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Background: Bernard–Soulier syndrome (BSS) is a rare inherited macrothrombocytopenia, usually autosomal recessive, which is characterized by prolonged bleeding, thrombocytopenia, and abnormally large platelets. Methods: For more than 6 years, we misdiagnosed a patient with BSS without an obvious bleeding tendency as having idiopathic thrombocytopenia purpura (ITP), prior to obtaining a genetic analysis. On admission, routine hematology showed a platelet count of 30 × 109/L and mean platelet volume (MPV) of 14.0 fL. Results: Whole-exome sequencing revealed two likely pathogenic heterozygous mutations (c.95_101del and c.1012del) in GP1BA. Flow cytometry analysis of platelet membrane glycoproteins indicated that the expression of GP1b was 0.28% of the normal level. Platelet aggregation tests indicated that platelet aggregation was inhibited by ristocetin- (1.7%), ADP- (14.5%), and arachidonic acid- (5.6%) induced platelet aggregation. A literature review identified reports on 53 mutations in the GP1BA gene in 253 patients, 29 mutations in the GP1BB gene in 90 patients, and 32 mutations in the GP9 gene in 114 patients. Conclusion: This case report describes two novel gene mutation sites that have not been reported previously, enriching understanding of the GP1BA mutation spectrum. [ABSTRACT FROM AUTHOR]

We present a case of a patient with Bernard–Soulier syndrome (BSS) who had his impacted third mandibular molar surgically extracted. An uncommon congenital bleeding condition called BSS is inherited in an autosomal recessive fashion. The syndrome, which has an incidence of fewer than 1 in 1,000,000, is characterized by delayed bleeding time, thrombocytopenia, and abnormally large platelets. Even simple surgical procedures become difficult in these patients due to their increased propensity for bleeding. There are no established standards for the management of perioperative bleeding linked to BSS because the condition is uncommon. The regular management of these bleeding episodes involves the delivery of platelets matched to the patient’s human leukocyte antigen, which carries certain challenges. We explain the treatment plan used for a patient with BSS whose impacted third molar was successfully extracted surgically.

Background: Bernard–Soulier syndrome (BSS) is a rare inherited macrothrombocytopenia, usually autosomal recessive, which is characterized by prolonged bleeding, thrombocytopenia, and abnormally large platelets.Methods: For more than 6 years, we misdiagnosed a patient with BSS without an obvious bleeding tendency as having idiopathic thrombocytopenia purpura (ITP), prior to obtaining a genetic analysis. On admission, routine hematology showed a platelet count of 30 × 109/L and mean platelet volume (MPV) of 14.0 fL.Results: Whole-exome sequencing revealed two likely pathogenic heterozygous mutations (c.95_101del and c.1012del) in GP1BA. Flow cytometry analysis of platelet membrane glycoproteins indicated that the expression of GP1b was 0.28% of the normal level. Platelet aggregation tests indicated that platelet aggregation was inhibited by ristocetin- (1.7%), ADP- (14.5%), and arachidonic acid- (5.6%) induced platelet aggregation. A literature review identified reports on 53 mutations in the GP1BA gene in 253 patients, 29 mutations in the GP1BB gene in 90 patients, and 32 mutations in the GP9 gene in 114 patients.Conclusion: This case report describes two novel gene mutation sites that have not been reported previously, enriching understanding of the GP1BA mutation spectrum.

Introduction and Objective: Flow Cytometry (FC) is one of the techniques, which allows the identification and characterization of platelets. The detection of absent or reduced expression of the glycoproteins is the main objective of this technique. Abnormalities of glycoproteins lead to hemorrhagic syndromes. Among the main diseases, the Bernard-Soulier syndrome (BSS) and Glanzmann thrombasthenia (GT) stand out. We aimed to show a FC-based platelet assessment test for diagnostic use, which measures the expression of markers in normal patients, and evaluate these markers in patients with platelet disorders. Methods: We examined a control group of 41 healthy adults to establish reference values and assess the variability of the relative expression of platelet markers and subsequently compared these findings to those of 30 patients with suspected platelet dysfunctions. We determined the mean fluorescent intensity (MFI) of the expressed parameters by FC using CD41, CD42a, CD42b and CD61 and SSC/FSC platelet-gated cells. Results: We determined our baseline panel of markers and compared them to suspected platelet dysfunctions. Patients with suspected BSS presented increased levels of the MFI for the GPIIIa (CD61) and GPIIb (CD41). They showed significantly reduced levels of the GPIb (CD42b) and GPIX (CD42a). Patients with suspected GT showed normal expression of the GPIX (CD42a), increased expression of the GPIb (CD42b) and reduced levels of the GPIIIa (CD61). In this case, with reduced levels of only one marker, the GPIIb (CD41), values showed normal expression. Conclusions: We describe the FC assay to support the diagnosis of different platelet disorders. Our study made it possible to implement a technique that brought benefits to care.

Bernard-Soulier syndrome (BSS) is a rare platelet function disorder due to an impaired GPIb-V-IX complex, with an estimated incidence of one per million. Usual presentations include gingival bleeding, epistaxis, easy bruising, and post-traumatic excessive bleeding, among others, but not hemoptysis. The patient was a 46-year-old male who presented with three cups of hemoptysis two days before the presentation. He also had moderate burning chest pain for the past two weeks, which was getting better. He was diagnosed with BSS 45 years ago and had approximately 100 prior presentations for bleeding from various locations, including three prior episodes of hemoptysis. The mainstay of treatment was platelet transfusions, and the patient was carefully observed. Only one case of hemoptysis in a patient with BSS was found, but the patient had hemoptysis due to underlying pulmonary tuberculosis. Therefore, hemoptysis or DAH were never reported in the literature due to BSS. This patient was the first case of massive hemoptysis and possible DAH related to BSS, emphasizing the need for proper attention due to its possible detrimental outcomes.

