Effect of 10-Day Treatment with 50 mg Prednisolone Once-Daily on Haemostasis in Healthy Men-A Randomised Placebo-Controlled Trial

Peter Kamstrup, Ema Rastoder, Pernille Høgh Hellmann, Pradeesh Sivapalan, Emil List Larsen, Jørgen Vestbo, Charlotte Suppli Ulrik, Jens P Goetze, Filip Krag Knop, Jens Ulrik Stæhr Jensen, Peter Kamstrup, Ema Rastoder, Pernille Høgh Hellmann, Pradeesh Sivapalan, Emil List Larsen, Jørgen Vestbo, Charlotte Suppli Ulrik, Jens P Goetze, Filip Krag Knop, Jens Ulrik Stæhr Jensen

Abstract

Synthetic corticosteroids are widely used due to their anti-inflammatory and immunosuppressant effects. Their use has been associated with venous thromboembolism, but it is unknown whether thromboembolism has a causal relationship with corticosteroid treatment. In a randomised, double-blind, placebo-controlled trial in normal to overweight healthy men, the effect of the corticosteroid prednisolone on haemostasis using either 50 mg prednisolone or matching placebo once daily for ten days was investigated. The primary outcome was a change from baseline in the viscoelastic measurement maximal amplitude of clot in kaolin-activated thromboelastography (TEG). Changes from baseline in other TEG measurements, D-dimer, von Willebrand factor (VWF) antigen, and ristocetin cofactor activity (RCo), antithrombin, protein C, prothrombin, fibrinogen, INR, APTT, and platelet count were secondary outcomes. Thirty-four men participated in this study. Compared to placebo, prednisolone treatment did not affect maximal amplitude of clot (difference -0.77 (95% confidence interval (CI) -2.48, 0.94) mm, p = 0.37, missing: n = 2), but it altered VWF antigen (28%, p = 0.0004), VWF:RCo (19%, p = 0.0006), prothrombin (5%, p = 0.05), protein C (31%, p < 0.0001), antithrombin (5%, p = 0.013), and fibrinogen (-15%, p = 0.004). Thus, prednisolone treatment did not alter TEG-assessed maximal amplitude of clot, despite that it affected prothrombotic markers (increased prothrombin, VWF antigen, VWF:RCo, prothrombin, and decreased fibrinogen) and increased antithrombotic markers (protein C and antithrombin).

Keywords: biomarkers; glucocorticoids; haemostasis; healthy volunteers; randomised controlled trial; thromboelastography.

Conflict of interest statement

C.S.U. has received grants from Sanofi, Boehringer Ingelheim, AstraZeneca, and Novartis and speaker fees from Orion Pharma, AstraZeneca, and TEVA and consulting fees from Chiesi, Orion Pharma, AstraZeneca, GSK, and TEVA, and been on advisory boards for Novartis, Sanofi, Glaxo-Smith Kline, Chiesi, AstraZeneca, and Boehringer Ingelheim. All other authors report no conflict of interest.

Figures

Figure 1
Figure 1
Study flowchart.
Figure 2
Figure 2
Spaghetti and scatter plots for the thromboelastography measurements split into the two treatment groups—before and after treatment. Red line denotes mean at baseline and EoT. Abbreviations: EoT: end of treatment.
Figure 3
Figure 3
Spaghetti and scatter plots for the primary haemostasis measurements. Split into the two treatment groups—before and after treatment. Red line denotes mean at baseline and EoT. Abbreviations: EoT: end of treatment; VWF: von Willebrand factor; kIU/L: kilo international units per litre.
Figure 4
Figure 4
Spaghetti and scatter plots for the secondary haemostasis measurements. Split into the two treatment groups—at baseline and end of treatment. Red line denotes mean at baseline and EoT Abbreviations: INR: international normalised ratio; EoT: end of treatment; APTT: activated partial thromboplastin clotting time; kIU/L: kilo international units per litre; FEU: fibrin equivalent unit.
Figure 5
Figure 5
Combined spaghetti and scatterplots for the regulatory mechanism measurements. Split into the two treatment groups—at baseline and end of treatment. Red line denotes mean at baseline and EoT. Abbreviations: kIU/L: kilo international units per litre; EoT: end of treatment.

