Glanzmann thrombasthenia: a review of ITGA2B and ITGB3 defects with emphasis on variants, phenotypic variability, and mouse models

Abstract

Characterized by mucocutaneous bleeding arising from a lack of platelet aggregation to physiologic stimuli, Glanzmann thrombasthenia (GT) is the archetypeinherited disorder of platelets. Transmitted by autosomal recessive inheritance, platelets in GT have quantitative or qualitative deficiencies of the fibrinogen receptor, ␣IIb␤3, an integrin coded by the ITGA2B and ITGB3 genes. Despite advances in our understanding of the disease, extensive phenotypic variability with respect to severity and intensity of bleeding remains poorly understood. Importantly, genetic defects of ITGB3 also potentially affect other tissues, for ␤3 has a wide tissue distribution when present as ␣v␤3 (the vitronectin receptor). We now look at the repertoire of ITGA2B and ITGB3 gene defects, reexamine the relationship between phenotype and genotype, and review integrin structure in the many variant forms. Evidence for modifications in platelet production is assessed, as is the multifactorial etiology of the clinical expression of the disease. Reports of cardiovascular disease and deep vein thrombosis, cancer, brain disease, bone disorders, and pregnancy defects in GT are discussed in the context of the results obtained for mouse models where nonhemostatic defects of ␤3-deficiency or nonfunction are being increasingly described. (Blood. 2011;118(23):5996-6005) IntroductionGlanzmann thrombasthenia (GT) is the most frequently encountered inherited disorder of platelet function. [1][2][3] Patients have a lifelong hemorrhagic syndrome typically characterized by episodes of spontaneous mucocutaneous bleeding. Platelets fail to aggregate in response to stimuli because they lack or have nonfunctional ␣IIb␤3 integrin (formerly known as GPIIb-IIIa). Resting normal platelets are suspected to have ␣IIb␤3 in a bent conformation; when platelets are stimulated, the integrin straightens in parallel to the exposure of determinants essential for the binding of fibrinogen (Fg) or other soluble adhesive proteins. 3,4 The latter assure aggregation by cross-linking adjacent platelets, a process that cannot occur in GT. Elucidation of this pathway led to the development of integrin-blocking drugs that are strong inhibitors of arterial thrombosis, thereby increasing interest in the clinical manifestations of GT. 3,4 Platelet ␣IIb␤3 also transmits the forces generated by intracellular cytoskeletal proteins during clot contraction and platelet spreading, processes that also fail in patients lacking adequate amounts of functional integrin.Although the GT phenotype is well defined, bleeding severity differs considerably between affected persons, even within the same family or ethnic group. 1,2 In this review, we discuss phenotypic variability, present variant types, and identify possible additional effects associated with ␤3 deletion, for although ␣IIb is largely restricted to the megakaryocyte (MK) lineage, ␤3 is much more widespread in its tissue distribution occurring as ␣v␤3, the vitronectin receptor. 5,6 Data for patients will be compared with those obtained for...

Cytoskeletal perturbation leads to platelet dysfunction and thrombocytopenia in variant forms of Glanzmann thrombasthenia

“…7,8 Mutations of ITGA2B and ITGB3, the genes coding for integrins α IIb and β 3 , generate Glanzmann thrombasthenia (GT), an autosomal recessive bleeding disorder characterized by absent platelet aggregation and a normal platelet count and volume, due to quantitative or qualitative defects of α IIb β 3 . Heterozygous carriers of GT are usually asymptomatic because 50% of normal α IIb β 3 is sufficient for platelet aggregation, 9 but rare autosomal dominant variants of GT, with platelet dysfunction and macrothrombocytopenia, have been associated with gain-of-function mutations of ITGA2B or ITGB3 leading to reduced expression and constitutive activation of α IIb β 3 .…”

Clinical utility gene card for: Glanzmann thrombasthenia

“…14 Kindlin-3 belongs to a family of proteins that cooperate in integrin activation. 3 Platelet aggregation defects restricted to specific agonists may imply abnormalities of a signaling pathway and should be distinguished from GT, where aggregation is defective for all physiological agonists in the presence of a normal platelet number and size. GPIb-related function as assessed by ristocetin-induced platelet agglutination is normal, although it can be cyclic.…”

“…In rare patients, gain-of-function mutations in either ITGA2B or ITGB3 can also interfere with megakaryocytopoiesis and lead to platelet anisocytosis and moderate thrombocytopenia. 3 …”

Thrombocytopathy

“…Тромбастения Гланцмана -наследственное заболе-вание, характеризующееся геморрагическими прояв-лениями, при которых отмечается удлинение времени кровотечения, а также полное отсутствие или резкое снижение интенсивности ретракции кровяного сгустка на фоне нормального содержания тромбоцитов в еди-нице объема крови [5,6]. Это является результатом снижения агрегационной способности тромбоцитов.…”