We present a case of a patient with Bernard–Soulier syndrome (BSS) who had his impacted third mandibular molar surgically extracted. An uncommon congenital bleeding condition called BSS is inherited in an autosomal recessive fashion. The syndrome, which has an incidence of fewer than 1 in 1,000,000, is characterized by delayed bleeding time, thrombocytopenia, and abnormally large platelets. Even simple surgical procedures become difficult in these patients due to their increased propensity for bleeding. There are no established standards for the management of perioperative bleeding linked to BSS because the condition is uncommon. The regular management of these bleeding episodes involves the delivery of platelets matched to the patient’s human leukocyte antigen, which carries certain challenges. We explain the treatment plan used for a patient with BSS whose impacted third molar was successfully extracted surgically. [ABSTRACT FROM AUTHOR]

Bernard–Soulier syndrome (BSS) is caused by defects in GP1BA, GP1BB, or GP9 genes. Patients with 22q11.2 deletion syndrome (22q11.2DS) are obligate carriers of BSS because GP1BB resides on chromosome 22q11.2. A 15-month-old girl without bleeding symptoms had giant platelets and thrombocytopenia. Physical findings and macrothrombocytopenia suggested 22q11.2DS, which was confirmed by fluorescence in situ hybridization. Flow cytometry showed decreased GPIbα on the platelets. Gene panel testing revealed a novel variant in GP1BB, p.(Val169_Leu172del). These findings confirmed that the patient had BSS. This case suggests that any patient with 22q11.2DS and macrothrombocytopenia should be further tested for BSS. [ABSTRACT FROM AUTHOR]

Background: Glanzmann thrombasthenia (GT) and Bernard‐Soulier syndrome (BSS) patients require frequent platelet transfusions and hence have an increased risk for alloimmunization against donor Human Leukocyte Antigens (HLA) when no HLA‐matching is performed. Knowing that Human Platelet Antigens (HPA) are located on the platelet glycoproteins that can be absent in these patients, preventive HPA‐matching may also be considered. Uniform recommendations on this topic lack in transfusion guidelines making standard practice unclear, therefore, we aimed to provide a framework for matched platelet transfusions. Study Design and Methods: We conducted a targeted literature search and a national survey of Dutch (pediatric) hematologists from July to September 2021. Results: We found 20 articles describing platelet transfusion policies in 483 GT‐patients and 29 BSS‐patients, both adults and children. Twenty surveys were returned for full analysis. All responders treated patients with platelet disorders, including GT (n = 36 reported) and BSS (n = 29 reported). Of respondents, 75% estimated the risk of antibody formation as "likely" for HLA and 65% for HPA. Formation of HLA antibodies was reported in 5 GT and in 5 BSS‐patients, including one child. Fifteen respondents gave preventive HLA‐matched platelets in elective setting (75%). Three respondents additionally matched for HPA in GT‐patients (15%). Main argument for matched platelet transfusions was preventing alloimmunization to safeguard the effectivity of 'random' donor‐platelets in acute settings. Conclusion: Elective HLA‐matching for GT and BSS‐patients is already conducted by most Dutch (pediatric) hematologists. HPA‐matching is mainly applied when HPA‐antibodies are formed. Based on the current literature and the survey, recommendations are proposed. [ABSTRACT FROM AUTHOR]

The utility of mouse models to dissect the molecular basis of hemostasis and thrombosis is now well established. The anucleate properties of circulating blood platelet and their specialized release from mature megakaryocytes makes the use of in vivo models all the more informative and powerful. Indeed, they are powerful but there do exist limitations. Here, we review the contributions of mouse models to the pathogenesis of the Bernard–Soulier syndrome, their use in platelet-specific gene expression, the recent development of mice expressing both human GPIb-IX and human von Willebrand factor (VWF), and finally the use of GPIb-IX mouse models to examine the impact of platelet biology beyond clotting. The humanization of the receptor and ligand axis is likely to be a major advancement in the characterization of therapeutics in the complex pathogenesis that drives thrombosis. When appropriate, we highlight some limitations of each mouse model, but this is not to minimize the contributions these models to the field. Rather, the limitations are meant to provide context for any direct application to the important mechanisms supporting human primary hemostasis and thrombosis.

Abstract The glycoprotein (GP) Ib-IX complex is a platelet receptor that mediates the initial interaction with subendothelial von Willebrand factor (VWF) causing platelet arrest at sites of vascular injury even under conditions of high shear. GPIb-IX dysfunction or deficiency is the reason for the rare but severe Bernard-Soulier syndrome (BSS), a congenital bleeding disorder. Although knowledge on GPIb-IX structure, its basic functions, ligands, and intracellular signaling cascades have been well established, several advances in GPIb-IX biology have been made in the recent years. Thus, two mechanosensitive domains and a trigger sequence in GPIb were characterized and its role as a thrombin receptor was deciphered. Furthermore, it became clear that GPIb-IX is involved in the regulation of platelet production, clearance and thrombopoietin secretion. GPIb is deemed to contribute to liver cancer development and metastasis. This review recapitulates these novel findings highlighting GPIb-IX in its multiple functions as a key for immune regulation, host defense, and liver cancer development.

