Glanzmann's Thrombasthenia Mutation of the Genes ITGA2B and ITGB3.

Abstract 2411

Poster Board II-389

Glanzmann Thrombasthenia (GT) is a rare autosomal recessive bleeding disorder characterized by a life-long mucocutaneous bleeding tenedency and absence or severely reduced platelet aggregation in response to ADP, epinephrine, and collagen, but relatively normal in response to ristocetin, where the glycoprotein (GP) IIb/IIIa a calcium dependent heterodimer complex is deficient or present but dysfunctional. GPIIb 172kbp is composed of 30 exons and GPIIIa 65Kbp is composed of 15 exons, have their own separate genes on the long arm of chomosome 17 (17q21-32), specific genetic abnormalities of each GP include missense, non sense, splite site mutation, deletions and point mutation. Mutation abrogates ligand binding to the activate integrin to the adhesive protein: fibrinogen, vWF, fibronectin, vitronectin, CD40L and the platelet are unable to mediate outside-inside signaling promoting actin plymerization and cytoskeletal reorganization such as clot retraction, talin and kindlin protein activation. We have studied four patients with mutation of the gene encoding platelet GPIIb (ITGAIIB) exon 17 mutation 1750 C (cystein)-T (threonin) phenotype non sense R584X,the proband showed a platelet with 3%-10% a fibrinogen binding and GPIIb/IIIa receptors; exon 23 mutation 2333 A (alanin)-C (cystein) phenotype missense Q778P, produced truncated protein, cystein residue is ipermethylated with a reduction of adhesion <8% cystein is postulated to be critical for post translational processing of GPIIb; and the gene encoding platelet GPIIIa (ITGB3) exon 11 mutation 1813 G (glycin)-A (alanin) phenotype missense H306P,ifluencing the Ca2+ dependent stabilty of the GPIIb/IIIa complex to divalent cation chelation; exon 3 mutation 355 C (cystein)- T (threonin) phenotype missense R119W escluding at codon 355 leader sequence, producing a frame-shift and protein termination and a stop codon with a great abnormalities of GPIIb/IIIa heterodimer inter subunit surface interaction, and intracellular trafficking. The patients have all severe bleeding included epistaxis, petechiae, gum bleeding, and a high grade of relapsing, refractory bleeding often requiring the transfusion with HLA compatible platelet concentrats and/or administration of recombinant FVIIa. This study confirmed that the genetic mutation can be significatly associated with the frequency and severity of bleeding and these approach may be the future of the management of GT.