Cases reported "Bernard-Soulier Syndrome"

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1/9. Compound heterozygosity (554-589 del, C515-T transition) in the platelet glycoprotein Ib alpha gene in a patient with a severe bleeding tendency.

    Giant platelets in the blood smear, absent in vitro platelet agglutination in response to ristocetin, and normal aggregation, ATP secretion and thromboxane b2 formation were found in a young patient with a life-long bleeding tendency. ristocetin-induced von willebrand factor binding to her platelets was less than 10% of normal. Flow cytometric analysis with monoclonal antibodies LJ-Ib-1, LJ-Ib-10, and LJ-P3 was consistent with the latter finding. SDS-PAGE analysis of solubilized platelets showed a marked reduction of the platelet glycoprotein (GP) Ibalpha. Genetic characterisation demonstrated that the patient and her father were heterozygous for a deletion of 36 nucleotides (positions 554-589) leading to a mutant GPIalpha (deletion of aminoacids from residue 169 to 180 and a Glu --> Lys substitution at residue 181). In addition, a C --> T transition at nucleotide 515 in the other allele of the GPIbalpha gene was found in the patient and in her mother that results in the substitution of alanine for valine in codon 156 (Bernard-Soulier type Bolzano). These variations occurred within the VI and VII leucine-rich repeats. The novel variant of bernard-soulier syndrome identified further suggests that the integrity of leucine-rich repeats is important for normal function of the GP Ib-IX-V receptor complex.
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2/9. bernard-soulier syndrome in a Turkish family.

    This report describes the first Turkish family to be diagnosed with bernard-soulier syndrome. The family consists of nine members (two parents, three sons and four daughters). The parents were first cousins. The index case, a 22 year-old-man, had a history of haemorrhagic diathesis with thrombocytopenia, giant platelets in the peripheral blood smear and a prolonged bleeding time. Refractory idiopathic thrombocytopenic purpura had been diagnosed elsewhere and a splenectomy had been performed six months previously. ristocetin agglutination of platelets was defective and flow cytometry analysis of platelet membrane glycoprotein showed markedly reduced expression of glycoprotein lb (2.1%). bernard-soulier syndrome was diagnosed. Increased mean platelet volume was found in both parents, one son and three daughters. The other son and daughter were normal.
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3/9. Altered glycosylation leads to Tr polyagglutination.

    BACKGROUND: Polyagglutination refers to red blood cells (RBCs) that are agglutinated by a high proportion of ABO-matched adult sera but not by cord sera. Polyagglutinable RBCs have been associated with microbial infection, myeloproliferative disorders, and myelodysplasia. lectins aid in the identification of polyagglutination. CASE STUDY: A Hispanic male infant with mild hemolytic anemia, a "Bernard-Soulier-like" syndrome, intermittent neutropenia, mitral valve regurgitation, ligament hyperlaxity, and mild mental retardation was studied. The patient's Group O RBCs were polyagglutinable; they were agglutinated by normal human sera, several lectins [including Arachis hypogea, salvia sclarea, salvia horminum, glycine max, ulex europaeus, griffonia simplicifolia I, and Gr. simplicifolia II], and some monoclonal antibodies. His RBCs were not agglutinated by cord sera, dolichos biflorus, or phaseolus lunatus. sodium dodecyl sulfate-polyacrylamide gel electrophoresis on the RBC membranes followed by staining with periodic acid-Schiff stain showed markedly reduced staining of glycophorins A and B. Staining with Coomassie brilliant blue revealed that Band 3 has a faster mobility than normal. CONCLUSIONS: Collectively, the results suggest that the patient's RBCs have a reduction in n-acetylneuraminic acid on both N- and O-glycans, exposing, respectively, beta1,4-galactosidase and beta1,3-galactosidase. The patient likely has an altered glycosyltransferase that results in defective glycosylation in RBCs and other cell lineages. This type of polyagglutination was named Tr.
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4/9. Use of recombinant factor viia in the management of severe bleeding episodes in patients with bernard-soulier syndrome.