Summary: Constitutional thrombocytopenias are rare disorders, often difficult to discriminate from acquired thrombocytopenias. More than 80 genes have been described as being at the origin of these diseases. Among them, several variants of the glycoprotein Ib platelet subunit alpha (GP1BA) and glycoprotein Ib platelet subunit beta (GP1BB) genes, coding for the GpIb‐IX‐V glycoprotein complex, have been reported in the literature. The study reported here aimed at describing newly identified monoallelic anomalies affecting the GP1BA and GP1BB genes on a clinical, biological and molecular level. In a cohort of nine patients with macrothrombocytopenia, eight heterozygous variants of the GP1BA or GP1BB genes were identified. Five of them had never been described in the heterozygous state. Computer modelling disclosed structure/function relationships of these five variants. [ABSTRACT FROM AUTHOR]

Introduction and Objective: Flow Cytometry (FC) is one of the techniques, which allows the identification and characterization of platelets. The detection of absent or reduced expression of the glycoproteins is the main objective of this technique. Abnormalities of glycoproteins lead to hemorrhagic syndromes. Among the main diseases, the Bernard-Soulier syndrome (BSS) and Glanzmann thrombasthenia (GT) stand out. We aimed to show a FC-based platelet assessment test for diagnostic use, which measures the expression of markers in normal patients, and evaluate these markers in patients with platelet disorders., Methods: We examined a control group of 41 healthy adults to establish reference values and assess the variability of the relative expression of platelet markers and subsequently compared these findings to those of 30 patients with suspected platelet dysfunctions. We determined the mean fluorescent intensity (MFI) of the expressed parameters by FC using CD41, CD42a, CD42b and CD61 and SSC/FSC platelet-gated cells., Results: We determined our baseline panel of markers and compared them to suspected platelet dysfunctions. Patients with suspected BSS presented increased levels of the MFI for the GPIIIa (CD61) and GPIIb (CD41). They showed significantly reduced levels of the GPIb (CD42b) and GPIX (CD42a). Patients with suspected GT showed normal expression of the GPIX (CD42a), increased expression of the GPIb (CD42b) and reduced levels of the GPIIIa (CD61). In this case, with reduced levels of only one marker, the GPIIb (CD41), values showed normal expression., Conclusions: We describe the FC assay to support the diagnosis of different platelet disorders. Our study made it possible to implement a technique that brought benefits to care., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2023 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. All rights reserved.)

Either the glycoprotein (GP) Ib deficiency or hyper-function in humans can cause macrothrombocytopenia, the molecular mechanisms of which remain unclear. Herein, the investigations for disease pathogenesis were performed in the human induced pluripotent stem cell (hiPSC) model. The hiPSCs carrying a gain-of-function GP1BA p.M255V mutation which was described in platelet-type von Willebrand disease (PT-VWD) were generated using CRISPR/Cas9. The GP1BA-null hiPSCs were previously derived from a Bernard–Soulier syndrome (BSS) patient. After full megakaryocyte differentiation in culture, both hiPSC mutations showed large proplatelet tips under fluorescence microscopy and yielded fewer but larger platelets compared with those of wild-type cells. The Capillary Western analyses revealed the lower ERK1/2 activation and higher MLC2 (Myosin light chain 2) phosphorylation in megakaryocytes with mutated GPIb. Adding a mitogen-activated protein kinase (MAPK) pathway inhibitor to wild-type hiPSCs recapitulated the phenotypes of GPIb mutations and increased MLC2 phosphorylation. Notably, a ROCK inhibitor which could inhibit MLC2 phosphorylation rescued the macrothrombocytopenia phenotypes of both GPIb alterations and wild-type hiPSCs with a MAPK inhibitor. In conclusion, the genetically modified hiPSCs can be used to model disorders of proplatelet formation. Both loss- and gain-of-function GPIb reduced MAPK/ERK activation but enhanced ROCK/MLC2 phosphorylation resulting in dysregulated platelet generation.

The utility of mouse models to dissect the molecular basis of hemostasis and thrombosis is now well established. The anucleate properties of circulating blood platelet and their specialized release from mature megakaryocytes makes the use of in vivo models all the more informative and powerful. Indeed, they are powerful but there do exist limitations. Here, we review the contributions of mouse models to the pathogenesis of the Bernard–Soulier syndrome, their use in platelet-specific gene expression, the recent development of mice expressing both human GPIb-IX and human von Willebrand factor (VWF), and finally the use of GPIb-IX mouse models to examine the impact of platelet biology beyond clotting. The humanization of the receptor and ligand axis is likely to be a major advancement in the characterization of therapeutics in the complex pathogenesis that drives thrombosis. When appropriate, we highlight some limitations of each mouse model, but this is not to minimize the contributions these models to the field. Rather, the limitations are meant to provide context for any direct application to the important mechanisms supporting human primary hemostasis and thrombosis. [ABSTRACT FROM AUTHOR]

