resolved hepatic failure but also led to rapid normalization of platelet counts and function, highlighting the reversible nature of these coagulation disorders once hepatic function is restored. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-11-19 | Hemostatic Rescue with rFVIIa in Bernard–Soulier Syndrome Refractory to HLA-Matched Platelet Transfusion
We report the case of a man in his 50’s diagnosed with Bernard–Soulier syndrome (BSS) in childhood who developed refractory gluteal bleeding following a fall accident. The patient underwent four hematoma evacuation procedures and multiple platelet transfusions, including HLA (human leukocyte antigen) -matched platelet concentrates, without achieving sustained hemostatic control. Given the lack of response to platelet transfusion and ongoing bleeding risk, Eptacog Alfa (recombinant activated factor VII; rFVIIa) was administered for 4 days, following the dosing regimen recommended for Glanzmann thrombasthenia in surgical bleeding settings. Hemostasis was achieved shortly after rFVIIa administration, and no further surgical evacuation was necessary. Importantly, no thromboembolic complications occurred despite the use of rFVIIa. This case demonstrates that rFVIIa can serve as an effective adjunctive hemostatic therapy in patients with BSS who are refractory to platelet transfusions. We reviewed the existing literature on rFVIIa use in patients with BSS and summarized the clinical contexts, dosing strategies, efficacy, and safety outcomes. Our experience suggests that early consideration of rFVIIa may help prevent repeated surgical interventions and reduce bleeding-related morbidity in complex cases.
2025-11-19 | Recombinant Factor VIIa Prophylaxis in 2 Brothers with Bernard-Soulier Syndrome.
BACKGROUND Bernard-Soulier Syndrome (BSS) is a rare autosomal recessive platelet disorder characterized by thrombocytopenia, giant platelets, prolonged bleeding time, and defective platelet adhesion due to abnormalities in the glycoprotein 1b-IX-V complex. Management of BSS is challenging due to the risk of severe bleeding and complications associated with repeated platelet transfusions. Recombinant activated factor VIIa (rFVIIa, trade name: NovoSeven) has emerged as a potential alternative therapy. CASE REPORT We report the cases of 2 brothers with BSS who experienced recurrent mucocutaneous bleeding. The older brother, aged 19, presented with persistent gingival bleeding that was unresponsive to tranexamic acid and required hospital-based interventions, including platelet transfusions. The younger brother, aged 18, was diagnosed in infancy and had a complex medical history including neurological symptoms. Both were initiated on prophylactic rFVIIa (4.5 mg IV and 4 mg IV, respectively) on a weekly basis. Following initiation of prophylaxis, both patients experienced a marked reduction in the frequency and severity of bleeding episodes. CONCLUSIONS Prophylactic administration of rFVIIa was effective in reducing bleeding episodes in 2 siblings with severe BSS. This case highlights the potential role of rFVIIa as a viable alternative to platelet transfusions in patients with recurrent bleeding. Further studies are needed to establish standardized protocols for prophylactic rFVIIa use in BSS.
2024-08-16 | Novel GPIb-independent platelet aggregation induced by botrocetin: implications for diagnosis and antithrombotic therapy.
Snake venom botrocetin facilitates von Willebrand factor (VWF) binding to platelet GPIbα and has been widely used for the diagnosis of von Willebrand disease and GPIb-related disorders. Botrocetin is also commonly employed for the development/characterization of antithrombotics targeting the GPIb-VWF axis. To explore the alternative receptor(s)/mechanisms that participate in botrocetin-induced platelet aggregation. The effects of botrocetin on platelet aggregation were examined using platelets from wild-type, VWF- and fibrinogen-deficient, GPIbα-deficient, IL4Rα/GPIbα-transgenic, ITGA2B and ITGB3-deficient mice, and Bernard-Soulier syndrome and healthy human samples. Platelet-fibrinogen and platelet-VWF interaction were measured using flow cytometry. GPIbα-VWF binding was evaluated utilizing enzyme-linked immunosorbent assay. Botrocetin-αIIbβ3 and botrocetin-GPIbα interactions were measured using enzyme-linked immunosorbent assay and fluorescence anisotropy assays. Heparinized whole blood from healthy donors was examined for thrombus formation and growth in a perfusion chamber. Botrocetin could induce aggregation of platelets from a Bernard-Soulier syndrome patient and GPIbα-deficient mice as well as platelets lacking the N-terminal extracellular domain of GPIbα. Botrocetin could interact with αIIbβ3 and facilitated αIIbβ3-VWF interaction independent of GPIb. Botrocetin competitively bound to the ligand-binding domain of activated rather than resting αIIbβ3. Although botrocetin-induced platelet aggregation requires VWF, strikingly, in the absence of VWF, botrocetin blocked fibrinogen and other ligand binding to αIIbβ3 and inhibited platelet aggregation and thrombus formation. Consistently, recombinant botrocetin defective in VWF binding inhibited αIIbβ3- and GPIb-mediated platelet aggregation, spreading, and thrombus formation. Our study provides insights into avoiding the misdiagnosis of GPIb-related disorders and developing botrocetin mutants as potential new antithrombotics that may simultaneously target both αIIbβ3 and GPIbα.
gene therapies
2026-04-08 | Congenital thrombopathies in southern Tunisia : A multicenter study.
congenital thrombopathies (CTs) are rare bleeding disorders resulting from platelet dysfunction which may also be associated with thrombocytopenia. To date, the prevalence of CT in Tunisia has not been established. The aim of this study was to describe the various types of CT and the associated hemorrhagic manifestations observed in a cohort from southern Tunisia. We retrospectively collected clinical and laboratory data of patients with CT who were followed up over 43 years (1982 - 2024) in the pediatric and hematology departements of a university hospital center in southern Tunisia. The diagnosis of thrombopathy was established based on flow cytometry analysis and/or light transmission aggregometry and/or molecular analysis. We identified 60 patients (35 men and 25 women). The mean age at diagnosis was 61.7 months (1 month-70 years). Consanguinity was noted in 71.6% of cases (n=43). A family history of thrombopathy was reported in 51.6% of cases (n=31). The presenting symptoms at diagnosis were spontaneous or provoked bleeding (n=56) and easy bruising associated with thrombocytopenia within the first 48 hours of life (n=1). The etiologies of the thrombopathies were as follows : Glanzmann thrombasthenia (n=54), Bernard Soulier syndrome (n=5) and Wiskott Aldrich syndrome (n=1). Glanzmann thrombasthenia was the most prevalent thrombopathy in our cohort, likely attributed to the high rate of consanguinity in our region.
