Platelet functional changes secondary to hepatocholestasis and elevation of serum bile acids

Bowen, Diana J.; Clemmons, Roger M.; Meyer, Dennis J.; Dorsey-Lee, M. R.

doi:10.1016/0049-3848(88)90137-5

Cited by 15 publications

(14 citation statements)

References 6 publications

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“…This result agrees with previous data (Bowen et al, 1988; Shiao et al, 1993) but disagrees with those of McGregor (McGregor et al, 1980) showing that cholic acid increased thrombin and ADP-induced platelet aggregation and accelerated plasma clotting time. A similar result was obtained in fibroblasts, where DCA directly induced both Ca 2+ release from internal stores and persistent entry at the plasma membrane (Lau et al, 2005).…”

Section: Discussionsupporting

confidence: 78%

“…The underlying mechanisms for altered platelet function in cholestasis are unclear. Several mechanisms have been suggested (Bowen et al, 1988; Pihusch et al, 2002; Atucha et al, 2007; Witters et al, 2010; Tripodi et al, 2011), including an intrinsic change in platelet function, e.g., increased aggregation resulting from altered intracellular calcium (Ca 2+ ) homeostasis or decreased aggregation due to a storage pool deficiency, the effect of a plasmatic factor such as bile acids or bilirubin or because of the effect of release of ADP-degrading enzymes in the circulation. Regarding platelet activation, the necessary increase in cytoplasmic Ca 2+ levels, both by release from internal stores and entry of extracellular Ca 2+ , has been reported to be defective both in experimental models of liver cirrhosis and patients (Bandi et al, 1997; Atucha et al, 2007; Annie-Jeyachristy et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Bile Acids Do Not Contribute to the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis

et al. 2017

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Previously, we have found that intracellular calcium homeostasis is altered in platelets from an experimental model of liver cirrhosis, the bile-duct ligated (BDL) rat; these alterations are compatible with the existence of a hypercoagulable state and related to an enhanced intracellular calcium release evoked by thrombin and an increased amount of calcium stored in the intracellular organelles. In the present study we have investigated the role of bile acids in those alterations of the BDL cirrhotic model. Cholic acid (CA) or deoxycholic acid (DCA) did not change P-selectin expression or platelet aggregation in any group but elevated baseline platelet calcium levels. Incubation with both bile acids reduced calcium release after stimulation with thrombin in the absence of extracellular calcium. Pretreatment with CA but not with DCA reduced significantly thrombin-induced calcium entry in all three experimental groups. The capacitative calcium entry was also significantly lower in platelets pretreated with both bile acids. The simultaneous addition of thapsigargin and ionomycin to estimate the total amount of calcium in platelet internal stores was decreased by pretreatment with both CA and DCA, although these changes were significantly different in the control rats only with CA and in the BDL platelets with DCA. These results indicate that CA and DCA reduce calcium movements in platelets of control and BDL animals, thus suggesting that bile acids do not participate in the alterations observed in the BDL cirrotic model.

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Section: Discussionsupporting

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Bile Acids Do Not Contribute to the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis

et al. 2017

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“…In addition, the concentration of bile salts generally increases in hepatic failure ( 33) and can be up to 40 times higher than in healthy patients ( 8, 32). In patients with elevated bile acid levels in plasma, several problems arise including impaired coagulation ( 34) and platelet function( 35), and altered ion transport in red blood cells ( 36).…”

Section: Discussionmentioning

confidence: 99%

Cytotoxicity of Bile in Human Hep G2 Cells and in Primary Cultures of Rat Hepatocytes

et al. 1998

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There has been increasing interest in the development of a hepatocyte bioreactor for the treatment of acute hepatic failure; however, little is known about the effect of hepatocyte byproducts on the viability of the cells in the bioreactor environment. We investigated the effects of increasing concentrations of bile on the growth and viability of the human hepatoma cell line Hep G2 and on the cytochrome P-450 content and dependent mixed function oxidase (MFO) activities, reduced glutathione (GSH) content, and glutathione S-transferase (GST) activity of primary cultures of rat hepatocytes. Our purpose was to determine whether or not it would be necessary to pretreat the plasma from patients with acute liver failure to remove elevated bile concentrations which might be toxic to the hepatocytes in an artificial liver device. Bile was found to inhibit Hep G2 cell growth at concentrations as low as 0.1% and to decrease viability at concentrations above 0.5%. The cytochrome P-450 and GSH contents and the activities of the MFO system and of GST were decreased in the primary cultures of hepatocytes following 24 h treatment with concentrations of bile at and above 0.5%. The MFO activities associated with different cytochrome P-450 isoenzymes decreased to different extents in the presence of bile with the O-dealkylation of pentoxyresorufin being more labile than that of ethoxyresorufin. Our data indicate that elevated bile concentrations are cytotoxic to liver cells, and it may be necessary to pretreat patient plasma to decrease its bile content to protect the cells during the clinical operation of a hepatocyte bioreactor device.

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“…However, not all reports are equivocal with regard to platelet hyperaggregability, which could not be demonstrated by platelet aggregometry in either patients [7] or animal models [8–10]. Moreover, there is a prolonged bleeding time [8] and a loss of releasable ATP [7], as well as reduced expression of CD62P, after platelet stimulation [4]; all of these are indicative of decreased platelet function.…”

Section: Introductionmentioning

confidence: 99%

“…increased aggregation resulting from altered Ca 2+ homeostasis [6] or decreased aggregation due to a storage pool deficiency [7]), or the effect of a plasmatic factor (e.g. inhibition by bile acids [10], or stimulation by bilirubin [10]).…”

Section: Introductionmentioning

confidence: 99%

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

Witters¹,

Hoylaerts

Freson

et al. 2010

Journal of Thrombosis and Haemostasis

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Summary. Background: The effect of cholestatic liver disease on primary hemostasis function remains ill-defined. Objectives: 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 ductligated 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). Aditionally, 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.

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Platelet functional changes secondary to hepatocholestasis and elevation of serum bile acids

Cited by 15 publications

References 6 publications

Bile Acids Do Not Contribute to the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis

Bile Acids Do Not Contribute to the Altered Calcium Homeostasis of Platelets from Rats with Biliary Cirrhosis

Cytotoxicity of Bile in Human Hep G2 Cells and in Primary Cultures of Rat Hepatocytes

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

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