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PubMed | University of Pennsylvania, Autonomous University of Barcelona, University of Verona, University of Perugia and 9 more.
Type: Clinical Trial | Journal: British journal of haematology | Year: 2015

This study evaluated 65 pregnancies in 34 women with five different inherited platelet function disorders. Gestation was similar to that of the general population. Severe bleeds requiring blood transfusions were observed in 50% of deliveries in Glanzmann thrombasthenia (GT), but not in the patients with delta storage pool disease, Hermansky-Pudlak syndrome, P2Y12 defect or defect of thromboxane A2 receptor. Of note, severe haemorrhage also occurred in women with GT who had received prophylactic platelet transfusions, suggesting that better preventive treatments are required. Diagnosis and degree of spontaneous bleeding tendency before pregnancy were reliable parameters to predict the delivery-related bleeding risk.

Favier R.,French Institute of Health and Medical Research | Favier R.,Armand Trousseau Children Hospital | Raslova H.,French Institute of Health and Medical Research | Raslova H.,University Paris - Sud
British Journal of Haematology | Year: 2015

The inherited macrothrombocytopenias constitute a subgroup of congenital platelet disorders that is the best characterized from the genetic point of view. This clinically heterogeneous subgroup is characterized by a variable degree of bleeding but without predisposition to haematological malignancies, as seen in the two other subgroups. The classification of inherited thrombocytopenia is traditionally based on the description of different clinical and biological features, in particular the measurement of the mean platelet volume. In certain disorders, biochemical platelet components are abnormal, and their analyses are useful in diagnosis. However, these approaches present several limitations, and many cases remain undiagnosed, especially for patients without a clear family history. An analysis of genetic abnormalities was subsequently used for classification, demonstrating that some different clinical entities were, in fact, identical. The genomic approach that was used initially to accurately link some phenotypic diagnoses with the causal genetic alteration was positional cloning and DNA sequencing. More recently, next generation sequencing in the form of whole-genome or -exome sequencing and RNA sequencing has been developed. This review will focus on the progress in understanding the different macrothrombocytopenias that have been identified. © 2015 John Wiley & Sons Ltd.

Manchev V.T.,University Paris - Sud | Manchev V.T.,University Paris Diderot | Manchev V.T.,French Institute of Health and Medical Research | Hilpert M.,University Paris - Sud | And 26 more authors.
Blood | Year: 2014

Macrothrombocytopenias are the most important subgroup of inherited thrombocytopenias. This subgroup is particularly heterogeneous because the affected genes are involved in various functions such as cell signaling, cytoskeleton organization, and gene expression. Herein we describe the clinical and hematological features of a consanguineous family with a severe autosomal recessive macrothrombocytopenia associated with a thrombocytopathy inducing a bleeding tendency in the homozygous mutated patients. Platelet activation and cytoskeleton reorganization were impaired in these homozygous patients. Exome sequencing identified a c.222C>G mutation (missense p.74Ile>Met) in PRKACG, a gene encoding the γ-catalytic subunit of the cyclic adenosine monophosphate-dependent protein kinase, the mutated allele cosegregating with the macrothrombocytopenia. We demonstrate that the p.74Ile>Met PRKACG mutation is associated with a marked defect in proplatelet formation and a low level in filamin A in megakaryocytes (MKs). The defect in proplatelet formation was rescued in vitro by lentiviral vector-mediated overexpression of wild-type PRKACG in patien tMKs. We thus conclude that PRKACG is a new central actor in platelet biogenesis and a new gene involved in inherited thrombocytopenia with giant platelets associated with a thrombocytopathy. © 2014 by The American Society of Hematology.

