# 273800

GLANZMANN THROMBASTHENIA 1; GT1


Alternative titles; symbols

BLEEDING DISORDER, PLATELET-TYPE, 2; BDPLT2
GLANZMANN THROMBASTHENIA; GT
THROMBASTHENIA OF GLANZMANN AND NAEGELI
PLATELET GLYCOPROTEIN IIb-IIIa DEFICIENCY
GP IIb-IIIa COMPLEX DEFICIENCY
PLATELET FIBRINOGEN RECEPTOR DEFICIENCY
GLYCOPROTEIN COMPLEX IIb-IIIa DEFICIENCY


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q21.31 Glanzmann thrombasthenia 1 273800 AR 3 ITGA2B 607759
Clinical Synopsis
 
Phenotypic Series
 

INHERITANCE
- Autosomal recessive
HEAD & NECK
Eyes
- Hyphema
Nose
- Epistaxis
Mouth
- Gingival bleeding
RESPIRATORY
Nasopharynx
- Tonsil bleeding
ABDOMEN
Gastrointestinal
- Gastrointestinal hemorrhage
- Hematochezia
- Melena
GENITOURINARY
Internal Genitalia (Female)
- Menorrhagia
SKELETAL
Limbs
- Hemarthroses (rare)
SKIN, NAILS, & HAIR
Skin
- Easy bruisability
- Hematoma
- Ecchymoses
- Petechiae
- Purpura
MUSCLE, SOFT TISSUES
- Hematoma
NEUROLOGIC
Central Nervous System
- Intracranial hemorrhage (rare)
HEMATOLOGY
- Glanzmann thrombasthenia
- Normal platelet count
- Normal platelet size
- Absent or decreased platelet aggregation with agonists (ADP, collage, or thrombin receptor activating peptide)
- Decreased or absent platelet aggregation (<10%) with all physiologic agonists
- Normal agglutination response to ristocetin
PRENATAL MANIFESTATIONS
Delivery
- Risk of obstetric hemorrhage during delivery and postpartum period
LABORATORY ABNORMALITIES
- Hematuria
MISCELLANEOUS
- Glanzmann thrombasthenia 1 and Glanzmann thrombasthenia 2 (619267) are clinically indistinguishable and have 3 clinical subtypes
- Type I has absent glycoprotein IIb/IIIa expression (<5% normal)
- Type II has reduced glycoprotein IIb/IIIa expression (5-25%)
- Type III has normal levels of integrin, but the protein is nonfunctional
- Platelet alloimmunization may occur following platelet transfusion
- Estimated incidence of 1 in 1,000,000 (includes GT1 and GT2)
- Increased frequency in French Romani, South Indian Hindus, Iraqi Jews, and Jordanian nomadic tribes
MOLECULAR BASIS
- Caused by mutation in the integrin, alpha-2b gene (ITGA2B, 607759.0002)
Glanzmann thrombasthenia - PS273800 - 2 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
17q21.31 Glanzmann thrombasthenia 1 AR 3 273800 ITGA2B 607759
17q21.32 Glanzmann thrombasthenia 2 AR 3 619267 ITGB3 173470
Bleeding disorder, platelet-type - PS231200 - 28 Entries
Location Phenotype Inheritance Phenotype
mapping key
Phenotype
MIM number
Gene/Locus Gene/Locus
MIM number
1p36.12 ?Bleeding disorder, platelet-type, 22 AR 3 618462 EPHB2 600997
3p21.31 Gray platelet syndrome AR 3 139090 NBEAL2 614169
3q21.3 Bernard-Soulier syndrome, type C AR 3 231200 GP9 173515
3q25.1 Bleeding disorder, platelet-type, 8 AR 3 609821 P2RY12 600515
5q11.2 Bleeding disorder, platelet-type, 9 AD 2 614200 BDPLT9 614200
7q21.11 Platelet glycoprotein IV deficiency AR 3 608404 CD36 173510
7q34 Bleeding disorder, platelet-type, 14 AD 2 614158 BDPLT14 614158
9q21.11 ?Bleeding disorder, platelet-type, 19 AR 3 616176 PRKACG 176893
9q34.13 Bleeding disorder, platelet-type, 17 AD, AR 3 187900 GFI1B 604383
10q22.2 Quebec platelet disorder AD 3 601709 PLAU 191840
11q13.1 ?Bleeding disorder, platelet-type, 18 AR 3 615888 RASGRP2 605577
11q24.3 Bleeding disorder, platelet-type, 21 AD, AR 3 617443 FLI1 193067
12q12 Scott syndrome AR 3 262890 ANO6 608663
14q24.1 Bleeding disorder, platelet-type, 15 AD 3 615193 ACTN1 102575
17p13.2 von Willebrand disease, platelet-type AD 3 177820 GP1BA 606672
17p13.2 Bernard-Soulier syndrome, type A1 (recessive) AR 3 231200 GP1BA 606672
17q12 Bleeding disorder, platelet-type, 20 AD 3 616913 SLFN14 614958
17q21.31 Bleeding disorder, platelet-type, 16, autosomal dominant AD 3 187800 ITGA2B 607759
17q21.31 Glanzmann thrombasthenia 1 AR 3 273800 ITGA2B 607759
17q21.32 Bleeding disorder, platelet-type, 24, autosomal dominant AD 3 619271 ITGB3 173470
17q21.32 Glanzmann thrombasthenia 2 AR 3 619267 ITGB3 173470
19p13.3 {Bleeding disorder, platelet-type, 13, susceptibility to} AD 3 614009 TBXA2R 188070
19p13.12-p13.11 Bleeding disorder, platelet-type, 25 AD 3 620486 TPM4 600317
19q13.42 Bleeding disorder, platelet-type, 11 AR 3 614201 GP6 605546
22q11.21 Giant platelet disorder, isolated AR 3 231200 GP1BB 138720
22q11.21 Bernard-Soulier syndrome, type B AR 3 231200 GP1BB 138720
22q12.3 Macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss AD 3 155100 MYH9 160775
Not Mapped Bleeding disorder, platelet-type, 12 AD 605735 BDPLT12 605735

TEXT

A number sign (#) is used with this entry because Glanzmann thrombasthenia-1 (GT1) is caused by homozygous or compound heterozygous mutation in the gene encoding platelet glycoprotein alpha-IIb (ITGA2B; 607759) on chromosome 17q21.31.