2026-03-24 | Inherited Platelet Disorders During Pregnancy and Delivery: Overview of Management Strategies and Emerging Therapeutic Considerations.
Inherited platelet disorders (IPDs) comprise a heterogeneous group of rare conditions that present particular challenges during pregnancy, with bleeding risk increasing during labor and the immediate postpartum period. These disorders require coordinated, multidisciplinary management to mitigate maternal and neonatal bleeding risk. Although data remains limited, individuals with IPD, including Bernard-Soulier syndrome, Glanzmann thrombasthenia, MYH9-related disorders, Hermansky-Pudlak syndrome, and platelet storage pool disorders, are at an increased risk for obstetrical bleeding, with the degree of risk varying by underlying diagnosis. In severe inherited platelet disorders such as Glanzmann thrombasthenia, peripartum hemorrhage is common, with up to half of the deliveries in some series requiring red cell or platelet transfusion. Because these conditions are congenital, the fetus may also be affected, placing neonates at risk for serious bleeding complications, including intracranial hemorrhage, although available data is limited. Despite the considerable morbidity and mortality risk associated with inherited platelet disorders, management strategies during pregnancy and delivery remain poorly defined. This stands in contrast to other bleeding disorders, such as factor deficiencies, for which multiple therapeutic approaches have been evaluated in the peripartum setting. In this review, we summarize the available evidence and current management strategies for individuals with inherited platelet disorders during pregnancy and delivery.
2025-06-05 | Acquired Bernard-Soulier syndrome as the presenting feature of GATA2-related myeloid neoplasm in an adolescent: an insight into the mechanisms underlying the platelet defect
Not available.
2025-04-13 | Pediatric non-malignant blood disorders hospital-based registry: a ten-year report from Saudi Arabia
is dedicated to evaluate, diagnose and treat children with a wide range of non-malignant blood disorders (NMBDs) with an Institutional Review Board (IRB) approved hospital-based registry.Methodology: Retrospective analysis of registry data from REDCap (Vanderbilt University) web-based registry database collecting demographic, consanguinity, diagnostic and survival data since 2015.Results: This Hospital-based registry was established in 2015, and during the last ten-years a total of 1095 cases were registered.Among those 143 (13%) were screened and remain under work-up as they persistently continue to show symptoms (anemia,10%; coagulopathy,7%; bleeding,2%; cytopenia 2%; primary thrombocytosis,2%) .Total 786 (72%) patients reached a confirmed diagnosis of NMBDs with a median age at diagnosis of 7.3 (2 days -13.9) years, there were 463(59%) males and 323 (41%) females.Diagnostic statistics showed the majority of the cases were diagnosed with hemoglobinopathies in 338 (30%) followed by thrombosis in 103 (9%) and bleeding disorders in 84 (8%) patients.Positive consanguinity was observed in 32% (254) and when compared by diagnoses a statistically significant (p=0.001)correlation for hemoglobinopathies and bleeding disorders was observed.This registry is capable of pooling data to achieve sufficient sample size for epidemiological and/or clinical research for rare diseases: rare bleeding disorder (n=28), Glanzmann thrombasthenia (n=11), hypereosinophilic syndrome (n=3), and Bernard Soulier (n=2).
2023-06-12 | Lentiviral gene therapy reverts GPIX expression and phenotype in Bernard-Soulier syndrome type C
Bernard-Soulier syndrome (BSS) is a rare congenital disease characterized by macrothrombocytopenia and frequent bleeding. It is caused by pathogenic variants in three genes (GP1BA, GP1BB, or GP9) that encode for the GPIbα, GPIbβ, and GPIX subunits of the GPIb-V-IX complex, the main platelet surface receptor for von Willebrand factor, being essential for platelet adhesion and aggregation. According to the affected gene, we distinguish BSS type A1 (GP1BA), type B (GP1BB), or type C (GP9). Pathogenic variants in these genes cause absent, incomplete, or dysfunctional GPIb-V-IX receptor and, consequently, a hemorrhagic phenotype. Using gene-editing tools, we generated knockout (KO) human cellular models that helped us to better understand GPIb-V-IX complex assembly. Furthermore, we developed novel lentiviral vectors capable of correcting GPIX expression, localization, and functionality in human GP9-KO megakaryoblastic cell lines. Generated GP9-KO induced pluripotent stem cells produced platelets that recapitulated the BSS phenotype: absence of GPIX on the membrane surface and large size. Importantly, gene therapy tools reverted both characteristics. Finally, hematopoietic stem cells from two unrelated BSS type C patients were transduced with the gene therapy vectors and differentiated to produce GPIX-expressing megakaryocytes and platelets with a reduced size. These results demonstrate the potential of lentiviral-based gene therapy to rescue BSS type C.
other
2022-07-12 | Characterization of zebrafish gp1ba mutant and modelling Bernard Soulier syndrome.
