Glanzmann Thrombasthenia

A number sign (#) is used with this entry because Glanzmann thrombasthenia (GT) can be caused by mutation in the gene encoding platelet glycoprotein alpha-IIb (ITGA2B; 607759) on chromosome 17q21.31 or the gene encoding platelet glycoprotein IIIa (ITGB3; 173470) on chromosome 17q21.32.

Description

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.

Clinical Features

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.

Biochemical Features

Gross et al. (1960) found that the platelets of affected patients had greatly reduced glyceraldehydephosphate dehydrogenase (GAPDH) and pyruvate kinase (PK) activity. The platelets showed reduced adhesiveness; on blood smears there was notable absence of platelet aggregation, and by electron microscopy there were 'round' platelets.

Moser et al. (1968) found severe deficiency of glutathione reductase in platelets in 2 sibs. Karpatkin and Weiss (1972) found markedly decreased glutathione peroxidase activity of platelets in 3 patients.

Booyse et al. (1972) found that microquantitation of thrombosthenin by radial immunodiffusion and a specific immunohistochemical antibody staining technique indicated absence of the surface-localized thrombosthenin in platelets from patients with Glanzmann thrombasthenia. In addition, ADP- and ATP-induced changes of the surface of normal platelets could not be demonstrated.

Pathogenesis

Dautigny et al. (1975) used an IgG antibody derived from a multitransfused patient with thrombasthenia to test platelets in vitro. Platelets of all normal subjects reacted with it in fixing complement. Platelets of the patient of origin and 8 others with thrombasthenia did not react. The authors took this as evidence that a specific molecule of the platelet is lacking or structurally modified in this disease. Phillips and Agin (1977) found deficiency of 2 platelet membrane glycoproteins in this disorder.

McEver et al. (1980) used the hybridoma technique to characterize further the platelet glycoprotein abnormality in Glanzmann thrombasthenia. Spleen cells from mice immunized with human platelets were fused to mouse myeloma cells with HGPRT deficiency. Hybridoma lines producing a variety of antiplatelet antibodies were isolated by HAT selection and cloned. Purified monoclonal IgG from 6 lines was prepared. One of these bound to a protein (called Tab) on normal platelets but not on thrombasthenic platelets. The protein was isolated by affinity chromatography on Tab-Sepharose. SDS polyacrylamide gel electrophoresis showed the protein to be a complex of glycoproteins IIb and IIIa. Platelets of heterozygotes had intermediate Tab-binding. The platelet alloantigen Pl(A1) (see 173470) was not recognized by Tab, because platelets from 3 Pl(A1)-negative subjects bound Tab normally. Thus, a platelet membrane protein that may be required for platelet aggregation and clot retraction was demonstrated. The 2 bands shown to be deficient in thrombasthenia were glycoproteins GPIIb and GPIIIa. Following up on the work of McEver et al. (1980), McEver et al. (1982) separated the polypeptide subunits IIb and IIIa of the glycoprotein isolated by affinity chromatography using the specific monoclonal antibody, and they compared their structures. The peptide maps were found to be completely different, suggesting that they are products of 2 separate genes or cleaved from a single proprotein.

Montgomery et al. (1983) demonstrated that an assay using monoclonal antibodies raised in the mouse can recognize the deficiency of glycoprotein Ib in the Bernard-Soulier syndrome (BSS; 231200) and of the glycoprotein IIb/IIIa in Glanzmann thrombasthenia. They studied 3 patients with BSS and 6 with GT. Of the GT patients, 3 had negligible binding to the antibody (type I GT) and 3 had greatly reduced binding (type II GT). The platelets in GT are aggregation-defective; those in BSS are adhesion-defective.

Levy et al. (1971) and Tongio et al. (1982) studied GT in 2 large families belonging to the Manouche Gypsy tribe. In studies of these cases, Kunicki et al. (1981) showed that the molecular expression of type I thrombasthenia, absence of GPIIb and IIa, was controlled by a different gene from that determining the platelet antigen Pl(A1). This suggested that the lack of expression of Pl(A1) antigen on thrombasthenic platelets is the result of absence of GPIIIa, the glycoprotein carrier of the Pl(A1) determinant. A deletion of the platelet antigen Pl(A1) on platelets from 5 patients with GT was demonstrated by Kunicki and Aster (1978) and confirmed by others.

Nurden et al. (1987) described a patient with Glanzmann thrombasthenia whose platelets contained unstable GPIIb/IIIa complexes unable to support fibrinogen binding. Giltay et al. (1987) found that endothelial cells from patients with Glanzmann disease were normal in their ability to synthesize and express a GPIIb/IIIa complex. This suggested that the defect in platelets may be caused by a defect in a regulatory element affecting the transcription of these 2 genes in megakaryocytes, as proposed by Bray et al. (1986). Alternatively, some evidence suggested that platelet and endothelial GPIIb/IIIa are not identical. The electrophoretic mobility of the complexes and their subunits is different, and not all monoclonal antibodies directed against platelet GPIIb/IIIa crossreact with endothelial GPIIb/IIIa. The surface protein deficient in Glanzmann disease is related to the family that includes LFA1A (153370) and MAC1 (120980). Coller et al. (1987) found that immunoblot patterns of glycoprotein IIIa could distinguish the defect present in most Iraqi-Jewish cases from that in Arab cases in Israel.

To explain why both GPIIb and GPIIIa are deficient in Glanzmann disease, Bray et al. (1986) suggested that there may be a defect in a common regulatory element, or that a molecular defect in either protein may result in instability or improper processing of the other.

In a patient with features of Glanzmann thrombasthenia (see 173470) and leukocyte adhesion deficiency-1, McDowall et al. (2003) identified a novel form of integrin dysfunction involving ITGB1 (135630), ITGB2, and ITGB3 (173470). ITGB2 and ITGB3 were constitutively clustered. Although all 3 integrins were expressed on the cell surface at normal levels and were capable of function following extracellular stimulation, they could not be activated via the 'inside-out' signaling pathways.

Diagnosis

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.

Molecular Genetics

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.

Population Genetics

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.

History

Stevens and Meyer (2002) reviewed the work of 2 Swiss pioneer hematologists, Eduard Glanzmann (1887-1959) and Guido Fanconi (1892-1979).