Glucocorticoids as modulators of expression and activity of Antithrombin (At): Potential clinical relevance

Barettino, Domingo; Masiá, Susana; Montó, Fermí; Pérez, Paloma; D’Ocón, Pilar; Moreno, Lucrecia; Muedra, Vicente

doi:10.1016/j.thromres.2014.10.026

Cited by 7 publications

(14 citation statements)

References 33 publications

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“…This exactly means that CS affects the expression of the regulatory element of antithromine3. This came in tune with D. Barettino et al, they suggest that management with CS might be a good pharmacological alternative to exogenous administered antithrombin3 formulation (23).…”

Section: Discussionsupporting

confidence: 55%

“…Some authors reported that corticosteroids (dexamethasone) lead to a procoagulant state in healthy individuals (22). Whilst others reported an increase in coagulation time by enhancing antithrombin 3 activity associated with decreased incidence and complication of abnormal clotting through nuclear receptors related mechanism (23). Actually, the results of the current study revealed that high doses of both H.C and dexamethasone increased significantly clotting time in APPT test compared to control.…”

Section: Discussionmentioning

confidence: 38%

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Impact of some intravenously administered drugs (paracetamol, hydrocortisone, dexamethasone and amikacin) on coagulation hemostasis (in vitro evaluation study)

2019

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Background: Normally, the coagulation homeostasis prevents bleeding and retain the blood in the vascular system during periods of injury. Unfortunately, pathological factors, drugs or toxins could affect one or more stages of homeostasis mechanisms leading to bleeding or abnormal thrombi. Evaluation of prothrombin time is a favorable test for the screening of extrinsic coagulation mechanism whilst activated partial thromboplastin time measurement is a global coagulation screening method for intrinsic factor. Material and Methods: Blood samples were withdrawn from healthy adults volunteers for clotting times measurements from collected plasma. The effect of paracetamol, hydrocortisone, dexamethasone, and amikacin at different concentrations on coagulation homeostasis was in vitro investigated and compared to control and positive control. Results: High concentrations of all tested drugs except amikacin prolong significantly activated partial thromboplastin time, whilst the effect on the prothrombin time was conflicting. Conclusions: Paracetamol, hydrocortisone, dexamethasone, and amikacin could prolong clotting time expressed in prolongation of activated partial thromboplastin time comparable to the anticoagulants drugs.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 38%

Impact of some intravenously administered drugs (paracetamol, hydrocortisone, dexamethasone and amikacin) on coagulation hemostasis (in vitro evaluation study)

2019

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“…A recent study proposed that GC modulation of ATIII could represent a low-cost alternative to exogenous ATIII supplementation in several non-specific conditions when endogenous AT activity is decreased (e.g. in the early post-operative period following major surgery) (83).…”

Section: Coagulation Regulators: Protein C Protein S and Atiiimentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: The spectrum of haemostatic abnormalities in glucocorticoid excess and defect

Isidori

Minnetti

Sbardella

et al. 2015

European Journal of Endocrinology

101

107

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Glucocorticoids (GCs) target several components of the integrated system that preserves vascular integrity and free blood flow. Cohort studies on Cushing's syndrome (CS) have revealed increased thromboembolism, but the pathogenesis remains unclear. Lessons from epidemiological data and post-treatment normalisation time suggest a bimodal action with a rapid and reversible effect on coagulation factors and an indirect sustained effect on the vessel wall. The redundancy of the steps that are potentially involved requires a systematic comparison of data from patients with endogenous or exogenous hypercortisolism in the context of either inflammatory or non-inflammatory disorders. A predominant alteration in the intrinsic pathway that includes a remarkable rise in factor VIII and von Willebrand factor (vWF) levels and a reduction in activated partial thromboplastin time appears in the majority of studies on endogenous CS. There may also be a rise in platelets, thromboxane B2, thrombin-antithrombin complexes and fibrinogen (FBG) levels and, above all, impaired fibrinolytic capacity. The increased activation of coagulation inhibitors seems to be compensatory in order to counteract disseminated coagulation, but there remains a net change towards an increased risk of venous thromboembolism (VTE). Conversely, GC administered in the presence of inflammation lowers vWF and FBG, but fibrinolytic activity is also reduced. As a result, the overall risk of VTE is increased in long-term users. Finally, no studies have assessed haemostatic abnormalities in patients with Addison's disease, although these may present as a consequence of bilateral adrenal haemorrhage, especially in the presence of antiphospholipid antibodies or anticoagulant treatments. The present review aimed to provide a comprehensive overview of the complex alterations produced by GCs in order to develop better screening and prevention strategies against bleeding and thrombosis.

