Trombastenia de Glanzmann: conceptos clave de la enfermedad / Glanzmann thrombasthenia: key concepts of the disease

La trombastenia de Glanzmann (TG), es un trastorno autosómico recesivo en el cual hay una reducción grave o ausencia de la agregación plaquetaria. Se debe a las alteraciones cualitativas o cuantitativas de la integrina α IIb o de integrina β 3, codificados por los genes ITGA2B e ITGB3 y relacionadas con la glicoproteína IIb/IIIa, que intervienen en la activación plaquetaria. La mayor incidencia de TG ha sido reportada en la población judía-iraquí, pero también se ha presentado en Israel, Jordania, Arabia saudita, Italia y, en menor número, en familias gitanas y pakistaníes. A pesar de ser poco frecuente, este trastorno se debe sospechar en casos de trastornos hemorrágicos graves espontáneos o inducidos por traumatismos, que varían desde hemorragias gastrointestinales y mucocutáneas, como epistaxis y hemorragias gingivales recurrentes de difícil manejo, las cuales son potencialmente mortales y en más del 75 por ciento de los casos requieren transfusión sanguínea o plaquetaria. Para realizar la confirmación del diagnóstico, los hallazgos de laboratorio se caracterizan por tiempos de sangrado prolongados, retracción del coágulo disminuida y respuestas anormales de agregación plaquetaria a estímulos fisiológicos. Aunque, actualmente no existe una cura para la enfermedad, el tratamiento adecuado con transfusiones plaquetarias y en caso de refractariedad, el uso del factor VIIa, permiten un buen pronóstico para los pacientes. Aún queda mucho por estudiar en estos casos debido a esto se están realizando nuevos estudios para la posibilidad de otros tratamientos, entre ellos la terapia génica plaquetaria(AU)

Glanzmann's thrombasthenia (GT) is an autosomal recessive disorder in which there is a severe reduction or absence of platelet aggregation. It is due to the qualitative or quantitative alterations of integrin #945; IIb or integrin #946; 3, encoded by the ITGA2B and ITGB3 genes and related to glycoprotein IIb / IIIa, which intervene in platelet activation. The highest incidence of GT has been reported in the Jewish-Iraqi population, but it has also been reported in Israel, Jordan, Saudi Arabia, Italy, and in smaller numbers in Gypsy and Pakistani families. Despite being uncommon, this disorder should be suspected in cases of severe spontaneous or trauma-induced bleeding disorders, ranging from gastrointestinal and mucocutaneous hemorrhages such as epistaxis and recurrent, difficult to manage gingival hemorrhages, which are potentially fatal and more than 75 percent of cases require blood or platelet transfusion. To confirm the diagnosis, the laboratory findings are characterized by prolonged bleeding times, decreased clot retraction and abnormal platelet aggregation responses to physiological stimuli. Although there is currently no cure for the disease, adequate treatments with platelet transfusions and in case of refractoriness, the use of factor VIIa, allow a good prognosis for patients. There is still much to study in these cases, because of this, new studies are being conducted for the possibility of other treatments, including platelet gene therapy(AU)

Glanzmann Thrombasthenia in Children: Experience From a Tertiary Care Center in Southern India.

BACKGROUND: Glanzmann thrombasthenia (GT) is a globally rare inherited disorder of hemostasis. OBJECTIVES: To describe the clinical profile of GT in a tertiary care center in Southern India. METHODS: A retrospective chart review of all children with GT was performed between January 2005 and August 2017 in the Department of Paediatrics. RESULTS: A total of 48 patients (representing 43 families) were included. Median age at diagnosis was 2.75 years (interquartile range: 1.5 to 6.75). Two thirds had an onset of bleeding within the first 2 years of life. Sixty-seven percent were born out of consanguineous marriage. The common symptoms were epistaxis, gingival bleeding, and ecchymoses. Neonatal onset of bleeding manifested as purpura, epistaxis, and intracranial hemorrhage. Postsurgical bleeding and menorrhagia were unique presentations in adolescence. About 25% had life-threatening hemorrhage while 50% had growth retardation due to chronic anemia. CONCLUSIONS: GT is relatively more common in areas of Southern India due to the higher prevalence of consanguinity. Chronic anemia can contribute to growth stunting in these patients.

Clinical and molecular insights into Glanzmann's thrombasthenia in China.

Glanzmann's thrombasthenia (GT) is a rare bleeding disorder characterized by spontaneous mucocutaneous bleeding. The disorder is caused by quantitative or qualitative defects in integrin αIIbß3 (encoded by ITGA2B and ITGB3) on the platelet and is more common in consanguineous populations. However, the prevalence rate and clinical characteristics of GT in non-consanguineous populations have been unclear. We analyzed 97 patients from 93 families with GT in the Han population in China. This analysis showed lower consanguinity (18.3%) in Han patients than other ethnic populations in GT-prone countries. Compared with other ethnic populations, there was no significant difference in the distribution of GT types. Han females suffered more severe bleeding and had a poorer prognosis. We identified a total of 43 different ITGA2B and ITGB3 variants, including 25 previously unidentified, in 45 patients. These variants included 14 missense, 4 nonsense, 4 frameshift, and 3 splicing site variants. Patients with the same genotype generally manifested the same GT type but presented with different bleeding severities. This suggests that GT clinical phenotype does not solely depend on genotype. Our study provides an initial, yet important, clinical and molecular characterization of GT heterogeneity in China.