Introduction: Frequent and severe bleeding events (SBE) in patients with inherited qualitative platelet disorders Bernard‐Soulier Syndrome (BSS) and Glanzmann Thrombasthenia (GT) can lead to secondary iron deficiency anemia (IDA). SBE are primarily treated with platelet transfusions or recombinant activated factor VII (rFVIIa) infusions. The impact of IDA on bleeding management and disease outcomes is understudied. Aim: To evaluate bleeding management, outcomes, and any association with IDA in pediatric patients with BSS and GT. Methods: Retrospective chart‐review of pediatric patients with BSS or GT followed at a single hemophilia treatment center between 2007 and 2019. Results: We identified 14 patients with BSS (n = 2) or GT (n = 12). Patients received rFVIIa (7%), platelet transfusions (7%), or a combination of both (57%) for SBE. Eleven patients (79%) had IDA requiring oral and/or intravenous iron replacement and 50% required red blood cell transfusions. Due to recurrent SBE and refractory IDA, three patients (21%) received rFVIIa prophylaxis at 90 μg/kilogram 2‐3 times/week for ≥15 months. Patients initiated on rFVIIa prophylaxis had a median baseline hemoglobin of 9.8 g/dL (min‐max: 8.0–10.7 g/dL) compared to 11.7 g/dL (8.4–13.8 g/dL) for patients treated on‐demand. Following initiation of rFVIIa prophylaxis, median hemoglobin and ferritin increased by 1.3 g/dL (0.7–2.5 g/dL) and 14.6 ng/mL (0.2–42.9 ng/mL), respectively, and bleeding rates were reduced by 7–78%. Conclusion: IDA is a known complication of recurrent bleeding events in individuals with inherited bleeding disorders. Routine monitoring for IDA may help improve bleeding management and reduce bleed burden in BSS/GT. [ABSTRACT FROM AUTHOR]

The glycoprotein (GP) Ib-IX complex is a platelet receptor that mediates the initial interaction with subendothelial von Willebrand factor (VWF) causing platelet arrest at sites of vascular injury even under conditions of high shear. GPIb-IX dysfunction or deficiency is the reason for the rare but severe Bernard-Soulier syndrome (BSS), a congenital bleeding disorder. Although knowledge on GPIb-IX structure, its basic functions, ligands, and intracellular signaling cascades have been well established, several advances in GPIb-IX biology have been made in the recent years. Thus, two mechanosensitive domains and a trigger sequence in GPIb were characterized and its role as a thrombin receptor was deciphered. Furthermore, it became clear that GPIb-IX is involved in the regulation of platelet production, clearance and thrombopoietin secretion. GPIb is deemed to contribute to liver cancer development and metastasis. This review recapitulates these novel findings highlighting GPIb-IX in its multiple functions as a key for immune regulation, host defense, and liver cancer development. [ABSTRACT FROM AUTHOR]

Bernard–Soulier syndrome is an inherited coagulopathy, with an incidence of one per million. Hemorrhagic cholecystitis is a rare and life-threatening complication of acute cholecystitis. Less than 50 patients have been reported in the previous literature. Bleeding diathesis and anticoagulant treatment are well-known predisposing factors for hemorrhagic cholecystitis. We present a 57-year-old male patient who was referred to our department with a complaint of right upper quadrant abdominal pain. Contrast-enhanced computed tomography revealed a high-density mass associated with the gallbladder lumen, and blood clot in the gallbladder lumen and hemoperitoneum which were compatible for hemorrhagic cholecystitis and gallbladder perforation. The patient underwent urgent cholecystectomy. Hemorrhagic cholecystitis often manifests as typical acute cholecystitis presentation; but several clinical findings such as fever, lower gastrointestinal bleeding or severe intraabdominal bleeding-related hypovolemic shock may also occur. Most of the described cases in prior literature have been reported to use anticoagulant medications. This report describes the second hemorrhagic cholecystitis patient with inherited bleeding diathesis and the first case with Bernard–Soulier syndrome. [ABSTRACT FROM AUTHOR]

Bernard-Soulier syndrome, a congenital bleeding disorder, can rarely present with atherosclerosis and thrombosis. Acute coronary syndrome in such patients present a unique challenge as no standard set of guidelines exist for successful treatment. (Level of Difficulty: Intermediate.)

Inherited platelet function disorders (IPFDs) are rare and underdiagnosed in individuals with clinically significant bleeding diathesis. IPFDs are classified according to the causative molecular defects involved in the process of primary hemostasis of platelets, which include the following: 1) adhesion (e.g., Bernard?Soulier syndrome and pseudo-von Willebrand disease), 2) activation (e.g., adenosine diphosphatase receptor defect and thromboxane A2 receptor defect), 3) signal transduction and granule secretion (e.g., gray platelet syndrome, Paris?Trousseau/Jacobsen syndrome, Chediak?Higashi syndrome, and Hermansky?Pudlak syndrome), 4) aggregation (e.g., Glanzmann thrombasthenia), and 5) procoagulant activity (e.g., Scott syndrome). Patients with IPFDs typically present with unexpected mucocutaneous bleeding during early childhood. The diagnosis of these conditions requires several laboratory tests including complete blood cell count, peripheral blood smear, platelet function analysis, light-transmission aggregometry, flow cytometry, electron microscopy, and genetic analysis. Platelet transfusion has been the mainstay of treatment. However, antifibrinolytics, desmopressin, and recombinant activated factor VII are also effective when used as a monotherapy or adjunctive therapy. Importantly, the prevention of bleeding event is the most basic strategy in the management of IPFDs. This review aimed to assess the normal platelet physiology and summarize the current knowledge about the molecular defects, diagnostic evaluation, and treatment strategies of the respective IPFDs. If the cause of the bleeding tendency is difficult to identify, IPFDs should be considered.

