1/34. Severe and relapsing upper gastrointestinal bleeding in a patient with Glanzmann's thrombasthenia.Glanzmann's thrombasthenia (GT) is a rare familial thrombocytic disease inherited as an autosomal recessive disorder that can induce hemorrhages due to a defect of platelet aggregation, resulting from the absence or reduced concentration of the membrane glycoproteic receptor binding the fibrinogen (integrin alpha(IIb)beta3). The gastrointestinal tract is the site of bleeding in only about 10% of cases but the related mortality is high (12.8%). Among the deaths due to hemorrhage, digestive bleeding causes 57.1%. According to reported data, the source of bleeding may be from preexisting gastroduodenal chronic and acute lesions. We report a case of severe and relapsing upper digestive bleeding in a woman with GT and coexisting thrombocytopenia (from HCV-related liver cirrhosis) and H. pylori-positive duodenal ulcer.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
2/34. Clinical spectrum of Glanzmann's thrombasthenia.Glanzmann's thrombasthenia is a well defined inherited disorder of platelet function characterized by qualitative and qualitative defect in cytoadhesive membrane protein, glycoprotein IIb-IIIa (the platelet fibrinogen receptor). From January 1990 to October, 1999, five patients who presented with mucocutaneous bleeding were detected to have Glanzmann's thrombasthenia. Clinical and laboratory spectrum of this rare disorder was studied which revealed heterogeneity of disease with respect to nature and severity of bleeding unpredictable by laboratory findings.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
3/34. A Ser752-->Pro substitution in the cytoplasmic domain of beta3 in a Glanzmann thrombasthenia variant fails to prevent interactions between the alphaIIbbeta3 integrin and the platelet granule pool of fibrinogen.A Glanzmann thrombasthenia variant with a beta3 Ser752-->Pro cytoplasmic domain substitution has platelets that fail to aggregate or bind soluble fibrinogen (Fg) after activation. Despite this, Fg is normally present in the alpha-granules. We have used immunoelectron microscopy to examine the reactivity of Fg with the different pools of alphaIIbbeta3 in the patient's platelets. Immunogold labelling was performed on cryosections using an anti-ligand-induced binding site (LIBS) monoclonal antibody (mAb), which binds to alphaIIbbeta3 only when Fg is bound, or a mixture of two anti-receptor-induced binding site (ribs) mAbs that specifically recognize receptor-bound Fg. Labelling of the alpha-granule membrane and channels of the surface-connected canalicular system in unstimulated platelets confirmed that the mutated alphaIIbbeta3 retains the capacity to transport Fg. When the patient's platelets were stimulated with ADP in the presence of Fg, as expected there was a much-decreased activation of surface-exposed alphaIIbbeta3. However, thrombin-induced activation was associated with both secretion and a rapid increase in the labelling of internal membrane systems by anti-ribs and anti-LIBS mAbs, with mobilization of the internal Fg pool. Yet labelling on the surface of the patient's platelets was transient. Our studies implied that alphaIIbbeta3 in platelets may bind fibrinogen in different activation states and that this patient specifically lacked high-affinity binding.- - - - - - - - - - ranking = 2keywords = membrane (Clic here for more details about this article) |
4/34. Successful surgery using recombinant factor viia for recurrent, idiopathic nonulcer duodenal bleeding in a patient with Glanzmann's thrombasthenia.A 68-year-old man with Glanzmann's thrombasthenia suffered from recurrent cryptogenic bleeding originating in the upper duodenal flexure. Extensive endoscopic procedures and medical treatments were unsuccessful and proximal duodenectomy was proposed. In preceding years platelet transfusions had often had a suboptimal result and were complicated by allergic reactions. Surgery was carried out while he was being treated with recombinant factor viia. Neither major blood loss nor other complications occurred. Histological examination of the bleeding site failed to show abnormalities and the nature of this patient's bleeding problem remained unexplained. Glanzmann's thrombasthenia is a rare autosomal recessive disorder of platelet aggregation characterized by a lifelong bleeding tendency due to abnormalities of the glycoprotein IIb-IIIa membrane complex. Common clinical manifestations include purpuric type bleeding, epistaxis, menorrhagia and gingival bleeding. Spontaneous bleeding is uncommon but posttraumatic and postoperative hemorrhage may be particularly serious. There is no specific treatment. Prophylactic and therapeutic platelet transfusions are the cornerstone of supportive treatment. In many patients the efficacy of this approach is diminished by allo-anti-platelet antibodies. We report on a patient with Glanzmann's disease with recurrent nonulcer duodenal bleeding refractory to conservative medical treatment. Despite documented suboptimal effectiveness of platelet transfusions, he underwent successful surgery with administration of recombinant factor viia (rFVIIa).- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