Heterozygous mutation in the ITGA2B gene causes Glanzmann thrombasthenia-like with macrothrombocytopenia (BDPLT16; 187800).


Description

Glanzmann thrombasthenia-1 (GT1) 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 (ITGB3; 173470) platelet surface fibrinogen receptor complex resulting from mutations in the GPIIb gene (Rosenberg et al., 1997).

Genetic Heterogeneity of Glanzmann Thrombasthenia

See Glanzmann thrombasthenia-2 (GT2; 619267), caused by mutation the ITGB3 gene (173470) on chromosome 17q21.32.

See review by Botero et al. (2020).


Clinical Features

Glanzmann thrombasthenia (GT) 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).

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).

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.

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 and leukocyte adhesion deficiency-1 (116920), 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 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.

Exclusion Studies

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.


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).

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).


REFERENCES

  1. Alagille, D., Josso, F., Binet, J. L., Blin, M. L. La dystrophie thrombocytaire hemorragipare: discussion nosologique. Nouv. Rev. Franc. Hemat. 4: 755-790, 1964. [PubMed: 14233375, related citations]

  2. Awidi, A. S. Increased incidence of Glanzmann's thrombasthenia in Jordan as compared with Scandinavia. Scand. J. Haemat. 30: 218-222, 1983. [PubMed: 6857142, related citations] [Full Text]

  3. Bellucci, S., Devergie, A., Gluckman, E., Tobelem, G., Lethielleux, P., Benbunan, M., Schaison, G., Boiron, M. Complete correction of Glanzmann's thrombasthenia by allogeneic bone-marrow transplantation. Brit. J. Haemat. 59: 635-641, 1985. [PubMed: 3885999, related citations] [Full Text]

  4. Beutler, E. Glanzmann's thrombasthenia and reduced glutathione. New Eng. J. Med. 287: 1094-1095, 1972. [PubMed: 4673007, related citations] [Full Text]

  5. Booyse, F. M., Kisieleski, D., Seeler, R., Rafelson, M., Jr. Possible thrombosthenin defect in Glanzmann's thrombasthenia. Blood 39: 377-381, 1972. [PubMed: 4110434, related citations]

  6. Botero, J. P., Lee, K., Branchford, B. R., Bray, P. F., Freson, K., Lambert, M. P., Luo, M., Mohan, S., Ross, J. E., Bergmeier, W., Di Paula, J. Glanzmann thrombasthenia: genetic basis and clinical correlates. Haematologica 105: 888-894, 2020. [PubMed: 32139434, images, related citations] [Full Text]

  7. Bowie, E. J. W., Owen, C. A., Jr. Thrombopathy. Semin. Hemat. 5: 73-82, 1968.

  8. Bowie, E. J. W., Thompson, J. H., Jr., Owen, C. A., Jr. A new abnormality of platelet function. Thromb. Diath. Haemorrh. 11: 195-203, 1964.

  9. Bray, P. F., Rosa, J.-P., Lingappa, V. R., Kan, Y. W., McEver, R. P., Shuman, M. A. Biogenesis of the platelet receptor for fibrinogen: evidence for separate precursors for glycoproteins IIb and IIIa. Proc. Nat. Acad. Sci. 83: 1480-1484, 1986. [PubMed: 3006053, related citations] [Full Text]

  10. Bray, P. F. Inherited diseases of platelet glycoproteins: considerations for rapid molecular characterization. Thromb. Haemost. 72: 492-502, 1994. [PubMed: 7878622, related citations]

  11. Caen, J. P., Castaldi, P. A., Leclerc, J. C., Inceman, S., Larrieu, M. J., Probst, M., Bernard, J. Congenital bleeding disorders with long bleeding time and normal platelet count. I. Glanzmann's thrombasthenia (report of fifteen patients). Am. J. Med. 41: 4-26, 1966.

  12. Coller, B. S., Seligsohn, U., Little, P. A. Type I Glanzmann thrombasthenia patients from the Iraqi-Jewish and Arab populations in Israel can be differentiated by platelet glycoprotein IIIa immunoblot analysis. Blood 69: 1696-1703, 1987. [PubMed: 3580574, related citations]

  13. Corby, D. G., Zirbel, C. L., Lindley, A., Schulman, I. Thrombasthenia. Am. J. Dis. Child. 121: 140-144, 1971. [PubMed: 5542851, related citations] [Full Text]

  14. Cronberg, S., Nilsson, I. M., Zetterqvist, E. Investigation of a family with members with both severe and mild degree of thrombasthenia. Acta Paediat. Scand. 56: 189-197, 1967. [PubMed: 6049801, related citations] [Full Text]

  15. Dautigny, A., Bernier, I., Colombani, J., Jolles, P. Human platelets as a source of HL-A antigens: a study of various solubilization techniques. Biochimie 57: 1197-1201, 1975. [PubMed: 1222125, related citations] [Full Text]

  16. Degos, L., Dautigny, A., Brouet, J. C., Colombani, M., Ardaillou, N., Caen, J. P., Colombani, J. A molecular defect in thrombasthenic platelets. J. Clin. Invest. 56: 236-240, 1975. [PubMed: 1141437, related citations] [Full Text]

