title: Differential effects of endogenous, phyto and synthetic cannabinoids on thrombogenesis and platelet activity.
abstract: This study analysed the impact of anandamide, cannabidiol (CBD), and WIN55,212-2 on platelet activity and thrombogenesis for the first time. The effects of the cannabinoids on venular thrombosis were studied in the ear of hairless mice. Cannabinoid treatment was performed either once or repetitive by a once-daily administration for three days. To assess the role of cyclooxygenase metabolites in the putative action of anandamide, in vivo studies likewise included a combined administration of anandamide with indomethacin. In vitro, the effect of the cannabinoids on human platelet activation was studied by means of P-selectin expression using flow cytometry. Platelets were analysed under resting or thrombin receptor activating peptide (TRAP)-stimulated conditions, both after cannabinoid treatment alone and after TRAP stimulation and subsequent cannabinoid exposure. Finally, platelet count was assessed after treatment with high concentrations of anandamide. Anandamide, but not CBD and WIN55,212-2, significantly accelerated thrombus growth after one-time treatment as compared to vehicle control. Co-administration with indomethacin neutralized this effect. However, thrombogenesis was not altered by repeated treatment with the cannabinoids. In vitro, anandamide was shown to elicit a concentration-dependent activation of resting human platelets. However, at higher concentrations anandamide reduced the response to TRAP activation associated with a decrease of platelet count. CBD and WIN55,212-2 neither increased nor reduced activation of platelets. Acute exposure to anandamide elicits a cyclooxygenase-dependent prothrombotic effect in vivo. Anandamide seems to affect human platelet activation by a concentration-dependent toxic effect. By contrast, CBD and WIN55,212-2 were not associated with induction of thrombosis or activation of platelets. © 2016 BioFactors, 42(6):581-590, 2016.
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany.|Department of General, Thoracic, Vascular and Transplantation Surgery, Rostock University Medical Center, Rostock, Germany.
authors.forename: Eberhard
authors.initials: E
authors.lastname: Grambow
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany.|Department of Otorhinolaryngology, Head and Neck Surgery, Rostock University Medical Center, Rostock, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Strüder
authors.affiliation: Department of General, Thoracic, Vascular and Transplantation Surgery, Rostock University Medical Center, Rostock, Germany.
authors.forename: Ernst
authors.initials: E
authors.lastname: Klar
authors.affiliation: Institute of Toxicology and Pharmacology, Rostock University Medical Center, Rostock, Germany.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Hinz
authors.affiliation: Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Vollmar
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D048588:Benzoxazines / Q000494:pharmacology* / Q000627:therapeutic use; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology; D002185:Cannabidiol / Q000494:pharmacology* / Q000627:therapeutic use; D063386:Cannabinoid Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D063388:Endocannabinoids / Q000494:pharmacology* / Q000627:therapeutic use; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008812:Mice, Hairless; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D010972:Platelet Activating Factor / Q000494:pharmacology* / Q000627:therapeutic use; D015539:Platelet Activation / Q000187:drug effects; D010976:Platelet Count; D053284:Polyunsaturated Alkamides / Q000494:pharmacology* / Q000627:therapeutic use; D013927:Thrombosis / Q000517:prevention & control*
chemical_list: D001095:Arachidonic Acids; D048588:Benzoxazines; D063386:Cannabinoid Receptor Agonists; D063388:Endocannabinoids; D005343:Fibrinolytic Agents; D009025:Morpholines; D009281:Naphthalenes; D010972:Platelet Activating Factor; D053284:Polyunsaturated Alkamides; D002185:Cannabidiol; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C078814:anandamide
keywords: cannabinoids; flow cytometry; microcirculation; platelets; thrombosis