Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients.
BACKGROUND
Soluble CD40L (sCD40L), a substance that maximally reflects in vivo platelet activation, is increased in patients with hypercholesterolemia. We investigated the relation between sCD40L and platelet CD4OL in hypercholesterolemic patients before and after a short-term treatment with atorvastatin.


RESULTS
Collagen-induced platelet CD40L and plasma levels of sCD40L and prothrombin fragment F1+2, a marker of thrombin generation, were investigated in 30 hypercholesterolemic patients and 20 healthy subjects. Hypercholesterolemic patients were then randomized to either diet (n=15; group A) or atorvastatin 10 mg/d (group B); the aforementioned variables were measured at baseline and after 3 days of treatment. Compared with referents, hypercholesterolemic patients showed higher values of platelet CD40L (P<0.005), sCD40L (P<0.005), and F1+2 (P<0.003). Platelet CD40L was significantly correlated with sCD40L (P<0.001), and the latter was significantly correlated with F1+2 (P<0.001). The intervention trial showed no changes in group A but a significant decrease in platelet CD40L (P<0.01), sCD40L (P<0.002), and F1+2 (P<0.03) in group B. In vitro studies demonstrated that cholesterol enhanced platelet CD40L and CD40L-mediated clotting activation by human monocytes; also, atorvastatin dose-dependently inhibited platelet CD40L expression and clotting activation by CD40L-stimulated monocytes.


CONCLUSIONS
This study shows that, in hypercholesterolemia, platelet overexpression of CD40L may account for enhanced plasma levels of sCD40L and F1+2. Atorvastatin exerts a direct antithrombotic effect via inhibition of platelet CD40L and CD40L-mediated thrombin generation, independently of its cholesterol-lowering effect.
Sanguigni
Valerio
V
Department of Experimental Medicine and Pathology, University of Rome La Sapienza, Rome, Italy.
Pignatelli
Pasquale
P
Lenti
Luisa
L
Ferro
Domenico
D
Bellia
Alfonso
A
Carnevale
Roberto
R
Tesauro
Manfredi
M
Sorge
Roberto
R
Lauro
Renato
R
Violi
Francesco
F
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000069059:Atorvastatin; D015415:Biomarkers; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D023201:CD40 Ligand / Q000097:blood*; D003094:Collagen / Q000494:pharmacology; D003327:Coronary Disease / Q000188:drug therapy; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006538:Heptanoic Acids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000178:diet therapy / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D020412:Multifactorial Inheritance; D010446:Peptide Fragments / Q000032:analysis; D011516:Prothrombin / Q000032:analysis; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012995:Solubility; D013917:Thrombin / Q000096:biosynthesis* / Q000494:pharmacology; D013925:Thromboplastin / Q000096:biosynthesis; D016896:Treatment Outcome
D015415:Biomarkers; D005343:Fibrinolytic Agents; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010446:Peptide Fragments; D011758:Pyrroles; C045879:prothrombin fragment 1.2; D023201:CD40 Ligand; D000244:Adenosine Diphosphate; D011516:Prothrombin; D003094:Collagen; D013925:Thromboplastin; D000069059:Atorvastatin; D013917:Thrombin