5/34. Analysis of the amino acid requirement for a normal alphaIIbbeta3 maturation at alphaIIbGlu324 commonly mutated in Glanzmann thrombasthenia.Glanzmann thrombasthenia is an inherited bleeding disorder arising from quantitative or qualitative defects of the alphaIIbbeta3 integrin of platelets. Here, we report that PCR-SSCP analysis and dna sequencing revealed a homozygous single base pair substitution in exon 12 of the IIb gene leading to a Glu(324) (E) to Lys (K) substitution in the alphaIIb subunit in a patient with Type I disease. As this mutation is found on at least 3 continents, the codon for Glu(324) may be a mutational hotspot of the disease. To better understand this mutation, we analyzed the effect of substituting E(324) with A(324), L(324), D(324), Q(324), N(324), S(324), as well as K(324), looking at both alphaIIbbeta3 maturation and cell surface expression in transiently transfected Cos-7 cells. The maturation state of the receptor clearly correlated with the level of cell membrane expression. Maturation efficiency was dependent on the electric charge as well as the size of the side chain of the amino acid present in what is a highly conserved N-terminal position in the third beta-strand of blade 5 of the alphaIIbeta beta-propeller.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
6/34. Ser-752-->Pro mutation in the cytoplasmic domain of integrin beta 3 subunit and defective activation of platelet integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) in a variant of Glanzmann thrombasthenia.integrins are membrane receptors which mediate cell-cell or cell-matrix adhesion. Integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) acts as a fibrinogen receptor of platelets and mediates platelet aggregation. platelet activation is required for alpha IIb beta 3 to shift from noncompetent to competent for binding soluble fibrinogen. The steps involved in this transition are poorly understood. We have studied a variant of Glanzmann thrombasthenia, a congenital bleeding disorder characterized by absence of platelet aggregation and fibrinogen binding. The patient's platelets did not bind fibrinogen after platelet activation by ADP or thrombin, though his platelets contained alpha IIb beta 3. However, isolated alpha IIb beta 3 was able to bind to an Arg-Gly-Asp-Ser affinity column, and binding of soluble fibrinogen to the patient's platelets could be triggered by modulators of alpha IIb beta 3 conformation such as the Arg-Gly-Asp-Ser peptide and alpha-chymotrypsin. These data suggested that a functional Arg-Gly-Asp binding site was present within alpha IIb beta 3 and that the patient's defect was not secondary to a blockade of alpha IIb beta 3 in a noncompetent conformational state. This was evocative of a defect in the coupling between platelet activation and alpha IIb beta 3 up-regulation. We therefore sequenced the cytoplasmic domain of beta 3, following polymerase chain reaction (PCR) on platelet rna, and found a T-->C mutation at nucleotide 2259, corresponding to a Ser-752-->Pro substitution. This mutation is likely to be responsible for the uncoupling of alpha IIb beta 3 from cellular activation because (i) it is not a polymorphism, (ii) it is the only mutation in the entire alpha IIb beta 3 sequence, and (iii) genetic analysis of the family showed that absence of the Pro-752 beta 3 allele was associated with the normal phenotype. Our data thus identify the C-terminal portion of the cytoplasmic domain of beta 3 as an intrinsic element in the coupling between alpha IIb beta 3 and platelet activation.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