The aim of this study is to model classical Bernard Soulier Syndrome in the zebrafish by targeting Gp1ba. We obtained gp1ba mutant embryos from Zebrafish International Resource Center and grew them to adulthood. The tail clips from these fish were used to prepare DNA and sequenced to identify heterozygotes. They were then bred to obtain homozygotes. The mutation was confirmed by DNA sequencing as a termination codon UAA in place of AAA codon at position 886 in the gp1ba transcript. Thus, at the Pro-295, the Gp1ba protein could be terminated. The blood from gp1ba homozygous and heterozygous mutants showed decreased ristocetin-mediated agglutination in the whole blood agglutination assay. The gp1ba heterozygous and homozygous larvae were subjected to a laser-assisted arterial thrombosis assay, and the results showed the prolonged occlusion in the caudal artery. These results suggested that the gp1ba mutant had a bleeding phenotype. The blood smears from the adult gp1ba, heterozygous and homozygous mutants, showed macrothrombocytes, similar to the human GP1BA deficiency that showed giant platelets. The bleeding assay on these heterozygous and homozygous mutants showed greater bleeding than wildtype, confirming the above findings. Taken together, the characterization of gp1ba zebrafish mutant suggested an autosomal dominant mode of inheritance. The zebrafish gp1ba mutant models classical Bernard Soulier Syndrome and could be used for reversing this phenotype to identify novel factors by the genome-wide piggyback knockdown method.
2022-02-11 | Acquired Bernard-Soulier syndrome and hypodysfibrinogenaemia because of multiple myeloma.
We describe a case of a patient with multiple myeloma with initial presentation simulating a bleeding disorder. Detailed coagulation work-up showed hypodysfibrinogenaemia along with a platelet function defect consistent with acquired Bernard-Soulier syndrome (BSS). Multiple plasma exchanges led to significant improvement in his bleeding symptoms. To the best of our knowledge, this is the first described case of simultaneous presentation of hypodysfibrinogenaemia and BSS secondary to multiple myeloma.
2015-07-15 | Artificial MiRNA Knockdown of Platelet Glycoprotein lbα: A Tool for Platelet Gene Silencing
In recent years, candidate genes and proteins implicated in platelet function have been identified by various genomic approaches. To elucidate their exact role, we aimed to develop a method to apply miRNA interference in platelet progenitor cells by using GPIbα as a proof-of-concept target protein. After in silico and in vitro screening of siRNAs targeting GPIbα (siGPIBAs), we developed artificial miRNAs (miGPIBAs), which were tested in CHO cells stably expressing GPIb-IX complex and megakaryoblastic DAMI cells. Introduction of siGPIBAs in CHO GPIb-IX cells resulted in 44 to 75% and up to 80% knockdown of GPIbα expression using single or combined siRNAs, respectively. Conversion of siGPIBAs to miGPIBAs resulted in reduced silencing efficiency, which could however be circumvented by tandem integration of two hairpins targeting different regions of GPIBA mRNA where 72% GPIbα knockdown was achieved. CHO GPIb-IX cells transfected with the miGPIBA construct displayed a significant decrease in their ability to aggregate characterized by lower aggregate numbers and size compared to control CHO GPIb-IX cells. More importantly, we successfully silenced GPIbα in differentiating megakaryoblastic DAMI cells that exhibited morphological changes associated with actin organization. In conclusion, we here report the successful use of miRNA technology to silence a platelet protein in megakaryoblastic cells and demonstrate its usefulness in functional assays. Hence, we believe that artificial miRNAs are suitable tools to unravel the role of a protein of interest in stem cells, megakaryocytes and platelets, thereby expanding their application to novel fields of basic and translational research.
small molecules
2026-05-07 | Genetic depletion in zebrafish uncovers requirement for septins in haematopoiesis
Abstract Haematopoiesis and differentiation of immune cells from haematopoietic stem and progenitor cells (HSPCs) are essential to core aspects of health and disease. A key player in haematopoiesis and HSPC differentiation is the cytoskeleton, which governs cell division and lineage bias. Despite insights using mouse models, regulation of haematopoiesis by the septin cytoskeleton is mostly unknown. Septins are unconventional filament forming proteins best known for roles in cell division and host defence. To investigate septin-mediated host defence in vivo , we generated septin-deficient zebrafish models for infection with Mycobacterium marinum . Unexpectedly, septin-deficient larvae were protected from mycobacterial infection due to significantly increased macrophage numbers, reduced cell death, and enhanced inflammatory responses. Underlying this, we found that septin-deficient larvae produce significantly more HSPCs and show myeloid lineage bias, establishing a requirement for septins in haematopoiesis. In agreement with classical HSPC hierarchy, increased myeloid production in septin-deficient larvae is at the expense of erythroid lineage production. Our findings that septins play a role in haematopoiesis is consistent with hallmarks of haematological disorders in which septin dysfunction has been implicated, including acute myeloid leukaemia, myelodysplastic syndrome, and platelet disorder Bernard-Soulier syndrome. These results highlight zebrafish as a new model to investigate septin-mediated haematopoiesis and application of septin-based medicines to treat blood disorders.
2025-09-11 | An Infectious Accelerant: Dual Hemostatic and Antimicrobial Therapy for Catastrophic Hemoptysis in Bernard–Soulier Syndrome
IntroductionBernard-Soulier syndrome (BSS), or hemorrhagiparous thrombocytic dystrophy, is a rare autosomal recessive bleeding disorder caused by genetic mutations affecting the platelet glycoprotein Ib-IX-V complex [1]. This defect impairs platelet a
2025-05-19 | Anesthesia Management Using Remimazolam in A Patient With Bernard-Soulier Syndrome: A Case Report.
Bernard-Soulier syndrome (BSS) is a platelet dysfunction disorder characterized by massive thrombocytopenia and a lack of platelet aggregation. Remimazolam, a short-acting benzodiazepine sedative, is believed to have minimal effects on platelets. Here, we report the safe use of remimazolam for anesthesia management in a patient with BSS.
2025-03-06 | Increased RhoA pathway activation downstream of αIIbβ3/SRC contributes to heterozygous Bernard Soulier syndrome.
