Novel GPIb-independent platelet aggregation induced by botrocetin: implications for diagnosis and antithrombotic therapy.

BACKGROUND: 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. OBJECTIVES: To explore the alternative receptor(s)/mechanisms that participate in botrocetin-induced platelet aggregation. METHODS: 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-αIIbß3 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. RESULTS: 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 αIIbß3 and facilitated αIIbß3-VWF interaction independent of GPIb. Botrocetin competitively bound to the ligand-binding domain of activated rather than resting αIIbß3. Although botrocetin-induced platelet aggregation requires VWF, strikingly, in the absence of VWF, botrocetin blocked fibrinogen and other ligand binding to αIIbß3 and inhibited platelet aggregation and thrombus formation. Consistently, recombinant botrocetin defective in VWF binding inhibited αIIbß3- and GPIb-mediated platelet aggregation, spreading, and thrombus formation. CONCLUSION: 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 αIIbß3 and GPIbα.

Bernard-Soulier syndrome caused by a novel GP1BB variant and 22q11.2 deletion.

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.

Bernard-Soulier syndrome caused by two novel heterozygous GP1BA gene mutations: a case report and literature review.

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.

Should HLA and HPA-matched platelet transfusions for patients with Glanzmann Thrombasthenia or Bernard-Soulier syndrome be standardized care? A Dutch survey and recommendations.

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.

Point-of-care platelet function testing results in a dog with Bernard-Soulier syndrome.

Bernard-Soulier syndrome (BSS), also known as hemorrhagiparous thrombocytic dystrophy (OMIA 002207-9615), is a rare defect in platelet function recognized in both dogs and humans. It is caused by a deficiency in glycoprotein 1b-IX-V, the platelet surface protein which acts as a receptor for the von Willebrand factor. The characteristic features of BSS in humans and dogs include macrothrombocytes and mild-to-moderate thrombocytopenia with a bleeding tendency. This condition has previously been reported in European Cocker Spaniel dogs; however, the results of platelet function tests in these animals have not been reported. This case report describes a European Cocker Spaniel dog with spontaneously occurring Bernard-Soulier syndrome and the results of point-of-care platelet function tests, including a prolonged buccal mucosal bleeding time (>8 min), prolongation (>300 s) of PFA-200 COL/ADP, COL/EPI, and P2Y closure times, and reduced aggregation (15%-48%) with Plateletworks ADP, but with normal aggregation (92%) with Plateletworks AA. This is the first description of the results of platelet function tests in canine Bernard-Soulier syndrome.

Clinical Dilemma, Bernard Soulier Syndrome versus Immune Thrombocytopenic Purpura: A Case Report.

BACKGROUND: Bernard Soulier Syndrome (BSS) is a rare autosomal recessive disorder due to deficiency or dysfunction of the glycoprotein GPIb-V-IX complex on the platelet surface. It is also known as hemorrhagiparous thrombocytic dystrophy or congenital hemorrhagiparous thrombocytic dystrophy. The patient usually presents with severe and prolonged bleeding along with characteristics of giant blood platelets and low platelet counts. Manifestations of BSS include epistaxis, gum bleeding, purpuric rashes, menorrhagia, rarely melena, and hematemesis. On the other hand, immune thrombocytopenic purpura (ITP) is an acquired autoimmune disorder in which there is accelerated platelet destruction and reduced platelet production. Isolated thrombocytopenia without fever, lymphadenopathy, and organomegaly usually lead to the diagnosis of immune thrombocytopenia. CASE PRESENTATION: A 20 years old female presented with complaints of recurrent episodes of epistaxis since childhood and menorrhagia during menarche. She was misdiagnosed as ITP elsewhere. Later, based on thorough clinical examination and investigation, the diagnosis was confirmed as BSS. CONCLUSION: BSS should always be taken in the differential diagnosis of ITP, especially when persistent, refractory, and treated unsuccessfully with steroids or splenectomy.