7/34. Insertion of a C in the exon 28 of integrin alphaIIb gene leading to a frameshift mutation is responsible for Glanzmann thrombasthenia in a Japanese case.BACKGROUND: Glanzmann thrombasthenia (GT) is a hereditary bleeding disorder caused by a qualitative or quantitative defect in the integrin alphaIIbbeta3. OBJECTIVE: Our objective is to identify the gene mutation that resulted in GT. patients AND methods: The patient was a 66-year-old male with a history of frequent bleeding. The expression levels of the integrin proteins in the platelets were determined by flow cytometry and Western blot analysis. The sequences of genomic dna and mRNA encoding for alphaIIb and beta3 were analyzed by the dye-terminator cycle sequencing method. For transfection experiments, expression vectors encoding for wild-type alphaIIb, mutated alphaIIb, beta3, green fluorescent protein (GFP) fusion wild-type alphaIIb, GFP fusion mutated alphaIIb and DsRed fusion beta3 were constructed. These vectors were transfected to COS-7 cells, and the expression levels were determined. RESULTS: The alphaIIb protein was remarkably reduced in the patient's platelets, and gene analysis showed that the patient possessed compound heterozygous mutations in the alphaIIb gene. One was a C --> G substitution at the splice acceptor site (- 3) of exon 26 (CAG -->GAG) and the other was the insertion of an additional C at the region including six C bases between 2911 and 2916 in exon 28 (InsC). transfection experiments using COS-7 cells showed that alphaIIb containing InsC had expressed and formed a complex with beta3, but had not been transported to the golgi apparatus. CONCLUSIONS: In the present study the novel mutation InsC, leading to a frameshift that affects the transmembrane domain and the cytoplasmic tail, was found to be responsible for GT.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
8/34. Fetal-neonatal alloimmune thrombocytopenia and unexpected Glanzmann thrombasthenia carrier: report of two cases.BACKGROUND: Discrepancy between phenotyping and genotyping during the investigation of maternofetal alloimmunization leads to the identification of defects on genes encoding membrane glycoproteins (GPs) IIb and IIIa. STUDY DESIGN AND methods: Human platelet (PLT) alloantigen (HPA)-1 and -3 PLT phenotypes and genotypes were performed by use of, respectively, the monoclonal antibody-specific immobilization of PLT antigens and the polymerase chain reaction (PCR)-sequence-specific priming techniques for up to 2400 families with thrombocytopenic newborn. When a discrepancy was detected, genomic dna from the mother was amplified for coding sequences of either the GPIIb or GPIIIa genes. The genetic abnormality responsible for the discrepancy was determined by direct sequencing of the PCR products. RESULTS: Two cases of discrepancy were identified among 2400 families tested. In the first case, Mother L, serologically assigned as HPA-1b-homozygous, was genotyped HPA-1a/1b. In the second case, Mother S, serogically defined HPA-3b-homozygous, was genotyped HPA-3a/3b. dna sequence analysis revealed for Mother L a T(1447)-->C a point mutation within exon 10 of the GPIIIa gene and for Mother S a C(480)-->G point mutation within exon 4 of the GPIIb gene. These mutations reported in Glanzmann thrombasthenia (GT) patients account for nonexpression of the implicated allele on the PLT surface. Thus, the mothers are GT carriers. Alloantibodies, hallmarks of immunization, were not detected in the maternal serum samples. CONCLUSION: Although this situation is rarely encountered, it is important to combine phenotyping and genotyping to avoid false PLT typing assignation and erroneous diagnosis when alloimmunization might occur.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
9/34. coronary artery bypass grafting in a patient with Glanzmann's thrombasthenia.Glanzmann's thrombasthenia is a platelet aggregation disorder resulting from a functional loss of platelet membrane glycoprotein iib-IIIa. First described by Dr. Glanzmann in 1918, the disorder is characterized clinically by mucocutaneous bleeding and physiologically by absent platelet aggregation to collagen, epinephrine, and adenosine diphosphate stimulation. While there are multiple reports of patients with Glanzmann's thrombasthenia undergoing surgery, to our knowledge there has been no report of a patient with Glanzmann's undergoing coronary artery bypass grafting. We present the first such report of a patient who successfully underwent operative coronary artery revascularization, and offer suggestions for future management of these patients.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
10/34. Perioperative management of a heterozygous carrier of Glanzmann's thrombasthenia submitted to coronary artery bypass grafting with cardiopulmonary bypass.Glanzmann's thrombasthenia is a congenital hemorrhagic disorder transmitted as an autosomal recessive trait and characterized by altered production and/or assembly of the platelet membrane glycoprotein iib/IIIa receptor. We describe the perioperative management of a heterozygous carrier of Glanzmann's thrombasthenia submitted to cardiac surgery with cardiopulmonary bypass and the case was complicated by early excessive postoperative bleeding.- - - - - - - - - - ranking = 1keywords = membrane (Clic here for more details about this article) |
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