  17. Ferrer, M., Tao, J., Iruin, G., Sanchez-Ayuso, M., Gonzalez-Rodriguez, J., Parrilla, R., Gonzalez-Manchon, C. Truncation of glycoprotein (GP) IIIa (delta 616-762) prevents complex formation with GPIIb: novel mutation in exon 11 of GPIIIa associated with thrombasthenia. Blood 92: 4712-4720, 1998. [PubMed: 9845537, related citations]

  18. Fiore, M., Pillois, X., Nurden, P., Nurden, A. T., Austerlitz, F. Founder effect and estimation of the age of the French Gypsy mutation associated with Glanzmann thrombasthenia in Manouche families. Europ. J. Hum. Genet. 19: 981-987, 2011. [PubMed: 21487445, images, related citations] [Full Text]

  19. Friedman, L. L., Bowie, E. J. W., Thompson, J. H., Jr., Brown, A. L., Jr., Owen, C. A., Jr. Familial Glanzmann's thrombasthenia. Mayo Clin. Proc. 39: 908-918, 1964. [PubMed: 14250111, related citations]

  20. Giltay, J. C., Leeksma, O. C., Breederveld, C., van Mourik, J. A. Normal synthesis and expression of endothelial IIb/IIIa in Glanzmann's thrombasthenia. Blood 69: 809-812, 1987. [PubMed: 3545321, related citations]

  21. Gross, R., Gerok, W., Lohr, G. W., Vogell, W., Waller, H. D., Theopold, W. Ueber die Natur der Thrombasthenie. Thrombopathie Glanzmann-Naegeli. Klin. Wschr. 38: 193-206, 1960.

  22. Hathaway, W. E. Bleeding disorders due to platelet dysfunction. Am. J. Dis. Child. 121: 127-134, 1971. [PubMed: 5100795, related citations] [Full Text]

  23. Herrmann, F. H., Meyer, M., Gogstad, G. O., Solum, N. O. Glycoprotein IIb-IIIa complex in platelets of patients and heterozygotes of Glanzmann's thrombasthenia. Thromb. Res. 32: 615-622, 1983. [PubMed: 6229900, related citations] [Full Text]

  24. Herrmann, F. H., Meyer, M., Ihle, E. Protein and glycoprotein abnormalities in an unusual subtype of Glanzmann's thrombasthenia. Haemostasis 12: 337-344, 1982. [PubMed: 7152371, related citations] [Full Text]

  25. Jallu, V., Dusseaux, M., Panzer, S., Torchet, M.-F., Hezard, N., Goudemand, J., de Brevern, A. G., Kaplan, C. Alpha-IIb-beta-3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression, and structure-function. Hum. Mutat. 31: 237-246, 2010. [PubMed: 20020534, related citations] [Full Text]

  26. Kanska, B., Niewiarowski, S., Ostrowski, L., Poplawski, A., Prokopowicz, J. Macrothrombocytic thrombopathia. Clinical, coagulation and hereditary aspects. Thromb. Diath. Haemorrh. 10: 88-100, 1963. [PubMed: 14081293, related citations]

  27. Karpatkin, S., Weiss, H. J. Deficiency of glutathione peroxidase associated with high levels of reduced glutathione in Glanzmann's thrombasthenia. New Eng. J. Med. 287: 1062-1066, 1972. [PubMed: 4673006, related citations] [Full Text]

  28. Khanduri, U., Pulimood, R., Sudarsanam, A., Carman, R. H., Jadhav, M., Pereira, S. Glanzmann's thrombasthenia: a review and report of 42 cases from South India. Thromb. Haemost. 46: 717-721, 1981. [PubMed: 7330822, related citations]

  29. Kunicki, T. J., Aster, R. H. Deletion of the platelet-specific alloantigen Pl(A1) from platelets in Glanzmann's thrombasthenia. J. Clin. Invest. 61: 1225-1231, 1978. [PubMed: 566280, related citations] [Full Text]

  30. Kunicki, T. J., Pidard, D., Cazenave, J.-P., Nurden, A. T., Caen, J. P. Inheritance of the human platelet alloantigen, Pl(A1), in type I Glanzmann's thrombasthenia. J. Clin. Invest. 67: 717-724, 1981. [PubMed: 7193688, related citations] [Full Text]

  31. Lelong, J. C. La thrombopathie de Glanzmann-Naegeli. Paris: R. Foulon et Cie. (pub.) 1960.

  32. Levy, J. M., Mayer, G., Sacrez, R., Ruff, R., Francfort, J. J., Rodier, L. Thrombasthenie de Glanzmann-Naegeli: etude d'un groupe ethnique a forte endogamie. Ann. Pediat. 18: 129-137, 1971. [PubMed: 5102406, related citations]

  33. Marx, R., Jean, G. Studien zur Pathogenese der Thrombasthenie Glanzmann-Naegeli. Klin. Wschr. 40: 942-953, 1962. [PubMed: 13933227, related citations] [Full Text]

  34. McDowall, A., Inwald, D., Leitinger, B., Jones, A., Liesner, R., Klein, N., Hogg, N. A novel form of integrin dysfunction involving beta-1, beta-2, and beta-3 integrins. J. Clin. Invest. 111: 51-60, 2003. [PubMed: 12511588, images, related citations] [Full Text]

  35. McEver, R. P., Baenziger, J. U., Majerus, P. W. Isolation and structural characterization of the polypeptide subunits of membrane glycoprotein IIb-IIIa from human platelets. Blood 59: 80-85, 1982. [PubMed: 7053767, related citations]

  36. McEver, R. P., Baenziger, N. L., Majerus, P. W. Isolation and quantitation of the platelet membrane glycoprotein deficient in thrombasthenia using a monoclonal hybridoma antibody. J. Clin. Invest. 66: 1311-1318, 1980. [PubMed: 6449521, related citations] [Full Text]