Bernard-Soulier Syndrome from the Perspective of the Obstetrician: A Case Report with a Review of the Literature.

OBJECTIVE: Bernard-Soulier syndrome (BSS) is one of the rare inherited platelet disorders that is characterized by macrothrombocytopenia and adhesion abnormality due to the absence or malfunctioning of the membrane GPIb-IX-V complex. There is no high-quality evidence on obstetric management of BSS owing to its rarity. Here we report an uncomplicated delivery of an adolescent with BSS and review the literature on the topic of BSS and pregnancy. METHODS: PUBMED, EMBASE, COCHRANE, and Google Scholar databases were searched up to April 2022 without language and year restriction using the terms "Bernard Soulier" and "Pregnancy". The primary objectives were to evaluate maternal and fetal outcomes. The secondary objectives were to analyze pregnancy complications, gestational age at delivery, mode of delivery, administered prophylaxis, treatment approaches, duration of postpartum hospitalization, and the postpartum requirement of blood and blood product. RESULTS: The patient was a 19-year-old and 39-week pregnant woman who was diagnosed with BSS at the age of 10 by flow cytometry and genetic analysis. Single donor platelet transfusions and oral tranexamic acid were administered as prophylaxis at the peripartum period. She was delivered by cesarean section due to failure of labor. The postpartum period was uneventful for both mother and neonate. In the literature review, postpartum hemorrhage (PPH) was found in 52.9% (27/51) of deliveries. Late PPH occurred more frequently than early PPH (35.3 and 31.4%, respectively). 49% (25/51) of pregnancies had severe thrombocytopenia, and antepartum hemorrhage was observed in 11.8% (6/51) of those. The platelet count was in close relation to antenatal complications. 64.7% (33/51) of the patients were delivered via cesarean section. PPH and late PPH were found to be more common in those who delivered vaginally compared to those who delivered by caesarean section. It was observed that PPH was less common in women who were given prophylaxis in the peripartum period. CONCLUSION: BSS is an inherited macro-thrombocytopathy that may cause adverse maternal and neonatal outcomes. The optimal mode and timing of delivery remain unclear. A multidisciplinary approach with prophylaxis at the peripartum period should be applied.

Opening Pandora's box: abnormal genetic carrier screening and need for lifetime follow-up.