Bernard Soulier syndrome (BSS) is a severe bleeding disorder with moderate to severe thrombocytopenia, giant platelets, and platelet dysfunction, caused by biallelic mutations in GP1BA, GP1BB, or GP9 genes. We generated induced pluripotent stem cells (iPSC) from a BSS patient with a novel heterozygous GP1BA p.N103D mutation, resulting in moderate macrothrombocytopenia. The mutation does not affect megakaryocyte (MK) differentiation or GPIb-GPIX complex expression but reduces affinity to von Willebrand factor (VWF). It induces increased signaling independent of VWF and αIIbβ3-mediated outside-in signaling, causing a profound defect in proplatelet formation after adhesion on fibrinogen. Pre-activation of αIIbβ3 integrin and heightened stress fiber formation linked to RhoA pathway overactivation were observed, likely due to increased phosphorylation of SRC at Y419 downstream of GPIbα. Dasatinib, a SRC inhibitor, restored stress fiber formation. Using a 3D bone marrow model to mimic platelet release under flow, we demonstrated that the ROCK1/2 inhibitor Y27632 increased platelet number and restored platelet size in GPIbαN103D MK, as well as in MK from two other patients with heterozygous GP1BA mutations (p.L160P and p.N150S). However, Y27632 had no additional effect on platelet generation from MK of two patients with biallelic BSS, suggesting a distinct molecular mechanism in biallelic cases.
2024-12-19 | Roles of ROCK/Myosin Pathway in Macrothrombocytopenia in Bernard-Soulier Syndrome.
Megakaryocytes (MK) from Bernard-Soulier syndrome (BSS) induced pluripotent stem cells (iPSCs) yielded reduced numbers but increased sizes of platelets. The molecular mechanisms remain unclear. This study aims to determine roles of signaling molecules involved in this process.Wild-type (WT) iPSCs and iPSCs from BSS patients with GP1BA (BSS-A) or GP1BB (BSS-B) mutations were differentiated into MKs and platelets with or without myosin II inhibitor (blebbistatin), ROCK inhibitor (Y27632), and procaspase-3 activator (PAC-1). Proplatelet and platelet numbers and sizes were characterized. The iPSC lines containing tubulin-green fluorescent protein (GFP) reporters were constructed to observe proplatelet formation under time-lapse microscopy.BSS-derived MKs (BSS-MKs) yielded fewer but larger platelets compared with the WT. In the presence of blebbistatin, ROCK inhibitor, or PAC-1, WT, BSS-A, and BSS-B MKs could generate more platelets with decreased sizes, but PAC-1 caused CD42 loss on WT platelets. The proportions of proplatelet formation from MKs carrying tubulin-GFP were not different between WT and BSS-MKs, as well as among inhibitors. Notably, initially thick cytoplasmic processes were transformed into thin branching proplatelets over the observation time. The proplatelet shafts of BSS-MK became thinner in the presence of blebbistatin or ROCK inhibitor, but not of PAC-1, which displayed uneven F-actin distribution.Inhibition of the ROCK/myosin pathway, downstream of GpIb, could restore normal morphology of proplatelets in BSS-MKs. Procaspase-3 activation could increase platelet yields, but with abnormal proplatelet and platelet structures. Our model can be used for therapeutic drug screening and a disease model for platelet production in the future.
antibodies
2025-04-23 | Acquired Bernard-Soulier-like syndrome due to a plasma-based inhibitor treated successfully with rituximab.
Bernard-Soulier syndrome (BSS) is an autosomal recessive disorder caused by deficient platelet glycoprotein Ib-IX-V expression resulting in abnormal bleeding, thrombocytopenia, giant platelets, and reduced platelet aggregation response to ristocetin that manifests in childhood. Acquired BSS is a rare disorder characterized by Bernard-Soulier (BS)-like platelet dysfunction in a patient without a history consistent with a bleeding disorder. Can acquired BSS respond to immune-directed therapy? We describe a case of a 79-year-old man presenting with refractory epistaxis found to have an isolated BS-like platelet function defect due to a plasma-based inhibitor. He was treated with rituximab with immediate cessation of bleeding and normalization of platelet function studies. To our knowledge, this is the first case of acquired BS-like syndrome described in the absence of systemic illness due to a presumed autoantibody, and we report the successful use of rituximab for treatment of this rare disorder.
2022-04-01 | Activated Platelets Upregulate β2 Integrin Mac-1 (CD11b/CD18) on Dendritic Cells, Which Mediates Heterotypic Cell–Cell Interaction
Abstract Recent evidence suggests interaction of platelets with dendritic cells (DCs), while the molecular mechanisms mediating this heterotypic cell cross-talk are largely unknown. We evaluated the role of integrin Mac-1 (αMβ2, CD11b/CD18) on DCs as a counterreceptor for platelet glycoprotein (GP) Ibα. In a dynamic coincubation model, we observed interaction of human platelets with monocyte-derived DCs, but also that platelet activation induced a sharp increase in heterotypic cell binding. Inhibition of CD11b or GPIbα led to significant reduction of DC adhesion to platelets in vitro independent of GPIIbIIIa, which we confirmed using platelets from Glanzmann thrombasthenia patients and transgenic mouse lines on C57BL/6 background (GPIbα−/−, IL4R-GPIbα-tg, and muMac1 mice). In vivo, inhibition or genetic deletion of CD11b and GPIbα induced a significant reduction of platelet-mediated DC adhesion to the injured arterial wall. Interestingly, only intravascular antiCD11b inhibited DC recruitment, suggesting a dynamic DC–platelet interaction. Indeed, we could show that activated platelets induced CD11b upregulation on Mg2+-preactivated DCs, which was related to protein kinase B (Akt) and dependent on P-selectin and P-selectin glycoprotein ligand 1. Importantly, specific pharmacological targeting of the GPIbα–Mac-1 interaction site blocked DC–platelet interaction in vitro and in vivo. These results demonstrate that cross-talk of platelets with DCs is mediated by GPIbα and Mac-1, which is upregulated on DCs by activated platelets in a P-selectin glycoprotein ligand 1–dependent manner.