  37. Meyer, M., Herrmann, F. H. Diversity of glycoprotein deficiencies in Glanzmann's thrombasthenia. Thromb. Haemost. 54: 626-629, 1985. [PubMed: 2935964, related citations]

  38. Montgomery, R. R., Kunicki, T. J., Taves, C., Pidard, D., Corcoran, M. Diagnosis of Bernard-Soulier syndrome and Glanzmann's thrombasthenia with a monoclonal assay on whole blood. J. Clin. Invest. 71: 385-389, 1983. [PubMed: 6822670, related citations] [Full Text]

  39. Moser, K., Lechner, K., Vinazzer, H. A hitherto not described enzyme defect in thrombasthenia: glutathione reductase deficiency. Thromb. Diath. Haemorrh. 19: 46-52, 1968. [PubMed: 5652240, related citations]

  40. Nachman, R. L. Thrombasthenia: immunologic evidence of a platelet protein abnormality. J. Lab. Clin. Med. 67: 411-419, 1966. [PubMed: 5910148, related citations]

  41. Newman, P. J., Seligsohn, U., Lyman, S., Coller, B. S. The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. Proc. Nat. Acad. Sci. 88: 3160-3164, 1991. [PubMed: 2014236, related citations] [Full Text]

  42. Nurden, A. T., Caen, J. P. An abnormal platelet glycoprotein pattern in three cases of Glanzmann's thrombasthenia. Brit. J. Haemat. 28: 253-260, 1974. [PubMed: 4473996, related citations] [Full Text]

  43. Nurden, A. T., Didry, D., Kieffer, N., McEver, R. P. Residual amounts of glycoproteins IIb and IIIa may be present in the platelets of most patients with Glanzmann's thrombasthenia. Blood 65: 1021-1024, 1985. [PubMed: 3156640, related citations]

  44. Nurden, A. T., Rosa, J.-P., Fournier, D., Legrand, C., Didry, D., Parquet, A., Pidard, D. A variant of Glanzmann's thrombasthenia with abnormal glycoprotein IIb-IIIa complexes in the platelet membrane. J. Clin. Invest. 79: 962-969, 1987. [PubMed: 3818957, related citations] [Full Text]

  45. Papayannis, A. G., Israels, M. C. G. Glanzmann's disease and trait. (Letter) Lancet 296: 44 only, 1970. Note: Originally Volume II. [PubMed: 4193778, related citations] [Full Text]

  46. Peretz, H., Rosenberg, N., Landau, M., Usher, S., Nelson, E. J. R., Mor-Cohen, R., French, D. L., Mitchell, B. W., Nair, S. C., Chandy, M., Coller, B. S., Srivastava, A., Seligsohn, U. Molecular diversity of Glanzmann thrombasthenia in southern India: new insights into mRNA splicing and structure-function correlations of alpha-IIb-beta-3 integrin (ITGA2B, ITGB3). Hum. Mutat. 27: 359-369, 2006. [PubMed: 16463284, related citations] [Full Text]

  47. Phillips, D. R., Agin, R. P. Platelet membrane defects in Glanzmann's thrombasthenia: evidence for decreased amounts of two major glycoproteins. J. Clin. Invest. 60: 535-545, 1977. [PubMed: 70433, related citations] [Full Text]

  48. Pittman, M. A., Jr., Graham, J. B. Glanzmann's thrombopathy: an autosomal recessive trait in one family. Am. J. Med. Sci. 247: 293-303, 1964. [PubMed: 14130322, related citations]

  49. Poncz, M., Rifat, S., Coller, B. S., Newman, P. J., Shattil, S. J., Parrella, T., Fortina, P., Bennett, J. S. Glanzmann thrombasthenia secondary to a gly273-to-asp mutation adjacent to the first calcium-binding domain of platelet glycoprotein IIb. J. Clin. Invest. 93: 172-179, 1994. [PubMed: 8282784, related citations] [Full Text]

  50. Rosenberg, N., Yatuv, R., Orion, Y., Zivelin, A., Dardik, R., Peretz, H., Seligsohn, U. Glanzmann thrombasthenia caused by an 11.2-kb deletion in the glycoprotein IIIa (beta-3) is a second mutation in Iraqi Jews that stemmed from a distinct founder. Blood 89: 3654-3662, 1997. [PubMed: 9160670, related citations]

  51. Ruggeri, Z. M., Bader, R., de Marco, L. Glanzmann thrombasthenia: deficient binding of von Willebrand factor to thrombin-stimulated platelets. Proc. Nat. Acad. Sci. 79: 6038-6041, 1982. [PubMed: 6310559, related citations] [Full Text]

  52. Russell, M. E., Seligsohn, U., Coller, B. S., Ginsberg, M. H., Skoglund, P., Quertermous, T. Structural integrity of the glycoprotein IIb and IIIa genes in Glanzmann thrombasthenia patients from Israel. Blood 72: 1833-1836, 1988. [PubMed: 3179450, related citations]

  53. Seligsohn, U., Mibashan, R. S., Rodeck, C. H., Nicolaides, K. H., Millar, D. S., Coller, B. S. Prenatal diagnosis of Glanzmann's thrombasthenia. (Letter) Lancet 326: 1419 only, 1985. Note: Originally Volume II. [PubMed: 2867408, related citations] [Full Text]

  54. Stevens, R. F., Meyer, S. Fanconi and Glanzmann: the men and their works. Brit. J. Haemat. 119: 901-904, 2002. [PubMed: 12472566, related citations] [Full Text]

  55. Tongio, M. M., Lutz, P., Hauptmann, G., Rodier, L., Levy, J.-M., Mayer, S., Cazenave, J.-P. Type I Glanzmann's thrombasthenia segregates independently of Ss and Duffy systems and the A, B, C, factor B, C2 and C4 loci of the HLA complex. Tissue Antigens 20: 22-27, 1982. [PubMed: 6214871, related citations] [Full Text]

