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Platelet Biology & its Disorders
Identification of a homozygous recessive variant in PTGS1 resulting in a congenital aspirin-like defect in platelet function
Ferrata Storti Foundation
Haematologica 2021 Volume 106(5):1423-1432
Melissa V. Chan,1* Melissa A. Hayman,1* Suthesh Sivapalaratnam,2,3,4* Marilena Crescente,1 Harriet E. Allan,1 Matthew L. Edin,5 Darryl C. Zeldin,5 Ginger L. Milne,6 Jonathan Stephens,2,3 Daniel Greene,2,3,7 Moghees Hanif,4 Valerie B. O’Donnell,8 Liang Dong,9 Michael G. Malkowski,9 Claire Lentaigne,10,11 Katherine Wedderburn,2 Matthew Stubbs,10,11 Kate Downes,2,3,12 Willem H. Ouwehand,2,3,7,13 Ernest Turro,2,3,7,12 Daniel P. Hart,1,4 Kathleen Freson,14 Michael A. Laffan,10,11# and Timothy D. Warner1#
1The Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary University of London, London, UK; 2Department of Hematology, University of Cambridge, Cambridge, UK; 3National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, UK; 4Department of Hematology, Barts Health National Health Service Trust, London, UK; 5National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, Durham, NC, USA; 6Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA; 7Medical Research Council Biostatistics Unit, Cambridge Institute of Public Health, Cambridge Biomedical Campus, Cambridge, UK; 8Systems Immunity Research Institute, and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, South Glamorgan, UK; 9Department of Structural Biology, Jacobs School of Medicine and Biomedical Sciences, University of Buffalo, The State University of New York, Buffalo, NY, USA; 10Imperial College Healthcare National Health Service Trust, London, UK; 11Center for Hematology, Hammersmith Campus, Imperial College Academic Health Sciences Center, Imperial College London, London, UK; 12NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, UK; 13Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK and 14Department of Cardiovascular Sciences, Center for Molecular and Vascular Biology, Gasthuisberg, University of Leuven, Leuven, Belgium
*MVC, MAH and SS contributed equally as co-first authors #MAL and TDW contributed equally as co-senior authors
ABSTRACT
We have identified a rare missense variant on chromosome 9, position 125145990 (GRCh37), in exon 8 in prostaglandin endoperoxide syn- thase 1 (PTGS1) (the gene encoding cyclo-oxygenase 1 [COX-1], the target of anti-thrombotic aspirin therapy). We report that in the homozygous state within a large consanguineous family this variant is associated with a bleeding phenotype and alterations in platelet reactivity and eicosanoid produc- tion. Western blotting and confocal imaging demonstrated that COX-1 was absent in the platelets of three family members homozygous for the PTGS1 vari- ant but present in their leukocytes. Platelet reactivity, as assessed by aggregom- etry, lumi-aggregometry and flow cytometry, was impaired in homozygous fam- ily members, as were platelet adhesion and spreading. The productions of COX- derived eicosanoids by stimulated platelets were greatly reduced but there were no changes in the levels of urinary metabolites of COX-derived eicosanoids. The proband exhibited additional defects in platelet aggregation and spreading which may explain why her bleeding phenotype was slightly more severe than those of other homozygous affected relatives. This is the first demonstration in humans of the specific loss of platelet COX-1 activity and provides insight into its consequences for platelet function and eicosanoid metabolism. Notably despite the absence of thromboxane A2 formation by platelets, urinary throm- boxane A2 metabolites were in the normal range indicating these cannot be assumed as markers of in vivo platelet function. Results from this study are important benchmarks for the effects of aspirin upon platelet COX-1, platelet function and eicosanoid production as they define selective platelet COX-1 abla- tion within humans.
Correspondence:
TIM WARNER
t.d.warner@qmul.ac.uk
Received: September 18, 2019. Accepted: April 9, 2020. Pre-published: April 16, 2020.
https://doi.org/10.3324/haematol.2019.235895
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