The mode of action of primary bile salts on human platelets

doi:10.1016/0005-2736(93)90367-9

Biochimica et Biophysica Acta (BBA) - Biomembranes

Volume 1146, Issue 2, 14 March 1993, Pages 282-293

https://doi.org/10.1016/0005-2736(93)90367-9 Get rights and content

Abstract

Cholate and its conjugated amide derivatives glycocholate and taurocholate solubilized human platelets differently as studied by the observations on: (1) the change in optical absorbance of platelet suspension, (2) marker leakiness and (3) component solubility. Cholate ruptures the membrane in an all-or-none process, while both conjugated derivatives shed off both proteins and lipids. The shed lipids formed vesicles and could be separated from the proteins. The conjugated salts gradually chop off the cell membrane into pieces causing the cells to become small spheres (1.5 μm in diameter) as revealed by scanning electron microscopy, which also revealed that morphological change of platelet in these bile salts depended on both concentration and incubation period. Platelets at the prelytic-stage concentration of these three salts deformed initially to spiculate disc and finally to a stretched-out flat form. Also, in the prelytic stage of these bile salts, platelets showed inhibited responses to thrombin which did not happen to platelets in deoxycholate (Shiao et al. (1989) Biochim. Biophys. Acta 980, 56–68.).

References (36)

A. Helenius et al.
Biochim. Biophys. Acta
(1975)
R. Coleman et al.
Biochim. Biophys. Acta
(1976)
D. Lichtenberg et al.
Biochim. Biophys. Acta
(1983)
R. Coleman et al.
Biochim. Biophys. Acta
(1980)
W.C. Duane
Biochem. Biophys. Res. Commun.
(1977)
P. Eneroth
J. Lipid Res.
(1963)
C.-T. Wang et al.
Biochim. Biophys. Acta
(1986)
W.-J. Tsai et al.
Biochim. Biophys. Acta
(1988)
C.A. Dangelmaier et al.
Anal. Biochem.
(1980)
O.H. Lowry et al.
J. Biol. Chem.
(1951)

C.-N. Wang et al.

Biochim. Biophys. Acta

(1989)

O.S. Vyvoda et al.

Biochim. Biophys. Acta

(1977)

P. Walde et al.

Biochim. Biophys. Acta

(1987)

J. Philippot

Biochim. Biophys. Acta

(1971)

R. Coleman

Biochem. J.

(1987)

R.R.H. Anholt et al.

Biochemistry

(1986)

J.M. Graham et al.

Biochem. J.

(1987)

G. Holdsworth et al.

Biochem. J.

(1976)