  56. Waller, H. D., Gross, R. Genetische Enzymdefecte als Ursache von Thrombocytopathien. Verh. Dtsch. Ges. Inn. Med. 70: 476-494, 1964. [PubMed: 14294266, related citations]

  57. Zaizov, R., Cohen, I., Matoth, Y. Thrombasthenia: a study of two siblings. Acta Paediat. Scand. 57: 522-526, 1968. [PubMed: 5706368, related citations] [Full Text]


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# 273800

GLANZMANN THROMBASTHENIA 1; GT1


Alternative titles; symbols

BLEEDING DISORDER, PLATELET-TYPE, 2; BDPLT2
GLANZMANN THROMBASTHENIA; GT
THROMBASTHENIA OF GLANZMANN AND NAEGELI
PLATELET GLYCOPROTEIN IIb-IIIa DEFICIENCY
GP IIb-IIIa COMPLEX DEFICIENCY
PLATELET FIBRINOGEN RECEPTOR DEFICIENCY
GLYCOPROTEIN COMPLEX IIb-IIIa DEFICIENCY


SNOMEDCT: 32942005;   ICD10CM: D69.1;   ORPHA: 849;   DO: 2219;  


Phenotype-Gene Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
Gene/Locus Gene/Locus
MIM number
17q21.31 Glanzmann thrombasthenia 1 273800 Autosomal recessive 3 ITGA2B 607759

TEXT

A number sign (#) is used with this entry because Glanzmann thrombasthenia-1 (GT1) is caused by homozygous or compound heterozygous mutation in the gene encoding platelet glycoprotein alpha-IIb (ITGA2B; 607759) on chromosome 17q21.31.

Heterozygous mutation in the ITGA2B gene causes Glanzmann thrombasthenia-like with macrothrombocytopenia (BDPLT16; 187800).


Description

Glanzmann thrombasthenia-1 (GT1) 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 (ITGB3; 173470) platelet surface fibrinogen receptor complex resulting from mutations in the GPIIb gene (Rosenberg et al., 1997).

Genetic Heterogeneity of Glanzmann Thrombasthenia

See Glanzmann thrombasthenia-2 (GT2; 619267), caused by mutation the ITGB3 gene (173470) on chromosome 17q21.32.

See review by Botero et al. (2020).


Clinical Features

Glanzmann thrombasthenia (GT) 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).

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).

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.

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 and leukocyte adhesion deficiency-1 (116920), 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 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.

Exclusion Studies

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.


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).

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).


See Also:

Bellucci et al. (1985); Beutler (1972); Degos et al. (1975); Herrmann et al. (1983); Herrmann et al. (1982); Khanduri et al. (1981); Meyer and Herrmann (1985); Nachman (1966); Nurden and Caen (1974); Nurden et al. (1985); Pittman and Graham (1964); Ruggeri et al. (1982); Waller and Gross (1964)

REFERENCES

  1. Alagille, D., Josso, F., Binet, J. L., Blin, M. L. La dystrophie thrombocytaire hemorragipare: discussion nosologique. Nouv. Rev. Franc. Hemat. 4: 755-790, 1964. [PubMed: 14233375]

  2. Awidi, A. S. Increased incidence of Glanzmann's thrombasthenia in Jordan as compared with Scandinavia. Scand. J. Haemat. 30: 218-222, 1983. [PubMed: 6857142] [Full Text: https://doi.org/10.1111/j.1600-0609.1983.tb01477.x]

  3. Bellucci, S., Devergie, A., Gluckman, E., Tobelem, G., Lethielleux, P., Benbunan, M., Schaison, G., Boiron, M. Complete correction of Glanzmann's thrombasthenia by allogeneic bone-marrow transplantation. Brit. J. Haemat. 59: 635-641, 1985. [PubMed: 3885999] [Full Text: https://doi.org/10.1111/j.1365-2141.1985.tb07358.x]

  4. Beutler, E. Glanzmann's thrombasthenia and reduced glutathione. New Eng. J. Med. 287: 1094-1095, 1972. [PubMed: 4673007] [Full Text: https://doi.org/10.1056/NEJM197211232872111]

  5. Booyse, F. M., Kisieleski, D., Seeler, R., Rafelson, M., Jr. Possible thrombosthenin defect in Glanzmann's thrombasthenia. Blood 39: 377-381, 1972. [PubMed: 4110434]

  6. Botero, J. P., Lee, K., Branchford, B. R., Bray, P. F., Freson, K., Lambert, M. P., Luo, M., Mohan, S., Ross, J. E., Bergmeier, W., Di Paula, J. Glanzmann thrombasthenia: genetic basis and clinical correlates. Haematologica 105: 888-894, 2020. [PubMed: 32139434] [Full Text: https://doi.org/10.3324/haematol.2018.214239]

  7. Bowie, E. J. W., Owen, C. A., Jr. Thrombopathy. Semin. Hemat. 5: 73-82, 1968.

  8. Bowie, E. J. W., Thompson, J. H., Jr., Owen, C. A., Jr. A new abnormality of platelet function. Thromb. Diath. Haemorrh. 11: 195-203, 1964.

  9. Bray, P. F., Rosa, J.-P., Lingappa, V. R., Kan, Y. W., McEver, R. P., Shuman, M. A. Biogenesis of the platelet receptor for fibrinogen: evidence for separate precursors for glycoproteins IIb and IIIa. Proc. Nat. Acad. Sci. 83: 1480-1484, 1986. [PubMed: 3006053] [Full Text: https://doi.org/10.1073/pnas.83.5.1480]

  10. Bray, P. F. Inherited diseases of platelet glycoproteins: considerations for rapid molecular characterization. Thromb. Haemost. 72: 492-502, 1994. [PubMed: 7878622]

  11. Caen, J. P., Castaldi, P. A., Leclerc, J. C., Inceman, S., Larrieu, M. J., Probst, M., Bernard, J. Congenital bleeding disorders with long bleeding time and normal platelet count. I. Glanzmann's thrombasthenia (report of fifteen patients). Am. J. Med. 41: 4-26, 1966.