    bernard-soulier syndrome (BSS) is a rare congenital platelet disorder characterized by defective platelet adhesion and manifested by spontaneous and often profuse bleeding. Recombinant factor viia (rFVIIa) is a haemostatic agent licensed for the treatment of bleeding episodes in patients with haemophilia and inhibitors, which may represent a low-risk alternative to existing therapies in the management of patients with BSS. Here, we describe the use of rFVIIa for the treatment of three severe bleeding episodes in two patients with BSS. Data were extracted by automated searching of the international, internet-based registry http://www.haemostasis.com . Patient 1, a 24-year-old woman, was admitted with severe epistaxis and hypotension. The diagnosis of BSS was confirmed by macrothrombocytopenia, absence of ristocetin-induced platelet agglutination (RIPA) and absence of glycoprotein (GP) Ibalpha and IX on the platelet surface. Epsilon aminocaproic acid (EACA; two 50-mg/kg doses), packed red blood cells (PRBCs, 2 U) and platelets (30 U) failed to control the bleeding and, after 13 h, three bolus doses of rFVIIa (90 microg/kg body weight) and a third dose of EACA were administered; bleeding stopped after the third dose of rFVIIa. Patient 2, a 15-year-old girl, initially presented with severe menorrhagia. A lack of RIPA and severe deficiency of GPIbalpha on the platelet surface confirmed the diagnosis of BSS. EACA and fresh-frozen plasma did not control the haemorrhage, but two bolus doses of rFVIIa (98 microg/kg body weight) resulted in a marked decrease in bleeding. On second admission, patient 2 had severe epistaxis and mild menorrhagia. Two rFVIIa doses (98 and 122.5 microg/kg body weight) were given, and the bleeding stopped. No adverse events were reported in these cases. These three admissions highlight the potential of rFVIIa for the treatment of severe bleeds in patients with BSS.
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5/9. Synthesis of GPIb beta with novel transmembrane and cytoplasmic sequences in a Bernard-Soulier patient resulting in GPIb-defective signaling in cho cells.

    The molecular defect of a new Bernard-Soulier patient, originating from morocco and presenting thrombocytopenia with large platelets and an absence of ristocetin-induced platelet agglutination, has been identified and reproduced in transfected heterologous cells. Gene sequencing revealed insertion of a guanine in the domain coding for the transmembrane region of the glycoprotein (GP) Ib beta subunit. This mutation causes a translational frame shift, which creates putative novel transmembrane and cytoplasmic 37 and 125 amino acids domains, respectively. A 34 kDa immunoreactive GPIb beta band, instead of the normal 26 kDa subunit, was detected by Western blotting in lysates from the patient's platelets and from transfected cells and in immunoprecipitates of metabolically labeled cells. The abnormal subunit did not associate with GPIb alpha and was mainly intracellular, although a significant fraction could reach the cell surface. Cells expressing the mutant GPIb-IX complex adhered to a von Willebrand factor matrix but were unable to change shape, unlike cells expressing the wild-type receptor. These results strongly suggest a novel role of the GPIb beta subunit and its transmembrane-intracellular region in GPIb-VWF-dependent signaling, in addition to a role in correct assembly and cell surface targeting of the GPIb-V-IX complex.
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6/9. A three-base deletion removing a leucine residue in a leucine-rich repeat of platelet glycoprotein Ib alpha associated with a variant of bernard-soulier syndrome (Nancy I).

    leucine-rich repeats are conserved structural motifs present in the four components of the human platelet glycoprotein Ib/IX/V complex receptor for the adhesive protein von willebrand factor. The absence or abnormality of this complex is responsible for Bernard-Soulier disease, an autosomal recessive bleeding disorder. We report a deletion of leucine 179, located in a highly conserved position of the seventh leucine-rich repeat of GPIb alpha, found in a variant form of Bernard-Soulier disease (Bernard-Soulier Nancy I). Three affected siblings of a family were characterized by absence of ristocetin-induced platelet agglutination, although ADP aggregation was normal. flow cytometry studies showed detectable amounts of all four members of the GPIb/IX/V complex on the surface of the patients' platelets. Western blotting revealed normal levels of GPIX, decreased levels of GPIb beta and GPV, and < 1% of GPIb alpha. RT-PCR studies showed the presence of mRNA coding for GPIb alpha, GPIb beta, GPIX and GPV. Sequencing showed a three-base deletion which results in the absence of a leucine residue, highly conserved across the seven leucine-rich repeats of GPIb alpha and also within the other members of the leucine-rich glycoprotein family. The absence of the leucine 179 in a patient's GPIb alpha is believed to cause a conformational change in the protein which would account for the lack of binding of most of the MoAbs tested and would be responsible for the absence of von willebrand factor binding. These results point to the leucine-rich region of GPIb alpha as being required for the correct exposure of the von Willebrand binding site as well as for the correct assembly and stability of the GPIb/IX/V complex on the platelet surface.
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7/9. bernard-soulier syndrome: a case report.