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The proteomic and metabolomic signatures of isolated and polytrauma traumatic brain injury
2023, American Journal of Surgery
The interactions of polytrauma, shock, and traumatic brain injury (TBI) on thromboinflammatory responses remain unclear and warrant investigation as we strive towards personalized medicine in trauma. We hypothesized that comprehensive omics characterization of plasma would identify unique metabolic and thromboinflammatory pathways following TBI.
Patients were categorized as TBI vs Non-TBI, and stratified into Polytrauma or minimally injured. Discovery ‘omics was employed to quantify the top differently expressed proteins and metabolites of TBI and Non-TBI patient groups.
TBI compared to Non-TBI showed gene enrichment in coagulation/complement cascades and neuronal markers. TBI was associated with elevation in glycolytic metabolites and conjugated bile acids. Division into isolated TBI vs polytrauma showed further distinction of proteomic and metabolomic signatures.
Identified mediators involving in neural inflammation, blood brain barrier disruption, and bile acid building leading to TBI associated coagulopathy offer suggestions for follow up mechanistic studies to target personalized interventions.
Viscoelastic measurements of platelet function, not fibrinogen function, predicts sensitivity to tissue-type plasminogen activator in trauma patients
2015, Journal of Thrombosis and Haemostasis
Systemic hyperfibrinolysis is a lethal phenotype of trauma‐induced coagulopathy. Its pathogenesis is poorly understood. Recent studies have support a central role of platelets in hemostasis and in fibrinolysis regulation, implying that platelet impairment is integral to the development of postinjury systemic hyperfibrinolysis.
The objective of this study was to identify if platelet function is associated with blood clot sensitivity to fibrinolysis. We hypothesize that platelet impairment of the ADP pathway correlates with fibrinolysis sensitivity in trauma patients.
A prospective observational study of patients meeting the criteria for the highest level of activation at an urban trauma center was performed. Viscoelastic parameters associated with platelet function (maximum amplitude [MA]) were measured with native thrombelastography (TEG), and TEG platelet mapping of the ADP pathway (ADP‐MA). The contribution of fibrinogen to clotting was measured with TEG (angle) and the TEG functional fibrinogen (FF) assay (FF‐MA). Another TEG assay containing tissue‐type plasminogen activator (t‐PA) (75 ng mL⁻¹) was used to assess clot sensitivity to an exogenous fibrinolytic stimulus by use of the TEG lysis at 30 min (LY30) variable. Multivariate linear regression was used to identify which TEG variable correlated with t‐PA‐LY30 (quantification of fibrinolysis sensitivity).
Fifty‐eight trauma patients were included in the analysis, with a median injury severity score of 17 and a base deficit of 6 mEq L⁻¹. TEG parameters that significantly predicted t‐PA‐LY30 were related to platelet function (ADP‐MA, P = 0.001; MA, P < 0.001) but not to fibrinogen (FF‐MA, P = 0.773; angle, P = 0.083). Clinical predictors of platelet ADP impairment included calcium level (P = 0.001), base deficit (P = 0.001), and injury severity (P = 0.001).
Platelet impairment of the ADP pathway is associated with increased sensitivity to t‐PA. ADP pathway inhibition in platelets may be an early step in the pathogenesis of systemic hyperfibrinolysis.
Fibrinolysis shutdown phenotype masks changes in rodent coagulation in tissue injury versus hemorrhagic shock
2015, Surgery (United States)
Citation Excerpt :
Nevertheless, rats are markedly resistant to tPA at baseline, and it is likely that other unmeasured regulators of fibrinolysis are present. TUCA has been shown to augment tPA-mediated fibrinolysis,11 but also has been shown to impair platelet function.21 Platelets have been proposed to provide a protective shell to a central fibrin clot, and support the clot by release of procoagulants and antifibrinolytics during degranulation.22
Systemic hyperfibrinolysis (accelerated clot degradation) and fibrinolysis shutdown (impaired clot degradation) are associated with increased mortality compared with physiologic fibrinolysis after trauma. Animal models have not reproduced these changes. We hypothesize rodents have a shutdown phenotype that require an exogenous profibrinolytic to differentiate mechanisms that promote or inhibit fibrinolysis.
Fibrinolysis resistance was assessed by thrombelastography (TEG) using exogenous tissue plasminogen activator (tPA) titrations in whole blood. There were 3 experimental groups: (1) tissue injury (laparotomy/bowel crush), (2) shock (hemorrhage to mean arterial pressure of 20 mmHg), and (3) control (arterial cannulation and tracheostomy). Baseline and 30-minute postintervention blood samples were collected, and assayed with TEG challenged with taurocholic acid (TUCA).