2018-02-21 | The search for new antithrombotic mechanisms and therapies that may spare hemostasis
Abstract Current antithrombotic drugs, including widely used antiplatelet agents and anticoagulants, are associated with significant bleeding risk. Emerging experimental evidence suggests that the molecular and cellular mechanisms of hemostasis and thrombosis can be separated, thereby increasing the possibility of new antithrombotic therapeutic targets with reduced bleeding risk. We review new coagulation and platelet targets and highlight the interaction between integrin αMβ2 (Mac-1, CD11b/CD18) on leukocytes and GPIbα on platelets that seems to distinguish thrombosis from hemostasis.
2016-10-01 | Platelets and platelet adhesion molecules: novel mechanisms of thrombosis and anti-thrombotic therapies
Platelets are central mediators of thrombosis and hemostasis. At the site of vascular injury, platelet accumulation (i.e. adhesion and aggregation) constitutes the first wave of hemostasis. Blood coagulation, initiated by the coagulation cascades, is the second wave of thrombin generation and enhance phosphatidylserine exposure, can markedly potentiate cell-based thrombin generation and enhance blood coagulation. Recently, deposition of plasma fibronectin and other proteins onto the injured vessel wall has been identified as a new "protein wave of hemostasis" that occurs prior to platelet accumulation (i.e. the classical first wave of hemostasis). These three waves of hemostasis, in the event of atherosclerotic plaque rupture, may turn pathogenic, and cause uncontrolled vessel occlusion and thrombotic disorders (e.g. heart attack and stroke). Current anti-platelet therapies have significantly reduced cardiovascular mortality, however, on-treatment thrombotic events, thrombocytopenia, and bleeding complications are still major concerns that continue to motivate innovation and drive therapeutic advances. Emerging evidence has brought platelet adhesion molecules back into the spotlight as targets for the development of novel anti-thrombotic agents. These potential antiplatelet targets mainly include the platelet receptors glycoprotein (GP) Ib-IX-V complex, β3 integrins (αIIb subunit and PSI domain of β3 subunit) and GPVI. Numerous efforts have been made aiming to balance the efficacy of inhibiting thrombosis without compromising hemostasis. This mini-review will update the mechanisms of thrombosis and the current state of antiplatelet therapies, and will focus on platelet adhesion molecules and the novel anti-thrombotic therapies that target them.
2013-04-05 | Targeting Platelet GPIbβ Reduces Platelet Adhesion, GPIb Signaling and Thrombin Generation and Prevents Arterial Thrombosis
Objective— The glycoprotein (GP) Ib-V-IX complex regulates the adhesion, activation, and procoagulant activity of platelets. We previously reported that RAM.1, a rat monoclonal antibody directed against the extracellular domain of mouse GPIbβ, diminished adhesion of platelets and chinese hamster ovary cells transfected with the human GPIb-IX complex to von Willebrand factor under flow conditions. Here, we further evaluated the functional importance of GPIbβ by studying the impact of RAM.1 on GPIb-mediated platelet responses and in vitro and in vivo thrombus formation. Approach and Results— We show that RAM.1 dramatically reduced GPIb-mediated filopodia extension of chinese hamster ovary GPIb-IX cells after adhesion to von Willebrand factor. RAM.1 also reduced filopodia extension and GPIb-mediated Ca 2+ signaling after adhesion of mouse platelets to von Willebrand factor. RAM.1 inhibited thrombin generation in platelet-rich plasma without impairing phosphatidylserine exposure. In addition, RAM.1 reduced thrombus formation after perfusion of mouse whole blood over collagen in a shear-dependent manner. This effect was confirmed in vivo, because injection of F(ab)′2 fragments of RAM.1 diminished thrombus formation induced by laser beam injury of mesenteric arterioles and forceps injury of the abdominal aorta. In contrast, RAM.1 F(ab)′2 did not prolong the tail-bleeding time or increase the volume of blood lost. Conclusions— These findings are the first evidence that targeting a subunit other than GPIbα can lead to an antithrombotic effect via the GPIb-V-IX complex. This could represent an alternative way to reduce thrombus formation with a minor impact on hemostasis.
proteins
2026-02-26 | Hemostatic rescue with rFVIIa in Bernard-Soulier syndrome refractory to HLA-matched platelet transfusion.
We report the case of a man in his 50’s diagnosed with Bernard-Soulier syndrome (BSS) in childhood who developed refractory gluteal bleeding following a fall accident. The patient underwent four hematoma evacuation procedures and multiple platelet transfusions, including HLA (human leukocyte antigen) -matched platelet concentrates, without achieving sustained hemostatic control. Given the lack of response to platelet transfusion and ongoing bleeding risk, Eptacog Alfa (recombinant activated factor VII; rFVIIa) was administered for 4 days, following the dosing regimen recommended for Glanzmann thrombasthenia in surgical bleeding settings. Hemostasis was achieved shortly after rFVIIa administration, and no further surgical evacuation was necessary. Importantly, no thromboembolic complications occurred despite the use of rFVIIa. This case demonstrates that rFVIIa can serve as an effective adjunctive hemostatic therapy in patients with BSS who are refractory to platelet transfusions. We reviewed the existing literature on rFVIIa use in patients with BSS and summarized the clinical contexts, dosing strategies, efficacy, and safety outcomes. Our experience suggests that early consideration of rFVIIa may help prevent repeated surgical interventions and reduce bleeding-related morbidity in complex cases.