References

    1. Hodgens A., Sharman T. StatPearls. StatPearls Publishing; Treasure Island, FL, USA: 2022. Corticosteroids.
    1. Li J.X., Cummins C.L. Fresh insights into glucocorticoid-induced diabetes mellitus and new therapeutic directions. Nat. Rev. Endocrinol. 2022;18:540–557. doi: 10.1038/s41574-022-00683-6.
    1. Isidori A.M., Minnetti M., Sbardella E., Graziadio C., Grossman A.B. Mechanisms in endocrinology: The spectrum of haemostatic abnormalities in glucocorticoid excess and defect. Eur. J. Endocrinol. 2015;173:R101–R113. doi: 10.1530/EJE-15-0308.
    1. Fardet L., Feve B. Systemic glucocorticoid therapy: A review of its metabolic and cardiovascular adverse events. Drugs. 2014;74:1731–1745. doi: 10.1007/s40265-014-0282-9.
    1. Johannesdottir S.A., Horvath-Puho E., Dekkers O.M., Cannegieter S.C., Jorgensen J.O., Ehrenstein V., Vandenbroucke J.P., Pedersen L., Sorensen H.T. Use of glucocorticoids and risk of venous thromboembolism: A nationwide population-based case-control study. JAMA Intern. Med. 2013;173:743–752. doi: 10.1001/jamainternmed.2013.122.
    1. Stuijver D.J.F., Majoor C.J., van Zaane B., Souverein P.C., de Boer A., Dekkers O.M., Buller H.R., Gerdes V.E.A. Use of oral glucocorticoids and the risk of pulmonary embolism: A population-based case-control study. Chest. 2013;143:1337–1342. doi: 10.1378/chest.12-1446.
    1. Wei L., MacDonald T.M., Walker B.R. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann. Intern. Med. 2004;141:764–770. doi: 10.7326/0003-4819-141-10-200411160-00007.
    1. Souverein P.C., Berard A., Van Staa T.P., Cooper C., Egberts A.C., Leufkens H.G., Walker B.R. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population based case-control study. Heart. 2004;90:859–865. doi: 10.1136/hrt.2003.020180.
    1. Majoor C.J., Sneeboer M.M., de Kievit A., Meijers J.C., van der Poll T., Lutter R., Bel E.H., Kamphuisen P.W. The influence of corticosteroids on hemostasis in healthy subjects. J. Thromb. Haemost. 2016;14:716–723. doi: 10.1111/jth.13265.
    1. Brotman D.J., Girod J.P., Posch A., Jani J.T., Patel J.V., Gupta M., Lip G.Y., Reddy S., Kickler T.S. Effects of short-term glucocorticoids on hemostatic factors in healthy volunteers. Thromb. Res. 2006;118:247–252. doi: 10.1016/j.thromres.2005.06.006.
    1. Jilma B., Cvitko T., Winter-Fabry A., Petroczi K., Quehenberger P., Blann A.D. High dose dexamethasone increases circulating P-selectin and von Willebrand factor levels in healthy men. Thromb. Haemost. 2005;94:797–801. doi: 10.1160/TH04-10-0652.
    1. Perry C.G., Spiers A., Cleland S.J., Lowe G.D., Petrie J.R., Connell J.M. Glucocorticoids and insulin sensitivity: Dissociation of insulin’s metabolic and vascular actions. J. Clin. Endocrinol. Metab. 2003;88:6008–6014. doi: 10.1210/jc.2002-021605.
    1. Hartmann J., Hermelin D., Levy J.H. Viscoelastic testing: An illustrated review of technology and clinical applications. Res. Pract. Thromb. Haemost. 2023;7:100031. doi: 10.1016/j.rpth.2022.100031.
