BDPLT2
BLEEDING DISORDER, PLATELET-TYPE, 2
THROMBASTHENIA OF GLANZMANN AND NAEGELI
PLATELET FIBRINOGEN RECEPTOR, DEFICIENCY OF
GT
GP IIb-IIIa COMPLEX, DEFICIENCY OF
PLATELET GLYCOPROTEIN IIb-IIIa DEFICIENCY
GLYCOPROTEIN COMPLEX IIb-IIIa, DEFICIENCY OF
Glanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. The abnormalities are related to quantitative or qualitative abnormalities of the GPIIb/IIIa platelet surface fibrinogen receptor complex ... Glanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. The abnormalities are related to quantitative or qualitative abnormalities of the GPIIb/IIIa platelet surface fibrinogen receptor complex resulting from mutations in either the GPIIb or GPIIIa genes (Rosenberg et al., 1997). See 187800 for discussion of a possible dominant form.
Seligsohn et al. (1985) demonstrated that in the form of Glanzmann thrombasthenia frequent in Iraqi Jews, prenatal diagnosis is possible by means of a monoclonal antibody against GPIIb/IIIa applied to fetal blood obtained by fetoscopic venipuncture. The method ... Seligsohn et al. (1985) demonstrated that in the form of Glanzmann thrombasthenia frequent in Iraqi Jews, prenatal diagnosis is possible by means of a monoclonal antibody against GPIIb/IIIa applied to fetal blood obtained by fetoscopic venipuncture. The method would not be applicable in the rare instances of variant thrombasthenia due to a functional rather than a quantitative defect of GPIIb/IIIa. They tested an earlier-born child in this family who was found to have had facial purpura soon after delivery by cesarean section, excessive bleeding with circumcision, and repeated episodes of gingival bleeding, epistaxis, and pharyngeal bleeding from 'injury caused by sweets.' The diagnosis of Glanzmann disease was based on lack of clot retraction, isolated (nonaggregated) platelets on blood smear, and failure of ADP-induced platelet aggregation. Bray (1994) reviewed the inherited diseases of platelet glycoproteins and made recommendations of general strategy for rapid molecular characterization of those disorders.
Glanzmann thrombasthenia has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb-IIIa complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express ... Glanzmann thrombasthenia has been classified clinically into types I and II. In type I, platelets show absence of the glycoprotein IIb-IIIa complexes at their surface and lack fibrinogen and clot retraction capability. In type II, the platelets express the GPIIb-IIIa complex at reduced levels (5-20% controls), have detectable amounts of fibrinogen, and have low or moderate clot retraction capability. The platelets of GT 'variants' have normal or near normal (60-100%) expression of dysfunctional receptors (Ferrer et al., 1998). The disorder is manifest soon after birth with episodic mucocutaneous bleeding and unprovoked bruising. Epistaxis frequently occurs and, in women, copious menstrual hemorrhage. Intracranial bleeding may also occur. Bleeding time is prolonged, with normal platelet count, normal platelet morphology, and normal coagulation times. Platelets fail to aggregate, either spontaneously or in response to agonists, such as ADP, thrombin, or epinephrine, although there may be a transient response to ristocetin (Ferrer et al., 1998; Poncz et al., 1994). Early cases were reported by Lelong (1960) and Marx and Jean (1962). Friedman et al. (1964) described the disease in a boy and girl who were double first cousins (the mother of one was a sister of the father of the other and vice versa). An apparently unique congenital platelet disorder was described by Bowie et al. (1964). Absent platelet aggregation and defective hemostatic plug formation in the disorder was emphasized by Caen et al. (1966). Cronberg et al. (1967) described a kindred in which 3 persons in 2 sibships had a severe clotting defect, whereas others, including all 4 parents of the affected sibships, had a minor defect. The most impressive abnormality in vitro was complete absence of ability of the platelets to aggregate or adhere to glass. The same was observed by Zaizov et al. (1968) in brother and sister whose parents were first cousins once removed. Papayannis and Israels (1970) concluded that the heterozygote can be identified by the clot retraction test. Some heterozygotes are mild bleeders. The difficult nosology of the heterogeneous category of platelet disorders was discussed by Kanska et al. (1963) and by Alagille et al. (1964). A classification of hereditary thrombopathies into 3 major categories was given by Bowie and Owen (1968): (1) thrombopathy (deficient or ineffective platelet factor-3); (2) thrombasthenia (diminished clot retraction); and (3) compound platelet defects (those associated with deficiency of either factor VIII or factor IX). Corby et al. (1971) reported a brother and sister who had bleeding diathesis, normal platelet counts, prolonged bleeding times, deficient platelet factor 3 and absent platelet aggregation in response to ADP, collagen and epinephrine. Hathaway (1971) reviewed disorders of platelet function. Awidi (1983) described 12 Jordanian patients in 9 families. The parents were consanguineous in all instances. All patients were children with mucosal bleeding. Awidi (1983) concluded that Glanzmann disease is the second most frequent bleeding disorder in Jordan. Poncz et al. (1994) reported an infant who presented at 2 days of age with subdural bleeding and extensive ecchymoses. She had a normal platelet count, prolonged bleeding time, and absent platelet aggregation.
