Glanzmann's thrombasthenia: the spectrum of clinical disease

George, JN; Caen, J; Nurden, AT

doi:10.1182/blood.v75.7.1383.1383

Cited by 601 publications

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“…Platelet preparation and fixation. After obtaining informed consent, blood was drawn from adult volunteers and a patient with Glanzmann's thrombasthenia type I (case 9; George et al, 1990) arising from a point mutation in the gene coding for GP IIb (Bourre et al, 1995). Samples were collected into acid-citrate-dextrose (ACD), NIH formula A (1 part anticoagulant to 6 parts blood).…”

Section: Methodsmentioning

confidence: 99%

Ultrastructural analysis of the distribution of the vitronectin receptor (α_vβ₃) in human platelets and megakaryocytes reveals an intracellular pool and labelling of the α‐granule membrane

Poujol

Nurden

1997

Br J Haematol

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Summary. The vitronectin receptor (VnR or a v b 3 ) belongs to the cytoadhesin subclass of the integrin family. This subclass consists of two receptors which have the b 3 subunit in common: GP IIb-IIIa complexes (or a IIb b 3 ) and VnR. We report the subcellular distribution of VnR within human platelets as determined by immunogold staining of ultrathin frozen sections and transmission electron microscopy. Monoclonal antibodies directed against: (i) the a v subunit (LM142, AMF7, CLB-706), or (ii) an epitope specific to the complex (LM609) were used. Although VnR is present on platelets, it is a minor component. We therefore first compared several different staining procedures to detect this integrin. Optimal localization of VnR was obtained using a multistep procedure in which biotinylated anti-mouse IgG and a monoclonal anti-biotin antibody provided staining enhancement. Results showed that although present on the surface, a v b 3 was mostly detected in internal membrane systems including those of a-granules. Occasionally, platelet sections showed special vesicular structures covered by gold particles. These were often localized at the edge or immediately under the plasma membrane and their origin remains unclear. An internal pool of a v b 3 was confirmed by flow cytometry and by using platelets from a patient with type I Glanzmann's thrombasthenia arising from a GP IIb gene defect. We also investigated the presence of VnR in megakaryocytes (MK) obtained from normal human bone marrow. A fluorescence study showed VnR in small MK with unilobulated nuclei, suggesting that synthesis of this integrin occurs early during megakaryocytopoiesis. In mature cells, VnR expression had decreased relative to GP IIb-IIIa, although intracellular staining was present in EM and a-granules were again labelled.

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Section: Methodsmentioning

confidence: 99%

Ultrastructural analysis of the distribution of the vitronectin receptor (α_vβ₃) in human platelets and megakaryocytes reveals an intracellular pool and labelling of the α‐granule membrane

Poujol

Nurden

1997

Br J Haematol

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“…GT typically presents before the age of 5 years with purpura, petechiae or abnormal bruising [4]. Abnormal mucocutaneous bleeding persists through childhood.…”

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confidence: 99%

“…Abnormal mucocutaneous bleeding persists through childhood. Gingival bleeding and epistaxis are commonplace [4]. Menorrhagia is frequently severe in GT and life-threatening bleeding has been reported at menarche [6].…”

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A systematic review of the management and outcomes of pregnancy in Glanzmann thrombasthenia

2011

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Glanzmann Thrombasthenia (GT) is a rare autosomal recessive disorder which usually manifests as severe mucocutaneous bleeding and is caused by deficiency of the platelet glycoprotein IIb-IIIa. Pregnancy in women with GT presents particular challenges as there is increased risk of both maternal and foetal bleeding. To improve understanding and clarify the optimum management of pregnancy in this disorder, we performed a systematic review of the world literature of pregnancy and GT. This identified three single-centre case series of patients with GT that included brief descriptions of women in pregnancy and 31 detailed case reports of 40 pregnancies in 35 women that resulted in 38 live births. Among the detailed case reports, ante-natal bleeding was described in 50% of pregnancies but was usually mild and occurred at mucocutaneous sites. Primary postpartum haemorrhage (PPH) was reported in 34% of pregnancies and secondary PPH in 24%. PPH was frequently severe and occurred up to 20 days after delivery. There was a wide variation in approach to prevention and treatment of PPH but most women received platelet transfusion, sometimes with additional recombinant FVIIa and anti-fibrinolytics. Maternal alloimmunization against platelet antigens was reported in 73% of pregnancies and was associated with four neonatal deaths. These data emphasize the need for multidisciplinary management of pregnancy in women with GT. Delivery plans should recognize the need for prevention and aggressive treatment of PPH and should minimize foetal bleeding risk in pregnancies complicated by alloimmunization.