Inherited platelet disorders (IPDs), which manifest as primary hemostasis defects, often underlie abnormal bleeding and a family history of thrombocytopenia, bone marrow failure, hematologic malignancies, undefined mucocutaneous bleeding disorder, or congenital bony defects. Wide heterogeneity in IPD types with regard to the presence or absence of thrombocytopenia, platelet dysfunction, bone marrow failure, and dysmegakaryopoiesis is observed in patients. The individual processes involved in platelet production and hemostasis are genetically controlled; to date, mutations of more than 50 genes involved in various platelet biogenesis steps have been implicated in IPDs. Representative IPDs resulting from defects in specific pathways, such as thrombopoietin/MPL signaling; transcriptional regulation; granule formation, trafficking, and secretion; proplatelet formation; cytoskeleton regulation; and transmembrane glycoprotein signaling are reviewed, and the underlying gene mutations are discussed based on the National Center for Biotechnology Information database and Online Mendelian Inheritance in Man accession number. Further, the status and prevalence of genetically confirmed IPDs in Korea are explored based on searches of the PubMed and KoreaMed databases. IPDs are congenital bleeding disorders that can be dangerous due to unexpected bleeding and require genetic counseling for family members and descendants. Therefore, the pediatrician should be suspicious and aware of IPDs and perform the appropriate tests if the patient has unexpected bleeding. However, all IPDs are extremely rare; thus, the domestic incidences of IPDs are unclear and their diagnosis is difficult. Diagnostic confirmation or differential diagnoses of IPDs are challenging, time-consuming, and expensive, and patients are frequently misdiagnosed. Comprehensive molecular characterization and classification of these disorders should enable accurate and precise diagnosis and facilitate improved patient management.

Background Glanzmann's thrombasthenia (GT) and Bernard-Soulier syndrome (BSS) are genetic bleeding syndromes characterized by defects in platelet aggregometry. Although these disorders are classified to be rare, their exact prevalence is still unknown; however, they are more frequent in communities where consanguineous marriages are common. Aim To study platelet surface glycoproteins expression using flow cytometry and to examine their correlation with bleeding severity using International Society of Thrombosis and Hemostasis–Bleeding Assessment Tools (ISTH-BAT) as bleeding score of choice. Patients and methods This case–control study included 51 patients with bleeding disorders recruited from the Department of Pediatric Hematology, Assiut University Hospital, in addition to 36 apparently healthy age- and sex-matched controls. All patients were tested for complete blood count (CBC), prothrombin time, partial thromboplastin time, platelet aggregation, and platelets surface glycoprotein analysis by flow cytometry. ISTH-BAT was used to register bleeding data for patients. Results GT and BSS had some similarities regarding the presentation and bleeding severity, but when CBC, platelet aggregation studies, and flow cytometric analysis were done, differentiation became much easier. GT patients showed a decrease in the expression of CD41 and CD61. Type I GT patients had more bleeding severity than type II and type III. BSS patients showed a decrease in expression of CD42b. There are correlations between the bleeding severity and CD41 in GT, and between the severity and CD42b in BSS. Conclusion Flow cytometric studies of platelet glycoproteins have great values in diagnosing BSS and GT, and further classifying GT cases into its three types. ISTH-BAT is a useful tool when dealing with platelet function disorders and has good sensitivity and ability to determine the severity. [ABSTRACT FROM AUTHOR]

Objectives: To assess the frequency and characteristics of children with inherited bleeding disorders that were initially misdiagnosed, leading to inappropriate disease management.Methods: This study was conducted at the Haematology/Pathology Department of Fauji Foundation Hospital, Rawalpindi, Pakistan, from August 2014 to August 2018. Children who were diagnosed with an inherited bleeding disorder but did not respond to initial therapy were reevaluated.Results: In total, 62 children were diagnosed with a bleeding disorder. Of these, 27 were diagnosed with an inherited bleeding disorder and 35 with an acquired bleeding disorder. Of the 27 children with inherited bleeding disorders, 18% (n = 5) were misdiagnosed and treated inappropriately. The median age of the misdiagnosed patients was 9 years (range, 5-13 years). Three patients with Bernard-Soulier syndrome had been misdiagnosed as having immune thrombocytopenic purpura, 1 patient with von Willebrand disease had been misdiagnosed as having hemophilia A, and 1 patient with haemophilia B had been misdiagnosed as having hemophilia A.Conclusions: There are chances of misdiagnosis and improper or invasive management if comprehensive laboratory evaluation and a thorough clinical evaluation are not performed in children with congenital bleeding disorders. [ABSTRACT FROM AUTHOR]

Either the glycoprotein (GP) Ib deficiency or hyper-function in humans can cause macrothrombocytopenia, the molecular mechanisms of which remain unclear. Herein, the investigations for disease pathogenesis were performed in the human induced pluripotent stem cell (hiPSC) model. The hiPSCs carrying a gain-of-function GP1BA p.M255V mutation which was described in platelet-type von Willebrand disease (PT-VWD) were generated using CRISPR/Cas9. The GP1BA-null hiPSCs were previously derived from a Bernard–Soulier syndrome (BSS) patient. After full megakaryocyte differentiation in culture, both hiPSC mutations showed large proplatelet tips under fluorescence microscopy and yielded fewer but larger platelets compared with those of wild-type cells. The Capillary Western analyses revealed the lower ERK1/2 activation and higher MLC2 (Myosin light chain 2) phosphorylation in megakaryocytes with mutated GPIb. Adding a mitogen-activated protein kinase (MAPK) pathway inhibitor to wild-type hiPSCs recapitulated the phenotypes of GPIb mutations and increased MLC2 phosphorylation. Notably, a ROCK inhibitor which could inhibit MLC2 phosphorylation rescued the macrothrombocytopenia phenotypes of both GPIb alterations and wild-type hiPSCs with a MAPK inhibitor. In conclusion, the genetically modified hiPSCs can be used to model disorders of proplatelet formation. Both loss- and gain-of-function GPIb reduced MAPK/ERK activation but enhanced ROCK/MLC2 phosphorylation resulting in dysregulated platelet generation. [ABSTRACT FROM AUTHOR]

