INFLUENCE OF NITRIC OXIDE AND CGMP ON AGONIST-INDUCED PLATELET ADHESION - AN IN VITRO STUDY IN PLATELETS ISOLATED FROM PATIENTS WITH LIVER CIRRHOSIS

Background: Variceal bleeding, one of the major complications of liver cirrhosis, is primarily due to platelet activation defect and secondarily due to coagulation defects. Platelet adhesion is the key event in hemostasis. Since nitric oxide (NO) related stress is known to influence platelet functions in liver cirrhosis, we undertook the present study to evaluate the possible mechanism involved in the inhibition of platelet adhesion by NO. Methods: Agonist-induced platelet adhesion in vitro was measured in platelets isolated from normal subjects and cirrhosis patients. The time-dependent changes in nitric oxide synthase (NOS), NO, 3',5'-cyclic guanosine monophosphate (cGMP) and cytosolic calcium (Ca2+) levels were monitored during adhesion. The percentage of platelet adhesion was also monitored in the presence of an eNOS inhibitor and a cGMP inhibitor. Results: The percentage of adhesion was significantly lower in cirrhosis platelets. Time-dependent changes in the cGMP NO and NOS level in platelets stimulated with collagen were significantly high, with a significantly low level of elevation of cytosolic Ca2+ in cirrhosis as adhesion proceeded. The results showed improved platelet adhesion with inhibitors of NOS and cGMP with concomitant elevation in Ca2+ level. Conclusions: It is inferred that elevation in the formation of cGMP due to stimulation of NOS activity inhibits Ca2+ mobilization from the internal store, an essential process to trigger platelet activation. The abnormal alterations were significantly lower in cirrhosis patients without bleeding complications. So, it could be stated that the bleeding abnormality in liver cirrhosis might be due to defective platelet adhesion influenced by the NO-cGMP pathway.