Disease relevance of Thrombasthenia

• Platelets from patients with afibrinogenemia, Gray platelet syndrome, and the Cam Variant of thrombasthenia, a form of thrombasthenia with near normal levels of glycoprotein IIb/IIIa (GPIIb/IIIa), showed minimal augmentation of plasminogen binding to thrombin-stimulated platelets but normal binding to unstimulated platelets [1].
• Platelets from two unrelated patients with type I Glanzmann's thrombasthenia (deficiency in glycoprotein (GP) GPIIb/IIIa) did not aggregate at all with osteosarcoma cells [2].
• Previous studies of the immune response in polytransfused Glanzmann thrombasthenia (GT) patients and in autoimmune thrombocytopenic purpura (AITP) have relied on serum analysis and have shown the frequent development of Abs directed against the alpha(IIb)beta(3) integrin [3].
• This method makes it possible to quickly detect patients who require further study for possible platelet function disorders such as cyclooxygenase deficiency, storage-pool defect, thrombasthenia, and von Willebrand's disease [4].
• Moreover, we review evidence that dysregulated integrin signalling contributes to pathological processes including arthritis, thrombasthenia, leucocyte adhesion deficiencies, and tumour angiogenesis and invasion [5].

High impact information on Thrombasthenia

• The glycoprotein (GP) IIB-III complex, absent or deleted in the aggregation-defective Glanzmann's thrombasthenia, has been identified as the platelet fibrinogen receptor [6].
• Ab2 als binds to IgG specific for alpha IIb beta 3 obtained from one nonrelated Glanzmann thrombasthenia patient ES who has developed isoantibodies of similar specificity [7].
• A patient (OG) with Glanzmann thrombasthenia became refractory to platelet transfusion after the production of an immunoglobulin G (IgG) isoantibody (Ab1) specific for the integrin subunit beta 3 [7].
• Mutations in either the alpha or beta subunit of alphaIIbbeta3 usually lead to integrin nonexpression and a bleeding tendency termed Glanzmann thrombasthenia [8].
• In this study, we have characterized a Japanese variant of Glanzmann thrombasthenia, KO, whose platelets express normal amounts of alphaIIb beta3 [9].

Chemical compound and disease context of Thrombasthenia

• Platelets of a patient with type I Glanzmann's thrombasthenia bound [3H]2-methylthio-ADP and responded normally to ADP in the presence of PGE1 [10].
• (ii) Platelets lacking gpIIb-IIIa (from a subject with Glanzmann thrombasthenia) did not undergo this subset of tyrosine phosphorylation in response to thrombin, although other serine, threonine, and tyrosine phosphorylations proceeded normally [11].
• A similar inhibition of aggregation to 4N1-1 was obtained in the presence of Arg-Gly-Asp-Ser in mouse platelets deficient in FcR gamma chain or SLP-76 and in patients with type I Glanzmann thrombasthenia [12].
• A Leu117-->Trp mutation within the RGD-peptide cross-linking region of beta3 results in Glanzmann thrombasthenia by preventing alphaIIb beta3 export to the platelet surface [13].
• We then determined whether nonfunctional alpha IIb beta 3 on platelets with a beta 3 Arg-214-->Trp mutation (Strasbourg I variant of Glanzmann's thrombasthenia or GTV) could be induced to aggregate after treatment with dithiothreitol (DTT) [14].

Biological context of Thrombasthenia

• This is exemplified by the bleeding disorder, Glanzmann thrombasthenia (GT), where abnormalities of the platelet-specific integrin, alphaIIbbeta3, prevent platelet aggregation following vascular injury [15].
• Molecular basis for Glanzmann's thrombasthenia (GT) in a compound heterozygote with glycoprotein IIb gene: a proposal for the classification of GT based on the biosynthetic pathway of glycoprotein IIb-IIIa complex [16].
• An exon 28 mutation resulting in alternative splicing of the glycoprotein IIb transcript and Glanzmann's thrombasthenia [17].
• These studies suggest that there are at least two phenotypic patterns of membrane abnormalities in Glanzmann's thrombasthenia involving GPIIb and GPIII and may indicate genetic heterogeneity in this disease [18].
• Knowing the genomic structure of beta3 has permitted the uncovering of new mechanisms of mutagenesis causing Glanzmann thrombasthenia (Jin et al, J Clin Invest 98:1745, 1996), and our findings will be valuable for such genetic analyses as well as for studies on the transcriptional regulation of beta3 and other integrin genes [19].

Anatomical context of Thrombasthenia

• Such cultured monocytes (macrophages) from a patient with type I Glanzmann's thrombasthenia, however, failed to express the VnR [20].
• Quantitative glycoprotein (GP) analysis of whole platelets or platelet membranes was performed by SDS-polyacrylamide gel electrophoresis (SDS-PAGE) and periodic acid Schiff staining in the families of two unrelated Glanzmann's thrombasthenia (GT) patients [21].
• Our results confirm a deficiency of GP IIb-IIIa complexes in megakaryocytes in thrombasthenia [22].
• Mutations in the alphaIIb and beta3 genes that cause Glanzmann thrombasthenia can be distinguished by a simple procedure using transformed B-lymphocytes [23].
• We further analysed the sequences of the two glycoprotein transcripts in lymphoblastoid cell lines from two previously characterized patients presenting with Glanzmann thrombasthenia [24].

Gene context of Thrombasthenia

• Coprecipitation of CD36, CD9, and alpha6beta1 was also observed on platelets from a patient with Glanzmann thrombasthenia, indicating that alphaII(b)beta3 is not required for the other proteins to associate [25].
• Knowledge of the sequence and organization of the GPIIb and GPIIIa genes will help in understanding evolutionary relationships and functional homologies of this family of adhesion protein receptors and will facilitate analysis of molecular defects responsible for thrombasthenia [26].
• Platelets from the patients with Glanzmann's thrombasthenia could also attach to the subendothelium, whereas those from a patient whose platelets lacked GPIa failed to attach to the extracellular matrix (ECM) [27].
• Platelets from most patients with the autosomal recessive bleeding disorder, Glanzmann's thrombasthenia, are deficient in GPIIb and GPIIIa [28].
• SFLLRN induced solubilization of CD40L also from the platelets of a Glanzmann's thrombasthenia patient lacking GPIIb-IIIa, albeit at a lower rate than from normal platelets, and fibrinogen enhanced the solubilization from washed normal platelets [29].

Analytical, diagnostic and therapeutic context of Thrombasthenia

• In two Glanzmann's thrombasthenia families, the Taq I RFLP studied by both Southern blotting and PCR methods identified the defective GPIIIa gene inherited by patients, and determined the genotype of asymptomatic subjects [30].
• An internal pool of alpha v beta 3 was confirmed by flow cytometry and by using platelets from a patient with type I Glanzmann's thrombasthenia arising from a GP IIb gene defect [31].
• Immunoprecipitation with lysates of normal platelets and platelets from a patient with Glanzmann's thrombasthenia revealed that the monoclonal antibodies were directed against glycoprotein GP IIIa [32].
• This antibody (i) precipitated GPIIb-IIIa from platelet Triton X-100-lysate, (ii) recognized the GPIIIa band in Western blotting of platelet SDS-lysate, and (iii) did not react with platelets from a Glanzmann's thrombasthenia patient lacking GPIIb-IIIa [33].
• Immunofluorescence study showed that both whole IgG and F(ab')2 fragments of Apt4 bound to fresh or formalin fixed platelets from normal subjects and a patient with Bernard Soulier syndrome but not to those from two patients with Glanzmann's thrombasthenia [34].

References