Bernard–Soulier syndrome (BSS) and Glanzmann Thrombasthenia (GT) are rare inherited platelet function disorders, defined by a permanent history of mucocutaneous bleeding. The objective of this project was to identify biological and clinical characteristics of BSS and GT patients. Methodology: This study included 52 patients with bleeding disorders, the clinical, haematological and demographic features of patients were determined and the level of GpIIb/IIIa and GPIb/IX was assessed. Results: From a total of 52 patient, 20 were diagnosis with BSS (9 females and 11 males), their age range from 6 to 42 year and 23 diagnoses with GT (10 females and 13 males), their age range from 4 to 50 year. Epistaxis, easy bruising, menorrhagia and ecchymosis were the most frequent symptoms. Prolonged bleeding time (BT), normal PT and PTT were seen in all cases. Variable thrombocytopenia, large platelets with decreased GPIb/IX level were seen in BSS patients, while the level of GPIIb/IIIa was decreased in GT cases. Conclusion: Since BSS and GT are infrequent disorders diagnosis may be postponed, both diseases are combined with crucial bleeding tendency, therefore earlier detection would have been important for patients management. [ABSTRACT FROM AUTHOR]

Background: Bernard–Soulier Syndrome (BSS) is a rare autosomal recessive bleeding disorder with large platelets and thrombocytopenia. It is caused by homozygous or compound heterozygous mutations in the GP1BA, GP1BB, or GP9 genes, which together encode the platelet surface receptor glycoprotein complex GPIb-IX-V.Objectives: We report two novel heterozygous mutations in the GP1BA and the GP9 genes, respectively.Patients/Methods: We analyzed the platelet glycoprotein expression by flow cytometry and screened the relevant genes for responsible mutations in two unrelated families.Results: Flow cytometric analyses revealed the absence of CD42a (GPIX) and CD42b (GPIb) on the platelets in the two affected siblings of family 1 and a significantly reduced expression of CD42b (GPIb) in the patient of family 2. In the two siblings, we identified a known frameshift (c.1601_1602delAT) and a novel nonsense mutation (c.1036C>T) in the GP1BA gene that abrogated the production of GP1bα. In the other patient, we found a novel missense mutation (c.112T>C) that was co-inherited with a common one (c.182A>G) in the GP9 gene, respectively. All analyzed heterozygous carriers were asymptomatic and had a normal GPIb-IX-V expression.Conclusions: The two novel GP1BA and GP9 mutations reported herein increment the number of causative genetic defects in BSS.

Introduction The platelet function analyzer (PFA) is widely used as a screening tool for bleeding disorders in various settings. The diagnostic performance regarding platelet function disorders (PFDs), which are among the most common inherited bleeding disorders, is however still elusive. We aimed to assess the diagnostic value of PFA for PFD in clinical practice. Methods Comprehensive clinical and laboratory data of all consecutive patients referred to a specialized outpatient between January 2012 and March 2017 with a suspected bleeding disorder were prospectively recorded. The diagnostic work-up was performed according to a prespecified protocol following current guidelines and platelet function was tested using light transmission aggregometry as well as flow cytometry. Results Five hundred and fifty-five patients were included (median age 43.7 years; interquartile range [IQR] 29.3, 61.7; 66.9% female). Possible PFD was diagnosed in 64 patients (11.5%) and confirmed PFD in 54 patients (9.7%). In patients with confirmed PFD, median closure times were 107 seconds (ADP or adenosine diphosphate; IQR 89, 130) and 169 seconds (EPI; IQR 121, 211). In patients without bleeding disorders, PFA closure times were 96 seconds (ADP; IQR 83, 109) and 137 seconds (EPI; IQR 116, 158). The sensitivity was 19.5% in case of PFA ADP (95%CI 12.6, 30.0; specificity 86.4%; 95% CI 82.4, 89.8), and 44.3% in case of PFA EPI (95% CI 34.9, 53.9; specificity 75.6%; 95% CI 70.8, 79.9). Conclusion The diagnostic performance of PFA for PFD was moderate to poor. Our results do not support the utilization of PFA for screening of PFD in clinical practice.

Menorrhagia is a common problem in women of reproductive age group and 5% of women between 30 and 49 years of age group consult their general practitioner for this problem. Menorrhagia occurring in adolescent age group and perimenopausal age group is chiefly due to anovulatory cycles. In perimenopausal age group, local pathology like leiomyomas can also contribute to menorrhagia. Recently, bleeding disorders like von Willebrand Disease, single coagulation factor deficiencies particularly factor XI, VIII, Factor V and platelet function disorders have been found to be prevalent in patients presenting with menorrhagia. Bernerd soulier syndrome is extremely rare haemostatic disorder due deficiency in GP IB/IX/V receptor complex present on platelet membrane which is necessary for platelet aggregation. As a result of the defect patients have prolonged bleeding time, which might vary in symptoms ranging from spontaneous self- limiting epistaxis to life threatening haemorrhage. Here we report a case of 31-year-old woman known case of Bernard soulier syndrome with severe menorrhagia treated with mirena insertion and course of complication and its management.