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“…A new therapeutic target could be the pharmacological modulation of endogenous AT synthesis as this would provide an alternative to purified (or recombinant) AT supplementation. This strategy could be more efficient than exogenous supplementation ( Barettino et al, 2015 ) to avoid the AT overcorrection observed ( Ranucci et al, 2013 ). Following this assumption, we analyzed the regulatory elements present in the SERPINC1 , encoding AT.…”

Section: Introductionmentioning

confidence: 99%

“…Our preliminary results showed that several compounds activating NHRs were able to increase the expression of SERPINC1 in human HepG2 hepatoma cells. In particular, retinoids activating the Retinoid X Receptor (RXR), glucocorticoids (methyl-prednisolone, cortisone or dexamethasone) and the Farnesoid X Receptor (FXR) ligand GW4064 appeared as the best activators of AT expression ( Barettino et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Dexamethasone Preconditioning in Cardiac Procedures Reduces Decreased Antithrombin Activity and Is Associated to Beneficial Outcomes: Role of Endothelium

et al. 2018

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Introduction: Decreased antithrombin (AT) activity in patients scheduled for cardiovascular surgery under cardiopulmonary bypass (CPB) is related to increased postoperative complications and hospitalization time. Indirect evidence suggests that glucocorticoids mitigate this decreased AT activity. To better understand the beneficial effects of AT we have analyzed: (i) the clinical relevance of acute dexamethasone (DX) administration before cardiac surgery on AT activity, (ii) the modulation by DX of AT expression in human endothelial cells (hECs), (iii) the activity of AT on migration and angiogenesis of hECs, or on angiogenesis of rat aorta.Methods: A retrospective cohort study in patients undergoing aortic valve replacement surgery was designed to evaluate the effect of DX administration on AT activity at five separate time points: preoperatively, during CPB, at intensive care unit admission and at 12 and 24 h post-intervention. We have analyzed also clinical differences in postoperative outcomes as safety and the length of stay in hospitalization. Changes in mRNA levels of AT induced by DX were determined by qRT-PCR in human coronary (hCEC), aorta (hAEC) and cardiac microvasculature (hCMEC) endothelial cells. AT activity on migration and angiogenesis were also assayed. Angiogenic growth of rat aortic rings incubated in Matrigel® was determined in presence and absence of AT.Results: The cohort comprised 51 patients in the control group and 29 patients in the group receiving dexamethasone. Preoperative DX supplementation reduced intraoperative decrease of AT activity (67.71 ± 10.49% DX treated vs. 58.12 ± 9.11% untreated, p < 0.001) that could be related to a decrease in the hospitalization time (7.59 ± 4.08 days DX treated vs. 13.59 ± 16.00 days untreated, p = 0.014). Treatment of hECs with 500 nM DX slightly increased AT expression. Incubation with 0.5 and 1 IU/mL of AT increased migration and angiogenesis in hCAECs and hAECs, but not in hCMECs. The same concentrations of AT potentiated angiogenic sprouting of new vessels from rat aorta.Conclusion: Preoperative DX supplementation could be an interesting procedure to avoid excessive decrease in AT levels during cardiac surgery. Positive outcomes associated with maintaining adequate AT levels could be related to its potential beneficial effect on endothelial function (migration and angiogenesis).

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Glucocorticoids as modulators of expression and activity of Antithrombin (At): Potential clinical relevance

Cited by 7 publications

References 33 publications

Impact of some intravenously administered drugs (paracetamol, hydrocortisone, dexamethasone and amikacin) on coagulation hemostasis (in vitro evaluation study)

Impact of some intravenously administered drugs (paracetamol, hydrocortisone, dexamethasone and amikacin) on coagulation hemostasis (in vitro evaluation study)

MECHANISMS IN ENDOCRINOLOGY: The spectrum of haemostatic abnormalities in glucocorticoid excess and defect

Dexamethasone Preconditioning in Cardiac Procedures Reduces Decreased Antithrombin Activity and Is Associated to Beneficial Outcomes: Role of Endothelium

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