Role of Protein Kinase C in Platelet Dysfunction in Acute Gastroduodenal Ulcer Bleeding

V.Yu. Deliy


It is known that platelets play a crucial role in thrombosis and haemostasis. Platelets adhere to the site of vascular injury and become activated. The protein kinase C (PKC) family is a major regulator of platelet granule secretion, integrin activation, aggregation, spreading and procoagulant activity. Members of the PKC family of serine/threonine kinases are classified into three subfamilies on the basis of the structure of their regulatory domains. Conventional (or classic) (cPKC) isoforms (α, βI/II and γ) contain a tandem C1 domain capable of binding diacylglycerol (DAG), and a Ca2+-binding C2 domain. Novel (nPKC) isoforms (δ, ε, η and θ) also contain C1 domains, but lack the ability to bind Ca2+ at the C2-like domain. Atypical isoforms (ζ and 1/λ) lack a C2 domain and have an atypical C1 domain. Human platelets highly express the conventional PKC isoforms α and β and the novel isoforms δ and θ. Early pharmacological studies, which had not been able to distinguish between different isoforms, had showed that key platelet activation processes, such as secretion, integrin αIIbβ3 activation, and aggregation, are positively regulated by PKC activity. However, there is also good evidence that PKC has a negative role in platelets, in particular by suppressing Ca2+ signal generation, for example by promoting Ca2+ extrusion and desensitizing agonist receptors. In consideration of the recent study which had showed that platelet dysfunction is one of the factors of pathogenesis of gastroduodenal ulcer bleeding the next question arised. What is effect of PKC on platelet aggregation among patients with gastroduodenal ulcer bleeding? For the purpose of in vitro estimation of PKC effect on ADP-induced platelet aggregation among patients with gastroduodenal ulcer bleeding the ADP-induced platelet aggregation was measured either with or without prior incubation with PKC inhibitor. The group of patients with gastroduodenal ulcer bleeding numbers 19 patients, aged 53 ± 4 years. The control group counts 85 volunteers of the same age. Measurement of platelet aggregation has been carried out by spectrophotometry. The inhibitor of PKC, neomycin, has been used in finite concentration 20 mkm/l. The finite concentration of ADP constituted 5 mkm/l (EC50). The distribution pattern of ADP-induced platelet aggregation in control group was statistically different from the studied index in group of patients with gastroduodenal ulcer bleeding (р = 0.005). That fact was connected with wide variability of distribution pattern of studied index among patients with gastroduodenal ulcer bleeding. The results of estimation of PKC inhibitor effect on ADP-induced platelet aggregation in control group showed statistically significant decrease of the studied index (p = 0.05). The same estimation among patients with gastroduodenal ulcer bleeding did not show statistically significant difference in the studied index (p = 0.156). The last result was consequence of the fact that positive, negative and absence of PKC effect on ADP-induced platelet aggregation was established. The prior incubation of platelets with PKC inhibitor decreased the ADP-induced platelet aggregation in 58 % of cases. The positive effect of PKC inhibitor on ADP-induced platelet aggregation was recorded in 31 % of cases. Absence of PKC inhibitor effect on ADP-induced platelet aggregation was recorded only in 11 % of cases. However, the high positive effect of PKC on ADP-induced platelet aggregation has not provided stabilization of thrombus, that was confirmed by recurrence of gastroduodenal ulcer bleeding. Moreover, neither negative nor absence of PKC effect on ADP-induced platelet aggregation has not ensured the phase of thrombus stabilization that was sustained by reversible or partly reversible character of ADP-induced platelet aggregation.


acute bleeding; gastroduodenal ulcer; platelets; protein kinase C


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