    An adopted Thai girl has been followed at Children's Hospital, Bangkok, since she was 8 months old. The diagnosis of bernard-soulier syndrome was made, based on the clinical features of easy bruising, purpura, petechial hemorrhages and recurrent epistaxis. The abnormal laboratory tests included giant platelets with dark stained granules, mild to moderate thrombocytopenia, prolonged bleeding time, absence of ristocetin induced agglutination but normal ristocetin cofactor, factor viii coagulant activity and von willebrand factor antigen. These findings suggested the absence of glycoprotein Ib (GPIb) on the platelet membrane. The genetic transmission can not be evaluated in this patient.
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8/9. Variant bernard-soulier syndrome associated with a homozygous mutation in the leucine-rich domain of glycoprotein IX.

    We describe a new variant of bernard-soulier syndrome. The patient (W.K.) showed the classic bleeding symptoms together with absence of platelet agglutination to restocetin plus von willebrand factor, whereas aggregation to ADP, collagen, and arachidonic acid was normal. Platelets were markedly larger than normal and the patient had life-long thrombocytopenia. Surface-labeling of the platelets and two-dimensional gel electrophoresis showed reduced but detectable amounts of glycoprotein (GP) Ib-IX-V present;however, there was markedly less GPIX (2% /- 1% of normal) than GPIb alpha, Ib beta, or V (7% /- 2% of normal). This disproportion was confirmed by Western blotting. sequence analysis was performed after polymerase chain reaction amplification of the coding region of the GPIX and GPI b alpha genes from the patient. A point mutation (A-->G) was found in GPIX converting 45Asn to Ser within the leucine-rich domain. No mutations were found in GPIb alpha. Both alleles of GPIX contained the same defect, which was confirmed by the appearance of a new cleavage site for the restriction enzyme Fnu4HI. This substitution did not affect glycosylation at the neighboring 44Asn as judged by the distribution on two-dimensional gels but did appear to change the conformation of the leucine-rich domain, thus reducing surface expression of the complex. The relationship between GPIb and GPV was not affected, indicating that GPIX does not regulate this. This homozygous mutation in GPIX indicates that, among other possible functions, the leucine-rich domains present on all components of GPIb-IX-V may play a role in the assembly and surface expression of the complex.
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9/9. Acquired pseudo-pseudo bernard-soulier syndrome complicating Gaucher's disease.

    AIMS--To investigate the abnormality in platelet function in two patients with type I Gaucher's disease causing a chronic bleeding tendency despite normalisation of the platelet count after spleen removal. methods--Routine laboratory methods were used to assess baseline coagulation. Platelet aggregometry was used to assess platelet responses to a range of agonists, and abnormalities were further assessed in mixing experiments using washed platelets and patients' plasma. RESULTS--Platelets from both patients with Gaucher's disease failed to agglutinate to ristocetin, despite normal platelet surface glycoprotein (GP) Ib and plasma von willebrand factor activity. The agglutination of normal washed platelets was abolished by incubation in patient plasma. The inhibitory activity did not lie in the IgG fraction of patient plasma, and was found to be loosely associated with the patient platelet surface. CONCLUSIONS--The inhibition of ristocetin induced platelet agglutination in patients with Gaucher's disease causes a prolonged skin bleeding time. This could be due to the accumulated glucocerebroside in the plasma coating the platelet membrane. It is suggested that the term pseudo-pseudo bernard-soulier syndrome would be appropriate, as on initial screening, the abnormality has the features of bernard-soulier syndrome, but further investigation shows normal plasma von Willebrand activity and platelet surface GP Ib concentrations. The inhibitory activity is not due to a platelet specific antibody as is the case in pseudo-Bernard Soulier syndrome.
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