    1. Coelho M.C., Vieira Neto L., Kasuki L., Wildemberg L.E., Santos C.V., Castro G., Gouvea G., Veloso O.C., Gadelha T., Gadelha M.R. Rotation thromboelastometry and the hypercoagulable state in Cushing’s syndrome. Clin. Endocrinol. 2014;81:657–664. doi: 10.1111/cen.12491.
    1. Swiatkowska-Stodulska R., Skibowska-Bielinska A., Wisniewski P., Sworczak K. Activity of selected coagulation factors in overt and subclinical hypercortisolism. Endocr. J. 2015;62:687–694. doi: 10.1507/endocrj.EJ14-0539.
    1. Kastelan D., Dusek T., Kraljevic I., Aganovic I. Hypercoagulable state in Cushing’s syndrome is reversible following remission. Clin. Endocrinol. 2013;78:102–106. doi: 10.1111/j.1365-2265.2012.04479.x.
    1. van der Pas R., de Bruin C., Leebeek F.W., de Maat M.P., Rijken D.C., Pereira A.M., Romijn J.A., Netea-Maier R.T., Hermus A.R., Zelissen P.M., et al. The hypercoagulable state in Cushing’s disease is associated with increased levels of procoagulant factors and impaired fibrinolysis, but is not reversible after short-term biochemical remission induced by medical therapy. J. Clin. Endocrinol. Metab. 2012;97:1303–1310. doi: 10.1210/jc.2011-2753.
    1. Van Zaane B., Nur E., Squizzato A., Dekkers O.M., Twickler M.T., Fliers E., Gerdes V.E., Buller H.R., Brandjes D.P. Hypercoagulable state in Cushing’s syndrome: A systematic review. J. Clin. Endocrinol. Metab. 2009;94:2743–2750. doi: 10.1210/jc.2009-0290.
    1. Fatti L.M., Bottasso B., Invitti C., Coppola R., Cavagnini F., Mannucci P.M. Markers of activation of coagulation and fibrinolysis in patients with Cushing’s syndrome. J. Endocrinol. Invest. 2000;23:145–150. doi: 10.1007/BF03343697.
    1. Patrassi G.M., Dal Bo Zanon R., Boscaro M., Martinelli S., Girolami A. Further studies on the hypercoagulable state of patients with Cushing’s syndrome. Thromb. Haemost. 1985;54:518–520. doi: 10.1055/s-0038-1657887.
    1. Dal Bo Zanon R., Fornasiero L., Boscaro M., Cappellato G., Fabris F., Girolami A. Increased factor VIII associated activities in Cushing’s syndrome: A probable hypercoagulable state. Thromb. Haemost. 1982;47:116–117.
    1. Klosowski P., Swiatkowska-Stodulska R., Stodulski D., Kaszubowski M., Karaszewski B., Sworczak K. Effect of Glucocorticoid Administration in Intravenous Pulses on Selected Parameters of the Coagulation System. Int. J. Clin. Pract. 2022;2022:3144685. doi: 10.1155/2022/3144685.
    1. van Zaane B., Nur E., Squizzato A., Gerdes V.E., Buller H.R., Dekkers O.M., Brandjes D.P. Systematic review on the effect of glucocorticoid use on procoagulant, anti-coagulant and fibrinolytic factors. J. Thromb. Haemost. 2010;8:2483–2493. doi: 10.1111/j.1538-7836.2010.04034.x.
    1. Costallat L.T., Ribeiro C.C., Annichino-Bizzacchi J.M. Antithrombin, protein S and protein C and antiphospholipid antibodies in systemic lupus erythematosus. Sangre. 1998;43:345–348.
    1. Uddhammar A., Rantapaa-Dahlqvist S., Nilsson T.K. Plasminogen activator inhibitor and von Willebrand factor in polymyalgia rheumatica. Clin. Rheumatol. 1992;11:211–215. doi: 10.1007/BF02207959.
    1. Poredos P., Poredos P. Involvement of Inflammation in Venous Thromboembolic Disease: An Update in the Age of COVID-19. Semin. Thromb. Hemost. 2022;48:93–99. doi: 10.1055/s-0041-1732372.
