Bernard Soulier syndrome: a rare, frequently misdiagnosed and poorly managed bleeding disorder

2021 ◽  
Vol 14 (8) ◽  
pp. e243518
Author(s):  
Manuel Monteiro ◽  
Luis Almeida ◽  
Mariana Morais ◽  
Luis Dias
Keyword(s):  
Correct Diagnosis ◽  
Autosomal Recessive Inheritance ◽  
Bleeding Disorder ◽  
Von Willebrand Disease ◽  
Homozygous Mutation ◽  
Severe Thrombocytopenia ◽  
Diagnostic Challenge ◽  
Genetic Sequencing ◽  
Von Willebrand ◽  
Bernard Soulier Syndrome

Bernard Soulier syndrome is a rare, congenital platelet bleeding disorder, with autosomal recessive inheritance. It is characterised by macrothrombocytopenia and platelet dysfunction, leading to mucocutaneous bleeding noted in early childhood. This entity poses an important diagnostic challenge, and blood smear and DNA sequencing are paramount for the correct diagnosis. Differential diagnosis includes May-Hegglin anomaly, Glanzmann Thrombasthenia and von Willebrand disease; it is also often misdiagnosed as idiopathic thrombocytopenic purpura. We report a 68-year-old man diagnosed with von Willebrand disease for three decades, admitted with gastrointestinal bleeding, anaemia and severe thrombocytopenia. Replacement with von Willebrand factor did not stop the haemorrhage, suggesting another aetiology for the bleeding disorder. Corticosteroids and intravenous immune globulin were also ineffective. Genetic sequencing showed a homozygous mutation in GP1BA gene, thus establishing the correct diagnosis.

Von Willebrand Disease

2018 ◽  
Author(s):  
Laura A. Downey ◽  
Nina A. Guzzetta
Keyword(s):  
Von Willebrand Factor ◽  
Treatment Plan ◽  
Correct Diagnosis ◽  
Postoperative Bleeding ◽  
Bleeding Disorder ◽  
Von Willebrand Disease ◽  
Normal Hemostasis ◽  
Von Willebrand ◽  
Willebrand Factor

Von Willebrand disease (vWD) is the most common bleeding disorder in humans. It is the result of an abnormality in the amount, structure, or function of von Willebrand factor (vWF), a glycoprotein important in maintaining normal hemostasis.. In children with vWD, the most frequent presentation is easy bruising and epistaxis. Other symptoms include hematomas, menorrhagia, and bleeding from minor wounds. Although intraarticular bleeding may occur, especially in certain subtypes, it is much more commonly seen with hemophilia. There are several subtypes of vWD based on the underlying defect in vWF, but, in general, they may be categorized as quantitative (types 1 and 3) or qualitative (all types 2). If vWD is suspected, consultation with a hematologist to establish the correct diagnosis and perioperative approach to hemostasis is essential. Avoidance of medications that interfere with coagulation, anticipation of intraoperative and postoperative bleeding, and an appropriate hemostatic treatment plan should be addressed.

scholarly journals Bernard Soulier Syndrome; A Rare Bleeding Disorder

2018 ◽  
Vol 7 (1) ◽  
pp. 1642 ◽  
Author(s):  
Preeti Tripathi ◽  
Karthika K. V. ◽  
H. P. Pati ◽  
Seema Tyagi
Keyword(s):  
Correct Diagnosis ◽  
Specific Treatment ◽  
Bleeding Disorder ◽  
Bleeding Disorders ◽  
Diagnostic Challenge ◽  
Platelet Aggregometry ◽  
Common Causes ◽  
Life Threatening ◽  
Low Platelet Count ◽  
Bernard Soulier Syndrome

Bleeding syndromes in the newborn are rare, but they may be life-threatening and demand immediate attention. Congenital bleeding disorders especially pose a diagnostic challenge to the clinician because of their rarity and the need to be differentiated from the other common causes of bleeding in children. We present a case of an infant presenting with bleeding symptoms early in his life (since 5 months of age) which was initially thought to be immune thrombocytopenic purpura (ITP) with low platelet count. No response to steroids and further evaluation by platelet aggregometry and flowcytometry led to the correct diagnosis – Bernard soulier syndrome(BSS). Though, there is no specific treatment available for this rare bleeding disorder, however it is imperative to have arrived at correct diagnosis in order to save unnecessary therapy and to take due precautions for prevention of bleeding.

