Evaluation of participants with suspected heritable platelet function disorders including recommendation and validation of a streamlined agonist panel
Open Access
- 13 December 2012
- journal article
- clinical trial
- Published by American Society of Hematology in Blood
- Vol. 120 (25), 5041-5049
- https://doi.org/10.1182/blood-2012-07-444281
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 A2 (TxA2) 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 TxA2 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 P2Y12 ADP and TxA2 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.Keywords
This publication has 30 references indexed in Scilit:
- An intact PDZ motif is essential for correct P2Y12 purinoceptor traffic in human plateletsBlood, 2011
- Guidelines for the laboratory investigation of heritable disorders of platelet functionBritish Journal of Haematology, 2011
- Bleeding tendency and impaired platelet function in a patient carrying a heterozygous mutation in the thromboxane A2 receptorJournal of Thrombosis and Haemostasis, 2011
- Src family kinases are essential for primary aggregation by Gi‐coupled receptorsJournal of Thrombosis and Haemostasis, 2010
- Absence of collagen-induced platelet activation caused by compound heterozygous GPVI mutationsBlood, 2009
- Diagnostic approach to platelet function disordersTransfusion and Apheresis Science, 2008
- Congenital disorders associated with platelet dysfunctionsThrombosis and Haemostasis, 2008
- Use of native or platelet count adjusted platelet rich plasma for platelet aggregation measurementsJournal of Clinical Pathology, 2005
- Inherited Defects in Platelet Signaling MechanismsSeminars in Thrombosis and Hemostasis, 2004
- Arg60 to Leu mutation of the human thromboxane A2 receptor in a dominantly inherited bleeding disorder.JCI Insight, 1994