Glanzmann thrombasthenia and Bernard-Soulier syndrome in south Iran.

Glanzmann thrombasthenia (GT) and Bernard-Soulier syndrome (BSS) are two rare inherited disorders of platelet function. In this study, we report the demographic, clinical and biological characteristics of 23 patients with GT and of seven patients with BSS from southern Iran who had been followed for many years but fully characterized only recently, when platelet aggregation tests and flow cytometric studies became available for the first time in the country. We found a high prevalence of both diseases that can be explained by the high rate of consanguineous marriages in south Iran. Patients affected by GT and BSS suffer mainly from mucocutaneous bleedings causing anemia and transfusion requirements.

[Genetic profile of Glanzmann's thrombasthenia in south Tunisia. Report of 17 cases (11 families)]. / Analyse de la genealogie de malades atteints de thrombasthenie de Glanzmann du Sud Tunisien: a propos de 17 cas (11 familles).

INTRODUCTION: Glanzmann's thrombasthenia (GT) is a rare congenital thrombopathy, with a recessive autosomal transmission. We present here the genealogic study of a series of patients suffering from GT. PATIENTS AND METHODS: This is a retrospective study about all the GT patients treated in Sfax hematology department during 18 years. Final diagnosis was established by agregometry. Genealogic study was based on clinical history. RESULTS: 17 cases of GT from 11 families from the south of Tunisia wen collected. The disease was paricularly frequent in the region of Moulares-Gafsa (7 patients). The percentage of consanguinity was also very high (82%), with a third degree consanguinity of 86%. Family investigation revealed 6 previously unknown cases, and 10 deaths subsequent to hemorrhagic manifestations. CONCLUSION: The high rate of consanguinity, the absence of clinical or biological manifestations in the parents, and the ratio of ill to normal subjects in the same family which was about one to four, are suggestive of an autosomal recessive mode of transmission.

Presentation and pattern of symptoms in 382 patients with Glanzmann thrombasthenia in Iran.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive disease characterized by prolonged bleeding time with normal platelet count and morphology. It is caused by the quantitative or qualitative deficiency of the platelet glycoprotein IIb-IIIa. In 382 Iranian patients with GT diagnosed at a single center during the period 1969-2001, consanguinity between parents was 86.6%, in accord with the high frequency of intrafamilial marriages in Iran. Almost all patients had had abnormal mucocutaneous bleeding (epistaxis and gum bleeding); at follow-up, 4/5 of the patients had been transfused at least once to control hemorrhagic episodes. As expected, almost all the patients had a normal platelet count while the leukocyte count was increased in 19.3%. Among women, an unexpected low rate of pregnancies was observed.

[Glanzmann's thrombasthenia: a rare example of an integrin deficit]. / La tromboastenia di Glanzmann: un raro esempio di deficit di un'integrina.

Glanzmann's thrombasthenia is an autosomal recessive life-long bleeding disorder, originated from a quantitative or qualitative defect of the major platelet membrane receptor: the GPIIb/IIIa complex. The GPIIb/IIIa complex is a calcium-dependent heterodimer, belonging to the integrin superfamily. The complex of activated platelets can bind fibrinogen, von Willebrand factor, fibronectin and vitronectin, which are proteins playing an important role in platelet adhesion and aggregation. Thrombasthenic platelets are deficient in GPIIb, GPIIIa and GPIIb/IIIa complex; however, platelets from few thrombasthenic patients content near-normal amounts of functionally abnormal complex. The GPIIb/IIIa quantitative or functional defect leads to defective platelet hemostatic plug formation. Hemorrhagic symptoms consist of purpura, gingival hemorrhage, menorrhagia and epistaxis. Some cases of Glanzmann's thrombasthenia have been characterized at the molecular genetic level. Molecular abnormalities include: GPIIb or GPIIIa partial gene deletion, GPIIIa gene insertion, a point mutation resulting in an amino acid substitution within the GPIIIa molecule. In spite of the contemporary reduction of both GPIIb and GPIIIa in most cases of Glanzmann's thrombasthenia, it appears that a molecular abnormality affecting only one of the glycoprotein genes may result in a thrombasthenic phenotype.

Biochemical and molecular basis of Glanzmann's thrombasthenia.

Glanzmann's thrombasthenia is a rare autosomal recessive bleeding disorder characterized by a quantitative deficiency or a functional abnormality of the major platelet membrane integrin receptor: the glycoprotein (GP) IIb/IIIa complex. The GPIIb/IIIa complex functions as a platelet receptor for fibrinogen, von Willebrand factor, fibronectin and vitronectin; therefore it plays an important role in platelet adhesion and aggregation. Thrombasthenic platelets are severely deficient in GPIIb/IIIa content or function, and fail to aggregate and form the hemostatic plug at the site of vessel injury. On the other hand, heterozygous subjects (having about half the number of normal GPIIb/IIIa complexes) do not show bleeding problems. It has been demonstrated that a molecular defect affecting one of the two GP coding genes is sufficient to determine a contemporary deficit of both GPIIb and GPIIIa, and hence the thrombasthenic phenotype. Up to now, few molecular abnormalities giving rise to Glanzmann's thrombasthenia have been characterized. Large rearrangements within the GPIIb or GPIIIa coding genes appear to be unusual, whereas small modifications in the nucleotide sequence of the coding regions occur with higher frequency.