    1. Ericson-Neilsen W., Kaye A.D. Steroids: Pharmacology, complications, and practice delivery issues. Ochsner. J. 2014;14:203–207.
    1. Hellmann P.H., Bagger J.I., Carlander K.R., Hansen K.B., Forman J.L., Storling J., Chabanova E., Holst J., Vilsboll T., Knop F.K. No effect of the turmeric root phenol curcumin on prednisolone-induced glucometabolic perturbations in men with overweight or obesity. Endocr. Connect. 2023;12:e220334. doi: 10.1530/EC-22-0334.
    1. Dahlback B. Advances in understanding pathogenic mechanisms of thrombophilic disorders. Blood. 2008;112:19–27. doi: 10.1182/blood-2008-01-077909.
    1. Mahmoodi B.K., Brouwer J.L., Ten Kate M.K., Lijfering W.M., Veeger N.J., Mulder A.B., Kluin-Nelemans H.C., Van Der Meer J. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin. J. Thromb. Haemost. 2010;8:1193–1200. doi: 10.1111/j.1538-7836.2010.03840.x.
    1. Emmerich J., Rosendaal F.R., Cattaneo M., Margaglione M., De Stefano V., Cumming T., Arruda V., Hillarp A., Reny J.L. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism. Thromb. Haemost. 2001;86:809–816.
    1. Kerachian M.A., Cournoyer D., Harvey E.J., Chow T.Y., Neagoe P.E., Sirois M.G., Seguin C. Effect of high-dose dexamethasone on endothelial haemostatic gene expression and neutrophil adhesion. J. Steroid. Biochem. Mol. Biol. 2009;116:127–133. doi: 10.1016/j.jsbmb.2009.05.001.
    1. Huang L.Q., Whitworth J.A., Chesterman C.N. Effects of cyclosporin A and dexamethasone on haemostatic and vasoactive functions of vascular endothelial cells. Blood. Coagul. Fibrinolysis. 1995;6:438–445. doi: 10.1097/00001721-199507000-00011.
    1. Fish R.J., Neerman-Arbez M. Fibrinogen gene regulation. Thromb. Haemost. 2012;108:419–426. doi: 10.1160/TH12-04-0273.
    1. Barettino D., Masia S., Monto F., Perez P., D’Ocon P., Moreno L., Muedra V. Glucocorticoids as modulators of expression and activity of Antithrombin (At): Potential clinical relevance. Thromb. Res. 2015;135:183–191. doi: 10.1016/j.thromres.2014.10.026.
    1. Molander V., Bower H., Frisell T., Askling J. Risk of venous thromboembolism in rheumatoid arthritis, and its association with disease activity: A nationwide cohort study from Sweden. Ann. Rheum. Dis. 2021;80:169–175. doi: 10.1136/annrheumdis-2020-218419.
    1. Colling M.E., Tourdot B.E., Kanthi Y. Inflammation, Infection and Venous Thromboembolism. Circ. Res. 2021;128:2017–2036. doi: 10.1161/CIRCRESAHA.121.318225.
    1. Wolberg A.S., Aleman M.M., Leiderman K., Machlus K.R. Procoagulant activity in hemostasis and thrombosis: Virchow’s triad revisited. Anesth. Analg. 2012;114:275–285. doi: 10.1213/ANE.0b013e31823a088c.
    1. Quarterman C., Shaw M., Johnson I., Agarwal S. Intra- and inter-centre standardisation of thromboelastography (TEG(R)) Anaesthesia. 2014;69:883–890. doi: 10.1111/anae.12748.
    1. Woodhams B., Girardot O., Blanco M.J., Colesse G., Gourmelin Y. Stability of coagulation proteins in frozen plasma. Blood Coagul. Fibrinolysis. 2001;12:229–236. doi: 10.1097/00001721-200106000-00002.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다