PubMed | University of Würzburg, University of Ryukyus, Armand Trousseau Children Hospital, University Paris - Sud and 5 more.
Type: | Journal: Nature communications | Year: 2016

Mg(2+) plays a vital role in platelet function, but despite implications for life-threatening conditions such as stroke or myocardial infarction, the mechanisms controlling [Mg(2+)]i in megakaryocytes (MKs) and platelets are largely unknown. Transient receptor potential melastatin-like 7 channel (TRPM7) is a ubiquitous, constitutively active cation channel with a cytosolic -kinase domain that is critical for embryonic development and cell survival. Here we report that impaired channel function of TRPM7 in MKs causes macrothrombocytopenia in mice (Trpm7(fl/fl-Pf4Cre)) and likely in several members of a human pedigree that, in addition, suffer from atrial fibrillation. The defect in platelet biogenesis is mainly caused by cytoskeletal alterations resulting in impaired proplatelet formation by Trpm7(fl/fl-Pf4Cre) MKs, which is rescued by Mg(2+) supplementation or chemical inhibition of non-muscle myosin IIA heavy chain activity. Collectively, our findings reveal that TRPM7 dysfunction may cause macrothrombocytopenia in humans and mice.

PubMed | Paris-Sorbonne University, Armand Trousseau Children Hospital, ALK Abello, University of Lorraine and 4 more.
Type: Journal Article | Journal: Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology | Year: 2016

The most emblematic members of Urticaceae at allergic risk level are wall pellitories (Parietaria), whereas nettle (Urtica) pollen is considered as poorly allergenic. No allergen from nettle pollen has yet been characterized, whereas 4 are listed for Parietaria pollen by the International Union of Immunological Societies. Clinical and biological profiles of 2 adult men who developed symptoms against nettle pollen and/or leaves were studied.To characterize the allergic reaction and identify the potential nettle pollen sensitizing allergens.IgE-mediated reaction to nettle pollen extract was evaluated by skin prick test, immunoassay, nasal provocation, and basophil activation test. To characterize specific nettle pollen allergens, an allergomic (IgE immunoproteomic) analysis was performed combining 1- and 2-dimensional electrophoresis, IgE immunoblots of nettle pollen extract, identification of allergens by mass spectrometry, and database queries.The results of biological and immunochemical analyses revealed that the allergic rhinitis was due to Urtica dioica pollen in both patients. The allergomic analysis of nettle pollen extract allowed the characterization of 4 basic protein allergens: a thaumatin-like protein (osmotin) with a relative molecular mass of 27 to 29 kDa, a pectinesterase (relative molecular mass, 40 kDa), and 2 other basic proteins with relative molecular masses of 14 to 16 kDa and 43 kDa. There is no or only very weak allergen associations between pellitory and nettle pollen.Exposure to nettle pollen can be responsible of allergic symptoms, and several allergens were characterized. Unravelling the allergens of this underestimated allergy might help to improve diagnosis and care for patients, to predict cross-reactivities and design adapted specific immunotherapy.

PubMed | University of Verona, Service de Nephrologie, IRCCS Policlinico San Matteo Foundation, Service de Biologie Clinique Secteur Hematologie and 36 more.
Type: Journal Article | Journal: Haematologica | Year: 2014

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 10(9)/L.

Halimi C.,Armand Trousseau Children Hospital | Halimi C.,University Pierre and Marie Curie | Nevoux J.,Armand Trousseau Children Hospital | Nevoux J.,University Pierre and Marie Curie | And 6 more authors.
International Journal of Pediatric Otorhinolaryngology | Year: 2012

Objectives: To assess the diagnostic strategy, treatment and outcome of acquired subglottic cysts. Materials and methods: Retrospective, monocentric, tertiary referential center study of 172 preterm neonates assessed by endoscopic examination over a 10. years period. Identification of patients presenting with subglottic cysts. Results: 17 children were diagnosed with subglottic cysts. Among them, 98% were prematurates (28±4weeks of gestation), and 76% had a history of hyaline membrane disease or a bronchopulmonary dysplasia. All patients were intubated during the neonatal period, for a mean duration of 14days. Mean age at diagnosis was 8months. An associated laryngotracheal anomaly was diagnosed in 30% of cases. Six procedures, including flexible controls, were needed to achieve full recovery. We used cold steel microinstruments, CO 2 or Thulium LASER. Mean follow up was 3years. Conclusions: Acquired subglottic cysts concern early preterm infants. Children treated for subglottic cysts should undergo a long term follow up, as there is a trend for cysts to recur, as well as a risk of secondary subglottic stenosis. © 2012 Elsevier Ireland Ltd.