Bernard–Soulier syndrome (BSS) is a rare autosomal recessive disease with bleeding diathesis due to platelet dysfunction secondary to the absence of the von Willebrand factor receptor on the platelet surface called glycoprotein Ib–V–IX. The deficiency results in prolonged bleeding time and spontaneous bleeds and may be with high risk for anesthesia and surgery. Here, we report a case of BSS coming for trabeculectomy.

Keywords: platelet count; genetic analysis; GP1BB; bernard-Soulier syndrome; platelet glycoproteins; functional studies EN platelet count genetic analysis GP1BB bernard-Soulier syndrome platelet glycoproteins functional studies e124 e128 5 12/07/20 20201201 NES 201201 Inherited platelets disorders can be severe, especially after trauma or surgical procedures in some monogenic disorders, as in Bernard-Soulier syndrome [BSS; Mendelian Inheritance in Man (MIM) #231200]. The cysteine knot of platelet glycoprotein Ib (GPIb-beta) is critical for the interaction of GPIb-beta with GPIX. 2015; 94: 2069 - 71. 19 Kunishima S, Naoe T, Kamiya T, Saito H. Novel heterozygous missense mutation in the platelet glycoprotein Ib beta gene associated with isolated giant platelet disorder. [Extracted from the article]

High prevalence of the natural Asn89Asp mutation in the GP1BB gene associated with Bernard-Soulier syndrome in French patients from the genetic isolate of Reunion Island Keywords: Bernard-Soulier syndrome; Reunion Island; platelet GPIb ; Leucin-rich repeat domain; GP1BB EN Bernard-Soulier syndrome Reunion Island platelet GPIb Leucin-rich repeat domain GP1BB e67 e71 5 04/30/20 20200501 NES 200501 Congenital defects in the platelet GPIb-IX-V complex result in quantitative deficiencies and cause the Bernard-Soulier syndrome (BSS) bleeding disorder (Nurden & Nurden, [4]). As illustrated in the Western Blot (WB) analysis of one patient (BSS SB 1 sb ), GPIb , GPIb and GPIX subunits, which are probably not correctly associated, were easily degraded leaving only trace amounts or absence of them in platelet lysates (Figure S3). [Extracted from the article]

Introduction: Women with inherited platelet receptor defects (IPRD) may have an increased risk of heavy menstrual bleeding (HMB) and postpartum haemorrhage (PPH). Aim: To present a systematic overview of the literature on the prevalence and management of menstrual and obstetrical bleeding in women with IPRD. Methods: Electronic databases were searched for original patient data on the prevalence and management of HMB and PPH in women with known IPRD or who were being investigated for IPRD. Results: Sixty‐nine papers (61 case reports/series and 8 cohort studies) were included. Overall, studies were rated as 'poor quality'. The included cohort studies reported HMB in 25% (13/52) of women with Bernard‐Soulier syndrome and in 22.1% (34/154) of women with Glanzmann thrombasthenia. In total, 164 deliveries in women with IPRD were described. Excessive bleeding occurred in 16.9% (11/65) of deliveries described in the largest cohort. PPH occurred in 63.2% (55/87) of deliveries described in case reports/series. PPH occurred in 73.7% (14/19) of deliveries that were not covered by prophylaxis compared with 54.2% (32/59) of deliveries that were (OR = 2.36, 95% CI 0.75‐7.40). Neonatal bleeding complications were reported in 10.0% (8/80) of deliveries. In all (6/6) deliveries with neonatal bleeding complications wherein the presence of alloantibodies was investigated, either antiplatelet or anti‐HLA antibodies were detected. Discussion/Conclusion: Menstrual and particularly obstetrical bleeding problems frequently occur in women with IPRD, based on small case reports and series of poor quality. International collaboration, preferably on prospective studies, is needed to improve clinical management of women‐specific bleeding in IPRD. [ABSTRACT FROM AUTHOR]

Abstract Background Autosomal recessive bleeding disorders (ARBDs) include deficiencies of clotting factors I, II, V, VII, X, XI, XIII, vitamin K dependent clotting factors, combined factor V & VIII, Von Willebrand Disease (vWD) type 3, Glanzmann’s thrombasthenia (GT) and Bernard–Soulier syndrome. Patients with primary bleeding disorders from all the major provincial capitals of Pakistan were screened for ARBDs. Prothrombin (PT), activated partial thromboplastin time (APTT), bleeding time (BT) and fibrinogen levels were measured. Cases with isolated prolonged APTT were tested for factors VIII and IX using factor assays This was followed by FXI:C level assessment in cases with normal FVIII and FIX levels. vWD was screened in patients with low FVIII levels. Factors II, V and X were tested in patients with simultaneous prolongation of PT and APTT. Peripheral blood film examination and platelet aggregation studies were performed to assess platelet disorders. Urea clot solubility testing was done to detect Factor XIII levels where platelet function tests were normal. Descriptive analysis was done using SPSS version 16. Results Of the 429 suspected bleeding disorder patients, 148 (35%) were diagnosed with hemophilia A and 211 (49.1%) patients had ARBDs. 70 patients (16.3%) remained undiagnosed. Out of 211 patients with ARBD; 95 (33.8%) had vWD type 3. Fibrinogen deficiency was found in 34 patients (12%), GT in 27 (9.6%), factor XIII deficiency in 13 (4.6%), factor VII deficiency in 12 (4.3%), factor V deficiency in 9 (3.2%). Eight patients (2.8%) had vitamin K-dependent clotting factor deficiency, Bernard–Soulier syndrome was diagnosed in seven patients (2.5%), factor X deficiency in 2 (0.7%), factor II deficiency in 2 (0.7%), factor XI deficiency and combined factor V and VIII deficiency in 1 (0.4%) patient each. Conclusion vWD type 3 was the most common ARBD found in our sample of patients in Pakistan, followed by fibrinogen deficiency and GT in respective order.

