ADP-degrading enzymes inhibit platelet activation in bile duct-ligated rats

The effect of cholestatic liver disease on primary hemostasis function remains ill-defined.

To determine platelet function and identify the mechanisms involved in the observed platelet function in cholestatic rats.

Platelet function was studied in a model of 2-week bile duct ligation and compared to that in sham-operated rats with and without a storage pool defect.

ADP-induced and collagen-induced platelet aggregation were clearly impaired following bile duct ligation (P<0.01 for areas under the curve). Crossover experiments, with sham platelets in bile duct-ligated plasma and vice versa, demonstrated that this is due to inhibition by a plasmatic factor, as sham platelets aggregated less in cholestatic plasma (P<0.03) and to an equal extent as platelets from bile duct-ligated rats when they were in the same sham or cholestatic plasma. Moreover, in bile duct-ligated rats, platelet ultrastructure was unaffected and platelet aggregation was similar to that of sham platelets when resuspended in the same plasma (P-value not significant). Additionally, studies in storage pool-deficient rats showed no role of platelet exhaustion. The plasmatic factor causing impaired aggregation was shown to be increased total activity of ADP-degrading enzymes upon bile duct ligation (P<0.01), as there was no decreased aggregation with a stable ADP analog in bile duct-ligated rats (P-value not significant vs. sham-operated rats). Furthermore, preincubation of plasma from bile duct-ligated rats with ADP decreased aggregation more than was seen with sham plasma (P<0.01).

Bile duct ligation does not affect intrinsic platelet function, but impairs platelet activation via release of ADP-degrading enzymes in the circulation.