Prothrombotic effects of diclofenac on arteriolar platelet activation and thrombosis in vivo.
BACKGROUND
Diclofenac, like selective cyclooxygenase-2 inhibitors, which alter vascular levels of platelet active prostaglandins, has been reported to increase rates of acute myocardial infarction.


OBJECTIVE
The study was performed to investigate, in an animal model of arterial thrombosis in vivo, whether diclofenac differentially influences platelet activation and thrombosis in vessels under non-stimulated conditions or during acute systemic inflammation, such as induced by tumor necrosis factor-alpha (TNF-alpha).


METHODS
Platelet-vessel wall interaction (PVWI), firm platelet adhesion and arterial thrombosis following vessel injury were analyzed by intravital microscopy in arterioles of hamsters in the dorsal skinfold chamber model. Prostacyclin [prostaglandin I(2) (PGI(2))] and thromboxane A(2) (TxA(2)) metabolites were measured. In vitro, endothelial adhesion molecule expression in cultured human microvascular endothelial cells was analyzed.


RESULTS
Under non-stimulated conditions, diclofenac (1 mg kg(-1)) enhanced PVWI, which was not mediated by increased adhesion molecule expression, but by decreased systemic PGI(2) levels. Following ferric chloride-induced endothelial injury, diclofenac accelerated thrombotic vessel occlusion time, an effect that was reversed by the stable PGI(2) analog iloprost. TNF-alpha, through induction of endothelial adhesion molecule expression, also enhanced PVWI, firm adhesion, and arterial thrombosis, but simultaneous treatment with TNF-alpha and diclofenac did not have an additive effect.


CONCLUSIONS
By decreasing levels of PGI(2) without, at the same time, altering prothrombotic TxA(2) levels, diclofenac can exert prothrombotic effects. However, this is not the case when an inflammatory situation is created by TNF-alpha treatment. These data may explain the enhanced risk of acute myocardial infarction observed in patients taking diclofenac.
Struthmann
L
L
Cardiology Division, Ludwig Maximilians University, 80336 Munich, Germany.
Hellwig
N
N
Pircher
J
J
Sohn
H-Y
HY
Buerkle
M A
MA
Klauss
V
V
Mannell
H
H
Pohl
U
U
Krötz
F
F
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000633:toxicity*; D001160:Arterioles / Q000187:drug effects; D002478:Cells, Cultured / Q000187:drug effects; D002712:Chlorides; D006224:Cricetinae; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D004008:Diclofenac / Q000494:pharmacology / Q000633:toxicity*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D005290:Ferric Compounds / Q000633:toxicity; D006801:Humans; D008647:Mesocricetus; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D015539:Platelet Activation / Q000187:drug effects*; D010973:Platelet Adhesiveness / Q000187:drug effects; D012884:Skin Window Technique; D013925:Thromboplastin / Q000032:analysis; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced*; D013929:Thromboxane B2 / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000894:Anti-Inflammatory Agents, Non-Steroidal; D002712:Chlorides; D016861:Cyclooxygenase Inhibitors; D005290:Ferric Compounds; D014409:Tumor Necrosis Factor-alpha; D004008:Diclofenac; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D013925:Thromboplastin; C024555:ferric chloride