Bernard–Soulier syndrome (BSS) is an autosomal recessive major thrombocytopathy, the symptoms of which are mainly marked by mucocutaneous bleeding. This rare disease, initially described in the 1970s, is the result of an abnormal formation of the glycoprotein complex Ib-IX-V (GP Ib-IX-V), a platelet receptor of von Willebrand factor. A large number of mutations, sometimes involving the GP9 gene, have been described as possibly responsible for the disease. We report here the case of a BSS patient who presented with persistent thrombocytopenia (31x109/L) and decreased surface expression of GPIb-IX-V on large platelets with anisocytosis. Thorough molecular analyses disclosed two previously unreported GP9 variants, respectively c.230T>A (p.Leu77Gln) and c.255C>A (p.Asn85Lys). Both are likely to modify the conformation of GP-IX interactions with other glycoproteins of the Ib-IX-V complex and thus proper expression of this complex on the membrane of platelets.

Bernard-Soulier syndrome (BSS) is an extremely rare autosomal recessive bleeding disorder clinically characterized by macrothrombocytopenia and a mucocutaneous bleeding tendency. A 1-year-old Chinese patient who was born to consanguineous parents was diagnosed with early onset of BSS. Gene sequencing and bioinformatics analysis were conducted. We identified a novel homozygous missense mutation (c.790T>C) in the GP1BAgene that causes an amino acid residue substitution of a cysteine with an arginine that might have a deleterious effect on the protein function as predicted by bioinformatics analysis. If a patient has clinical manifestations that include recurrent mucocutaneous bleeding, a mean platelet volume and platelet-large cell ratio above normal levels, and giant platelets on a peripheral smear and has consanguineous parents, a diagnosis of BSS can be suspected. In these situations, gene sequencing for mutations in the GPIb-IX-V complex is necessary. [ABSTRACT FROM AUTHOR]

The Bernard-Soulier syndrome ranked seventh among the most common coagulation disorders; it is a rare genetic disease, characterized by dysfunction or absence of the glycoprotein Ib-IX-V platelet complex, which is the main receptor of von Willebrand factor, important in platelet adhesion to the subendothelium. Its incidence can be more than 1 per 1 million because it is often misdiagnosed if the patient does not present with the typical clinic or if there are no conclusive laboratory results. The syndrome presents macrothrombocytopenia with variable platelet counts as well as prolongation of the coagulation time. To date, more than 100 mutations related to the components of the platelet complex have been described, the presentation of the disease can become very heterogeneous even in patients who have an identical mutation. [ABSTRACT FROM AUTHOR]

Abstract Inherited bleeding disorders increase the risk of bleeding in the obstetric patient. Randomized controlled trials to compare prophylactic or therapeutic interventions are rare, and guidance documents rely heavily on expert opinion. Here we report the results of a systematic review of the literature for the treatment and prevention of peripartum bleeding in women with an inherited bleeding disorder. The highest-quality evidence is for the use of tranexamic acid in postpartum hemorrhage, which has been shown to decrease bleeding-related mortality in women without bleeding disorders. There is limited evidence for prophylactic use of this agent in women with inherited bleeding disorders. Desmopressin has also been used in observational studies of patients with von Willebrand disease and carriers of hemophilia A with some success, although concerns about the risk of hyponatremia persist. In patients with deficiencies of specific factors, replacement is generally the preferred approach, and concentrates have been studied in deficiencies of VWF and factors VII, VIII, IX, XI, and XIII as well as in patients with fibrinogen deficiency. Because of the small size of these studies, neither safety nor efficacy is well established, although the literature suggests that bleeding history may be more predictive of outcomes than factor levels in many cases. Goal factor levels have not been studied or systematically established in any of these diseases, although observational data suggest that achieving normal levels may be inadequate, particularly for VWF and factor VIII, which are physiologically elevated in pregnancy. For factor deficiencies in which no specific concentrate is available, such as factors II (prothrombin) and V, prothrombin complex concentrate or fresh frozen plasma may be used, and for platelet defects or deficiencies, such as Glanzmann thrombasthenia or Bernard-Soulier syndrome, platelet transfusion is generally first line, although use of recombinant FVIIa has been reported in patients with Glanzmann thrombasthenia to avoid development of, or treat patients with, antibodies to platelet glycoprotein IIbIIIa. Ultimately, data are lacking to definitively support an evidence-based approach to management in any of these disorders, and prospective, controlled studies are desperately needed. Highlights • Data on management of bleeding disorders in pregnancy are extremely limited. • Tranexamic acid can be used in most obstetric patients with bleeding disorders. • A history of bleeding is a strong predictor of bleeding complications. • Correcting factor levels to within the prepregnant normal range may not prevent peripartum bleeding, particularly for von Willebrand disease and hemophilia A. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We need to be aware of rare causes of persistent thrombocytopenia as Bernard–Soulier syndrome (BSS). When BSS is suspected based on family history and giant platelets, genetic test for mutations of GPIbIXV is necessary. Management varies once you recognize the cause. Platelets transfusion and antifibrinolytics are the mainstay of therapy. [ABSTRACT FROM AUTHOR]