title: Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel.
abstract: Light transmission aggregometry (LTA) is used worldwide for the investigation of heritable platelet function disorders (PFDs), but interpretation of results is complicated by the feedback effects of ADP and thromboxane A(2) (TxA(2)) and by the overlap with the response of healthy volunteers. Over 5 years, we have performed lumi-aggregometry on 9 platelet agonists in 111 unrelated research participants with suspected PFDs and in 70 healthy volunteers. Abnormal LTA or ATP secretion test results were identified in 58% of participants. In 84% of these, the patterns of response were consistent with defects in Gi receptor signaling, the TxA(2) pathway, and dense granule secretion. Participants with defects in signaling to Gq-coupled receptor agonists and to collagen were also identified. Targeted genotyping identified 3 participants with function-disrupting mutations in the P2Y(12) ADP and TxA(2) receptors. The results of the present study illustrate that detailed phenotypic analysis using LTA and ATP secretion is a powerful tool for the diagnosis of PFDs. Our data also enable subdivision at the level of platelet-signaling pathways and in some cases to individual receptors. We further demonstrate that most PFDs can be reliably diagnosed using a streamlined panel of key platelet agonists and specified concentrations suitable for testing in most clinical diagnostic laboratories.
authors.affiliation: Department of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom. b.b.dawood@bham.ac.uk.
authors.forename: Ban B
authors.initials: BB
authors.lastname: Dawood
authors.forename: Gillian C
authors.initials: GC
authors.lastname: Lowe
authors.forename: Marie
authors.initials: M
authors.lastname: Lordkipanidzé
authors.forename: Danai
authors.initials: D
authors.lastname: Bem
authors.forename: Martina E
authors.initials: ME
authors.lastname: Daly
authors.forename: Mike
authors.initials: M
authors.lastname: Makris
authors.forename: Andrew
authors.initials: A
authors.lastname: Mumford
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Wilde
authors.forename: Steve P
authors.initials: SP
authors.lastname: Watson
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D001791:Blood Platelet Disorders / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002648:Child; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010974:Platelet Aggregation / Q000187:drug effects; D010979:Platelet Function Tests / Q000379:methods*; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D058925:Receptors, Purinergic P2Y12 / Q000235:genetics / Q000378:metabolism; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000235:genetics / Q000378:metabolism; D022142:Secretory Vesicles / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D013928:Thromboxane A2 / Q000378:metabolism; D055815:Young Adult
chemical_list: D010980:Platelet Membrane Glycoproteins; D058925:Receptors, Purinergic P2Y12; D044244:Receptors, Thromboxane A2, Prostaglandin H2; C098341:platelet membrane glycoprotein VI; D013928:Thromboxane A2; D000255:Adenosine Triphosphate