2026-02-01 | Immune-mediated platelet dysfunction with spontaneous formation of aggregates in pediatric end-stage liver disease: A case report
Introduction A 12-year-old girl with Alagille syndrome was admitted with progressive liver failure and subsequently listed for liver transplantation. Furthermore, the patient was born with tetralogy of Fallot, for which corrective surgery was performed. Eleven years after surgery, a stent was implanted in the pulmonary artery due to progressive pulmonary stenosis. As expected in advanced hepatic insufficiency, she developed thrombocytopenia (baseline 100-120 Tsd/µl) and reduced vitamin K-dependent clotting factors. In May, platelet counts suddenly became immeasurable due to pronounced spontaneous platelet aggregation, fluctuating over time. Pseudothrombocytopenia was excluded. Light transmission aggregometry revealed absent aggregation in response to arachidonic acid and ristocetin 1mg/ml, consistent with a Bernard–Soulier- and Aspirin-like phenotype. Since the glycoprotein profile was normal, it appeared to be an acquired disorder, even though there was no solid evidence of any specific antibodies. In order to demonstrate the presumed antibodies indirectly, mixing studies were performed. When donor platelets were combined with the patient’s plasma, aggregation responses to ristocetin 1M and arachidonic acid improved, followed by gradual desaggregation. However, donor plasma combined with the patient’s platelets did not improve aggregation, suggesting that antibodies were primarily platelet-bound. Peripheral blood smears showed fragmented erythrocytes and complement activity was elevated, indicating microangiopathy. During pre-transplant evaluation, acquired von Willebrand syndrome was also diagnosed, as expected following stent angioplasty. Method Light transmission aggregometry Glycoprotein-specific ELISA Results Subsequent to liver transplantation, the patient was treated with von-Willebrand-Factor-containing factor VIII concentrate and regular platelet transfusions regardless of the absolute count. Tranexamic acid was avoided because of possible microangiopathy. Standard anticoagulation with unfractionated heparin was administered perioperatively. The liver transplantation proceeded without bleeding or thrombotic complications. Within one week after the last platelet transfusion, platelet count had normalized completely, and light transmission aggregometry confirmed full recovery of platelet function. Conclusion This case illustrates the complex coagulation abnormalities observed in end-stage liver disease, where hemostatic impairment may extend beyond reduced clotting factors to include Bernard–Soulier-like phenotype, and microangiopathy. Despite severe preoperative coagulopathy, precise perioperative management with targeted replacement therapy and cautious avoidance of prothrombotic agents enabled successful transplantation without bleeding events. Liver transplantation not only resolved hepatic failure but also led to rapid normalization of platelet counts and function, highlighting the reversible nature of these coagulation disorders once hepatic function is restored. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
2025-11-19 | Hemostatic Rescue with rFVIIa in Bernard–Soulier Syndrome Refractory to HLA-Matched Platelet Transfusion
We report the case of a man in his 50’s diagnosed with Bernard–Soulier syndrome (BSS) in childhood who developed refractory gluteal bleeding following a fall accident. The patient underwent four hematoma evacuation procedures and multiple platelet transfusions, including HLA (human leukocyte antigen) -matched platelet concentrates, without achieving sustained hemostatic control. Given the lack of response to platelet transfusion and ongoing bleeding risk, Eptacog Alfa (recombinant activated factor VII; rFVIIa) was administered for 4 days, following the dosing regimen recommended for Glanzmann thrombasthenia in surgical bleeding settings. Hemostasis was achieved shortly after rFVIIa administration, and no further surgical evacuation was necessary. Importantly, no thromboembolic complications occurred despite the use of rFVIIa. This case demonstrates that rFVIIa can serve as an effective adjunctive hemostatic therapy in patients with BSS who are refractory to platelet transfusions. We reviewed the existing literature on rFVIIa use in patients with BSS and summarized the clinical contexts, dosing strategies, efficacy, and safety outcomes. Our experience suggests that early consideration of rFVIIa may help prevent repeated surgical interventions and reduce bleeding-related morbidity in complex cases.
2025-11-19 | Recombinant Factor VIIa Prophylaxis in 2 Brothers with Bernard-Soulier Syndrome.
BACKGROUND Bernard-Soulier Syndrome (BSS) is a rare autosomal recessive platelet disorder characterized by thrombocytopenia, giant platelets, prolonged bleeding time, and defective platelet adhesion due to abnormalities in the glycoprotein 1b-IX-V complex. Management of BSS is challenging due to the risk of severe bleeding and complications associated with repeated platelet transfusions. Recombinant activated factor VIIa (rFVIIa, trade name: NovoSeven) has emerged as a potential alternative therapy. CASE REPORT We report the cases of 2 brothers with BSS who experienced recurrent mucocutaneous bleeding. The older brother, aged 19, presented with persistent gingival bleeding that was unresponsive to tranexamic acid and required hospital-based interventions, including platelet transfusions. The younger brother, aged 18, was diagnosed in infancy and had a complex medical history including neurological symptoms. Both were initiated on prophylactic rFVIIa (4.5 mg IV and 4 mg IV, respectively) on a weekly basis. Following initiation of prophylaxis, both patients experienced a marked reduction in the frequency and severity of bleeding episodes. CONCLUSIONS Prophylactic administration of rFVIIa was effective in reducing bleeding episodes in 2 siblings with severe BSS. This case highlights the potential role of rFVIIa as a viable alternative to platelet transfusions in patients with recurrent bleeding. Further studies are needed to establish standardized protocols for prophylactic rFVIIa use in BSS.
2024-08-16 | Novel GPIb-independent platelet aggregation induced by botrocetin: implications for diagnosis and antithrombotic therapy.