A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

1996 ◽  
Vol 76 (02) ◽  
pp. 253-257 ◽  
Author(s):  
Takeshi Hagiwara ◽  
Hiroshi Inaba ◽  
Shinichi Yoshida ◽  
Keiko Nagaizumi ◽  
Morio Arai ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Point Mutations ◽  
Japanese Patients ◽  
Von Willebrand Disease ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Reaction Products ◽  
Type 3 ◽  
Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

Mutation-specific hemostatic variability in mice expressing common type 2B von Willebrand disease substitutions

Blood ◽  
2010 ◽  
Vol 115 (23) ◽  
pp. 4862-4869 ◽  
Author(s):  
Mia Golder ◽  
Cynthia M. Pruss ◽  
Carol Hegadorn ◽  
Jeffrey Mewburn ◽  
Kimberly Laverty ◽  
...  
Keyword(s):  
Ferric Chloride ◽  
Von Willebrand Disease ◽  
Expression Vectors ◽  
Severe Thrombocytopenia ◽  
Normal Platelet ◽  
Injury Model ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Type 2B von Willebrand disease (2B VWD) results from von Willebrand factor (VWF) A1 mutations that enhance VWF-GPIbα binding. These “gain of function” mutations lead to an increased affinity of the mutant VWF for platelets and the binding of mutant high-molecular-weight VWF multimers to platelets in vivo, resulting in an increase in clearance of both platelets and VWF. Three common 2B VWD mutations (R1306W, V1316M, and R1341Q) were independently introduced into the mouse Vwf cDNA sequence and the expression vectors delivered to 8- to 10-week-old C57Bl6 VWF−/− mice, using hydrodynamic injection. The resultant phenotype was examined, and a ferric chloride–induced injury model was used to examine the thrombogenic effect of the 2B VWD variants in mice. Reconstitution of only the plasma component of VWF resulted in the generation of the 2B VWD phenotype in mice. Variable thrombocytopenia was observed in mice expressing 2B VWF, mimicking the severity seen in 2B VWD patients: mice expressing the V1316M mutation showed the most severe thrombocytopenia. Ferric chloride–induced injury to cremaster arterioles showed a marked reduction in thrombus development and platelet adhesion in the presence of circulating 2B VWF. These defects were only partially rescued by normal platelet transfusions, thus emphasizing the key role of the abnormal plasma VWF environment in 2B VWD.

Coagulopathies

2020 ◽  
Author(s):  
Michael Levine
Keyword(s):  
Key Words ◽  
Bleeding Disorder ◽  
Von Willebrand Disease ◽  
Coagulation Cascade ◽  
Bleeding Disorders ◽  
Platelet Disorders ◽  
Von Willebrand

Coagulopathy can be caused by numerous hereditary or acquired etiologies. Although some of these conditions are known and the patient is aware of the bleeding disorder, other bleeding disorders are diagnosed only after the onset of excessive hemorrhage. This review discusses both hereditary and acquired disorders of coagulopathy. Platelet disorders are discussed elsewhere. This review contains 2 figures, 7 tables, and 72 references. Key words: Coagulopathies; Coagulopathy; Bleeding disorder; Hereditary bleeding disorder; Acquired bleeding disorder; von Willebrand disease; Hemophilia; Coagulation cascade; Hemorrhage; Anticoagulant-associated hemorrhage

Identification of Type 2 von Willebrand Disease in Previously Diagnosed Type 1 Patients: a Reappraisal Using Phenotypes, Genotypes and Molecular Modelling

2000 ◽  
Vol 84 (12) ◽  
pp. 998-1004 ◽  
Author(s):  
Ioana Nitu-Whalley ◽  
Anne Riddell ◽  
K. Pasi ◽  
Dale Owens ◽  
M. Enayat ◽  
...  
Keyword(s):  
Molecular Modelling ◽  
Correct Diagnosis ◽  
Von Willebrand Disease ◽  
Single Amino Acid ◽  
Elisa Assay ◽  
Modelling Analysis ◽  
A1 Domain ◽  
Von Willebrand

SummaryIn order to investigate the possibility that qualitative type 2 defects in von Willebrand factor (VWF) occurred in patients previously diagnosed with quantitative type 1 von Willebrand disease (VWD), the phenotypes and genotypes were reanalysed in 30 patients who exhibited discrepant VWF activity/VWF:Ag ratios of less than 0.7. The capacity of VWF to bind to glycoprotein Ib (GpIb) was reassessed using the ristocetin co-factor activity (VWF:RiCo) assay compared to an in-house and a commercial ELISA assay (based on a mAb directed against the GpIb binding site on VWF). This was supplemented by multimeric analysis and the amplification and sequencing of a 936 bp fragment of exon 28 of the VWF gene with the aim of identifying mutations in the A1 domain. On reappraisal, using the VWF:RiCo assay all patients demonstrated a disproportionately reduced VWF:RiCo/VWF:Ag ratio, indicative of a qualitative defect, while abnormal ratios were detected in only seven kindreds using the in-house ELISA assay and in only one kindred with the commercial ELISA assay. Eight single amino acid substitutions were found in nine kindreds, four of which were novel candidate VWF mutations and four previously described in association with type 2 VWD. In agreement with the phenotype, the novel VWF mutations were located in the VWF-A1 crystal structure at positions that corresponded to potential type 2M defects. This study underlines the difficulties of correct diagnosis of the subtype of VWD and emphasises the importance of using sensitive phenotypic assays, the relevance of the VWF:RiCo/ VWF:Ag ratio, multimeric analysis and molecular modelling analysis.

scholarly journals Rare Occurrence of Inhibitors in Von Willebrand Disease: A Case Report