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“…Consequently, Glanzmann thrombasthenia (GT) may be the result of mutations either in the GPIIb or the GPIIIa gene. This disease is an autosomal recessive platelet disorder responsible for a life-long chronic mucocutaneous bleeding tendency (George et al, 1990). The precise characterization of the gene abnormalities was facilitated by the amplification of platelet mRNA using reverse transcription and amplification by the polymerase chain reaction (Newman et al, 1988).…”

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confidence: 99%

Illegitimate transcription: its use for studying genetic abnormalities in lymphoblastoid cells from patients with Glanzmann thrombasthenia

et al. 1998

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Summary. Glanzmann thrombasthenia is the most common inherited disorder of platelets that may induce severe bleeding complications. Molecular biology techniques have offered the possibility to assess the basis of this chronic haemorrhagic disease at the molecular level. However, the accessibility of mRNA in platelets is limited by the availability of the patient's blood samples and the relatively weak amount of this material in these cells. Taking advantage of the genetic phenomenon of illegitimate transcription, we have demonstrated that glycoprotein IIb and glycoprotein IIIa mRNA could be detected in lymphoblastoid cell lines issued from normal EBV-transformed lymphoblasts. We further analysed the sequences of the two glycoprotein transcripts in lymphoblastoid cell lines from two previously characterized patients presenting with Glanzmann thrombasthenia. The results showed that illegitimate transcripts presented similar molecular abnormalities to those found in platelets. These data demonstrated that the nucleotide sequences of illegitimate transcripts were identical to tissue-specific mRNA found in platelets. We applied this methodology to screen for the genetic defect in a new thrombasthenic patient, and found a homozygous nonsense mutation GCA →TGA converting Arg8 to stop in the glycoprotein IIIa gene. This immortalized source of genetic material is therefore particularly useful for molecular genetic studies in inherited platelet disorders, avoiding repetitive and large blood samplings in frequently anaemic patients.

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Glanzmann's thrombasthenia: the spectrum of clinical disease

Cited by 601 publications

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Ultrastructural analysis of the distribution of the vitronectin receptor (α_vβ₃) in human platelets and megakaryocytes reveals an intracellular pool and labelling of the α‐granule membrane

Ultrastructural analysis of the distribution of the vitronectin receptor (α_vβ₃) in human platelets and megakaryocytes reveals an intracellular pool and labelling of the α‐granule membrane

A systematic review of the management and outcomes of pregnancy in Glanzmann thrombasthenia

Illegitimate transcription: its use for studying genetic abnormalities in lymphoblastoid cells from patients with Glanzmann thrombasthenia

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Glanzmann's thrombasthenia: the spectrum of clinical disease

Cited by 601 publications

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Ultrastructural analysis of the distribution of the vitronectin receptor (αvβ3) in human platelets and megakaryocytes reveals an intracellular pool and labelling of the α‐granule membrane

Ultrastructural analysis of the distribution of the vitronectin receptor (αvβ3) in human platelets and megakaryocytes reveals an intracellular pool and labelling of the α‐granule membrane

A systematic review of the management and outcomes of pregnancy in Glanzmann thrombasthenia

Illegitimate transcription: its use for studying genetic abnormalities in lymphoblastoid cells from patients with Glanzmann thrombasthenia

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Ultrastructural analysis of the distribution of the vitronectin receptor (α_vβ₃) in human platelets and megakaryocytes reveals an intracellular pool and labelling of the α‐granule membrane

Ultrastructural analysis of the distribution of the vitronectin receptor (α_vβ₃) in human platelets and megakaryocytes reveals an intracellular pool and labelling of the α‐granule membrane