Snake venom botrocetin facilitates von Willebrand factor (VWF) binding to platelet GPIbα and has been widely used for the diagnosis of von Willebrand disease and GPIb-related disorders. Botrocetin is also commonly employed for the development/characterization of antithrombotics targeting the GPIb-VWF axis. To explore the alternative receptor(s)/mechanisms that participate in botrocetin-induced platelet aggregation. The effects of botrocetin on platelet aggregation were examined using platelets from wild-type, VWF- and fibrinogen-deficient, GPIbα-deficient, IL4Rα/GPIbα-transgenic, ITGA2B and ITGB3-deficient mice, and Bernard-Soulier syndrome and healthy human samples. Platelet-fibrinogen and platelet-VWF interaction were measured using flow cytometry. GPIbα-VWF binding was evaluated utilizing enzyme-linked immunosorbent assay. Botrocetin-αIIbβ3 and botrocetin-GPIbα interactions were measured using enzyme-linked immunosorbent assay and fluorescence anisotropy assays. Heparinized whole blood from healthy donors was examined for thrombus formation and growth in a perfusion chamber. Botrocetin could induce aggregation of platelets from a Bernard-Soulier syndrome patient and GPIbα-deficient mice as well as platelets lacking the N-terminal extracellular domain of GPIbα. Botrocetin could interact with αIIbβ3 and facilitated αIIbβ3-VWF interaction independent of GPIb. Botrocetin competitively bound to the ligand-binding domain of activated rather than resting αIIbβ3. Although botrocetin-induced platelet aggregation requires VWF, strikingly, in the absence of VWF, botrocetin blocked fibrinogen and other ligand binding to αIIbβ3 and inhibited platelet aggregation and thrombus formation. Consistently, recombinant botrocetin defective in VWF binding inhibited αIIbβ3- and GPIb-mediated platelet aggregation, spreading, and thrombus formation. Our study provides insights into avoiding the misdiagnosis of GPIb-related disorders and developing botrocetin mutants as potential new antithrombotics that may simultaneously target both αIIbβ3 and GPIbα.
gene therapies
2026-04-08 | Congenital thrombopathies in southern Tunisia : A multicenter study.
congenital thrombopathies (CTs) are rare bleeding disorders resulting from platelet dysfunction which may also be associated with thrombocytopenia. To date, the prevalence of CT in Tunisia has not been established. The aim of this study was to describe the various types of CT and the associated hemorrhagic manifestations observed in a cohort from southern Tunisia. We retrospectively collected clinical and laboratory data of patients with CT who were followed up over 43 years (1982 - 2024) in the pediatric and hematology departements of a university hospital center in southern Tunisia. The diagnosis of thrombopathy was established based on flow cytometry analysis and/or light transmission aggregometry and/or molecular analysis. We identified 60 patients (35 men and 25 women). The mean age at diagnosis was 61.7 months (1 month-70 years). Consanguinity was noted in 71.6% of cases (n=43). A family history of thrombopathy was reported in 51.6% of cases (n=31). The presenting symptoms at diagnosis were spontaneous or provoked bleeding (n=56) and easy bruising associated with thrombocytopenia within the first 48 hours of life (n=1). The etiologies of the thrombopathies were as follows : Glanzmann thrombasthenia (n=54), Bernard Soulier syndrome (n=5) and Wiskott Aldrich syndrome (n=1). Glanzmann thrombasthenia was the most prevalent thrombopathy in our cohort, likely attributed to the high rate of consanguinity in our region.
2026-03-24 | Inherited Platelet Disorders During Pregnancy and Delivery: Overview of Management Strategies and Emerging Therapeutic Considerations.
Inherited platelet disorders (IPDs) comprise a heterogeneous group of rare conditions that present particular challenges during pregnancy, with bleeding risk increasing during labor and the immediate postpartum period. These disorders require coordinated, multidisciplinary management to mitigate maternal and neonatal bleeding risk. Although data remains limited, individuals with IPD, including Bernard-Soulier syndrome, Glanzmann thrombasthenia, MYH9-related disorders, Hermansky-Pudlak syndrome, and platelet storage pool disorders, are at an increased risk for obstetrical bleeding, with the degree of risk varying by underlying diagnosis. In severe inherited platelet disorders such as Glanzmann thrombasthenia, peripartum hemorrhage is common, with up to half of the deliveries in some series requiring red cell or platelet transfusion. Because these conditions are congenital, the fetus may also be affected, placing neonates at risk for serious bleeding complications, including intracranial hemorrhage, although available data is limited. Despite the considerable morbidity and mortality risk associated with inherited platelet disorders, management strategies during pregnancy and delivery remain poorly defined. This stands in contrast to other bleeding disorders, such as factor deficiencies, for which multiple therapeutic approaches have been evaluated in the peripartum setting. In this review, we summarize the available evidence and current management strategies for individuals with inherited platelet disorders during pregnancy and delivery.
2025-06-05 | Acquired Bernard-Soulier syndrome as the presenting feature of GATA2-related myeloid neoplasm in an adolescent: an insight into the mechanisms underlying the platelet defect
Not available.
2025-04-13 | Pediatric non-malignant blood disorders hospital-based registry: a ten-year report from Saudi Arabia
is dedicated to evaluate, diagnose and treat children with a wide range of non-malignant blood disorders (NMBDs) with an Institutional Review Board (IRB) approved hospital-based registry.Methodology: Retrospective analysis of registry data from REDCap (Vanderbilt University) web-based registry database collecting demographic, consanguinity, diagnostic and survival data since 2015.Results: This Hospital-based registry was established in 2015, and during the last ten-years a total of 1095 cases were registered.Among those 143 (13%) were screened and remain under work-up as they persistently continue to show symptoms (anemia,10%; coagulopathy,7%; bleeding,2%; cytopenia 2%; primary thrombocytosis,2%) .Total 786 (72%) patients reached a confirmed diagnosis of NMBDs with a median age at diagnosis of 7.3 (2 days -13.9) years, there were 463(59%) males and 323 (41%) females.Diagnostic statistics showed the majority of the cases were diagnosed with hemoglobinopathies in 338 (30%) followed by thrombosis in 103 (9%) and bleeding disorders in 84 (8%) patients.Positive consanguinity was observed in 32% (254) and when compared by diagnoses a statistically significant (p=0.001)correlation for hemoglobinopathies and bleeding disorders was observed.This registry is capable of pooling data to achieve sufficient sample size for epidemiological and/or clinical research for rare diseases: rare bleeding disorder (n=28), Glanzmann thrombasthenia (n=11), hypereosinophilic syndrome (n=3), and Bernard Soulier (n=2).