2022 ◽  
Vol 8 ◽  
Author(s):  
Bipin P. Kulkarni ◽  
Kirti Ghargi ◽  
Chandrakala Shanmukhaiah ◽  
Shrimati D. Shetty
Keyword(s):  
Correct Diagnosis ◽  
Severe Form ◽  
Von Willebrand Disease ◽  
Rare Occurrence ◽  
Standard Assay ◽  
Type 3 ◽  
Von Willebrand ◽  
High Degree ◽  
Willebrand Factor ◽  
Inhibitor Titer

Introduction: Type 3 Von Willebrand Disease (VWD) is the least common but the most severe form of a disease, with a prevalence of about 0. 5 to 1 per million in Western countries. The prevalence of type 3 VWD in the developing countries, with a high degree of consanguinity, is about 6 per million. Moreover, due to underdiagnosis of the milder cases, the prevalence of type 3 VWD is about 50% of the cases. Rarely, some patients develop the Von Willebrand Factor (VWF) inhibitors, which may subsequently develop severe anaphylactic reactions on further exposure to the VWF containing factor replacement therapy. The prevalence of inhibitor development in patients with type 3 VWD has been shown to be in the range of 5.8 to 9.5%. In the absence of a gold standard assay for the quantitation of VWF inhibitors, a correct diagnosis and management of these patients are often challenging.Objectives: The objective of this study is to standardize the Bethesda assay for the VWF inhibitors and to estimate the VWD inhibitor titer in two cases of congenital type 3 VWD, which developed the VWF inhibitors.Results and Conclusions: We could successfully standardize the Bethesda assay for the quantitation of VWF inhibitors in two patients with congenital type 3 VWD with inhibitors.

scholarly journals THE ROLE OF BLEEDING HISTORY AND CLINICAL MARKERS FOR THE CORRECT DIAGNOSIS OF VWD

2013 ◽  
Vol 5 (1) ◽  
pp. e2013051 ◽  
Author(s):  
Alberto Tosetto
Keyword(s):  
Correct Diagnosis ◽  
Von Willebrand Disease ◽  
Assessment Tools ◽  
Bleeding Tendency ◽  
Clinical Markers ◽  
Web Based ◽  
Bleeding Score ◽  
Bleeding History ◽  
Von Willebrand ◽  
Willebrand Factor

Quantification of the bleeding severity by use of bleeding assessment tools (BAT) and bleeding score (BS) has been consistently shown to improve the clinical diagnosis of von Willebrand disease (VWD) while helping researchers establish phenotype/genotype correlations.  Subjects with a BS equal or higher than 3 may be consider having a bleeding tendency, and should be referred for a laboratory investigation, particularly for VWD. In the diagnosis of type 1 VWD, the use of the BS has been shown to be highly specific (>95%) with reported sensitivities ranging from 40 to 100%. The BS is related to all available measurements of von Willebrand factor activity, including the PFA-100 closure time. Therefore, in clinical practice the use of BAT should always be the first step to standardize the assessment of patients with suspected VWD. The use of the recent ISTH consensus BAT is suggested to harmonize the collection of bleeding symptoms in patients with a suspected or confirmed hemostatic disorder, particularly VWD. The ISTH BAT is also coupled with a Web-based repository of bleeding symptoms, therefore providing an integrated framework for collaboration in the field of clinical evaluation of VWD and mild bleeding disorders.

Heavy Menstrual Bleeding in the Adolescent

2019 ◽  
Author(s):  
Kimberly Huhmann ◽  
Andrea Zuckerman
Keyword(s):  
Differential Diagnosis ◽  
Aminocaproic Acid ◽  
Bleeding Disorder ◽  
Von Willebrand Disease ◽  
Heavy Menstrual Bleeding ◽  
Menstrual Bleeding ◽  
Oral Contraceptive Pills ◽  
Sexually Transmitted ◽  
Contraceptive Pills ◽  
Von Willebrand

Heavy menstrual bleeding is a common presenting problem in the adolescent population. The average age of menarche is between 12 and 13 years. The most common reason for heavy menstrual bleeding soon after menarche is from an immature hypothalamic ovarian access, which spontaneously resolves once cycles become ovulatory. However, the broad differential diagnosis for heavy menses in adolescents includes coagulopathy, thyroid disease, sexually transmitted infections, specifically chlamydia, and chronic medical conditions. Von Willebrand disease is the most common bleeding disorder that can present with heavy menstrual bleeding at menarche or shortly after. A thorough history and physical exam with occasional labs needs to be completed and can assist in narrowing the differential diagnosis. Treatment of heavy menstrual bleeding consists of hormonal and nonhormonal options: combination oral contraceptive pills, patches, or rings taken continuously or cyclically; progesterone-only pills; progesterone implants; progesterone intrauterine devices; cyclic tranexamic acid; cyclic aminocaproic acid; and GnRH agonists with add-back therapy. This review contains 3 tables, and 28 references. Key Words: adolescent menses, anovulation, bleeding disorder, heavy menstrual bleeding, immature hypothalamic ovarian axis, menarche, treatment of heavy menses, Von Willebrand disease

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