  12. Coller, B. S., Seligsohn, U., Little, P. A. Type I Glanzmann thrombasthenia patients from the Iraqi-Jewish and Arab populations in Israel can be differentiated by platelet glycoprotein IIIa immunoblot analysis. Blood 69: 1696-1703, 1987. [PubMed: 3580574]

  13. Corby, D. G., Zirbel, C. L., Lindley, A., Schulman, I. Thrombasthenia. Am. J. Dis. Child. 121: 140-144, 1971. [PubMed: 5542851] [Full Text: https://doi.org/10.1001/archpedi.1971.02100130094011]

  14. Cronberg, S., Nilsson, I. M., Zetterqvist, E. Investigation of a family with members with both severe and mild degree of thrombasthenia. Acta Paediat. Scand. 56: 189-197, 1967. [PubMed: 6049801] [Full Text: https://doi.org/10.1111/j.1651-2227.1967.tb15363.x]

  15. Dautigny, A., Bernier, I., Colombani, J., Jolles, P. Human platelets as a source of HL-A antigens: a study of various solubilization techniques. Biochimie 57: 1197-1201, 1975. [PubMed: 1222125] [Full Text: https://doi.org/10.1016/s0300-9084(76)80583-4]

  16. Degos, L., Dautigny, A., Brouet, J. C., Colombani, M., Ardaillou, N., Caen, J. P., Colombani, J. A molecular defect in thrombasthenic platelets. J. Clin. Invest. 56: 236-240, 1975. [PubMed: 1141437] [Full Text: https://doi.org/10.1172/JCI108074]

  17. Ferrer, M., Tao, J., Iruin, G., Sanchez-Ayuso, M., Gonzalez-Rodriguez, J., Parrilla, R., Gonzalez-Manchon, C. Truncation of glycoprotein (GP) IIIa (delta 616-762) prevents complex formation with GPIIb: novel mutation in exon 11 of GPIIIa associated with thrombasthenia. Blood 92: 4712-4720, 1998. [PubMed: 9845537]

  18. Fiore, M., Pillois, X., Nurden, P., Nurden, A. T., Austerlitz, F. Founder effect and estimation of the age of the French Gypsy mutation associated with Glanzmann thrombasthenia in Manouche families. Europ. J. Hum. Genet. 19: 981-987, 2011. [PubMed: 21487445] [Full Text: https://doi.org/10.1038/ejhg.2011.61]

  19. Friedman, L. L., Bowie, E. J. W., Thompson, J. H., Jr., Brown, A. L., Jr., Owen, C. A., Jr. Familial Glanzmann's thrombasthenia. Mayo Clin. Proc. 39: 908-918, 1964. [PubMed: 14250111]

  20. Giltay, J. C., Leeksma, O. C., Breederveld, C., van Mourik, J. A. Normal synthesis and expression of endothelial IIb/IIIa in Glanzmann's thrombasthenia. Blood 69: 809-812, 1987. [PubMed: 3545321]

  21. Gross, R., Gerok, W., Lohr, G. W., Vogell, W., Waller, H. D., Theopold, W. Ueber die Natur der Thrombasthenie. Thrombopathie Glanzmann-Naegeli. Klin. Wschr. 38: 193-206, 1960.

  22. Hathaway, W. E. Bleeding disorders due to platelet dysfunction. Am. J. Dis. Child. 121: 127-134, 1971. [PubMed: 5100795] [Full Text: https://doi.org/10.1001/archpedi.1971.02100130081009]

  23. Herrmann, F. H., Meyer, M., Gogstad, G. O., Solum, N. O. Glycoprotein IIb-IIIa complex in platelets of patients and heterozygotes of Glanzmann's thrombasthenia. Thromb. Res. 32: 615-622, 1983. [PubMed: 6229900] [Full Text: https://doi.org/10.1016/0049-3848(83)90063-4]

  24. Herrmann, F. H., Meyer, M., Ihle, E. Protein and glycoprotein abnormalities in an unusual subtype of Glanzmann's thrombasthenia. Haemostasis 12: 337-344, 1982. [PubMed: 7152371] [Full Text: https://doi.org/10.1159/000214691]

  25. Jallu, V., Dusseaux, M., Panzer, S., Torchet, M.-F., Hezard, N., Goudemand, J., de Brevern, A. G., Kaplan, C. Alpha-IIb-beta-3 integrin: new allelic variants in Glanzmann thrombasthenia, effects on ITGA2B and ITGB3 mRNA splicing, expression, and structure-function. Hum. Mutat. 31: 237-246, 2010. [PubMed: 20020534] [Full Text: https://doi.org/10.1002/humu.21179]

  26. Kanska, B., Niewiarowski, S., Ostrowski, L., Poplawski, A., Prokopowicz, J. Macrothrombocytic thrombopathia. Clinical, coagulation and hereditary aspects. Thromb. Diath. Haemorrh. 10: 88-100, 1963. [PubMed: 14081293]

  27. Karpatkin, S., Weiss, H. J. Deficiency of glutathione peroxidase associated with high levels of reduced glutathione in Glanzmann's thrombasthenia. New Eng. J. Med. 287: 1062-1066, 1972. [PubMed: 4673006] [Full Text: https://doi.org/10.1056/NEJM197211232872103]

  28. Khanduri, U., Pulimood, R., Sudarsanam, A., Carman, R. H., Jadhav, M., Pereira, S. Glanzmann's thrombasthenia: a review and report of 42 cases from South India. Thromb. Haemost. 46: 717-721, 1981. [PubMed: 7330822]