2023-06-12 | Lentiviral gene therapy reverts GPIX expression and phenotype in Bernard-Soulier syndrome type C
Bernard-Soulier syndrome (BSS) is a rare congenital disease characterized by macrothrombocytopenia and frequent bleeding. It is caused by pathogenic variants in three genes (GP1BA, GP1BB, or GP9) that encode for the GPIbα, GPIbβ, and GPIX subunits of the GPIb-V-IX complex, the main platelet surface receptor for von Willebrand factor, being essential for platelet adhesion and aggregation. According to the affected gene, we distinguish BSS type A1 (GP1BA), type B (GP1BB), or type C (GP9). Pathogenic variants in these genes cause absent, incomplete, or dysfunctional GPIb-V-IX receptor and, consequently, a hemorrhagic phenotype. Using gene-editing tools, we generated knockout (KO) human cellular models that helped us to better understand GPIb-V-IX complex assembly. Furthermore, we developed novel lentiviral vectors capable of correcting GPIX expression, localization, and functionality in human GP9-KO megakaryoblastic cell lines. Generated GP9-KO induced pluripotent stem cells produced platelets that recapitulated the BSS phenotype: absence of GPIX on the membrane surface and large size. Importantly, gene therapy tools reverted both characteristics. Finally, hematopoietic stem cells from two unrelated BSS type C patients were transduced with the gene therapy vectors and differentiated to produce GPIX-expressing megakaryocytes and platelets with a reduced size. These results demonstrate the potential of lentiviral-based gene therapy to rescue BSS type C.
other
2022-07-12 | Characterization of zebrafish gp1ba mutant and modelling Bernard Soulier syndrome.
The aim of this study is to model classical Bernard Soulier Syndrome in the zebrafish by targeting Gp1ba. We obtained gp1ba mutant embryos from Zebrafish International Resource Center and grew them to adulthood. The tail clips from these fish were used to prepare DNA and sequenced to identify heterozygotes. They were then bred to obtain homozygotes. The mutation was confirmed by DNA sequencing as a termination codon UAA in place of AAA codon at position 886 in the gp1ba transcript. Thus, at the Pro-295, the Gp1ba protein could be terminated. The blood from gp1ba homozygous and heterozygous mutants showed decreased ristocetin-mediated agglutination in the whole blood agglutination assay. The gp1ba heterozygous and homozygous larvae were subjected to a laser-assisted arterial thrombosis assay, and the results showed the prolonged occlusion in the caudal artery. These results suggested that the gp1ba mutant had a bleeding phenotype. The blood smears from the adult gp1ba, heterozygous and homozygous mutants, showed macrothrombocytes, similar to the human GP1BA deficiency that showed giant platelets. The bleeding assay on these heterozygous and homozygous mutants showed greater bleeding than wildtype, confirming the above findings. Taken together, the characterization of gp1ba zebrafish mutant suggested an autosomal dominant mode of inheritance. The zebrafish gp1ba mutant models classical Bernard Soulier Syndrome and could be used for reversing this phenotype to identify novel factors by the genome-wide piggyback knockdown method.
2022-02-11 | Acquired Bernard-Soulier syndrome and hypodysfibrinogenaemia because of multiple myeloma.
We describe a case of a patient with multiple myeloma with initial presentation simulating a bleeding disorder. Detailed coagulation work-up showed hypodysfibrinogenaemia along with a platelet function defect consistent with acquired Bernard-Soulier syndrome (BSS). Multiple plasma exchanges led to significant improvement in his bleeding symptoms. To the best of our knowledge, this is the first described case of simultaneous presentation of hypodysfibrinogenaemia and BSS secondary to multiple myeloma.
2015-07-15 | Artificial MiRNA Knockdown of Platelet Glycoprotein lbα: A Tool for Platelet Gene Silencing
In recent years, candidate genes and proteins implicated in platelet function have been identified by various genomic approaches. To elucidate their exact role, we aimed to develop a method to apply miRNA interference in platelet progenitor cells by using GPIbα as a proof-of-concept target protein. After in silico and in vitro screening of siRNAs targeting GPIbα (siGPIBAs), we developed artificial miRNAs (miGPIBAs), which were tested in CHO cells stably expressing GPIb-IX complex and megakaryoblastic DAMI cells. Introduction of siGPIBAs in CHO GPIb-IX cells resulted in 44 to 75% and up to 80% knockdown of GPIbα expression using single or combined siRNAs, respectively. Conversion of siGPIBAs to miGPIBAs resulted in reduced silencing efficiency, which could however be circumvented by tandem integration of two hairpins targeting different regions of GPIBA mRNA where 72% GPIbα knockdown was achieved. CHO GPIb-IX cells transfected with the miGPIBA construct displayed a significant decrease in their ability to aggregate characterized by lower aggregate numbers and size compared to control CHO GPIb-IX cells. More importantly, we successfully silenced GPIbα in differentiating megakaryoblastic DAMI cells that exhibited morphological changes associated with actin organization. In conclusion, we here report the successful use of miRNA technology to silence a platelet protein in megakaryoblastic cells and demonstrate its usefulness in functional assays. Hence, we believe that artificial miRNAs are suitable tools to unravel the role of a protein of interest in stem cells, megakaryocytes and platelets, thereby expanding their application to novel fields of basic and translational research.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
3 orphan drug designations for Bernard-Soulier syndrome.
3 orphan drug designations for Bernard-Soulier syndrome.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
induced pluripotent stem cell (iPSC)-derived platelet injection | cell therapies | FDA | — | HemaCell Biotechnology Inc. |
platelets produced in vitro from proplatelets derived from peripheral blood | cell therapies | FDA | — | HemaCell Biotechnology Inc. |
umbilical cord blood derived megakaryocyte injection | cell therapies | FDA | — | HemaCell Biotechnology Inc. |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.