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...

Background-Isolated atrial fibrillation (AF) is associated with mild enlargement of the left atrium (LA) and left ventricular (LV) diastolic dysfunction. The impact of ablation of isolated AF on left chamber size and function is unclear, and whether diastolic dysfunction is the cause or the consequence of AF remains unknown. The objective of this prospective study was to evaluate the impact of sinus rhythm restoration by catheter ablation on LV diastolic dysfunction, LA morphology, and mechanical function. Methods and Results-Forty-eight patients with isolated AF were studied by serial echocardiographic studies at baseline and at 1-, 3-, 6-, 9-, and 12-month intervals after radiofrequency ablation. LA dimensions and mechanical function and LV systolic and diastolic functions were evaluated at each time interval. Diastolic function was assessed with conventional Doppler parameters and new indexes such as tissue Doppler imaging, mitral flow propagation velocity, and combined criteria. LV diastolic dysfunction was present in paroxysmal and chronic AF patients with a reduction of tissue Doppler imaging lateral early diastolic peak velocity in 37% (PϽ0.001) and 48% (PϽ0.01), respectively, compared with healthy control subjects. At the end of the follow-up, LA area decreased significantly by 18% (PϽ0.001) in paroxysmal and 23% (PϽ0.05) in chronic AF patients. Diastolic function improved significantly with an increase in lateral early diastolic peak velocity of 29% (PϽ0.001) in paroxysmal AF and 46% (PϽ0.05) in chronic AF patients. A significant increase in LV ejection fraction was also noted for both groups: 7.7% and 18.8%, respectively. Conclusions-This study demonstrates reverse morphological remodeling of the LA and improvement of LV diastolic and systolic functions after restoration of sinus rhythm by ablation for isolated AF. Because patients with isolated AF have none of the traditional causes of LV diastolic dysfunction, our findings suggest that AF may be partly the cause rather than the consequence of diastolic dysfunction.

First case of a human RASGRP2 mutation affecting Rap1 activation in platelets and causing severe bleeding.