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SUMMARY:Novel assays shows that coronary artery disease patients have heig
 htened procoagulant potential and implicates the Cyclophilin D dependent n
 ecrosis pathway - Dr Vivien Chen\, ANZAC Research Institute\, University o
 f Sydney
DTSTART:20160712T100000Z
DTEND:20160712T110000Z
UID:TALK66738@talks.cam.ac.uk
CONTACT:Katja Kivinen
DESCRIPTION:A subpopulation of platelets fulfil a procoagulant role in hae
 mostasis and thrombosis by enabling the thrombin burst required for fibrin
  formation and clot stability at the site of vascular injury. Excess proco
 agulant activity is linked with pathological thrombosis. The identity of t
 he procoagulant platelet has been elusive. The cell death marker GSAO rapi
 dly enters a subpopulation of agonist-stimulated platelets via an organic 
 anion-transporting polypeptide and is retained in the cytosol through cova
 lent reaction with protein dithiols. Labelling with GSAO together with exp
 osure of P-selectin distinguishes necrotic from apoptotic platelets.  Use 
 of GSAO labelling in vitro and in vivo identifies that the major subpopula
 tion of phosphatidylserine positive platelets involved in thrombus formati
 on are formed via cyclophilin D dependent regulated necrosis\, not apoptos
 is. GSAO+ platelets form in occluding murine thrombi after ferric chloride
  stimulation\, are attenuated with megakaryocyte directed deletion of the 
 cyclophilin D gene. These platelets form a procoagulant surface supporting
  fibrin formation in vivo and reduction in GSAO+ platelets is associated w
 ith reduction in platelet thrombus size and fibrin formation. Analysis of 
 platelets from human subjects on aspirin therapy indicates that these proc
 oagulant platelets form despite aspirin therapy\, but are attenuated by in
 hibition of the necrosis pathway. This indicates that necrotic platelets m
 ay be targeted independently of platelet activation indicating a potential
  therapeutic target in cardiovascular patients.\n\nTo facilitate investiga
 tion of the role of procoagulant platelets in patient samples\, we then de
 veloped a flow cytometry based assay based on GSAO/Pselectin labelling of 
 platelets using whole blood collected in standard citrate collection tubes
 . Using this assay we demonstrated the strong platelet agonists\, thrombin
  and collagen\, induce formation of procoagulant platelets via a mechanism
  that is largely independent of protease activated receptors. Patients wit
 h coronary artery disease have a heightened procoagulant platelet potentia
 l and are sensitised to thrombin and ADP stimulation. The procoagulant pla
 telet potential in these patients is insensitive to aspirin\, which target
 s platelet aggregation\, but modified by P2Y12 antagonists. This assay has
  potential prognostic and predictive potential in patients with platelet-b
 ased thrombosis disorders\, as well as potential screening tool for identi
 fying future anti-platelet therapies.\n
LOCATION:Sackler Lecture Theatre\, MRC/Wellcome Building\, Addenbrookes Ho
 spital
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