Defective signal transduction in platelets from cirrhotics is associated with increased cyclic nucleotides.
BACKGROUND
Patients with advanced cirrhosis show defective platelet aggregation, which is dependent, at least in part, on intrinsic platelet abnormalities. The aim of this study was to evaluate the activating and inhibitory pathways of platelet signal transduction in cirrhotic patients.


METHODS
Twelve cirrhotic patients and 12 control subjects participated in this study. Measurements were performed on washed platelets.


RESULTS
Thrombin-stimulated inositol 1,4,5-trisphosphate production was reduced fivefold, and the increase in cytosolic calcium concentration was significantly lower in platelets from cirrhotic patients following stimulation with thrombin, platelet activating factor, or U-46619. In addition, the activity of the platelet Na+/H+ antiporter, evaluated after an acid load, was significantly lower in platelets from cirrhotic patients (0.90 +/- 0.19 vs. 1.37 +/- 0.16 delta pHi/min, P = 0.07). Cirrhotic patients also showed a significantly increased basal intraplatelet content of both 5'-cyclic adenosine monophosphate (cAMP) (2724 +/- 330 vs. 1561 +/- 258 fmol/10(8) platelets, P < 0.05) and 5'-cyclic guanosine monophosphate (cGMP) (217 +/- 18 vs. 159 +/- 29 fmol/10(8) platelets, P < 0.05).


CONCLUSIONS
Our results indicate that in platelets from cirrhotic patients, defective early signal transduction is associated with an increase in platelet cAMP and cGMP, thus revealing new mechanisms contributing to the defective platelet function in this disease.
Istituto di Clinica Medica II, University of Florence, Italy.
G
G
Laffi
F
F
Marra
P
P
Failli
M
M
Ruggiero
E
E
Cecchi
V
V
Carloni
A
A
Giotti
P
P
Gentilini
D000328:Adult; D000368:Aged; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000502:physiology; D000242:Cyclic AMP / Q000097:blood*; D006152:Cyclic GMP / Q000097:blood*; D011464:Epoprostenol / Q000096:biosynthesis; D005260:Female; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008099:Liver / Q000503:physiopathology; D008103:Liver Cirrhosis / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D015398:Signal Transduction; D017923:Sodium-Hydrogen Exchangers
D002352:Carrier Proteins; D007295:Inositol Phosphates; D017923:Sodium-Hydrogen Exchangers; D009569:Nitric Oxide; D011464:Epoprostenol; D000242:Cyclic AMP; D006152:Cyclic GMP; D002118:Calcium