Rats were resistant to exogenous tPA; the percent clot remaining 30 minutes after maximum amplitude (CL30) at 150 ng/mL (P = .511) and 300 ng/mL (P = .931) was similar to baseline, whereas 600 ng/mL (P = .046) provoked fibrinolysis. Using the TUCA challenge, the percent change in CL30 from baseline was increased in tissue injury compared with control (P = .048.), whereas CL30 decreased in shock versus control (P = .048). tPA increased in the shock group compared with tissue injury (P = .009) and control (P = .012).
Rats have an innate fibrinolysis shutdown phenotype. The TEG TUCA challenge is capable of differentiating changes in clot stability with rats undergoing different procedures. Tissue injury inhibits fibrinolysis, whereas shock promotes tPA-mediated fibrinolysis.
Shock releases bile acidinducing platelet inhibition and fibrinolysis
2015, Journal of Surgical Research
Citation Excerpt :
An animal model of shock and resuscitation supports that TUCA levels can increase within 30 min of low blood pressure and remain elevated after resuscitation. Bile acids have previously been associated with platelet dysfunction [11]. The proposed mechanism was through membrane deformity.
Metabolites are underappreciated for their effect on coagulation. Taurocholic acid (TUCA), a bile acid, has been shown to regulate cellular activity and promote fibrin sealant degradation. We hypothesize that TUCA impairs whole blood clot formation and promotes fibrinolysis.
TUCA was exogenously added to whole blood obtained from volunteers. A titration from 250 μM–750 μM was used due to biologic relevance. Whole blood mixtures were assayed using thrombelastography for clot strength (maximum amplitude [MA]) and fibrinolysis (LY30) quantification. Tranexamic acid was used to block plasmin-mediated fibrinolysis. Platelet microfluidics were performed. A proteomic analysis was completed on citrated plasma obtained from a shock and resuscitation rat model.
Fibrinolysis increased when 750-μM TUCA was added to whole blood (median LY30 0.08–5.7, P = 0.010) and clot strength decreased (median MA of 53.3–43.8, P = 0.010). The addition of tranexamic acid, to a 750-μM TUCA titration, partially reversed the induced fibrinolysis (LY30: without 7.7 versus with 2.7) and the decrease in clot strength (MA: without 48.2 versus with 53.2), but did not reverse the effects to whole blood levels. Platelet function reduced by 50% in the presence of 100-μM TUCA. Rats had a median 52-fold increase in TUCA, after a shock state that stayed elevated after resuscitation.
TUCA reduces clot strength and promotes fibrinolysis. The clot strength reduction is attributable to platelet inhibition. This metabolic effect on coagulation warrants further investigation, as localized areas of the body, with high levels of bile acid, may be at risk for postoperative bleeding.
Vesiculation induced by amphiphiles and ionophore A23187 in porcine platelets: A transmission electron microscopic study
1996, Chemico-Biological Interactions
Amphiphiles, known to induce exo- and endovesiculation in human erythrocytes, were studied by means of transmission electron microscopy (TEM) for their ability to induce shedding of vesicles (microparticles) from the porcine platelet plasma membrane. While echinocytogenic amphiphiles induced shedding of vesicles to the extracellular medium (exovesiculation), stomatocytogenic amphiphiles did not induce endovesiculation. The rapid (< 1 min) formation of many thin spicules in platelets upon treatment with echinocytogenic amphiphiles, indicates that spicule-formation is caused by a primary interaction of the amphiphile with the plasma membrane. Agonist- (Ca²⁺-ionophore A23187, thrombin and collagen) induced shape changes, however, seem to involve contractile cytoskeletal processes since treated cells attained heavily irregular shapes with broad pseudopods. Our study indicates that the mechanisms involved in amphiphile- and agonist-induced exovesiculation differ. Amphiphile-induced exovesicles are mainly electron-dense spherical structures (φ 150–200 nm) which originate from the formed spicules. Ionophore A23187-induced exovesicles are large (φ 200–800 nm) predominantly electron-lucent structures which are mainly shed from the cell body and seem to originate from extrusions of the canalicular system. Our study shows that there are several similarities but also obvious differences in the response of platelets and erythrocytes to amphiphile-treatment.
In vivo effect of bile salts on platelet aggregation in rats
1995, Thrombosis Research

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Regular paperThe mode of action of primary bile salts on human platelets

Abstract

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochem. Biophys. Res. Commun.

J. Lipid Res.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Anal. Biochem.

J. Biol. Chem.

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochim. Biophys. Acta

Biochem. J.

Biochemistry

Biochem. J.

Biochem. J.

Regular paper
The mode of action of primary bile salts on human platelets