Phenotypic approaches to gene mapping in platelet function disorders - identification of new variant of P2Y12, TxA2 and GPVI receptors.
ABSTRACT Platelet number or function disorders cause a range of bleeding symptoms from mild to severe. Patients with platelet dysfunction but normal platelet number are the most prevalent and typically have mild bleeding symptoms. The study of this group of patients is particularly difficult because of the lack of a gold-standard test of platelet function and the variable penetrance of the bleeding phenotype among affected individuals. The purpose of this short review is to discuss the way in which this group of patients can be investigated through platelet phenotyping in combination with targeted gene sequencing. This approach has been used recently to identify patients with mutations in key platelet activation receptors, namely those for ADP, collagen and thromboxane A2 (TxA2). One interesting finding from this work is that for some patients, mild bleeding is associated with heterozygous mutations in platelet proteins that are co-inherited with other genetic disorders of haemostasis such as type 1 von Willebrand's disease. Thus, the phenotype of mild bleeding may be multifactorial in some patients and may be considered to be a complex trait.
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ABSTRACT: Heritable platelet function disorders (HPFD) are a heterogeneous group of bleeding disorders with diverse clinical and laboratory characteristics. In contrast to the severe phenotype disorders, Glanzmann thrombasthenia and Bernard–Soulier syndrome, most nonsevere HPFD are incompletely characterized. This is a consequence of the poor standardization of diagnostic tests and of the lack of consensus about diagnostic criteria for the different subgroups of nonsevere HPFD. Distinguishing patients who have a nonsevere HPFD from those who do not is an essential first step in diagnosis which may be aided by bleeding assessment tools and screening tests such as the Platelet Function Analyser-100. However, high diagnostic accuracy can only be achieved with both light transmission aggregation (LTA) and secretion tests, for which streamlined agonist panels may be of similar utility to extended panels. Standardization of the methodology of these tests and quality assurance are essential for robust diagnosis. Identification of which platelet pathway is defective in patients with nonsevere HPFD is also usually possible with LTA and secretion tests. This strategy also sometimes enables exact diagnosis by implicating a single candidate protein and gene. Next-generation sequencing may offer a rapid approach to diagnosis of nonsevere HPFD, although rigorous strategies must be adopted to distinguish causative gene defects from bystander variations.International journal of laboratory hematology 06/2014; 36(3). · 1.30 Impact Factor
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ABSTRACT: Although rare, the prevalence of inherited platelet function disorders (IPFD) is probably underestimated due to underdiagnosis . IPFD are heterogeneous in severity, mechanisms, and frequency and few are characterized at the molecular level. While severe IPFD, like Glanzmann Thrombasthenia (GT) or Bernard-Soulier Syndrome (BSS), are now rather straightforward to identify, the diagnosis of most other forms is cumbersome and requires complex assaysThis article is protected by copyright. All rights reserved.Journal of Thrombosis and Haemostasis 11/2014; · 6.08 Impact Factor
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ABSTRACT: Background Diagnosis of inherited platelet function disorders (IPFD) is important for appropriate management, and to improve epidemiologic and clinical knowledge. However, there is still a lack of consensus on the diagnostic approach.Objectives To gain knowledge on the current practices for the diagnosis of IPFD worldwide.MethodsA 67 item questionnaire was distributed to the ISTH members and to the members of several hemostasis and thrombosis national societies.ResultsA total of 202 laboratories from 37 countries participated in the survey. The most frequent criterion to define patients with a suspected IPFD was a history of mucocutaneous bleeding and no acquired cause, but heterogeneity on the identification criteria was evident. Only 64.5% of respondents performed a direct clinical interview. On average, each laboratory studied 72 patients/year. The most commonly used laboratory equipments were the light-transmission aggregometer (LTA), the platelet function analyzer-100 (PFA-100®), and flow-cytometer. Screening tests were platelet count, peripheral blood smear, LTA, PFA-100®. Second step tests were flow-cytometry, molecular genetic analysis and electron microscopy. Methodologies used varied widely. In total, around 14,000 patients were investigated yearly and 60% turned out not to have a defect. Of the remaining 40%, only 8.7% received a diagnosis at a molecular level.Conclusions Many laboratories worldwide are involved in the diagnosis of IPFD. A large fraction of the patients studied remain without a diagnosis. A high variability in the diagnostic approaches is evident.This article is protected by copyright. All rights reserved.Journal of Thrombosis and Haemostasis 06/2014; · 6.08 Impact Factor