OBJECTIVE: Expanded carrier screening (ECS) is rising in popularity because of its application in a diverse population, its decreasing cost, and efficiency.1 However, it has traditionally been used to assess fetal risk. The next generation sequencing ECS panel offered at our academic medical center consists of 283 genes associated with hereditary disorders. Of those, 20 (7.1%) are autosomal recessive conditions, notable for variable expression of the clinical phenotype in heterozygous carriers, which may increase maternal risk for malignancy, bleeding, cardiovascular, or rheumatologic disease. Another 21 (7.4%) are X-linked conditions. We aimed to evaluate the prevalence of variants that have a potential for maternal phenotypic expression and whether identification of specific variants prompted patients to pursue further care in our health system, namely comprehensive genetic counseling and further healthcare consults when recommended. STUDY DESIGN: An institutional review board-approved descriptive retrospective cohort study was performed in a New York City academic medical center at which reproductive aged women were offered universal ECS from 2018 to 2021 by their provider, inclusive of obstetrician-gynecologists, maternal-fetal medicine physicians, and genetic counselors. Pretest counseling was performed by the ordering provider. Patients found to carry mutations with the potential for maternal phenotypic expression were contacted by genetic counselors regarding their clinical risks. In addition, patients who were carriers for factor XI deficiency, Bernard Soulier syndrome, ataxia telangectesia, fumarase deficiency, Nijmegen breakage syndrome, Duchenne muscular dystrophy, and familial hypercholesterolemia were advised to seek specialized healthcare pertaining to their clinical risk. The genetic counseling summary was placed in the electronic medical records (EMRs) so that the primary provider could view the findings. Through our EMRs, we evaluated the rates of healthcare uptake among these patients for at least 1 year after delivery. RESULTS: In total, 168 of 1184 (14.2%) patients were identified as carriers of mutations with a potential for maternal phenotypic expression. Of these, 156 (93%) were pregnant and 12 (7%) were preconception. Of those patients, 143 (85%) were carriers of autosomal recessive traits (Figure 1), whereas 22 of 168 (13%) patients were carriers of X-linked conditions (Figure 2) and 3 of 168 (2%) patients carried both autosomal recessive traits and X-linked conditions. Of these carriers, 132 of 168 (78.6%) patients underwent genetic counseling. The most common heterozygous mutations were sickle cell trait (25.6%), thalassemia (alpha and/or beta) trait (14.2%), factor XI deficiency (4.7%), dystrophic epidermolysis bullosa (4.2%), and Alport syndrome (4.1%). Two patients were diagnosed as homozygous carriers of nonclassical congenital adrenal hyperplasia. During the study period, 23 of 168 (13.6%) patients were heterozygous for specific pathogenic variants (inclusive of factor XI, Bernard Soulier syndrome, ataxia telangectesia, fumarase deficiency, Nijmegen breakage syndrome, Duchenne muscular dystrophy, and familial hypercholesterolemia) and were advised to seek specialized healthcare pertaining to these findings. Of these, 20 (87.0%) received genetic counseling with standardized recommendations, however, only 4 of 23 (17%) patients pursued the recommended referrals during our study period. CONCLUSION: This study described the follow-up rates among patients identified as carriers of conditions with the potential for maternal phenotypic expression using ECS. We observed that 14.2% of patients who underwent ECS were identified as carriers of genetic mutations with the potential for maternal phenotypic expression, and of the 23 who were recommended specific care because a pathogenic variant was identified, only 17.4% of patients followed the recommendations. We believe that as ECS implementation becomes widespread, more maternal carriers with clinical risk to themselves will be identified. Therefore, as we open this Pandora's box, the burden of counseling and follow-up must be addressed.

Biological, clinical features and modelling of heterozygous variants of glycoprotein Ib platelet subunit alpha (GP1BA) and glycoprotein Ib platelet subunit beta (GP1BB) genes responsible for constitutional thrombocytopenia.

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.

Bernard-Soulier syndrome in pregnancy with retinal detachment: a rare phenomenon.

Bernard-Soulier syndrome (BSS) is a rare congenital bleeding disorder of the platelet, and it is mainly inherited as an autosomal recessive trait. It is caused by both qualitative and quantitative deficiency of the platelet membrane glycoprotein (GP) Ib-IX-V receptor complex, thereby causing abnormal platelets adhesion.We report a case of a primigravida in her 20s with history of BSS diagnosed in childhood due to family history. Her preconception period was challenging as she suffered from severe menorrhagia often requiring hospital admission, blood and platelet transfusions.At 35 weeks gestation, she developed temporal crowded retinal detachment of the left eye and had a successful left scleral buckling surgery under general anaesthesia (GA).She had a multidisciplinary team care with a successful elective GA caesarean section at 39+3 weeks gestation with peridelivery platelet transfusion and intravenous recombinant factor VIIa. Regional anaesthesia, intramuscular injections and anticoagulation were avoided.

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.

Iron deficiency anemia and bleeding management in pediatric patients with Bernard-Soulier syndrome and Glanzmann Thrombasthenia: A single-institution analysis.

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.

Murine models of glycoprotein Ib-IX.

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.

Perforated hemorrhagic cholecystitis in a patient with Bernard-Soulier syndrome.

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.

Elevated CD9 expression as a potential biomarker for diagnosis of Bernard-Soulier syndrome.

