title: Potentiation of platelet aggregation by heparin in human whole blood is attenuated by P2Y12 and P2Y1 antagonists but not aspirin.
abstract: BACKGROUND
  Unfractionated heparin (UFH) potentiates platelet aggregation induced by some agonists. P2Y12 and P2Y1 receptors play a major role in amplifying platelet aggregation. We assessed the ability of cangrelor, a selective P2Y12 antagonist, A2P5P, a selective P2Y1 antagonist, and aspirin to block the potentiating effects of heparin.
  
  
  METHODS
  Whole blood from healthy human volunteers was anticoagulated with either hirudin or UFH 10 IU/ml. Some tubes anticoagulated with hirudin also contained UFH 1 or 10 IU/ml. The low-molecular-weight heparin dalteparin was also assessed. Platelet aggregation was performed using whole blood single-platelet counting. Dense granule release was assessed using 14C-5HT-labelled platelets.
  
  
  RESULTS
  UFH and, to a lesser extent, dalteparin potentiated platelet aggregation induced by ADP, PAF, 5HT, U46619, epinephrine and TRAP in a concentration-dependent manner but inhibited aggregation induced by collagen. Cangrelor effectively opposed the potentiating effects of heparins on sustained aggregation induced by ADP, PAF, 5HT, U46619 and TRAP but had less effect on epinephrine-induced aggregation, whereas A2P5P was more effective at blocking both the initial phase of ADP-induced aggregation and the aggregation response to epinephrine, reflecting the differences in G protein coupling between the agonist receptors. Aspirin had no effect on potentiation by heparin. Heparins did not increase ADP- or TRAP-induced 14C-5HT release.
  
  
  CONCLUSIONS
  Heparins potentiate platelet responses to ADP and numerous other agonists. This potentiation is attenuated by cangrelor and A2P5P, and is not mediated by increased dense granule release. ADP receptor antagonists but not aspirin may have potential therapeutic benefits in counteracting the pro-thrombotic effects of heparins.
authors.affiliation: Cardiovascular Research Unit, Clinical Sciences Centre, Northern General Hospital, Sheffield S5 7AU, UK. r.f.storey@sheffield.ac.uk
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
authors.forename: Jane A
authors.initials: JA
authors.lastname: May
authors.forename: Stan
authors.initials: S
authors.lastname: Heptinstall
mesh_terms: D000244:Adenosine Diphosphate / Q000008:administration & dosage; D000249:Adenosine Monophosphate / Q000008:administration & dosage / Q000031:analogs & derivatives*; D001241:Aspirin / Q000008:administration & dosage; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D015550:Cell Degranulation / Q000187:drug effects; D017985:Dalteparin / Q000008:administration & dosage; D004357:Drug Synergism; D006493:Heparin / Q000008:administration & dosage*; D006629:Hirudins / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage; D058919:Purinergic P2 Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12
chemical_list: D006629:Hirudins; D008565:Membrane Proteins; C546382:P2RY1 protein, human; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D058472:Receptors, Purinergic P2Y1; D058925:Receptors, Purinergic P2Y12; C045716:adenosine 2',5'-diphosphate; D000249:Adenosine Monophosphate; D000244:Adenosine Diphosphate; C117446:cangrelor; D006493:Heparin; D001241:Aspirin; D017985:Dalteparin