  29. Kunicki, T. J., Aster, R. H. Deletion of the platelet-specific alloantigen Pl(A1) from platelets in Glanzmann's thrombasthenia. J. Clin. Invest. 61: 1225-1231, 1978. [PubMed: 566280] [Full Text: https://doi.org/10.1172/JCI109038]

  30. Kunicki, T. J., Pidard, D., Cazenave, J.-P., Nurden, A. T., Caen, J. P. Inheritance of the human platelet alloantigen, Pl(A1), in type I Glanzmann's thrombasthenia. J. Clin. Invest. 67: 717-724, 1981. [PubMed: 7193688] [Full Text: https://doi.org/10.1172/JCI110088]

  31. Lelong, J. C. La thrombopathie de Glanzmann-Naegeli. Paris: R. Foulon et Cie. (pub.) 1960.

  32. Levy, J. M., Mayer, G., Sacrez, R., Ruff, R., Francfort, J. J., Rodier, L. Thrombasthenie de Glanzmann-Naegeli: etude d'un groupe ethnique a forte endogamie. Ann. Pediat. 18: 129-137, 1971. [PubMed: 5102406]

  33. Marx, R., Jean, G. Studien zur Pathogenese der Thrombasthenie Glanzmann-Naegeli. Klin. Wschr. 40: 942-953, 1962. [PubMed: 13933227] [Full Text: https://doi.org/10.1007/BF01481417]

  34. McDowall, A., Inwald, D., Leitinger, B., Jones, A., Liesner, R., Klein, N., Hogg, N. A novel form of integrin dysfunction involving beta-1, beta-2, and beta-3 integrins. J. Clin. Invest. 111: 51-60, 2003. [PubMed: 12511588] [Full Text: https://doi.org/10.1172/JCI14076]

  35. McEver, R. P., Baenziger, J. U., Majerus, P. W. Isolation and structural characterization of the polypeptide subunits of membrane glycoprotein IIb-IIIa from human platelets. Blood 59: 80-85, 1982. [PubMed: 7053767]

  36. McEver, R. P., Baenziger, N. L., Majerus, P. W. Isolation and quantitation of the platelet membrane glycoprotein deficient in thrombasthenia using a monoclonal hybridoma antibody. J. Clin. Invest. 66: 1311-1318, 1980. [PubMed: 6449521] [Full Text: https://doi.org/10.1172/JCI109983]

  37. Meyer, M., Herrmann, F. H. Diversity of glycoprotein deficiencies in Glanzmann's thrombasthenia. Thromb. Haemost. 54: 626-629, 1985. [PubMed: 2935964]

  38. Montgomery, R. R., Kunicki, T. J., Taves, C., Pidard, D., Corcoran, M. Diagnosis of Bernard-Soulier syndrome and Glanzmann's thrombasthenia with a monoclonal assay on whole blood. J. Clin. Invest. 71: 385-389, 1983. [PubMed: 6822670] [Full Text: https://doi.org/10.1172/jci110780]

  39. Moser, K., Lechner, K., Vinazzer, H. A hitherto not described enzyme defect in thrombasthenia: glutathione reductase deficiency. Thromb. Diath. Haemorrh. 19: 46-52, 1968. [PubMed: 5652240]

  40. Nachman, R. L. Thrombasthenia: immunologic evidence of a platelet protein abnormality. J. Lab. Clin. Med. 67: 411-419, 1966. [PubMed: 5910148]

  41. Newman, P. J., Seligsohn, U., Lyman, S., Coller, B. S. The molecular genetic basis of Glanzmann thrombasthenia in the Iraqi-Jewish and Arab populations in Israel. Proc. Nat. Acad. Sci. 88: 3160-3164, 1991. [PubMed: 2014236] [Full Text: https://doi.org/10.1073/pnas.88.8.3160]

  42. Nurden, A. T., Caen, J. P. An abnormal platelet glycoprotein pattern in three cases of Glanzmann's thrombasthenia. Brit. J. Haemat. 28: 253-260, 1974. [PubMed: 4473996] [Full Text: https://doi.org/10.1111/j.1365-2141.1974.tb06660.x]

  43. Nurden, A. T., Didry, D., Kieffer, N., McEver, R. P. Residual amounts of glycoproteins IIb and IIIa may be present in the platelets of most patients with Glanzmann's thrombasthenia. Blood 65: 1021-1024, 1985. [PubMed: 3156640]

  44. Nurden, A. T., Rosa, J.-P., Fournier, D., Legrand, C., Didry, D., Parquet, A., Pidard, D. A variant of Glanzmann's thrombasthenia with abnormal glycoprotein IIb-IIIa complexes in the platelet membrane. J. Clin. Invest. 79: 962-969, 1987. [PubMed: 3818957] [Full Text: https://doi.org/10.1172/JCI112907]

  45. Papayannis, A. G., Israels, M. C. G. Glanzmann's disease and trait. (Letter) Lancet 296: 44 only, 1970. Note: Originally Volume II. [PubMed: 4193778] [Full Text: https://doi.org/10.1016/s0140-6736(70)92507-9]

  46. Peretz, H., Rosenberg, N., Landau, M., Usher, S., Nelson, E. J. R., Mor-Cohen, R., French, D. L., Mitchell, B. W., Nair, S. C., Chandy, M., Coller, B. S., Srivastava, A., Seligsohn, U. Molecular diversity of Glanzmann thrombasthenia in southern India: new insights into mRNA splicing and structure-function correlations of alpha-IIb-beta-3 integrin (ITGA2B, ITGB3). Hum. Mutat. 27: 359-369, 2006. [PubMed: 16463284] [Full Text: https://doi.org/10.1002/humu.20304]

  47. Phillips, D. R., Agin, R. P. Platelet membrane defects in Glanzmann's thrombasthenia: evidence for decreased amounts of two major glycoproteins. J. Clin. Invest. 60: 535-545, 1977. [PubMed: 70433] [Full Text: https://doi.org/10.1172/JCI108805]

