ADP-degrading enzymes inhibit platelet activation in bile duct-ligated rats.
BACKGROUND
The effect of cholestatic liver disease on primary hemostasis function remains ill-defined.


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


METHODS
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.


RESULTS
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).


CONCLUSIONS
Bile duct ligation does not affect intrinsic platelet function, but impairs platelet activation via release of ADP-degrading enzymes in the circulation.
Witters
P
P
Liver Research Facility, Centre for Molecular and Vascular Biology, Department of Pathology, KU Leuven, Leuven, Belgium. peter.witters@gmail.com
Hoylaerts
M
M
Freson
K
K
de Vos
R
R
van Pelt
J
J
Nevens
F
F
van Geet
C
C
Cassiman
D
D
D015720:5'-Nucleotidase / Q000097:blood*; D000244:Adenosine Diphosphate / Q000097:blood*; D000469:Alkaline Phosphatase / Q000097:blood*; D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D001792:Blood Platelets / Q000201:enzymology* / Q000648:ultrastructure; D002779:Cholestasis / Q000097:blood* / Q000201:enzymology / Q000473:pathology; D003094:Collagen; D004195:Disease Models, Animal; D006801:Humans; D008026:Ligation; D010974:Platelet Aggregation; D010976:Platelet Count; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
D000244:Adenosine Diphosphate; D003094:Collagen; D000469:Alkaline Phosphatase; D015720:5'-Nucleotidase