Newman et al. (1991) demonstrated that the form of Glanzmann thrombasthenia frequent in Iraqi Jews is due to a truncated GPIIIa as a result of an 11-bp deletion within the GP3A gene (173470.0014), whereas the form of the ... Newman et al. (1991) demonstrated that the form of Glanzmann thrombasthenia frequent in Iraqi Jews is due to a truncated GPIIIa as a result of an 11-bp deletion within the GP3A gene (173470.0014), whereas the form of the disease frequent in Arabs in Israel is due to a 13-bp deletion in the GP2B gene (607759.0002). In 2 kindreds from Israel with Glanzmann thrombasthenia, Russell et al. (1988) could find no major insertions, deletions, or rearrangements in either the GP2B or the GP3A gene. In a patient with Glanzmann thrombasthenia, Bajt et al. (1992) identified a mutation in the ITGB3 gene (173470.0001). The patient's platelets failed to aggregate in response to stimuli. In an Ashkenazi Jewish female infant with Glanzmann thrombasthenia, born of a consanguineous marriage, Poncz et al. (1994) identified a homozygous mutation in the ITGA2B gene (607759.0007). Peretz et al. (2006) investigated the molecular basis of Glanzmann thrombasthenia in 40 families from southern India. Of 23 identified mutations, 13 in the ITGA2B gene and 10 in the ITGB3 gene, 20 were novel. A founder effect was observed for 2 mutations. Alternative splicing was predicted in silico for the normal variant and a missense variant of the ITGB3 gene, and for 10 of 11 frameshift or nonsense mutations in ITGA2B or ITGB3. Among 24 patients with Glanzmann thrombasthenia and 2 asymptomatic carriers of the disorder, Jallu et al. (2010) identified 20 different mutations in the ITGA2B gene (see, e.g., 607759.0015-607759.0016) in 18 individuals and 10 different mutations in the ITGB3 (see, e.g., 173470.0016-173470.0017) gene in 8 individuals. There were 17 novel mutations described. Four mutations in the ITGB3 gene were examined for pathogenicity and all were found to decrease cell surface expression of the IIb/IIIa complex, consistent with the severe type I phenotype. One in particular, K253M (173470.0016), defined a key role for the lys253 residue in the interaction of the alpha-IIb propeller and the beta-I domain of IIIa, and loss of lys253 would interrupt complex formation.
A splice site mutation in the ITGA2B gene (607759.0008) has been identified exclusively in patients with Glanzmann thrombasthenia from the French Gypsy Manouche community. By genotyping and haplotype analysis of 23 individuals, including 9 patients with Glanzmann thrombasthenia, ... A splice site mutation in the ITGA2B gene (607759.0008) has been identified exclusively in patients with Glanzmann thrombasthenia from the French Gypsy Manouche community. By genotyping and haplotype analysis of 23 individuals, including 9 patients with Glanzmann thrombasthenia, from 16 families from the French Manouche community, Fiore et al. (2011) identified a 4-Mb ancestral common core haplotype, indicating a founder effect. The mutation was estimated to have occurred about 300 to 400 years ago. Gypsies are believed to be a population with Indian origins with an initial exodus into the Byzantine Empire during the 11th century. Fiore et al. (2011) suggested that the Manouche families moved from Germany to the north of France between the 17th and 18th centuries.