  48. Pittman, M. A., Jr., Graham, J. B. Glanzmann's thrombopathy: an autosomal recessive trait in one family. Am. J. Med. Sci. 247: 293-303, 1964. [PubMed: 14130322]

  49. Poncz, M., Rifat, S., Coller, B. S., Newman, P. J., Shattil, S. J., Parrella, T., Fortina, P., Bennett, J. S. Glanzmann thrombasthenia secondary to a gly273-to-asp mutation adjacent to the first calcium-binding domain of platelet glycoprotein IIb. J. Clin. Invest. 93: 172-179, 1994. [PubMed: 8282784] [Full Text: https://doi.org/10.1172/JCI116942]

  50. Rosenberg, N., Yatuv, R., Orion, Y., Zivelin, A., Dardik, R., Peretz, H., Seligsohn, U. Glanzmann thrombasthenia caused by an 11.2-kb deletion in the glycoprotein IIIa (beta-3) is a second mutation in Iraqi Jews that stemmed from a distinct founder. Blood 89: 3654-3662, 1997. [PubMed: 9160670]

  51. Ruggeri, Z. M., Bader, R., de Marco, L. Glanzmann thrombasthenia: deficient binding of von Willebrand factor to thrombin-stimulated platelets. Proc. Nat. Acad. Sci. 79: 6038-6041, 1982. [PubMed: 6310559] [Full Text: https://doi.org/10.1073/pnas.79.19.6038]

  52. Russell, M. E., Seligsohn, U., Coller, B. S., Ginsberg, M. H., Skoglund, P., Quertermous, T. Structural integrity of the glycoprotein IIb and IIIa genes in Glanzmann thrombasthenia patients from Israel. Blood 72: 1833-1836, 1988. [PubMed: 3179450]

  53. Seligsohn, U., Mibashan, R. S., Rodeck, C. H., Nicolaides, K. H., Millar, D. S., Coller, B. S. Prenatal diagnosis of Glanzmann's thrombasthenia. (Letter) Lancet 326: 1419 only, 1985. Note: Originally Volume II. [PubMed: 2867408] [Full Text: https://doi.org/10.1016/s0140-6736(85)92579-6]

  54. Stevens, R. F., Meyer, S. Fanconi and Glanzmann: the men and their works. Brit. J. Haemat. 119: 901-904, 2002. [PubMed: 12472566] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.03812.x]

  55. Tongio, M. M., Lutz, P., Hauptmann, G., Rodier, L., Levy, J.-M., Mayer, S., Cazenave, J.-P. Type I Glanzmann's thrombasthenia segregates independently of Ss and Duffy systems and the A, B, C, factor B, C2 and C4 loci of the HLA complex. Tissue Antigens 20: 22-27, 1982. [PubMed: 6214871] [Full Text: https://doi.org/10.1111/j.1399-0039.1982.tb00325.x]

  56. Waller, H. D., Gross, R. Genetische Enzymdefecte als Ursache von Thrombocytopathien. Verh. Dtsch. Ges. Inn. Med. 70: 476-494, 1964. [PubMed: 14294266]

  57. Zaizov, R., Cohen, I., Matoth, Y. Thrombasthenia: a study of two siblings. Acta Paediat. Scand. 57: 522-526, 1968. [PubMed: 5706368] [Full Text: https://doi.org/10.1111/j.1651-2227.1968.tb06973.x]


Contributors:
Cassandra L. Kniffin - updated : 9/22/2011
Cassandra L. Kniffin - updated : 4/8/2010
Victor A. McKusick - updated : 6/6/2006
Cassandra L. Kniffin - reorganized : 5/14/2003
Ada Hamosh - updated : 5/6/2003
Victor A. McKusick - updated : 2/5/2003
Paul J. Converse - updated : 2/28/2002
Victor A. McKusick - updated : 1/14/2000
Ada Hamosh - updated : 5/11/1999
Victor A. McKusick - updated : 2/19/1999
Jennifer P. Macke - updated : 8/27/1996
Stylianos E. Antonarakis - updated : 7/4/1996

Creation Date:
Victor A. McKusick : 6/4/1986

Edit History:
alopez : 02/09/2022
carol : 04/19/2021
carol : 04/13/2021
carol : 05/20/2019
carol : 09/23/2011
ckniffin : 9/22/2011
carol : 9/21/2011
carol : 9/12/2011
ckniffin : 9/8/2011
wwang : 4/12/2010
ckniffin : 4/8/2010
terry : 3/25/2009
alopez : 6/13/2006
terry : 6/6/2006
ckniffin : 6/28/2004
terry : 6/25/2004
carol : 5/14/2003
ckniffin : 5/13/2003
ckniffin : 5/13/2003
ckniffin : 5/13/2003
ckniffin : 5/13/2003
alopez : 5/8/2003
terry : 5/6/2003
tkritzer : 2/11/2003
tkritzer : 2/11/2003
terry : 2/5/2003
carol : 4/8/2002
alopez : 2/28/2002
mgross : 1/14/2000
alopez : 5/14/1999
terry : 5/11/1999
carol : 2/22/1999
terry : 2/19/1999
terry : 6/24/1997
mark : 6/12/1997
alopez : 6/5/1997
alopez : 6/5/1997
alopez : 6/5/1997
alopez : 5/8/1997
mark : 3/17/1997
jenny : 12/9/1996
terry : 11/25/1996
terry : 7/24/1996
carol : 7/22/1996
carol : 7/4/1996
terry : 7/2/1996
mark : 2/9/1996
terry : 1/30/1996
mark : 7/6/1995
terry : 1/5/1995
mimadm : 5/18/1994
warfield : 3/10/1994
carol : 3/5/1994
carol : 11/18/1993