Diagnosis of inherited platelet glycoprotein disorders is based on specific laboratory techniques such as aggregometry and flow cytometry. Flowcytometry is a powerful method, but equivocal results are produced in some cases. New cluster of differentiation markers could resolve the diagnostic dilemmas. Abnormal expression of CD9 in Bernard-Soulier syndrome (BSS) is recently reported. We aimed to determine the diagnostic significance of CD9 expression in a cohort of Iranian patients with inherited platelet glycoprotein defects. Twelve BSS, 21 Glanzmann thrombasthenia and 16 healthy controls were included in the present study. Flowcytometric diagnosis of BSS and Glanzmann thrombasthenia was made by analysis of CD41/61 and CD42a/42b CD markers. Moreover, phycoerythrin-labelled anti CD9 was examined in patients and healthy controls. The mean fluorescence intensity (MFI) of CD9 among the three groups was compared using suitable statistical methods and a P value of less than 0.05 considered statistically significant. Mean MFI of CD9 was 990.0 in BSS patients versus 421.2 and 317.3 in individuals with Glanzmann thrombasthenia and healthy controls, respectively (P < 0.05). Between the two-group comparison of means by the Mann-Whitney test revealed a P value of less than 0.001 for BSS group versus GT (2.4-fold) and BSS versus healthy controls (2.9-fold). CD9 molecule also expressed differently in patients with Glanzmann thrombasthenia in comparison with healthy controls (P < 0.001), although with a less magnitude (1.3-fold). According to our findings, CD9 is a potential biomarker for laboratory diagnosis of inherited glycoprotein defects, especially to elucidate the ambiguous results in BSS cases.

A GP1BA Variant in a Czech Family with Monoallelic Bernard-Soulier Syndrome.

Bernard-Soulier syndrome (BSS) is a rare inherited disorder characterized by unusually large platelets, low platelet count, and prolonged bleeding time. BSS is usually inherited in an autosomal recessive (AR) mode of inheritance due to a deficiency of the GPIb-IX-V complex also known as the von Willebrand factor (VWF) receptor. We investigated a family with macrothrombocytopenia, a mild bleeding tendency, slightly lowered platelet aggregation tests, and suspected autosomal dominant (AD) inheritance. We have detected a heterozygous GP1BA likely pathogenic variant, causing monoallelic BSS. A germline GP1BA gene variant (NM_000173:c.98G > A:p.C33Y), segregating with the macrothrombocytopenia, was detected by whole-exome sequencing. In silico analysis of the protein structure of the novel GPIbα variant revealed a potential structural defect, which could impact proper protein folding and subsequent binding to VWF. Flow cytometry, immunoblot, and electron microscopy demonstrated further differences between p.C33Y GP1BA carriers and healthy controls. Here, we provide a detailed insight into its clinical presentation and phenotype. Moreover, the here described case first presents an mBSS patient with two previous ischemic strokes.

Invasive procedures in the oral cavity of individuals with Bernard-Soulier syndrome: An integrative review.

AIM: Bernard-Soulier syndrome (BSS) is an inherited bleeding disorder characterized by macroplatelets and thrombocytopenia, prolonged bleeding time, and a prevalence of less than 1 in 1,000,000. In view of the recognition of the risk of bleeding and the management of daily surgical practice in these patients, adequate strategies are necessary to provide the safest care. This article aims to perform an integrative review of the literature on the management of invasive procedures in the oral cavity of individuals with BSS. METHOD: The PubMed/Medline and LILACS databases were searched using Boolean operators related to BSS, bleeding disorders, and oral care. RESULTS: As a result, only five articles with the main theme were included: one letter to the editor and four case reports, described chronologically as to date of publication, classification of the article, and medical/odontological measures taken. CONCLUSION: We conclude with this review the need for adequate knowledge of surgeons regarding coagulation disorders and the need to discuss and plan procedures with the hematology team, as well as the importance of the notion of management of possible complications resulting from invasive treatments in the oral cavity of patients with BSS.