Denoyelle F.,Armand Trousseau Children Hospital | Denoyelle F.,French Institute of Health and Medical Research | Leboulanger N.,Armand Trousseau Children Hospital | Leboulanger N.,French Institute of Health and Medical Research | And 9 more authors.
Otology and Neurotology | Year: 2013

OBJECTIVE: To report preliminary results of a new closed-skin, transcutaneous bone conduction device (BCD) in 6 children with high-grade ear atresia SETTINGS: Tertiary care center; prospective study; we evaluated the gain with masking of the contralateral ear and the benefit of hearing rehabilitation with the transcutaneous BCD in noise: speech-in-noise tests, conducted in real life condition (with contralateral ear unmasked and fitted with a hearing device if done before implantation), with and without BCD, with determination of the speech reception threshold (SRT). Children and parent's satisfaction was assessed. RESULTS: Patients' ages ranged from 6 to 9 years. All had high-grade ear atresia with a preoperative mean pure-tone average (PTA) loss of 71.46 ± 6.59 dB on air conduction and 14 ± 4.98 dB on bone conduction. At M6, all children used the implant 5 to 12 hours daily (mean, 10) without pain or cutaneous complications. At M6, the mean air conduction PTA with transcutaneous BCD was 28.45 ± 1.68 dB, the mean gain 43 ± 6.96 dB, and the mean SRT gain 33.33 ± 10.75 dB. Using speech-in-noise tests in real-life conditions, the mean SRT was statistically improved with the transcutaneous BCD (-8 ± 2.83 dB, p = 0.0313). Both children and parents reported being satisfied or very satisfied. CONCLUSION: These preliminary results show satisfactory functional gain, cutaneous tolerance, and patients' satisfaction with the new transcutaneous BCD. Copyright © 2013 Otology & Neurotology, Inc.

Harterink E.,Armand Trousseau Children Hospital | Harterink E.,University Utrecht | Leboulanger N.,Armand Trousseau Children Hospital | Kotti S.,Unite de Recherche Clinique de LEst Parisien | And 2 more authors.
Otology and Neurotology | Year: 2014

OBJECTIVES: To assess the anatomic and functional outcome of underlay cartilage myringoplasty in children with cleft palate, at different postoperative periods compared with a patients-matched control group STUDY DESIGN: Case control study, tertiary referral center. METHODS: An otologic database was used to select children with cleft palate and perforated tympanic membrane who underwent myringoplasty between 1995 and 2012. These subjects were matched with control patients, without cleft palate, using the following criteria: age, size of perforation, status of contralateral ear, and status of middle ear mucosa. Charts were reviewed for the following: patients characteristics, preoperative findings, surgical data, postoperative anatomic and functional outcomes, and reinterventions. The postoperative findings were divided into 5 different periods. RESULTS: A group of 32 cleft palate patients as well as 32 control patients were included in this study, with a mean follow up of 63.6 ± 41 months. There were no differences between the groups in anatomic success as it was achieved in 84% in both groups. No differences were seen in functional outcome when compared with each different postoperative period. Using the last available audiogram, the postoperative mean air conduction and the air-bone gap were significantly worse in the cleft group compared with the control group, respectively, 26.1 ± 13.7 dB versus 18.4 ± 10.1 dB, p = 0.042; and 16.5 ± 9.4 dB and 11.3 ± 6.4 dB, p = 0.046. Additionally, the functional success was significantly worse in the cleft group; 58% versus 87% in the control group (OR, 5.5 [95% CI, 1.22-24.81], p = 0.027). CONCLUSION: Children with cleft palate can benefit from cartilage underlay myringoplasty in terms of closure of tympanic membrane, although there is a worse functional outcome. Copyright © 2014 Otology & Neurotology, Inc.

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