title: Transient heparin-induced platelet activation linked to generation of platelet 12-lipoxygenase. Findings from a randomised controlled trial.
abstract: Previously we demonstrated that heparin administration during carotid endarterectomy (CEA) caused a marked, but transient increase in platelet aggregation to arachidonic acid (AA) and adenosine diphosphate (ADP), despite effective platelet cyclo-oxygenase-1 (COX-1) inhibition with aspirin. Here we investigated the metabolism of AA via platelet 12-lipoxygenase (12-LOX) as a possible mediator of the observed transient aspirin resistance, and compared the effects of unfractionated (UFH) and low-molecular-weight (LMWH) heparin. A total of 43 aspirinated patients undergoing CEA were randomised in the trial to 5,000 IU UFH (n=22) or 2,500 IU LMWH (dalteparin, n=21). Platelet aggregation to AA (4x10⁻³) and ADP (3x10⁻⁶) was determined, and the products of the COX-1 and 12-LOX pathways; thromboxane B₂ (TXB₂) and 12-hydroxyeicosatretraenoic acid (12-HETE) were measured in plasma, and in material released from aggregating platelets.Aggregation to AA increased significantly (~10-fold) following heparinisation (p<0.0001), irrespective of heparin type (p=0.33). Significant, but smaller (~2-fold) increases in aggregation to ADP were also seen, which were significantly lower in the platelets of patients randomised to LMWH (p<0.0001). Plasma levels of TxB2 did not rise following heparinisation (p=0.93), but 12-HETE increased significantly in the patients' plasma, and released from platelets stimulated in vitro withADP, with both heparin types (p<0.0001). The magnitude of aggregation to ADP correlated with 12-HETE generation (p=0.03). Heparin administration during CEA generates AA that is metabolised to 12-HETE via the 12-LOX pathway, possibly explaining the phenomenon of transient heparin-induced platelet activation. LMWH has less effect on aggregation and 12-HETE generation than UFH when the platelets are stimulated with ADP.
authors.affiliation: Department of Cardiovascular Sciences, University of Leicester, Clinical Sciences Wing, Glenfield Hospital, Leicester, LE3 9QP, UK.
authors.forename: Greg S
authors.initials: GS
authors.lastname: McMahon
authors.forename: Chris I
authors.initials: CI
authors.lastname: Jones
authors.forename: Paul D
authors.initials: PD
authors.lastname: Hayes
authors.forename: A Ross
authors.initials: AR
authors.lastname: Naylor
authors.forename: Alison H
authors.initials: AH
authors.lastname: Goodall
mesh_terms: D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid / Q000378:metabolism; D000244:Adenosine Diphosphate / Q000737:chemistry; D000368:Aged; D001092:Arachidonate 12-Lipoxygenase / Q000097:blood* / Q000378:metabolism*; D001241:Aspirin / Q000737:chemistry; D001792:Blood Platelets / Q000187:drug effects; D017985:Dalteparin / Q000627:therapeutic use; D016894:Endarterectomy, Carotid; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006493:Heparin / Q000378:metabolism* / Q000627:therapeutic use; D006801:Humans; D008049:Lipase / Q000097:blood; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D013929:Thromboxane B2 / Q000097:blood
chemical_list: D013929:Thromboxane B2; D019377:12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; D000244:Adenosine Diphosphate; D006493:Heparin; D001092:Arachidonate 12-Lipoxygenase; D008049:Lipase; D001241:Aspirin; D017985:Dalteparin