Evidencia y controversias sobre el ácido tranexámico: una revisión ilustrada / Tranexamic acid evidence and controversies: An illustrated review

1. Tranexamic acid evidence and controversies: An illustrated review

TXA ILLUSTRATED REVIEW

Tranexamic acid evidence and controversies: An illustrated review

Nicole Relke MD,Nicholas L. J. Chornenki MD,Michelle Sholzberg MDCM, MSc, FRCPC

First published: 14 July 2021 https://doi.org/10.1002/rth2.12546Citations: 3

Handling Editor: Alisa Wolberg.

download PDF 

Resumen

El ácido tranexámico (TXA) es un agente antifibrinolítico comúnmente utilizado para el tratamiento o prevención de hemorragias. Las indicaciones para TXA son diversas, incluyendo sangrado menstrual abundante, traumatismo, hemorragia posparto, lesión cerebral traumática y sangrado en el sitio quirúrgico. A pesar de décadas de uso y un sólido cuerpo de evidencia, las dudas sobre el uso de TXA persisten en muchos entornos clínicos. Esta revisión ilustrada describe la historia, la farmacología y las consideraciones prácticas del uso de TXA. También describimos los principales ensayos controlados aleatorizados de TXA y sus implicaciones. Finalmente, revisamos la evidencia sobre controversias comunes en torno al ATX, como el riesgo de trombosis, la prescripción junto con anticonceptivos hormonales combinados y el uso en pacientes con hematuria macroscópica.

Esenciales

El ácido tranexámico (TXA) disminuye el riesgo de sangrado y, a menudo, el riesgo de muerte por sangrado.

En general, TXA no aumenta el riesgo de coágulos de sangre.

Considere la posibilidad de tomar decisiones compartidas en pacientes que toman ATX y anticonceptivos hormonales combinados.

Se desconoce si el TXA causa daño en pacientes con sangre en la orina.

Abstract

Tranexamic acid (TXA) is an antifibrinolytic agent commonly used for the treatment or prevention of bleeding. Indications for TXA are diverse, including heavy menstrual bleeding, trauma, postpartum hemorrhage, traumatic brain injury, and surgical site bleeding. Despite decades of use and a robust body of evidence, hesitancy using TXA persists in many clinical settings. This illustrated review describes the history, pharmacology, and practical considerations of TXA use. We also describe the major landmark randomized controlled trials of TXA and their implications. Finally, we review the evidence around common controversies surrounding TXA such as the risk of thrombosis, prescription along with combined hormonal contraceptives, and use in patients with gross hematuria.

Essentials

Tranexamic acid (TXA) decreases the risk of bleeding and often the risk of death from bleeding.

In general, TXA does not increase the risk of blood clots.

Consider shared decision making in patients taking TXA and combined hormonal contraceptives.

It is unknown if TXA causes harm in patients with blood in the urine.

ACKNOWLEDGMENTS

Select images in this review were taken from https://smart.servier.com and are licensed under a Creative Commons Attribution 3.0 Unported License. Blood drop image (pages 1, 4-5, 9-11) was purchased from shutterstock (stock vector ID: 641207020)

RELATIONSHIP DISCLOSURE

The authors declare no conflicts of interest.

AUTHOR CONTRIBUTIONS

NR and MS conceived and designed the manuscript. NR, NLJC, and MS wrote the paper.

REFERENCES

1Watts G. Utako Okamoto (Obituary). Lancet. 2016; 387: 2286.

CrossrefPubMedWeb of Science®Google Scholar

2Okamoto S, Okamoto U. Amino-methyl-cyclohexane-carboxylic acid: AMCHA. A new potent inhibitor of fibrinolysis. Keio J Med. 1962; 11: 105- 115.

CrossrefCASGoogle Scholar

3Olldashi F, Kerçi M, Zhurda T, et al. Effects of tranexamic acid on death, vascular occlusive events, and blood transfusion in trauma patients with significant haemorrhage (CRASH-2): a randomised, placebo-controlled trial. Lancet. 2010; 376: 23- 32.

CrossrefPubMedWeb of Science®Google Scholar

4 WHO Expert Committee. The selection and use of essential medicines (including the 17th WHO model list of essential medicines). WHO Tech Rep Ser [Internet]. 2011; 2011: 1- 249.

Google Scholar

5Shakur H, Roberts I, Fawole B, et al. Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial. Lancet. 2017; 389: 2105- 2116.

CrossrefCASPubMedWeb of Science®Google Scholar

6Thibault GE. Women in academic medicine. Acad Med. 2016; 91: 1045- 1046.

CrossrefPubMedWeb of Science®Google Scholar

7Mannucci PM. Hemostatic drugs. NEJM. 1998; 339; 245- 253.

CrossrefCASPubMedWeb of Science®Google Scholar

8Chapin JC, Hajjar KA. Fibrinolysis and the control of blood coagulation. Blood Rev. 2015; 29: 17- 24.

CrossrefCASPubMedWeb of Science®Google Scholar

9Lin H, Xu L, Yu S, Hong W, Huang M, Xu P. Therapeutics targeting the fibrinolytic system. Exp Mol Med. 2020; 52: 367- 379.

CrossrefCASPubMedWeb of Science®Google Scholar

10Linkins LA, Takach LS. Review of D-dimer testing: Good, Bad, and Ugly. Int J Lab Hematol. 2017; 39: 98- 103.

Wiley Online LibraryPubMedWeb of Science®Google Scholar

11Johnson ED, Schell JC, Rodgers GM. The D-dimer assay. Am J Hematol. 2019; 94: 833- 839.

Wiley Online LibraryPubMedWeb of Science®Google Scholar

12Tengborn L, Blombäck M, Berntorp E. Tranexamic acid - an old drug still going strong and making a revival. Thromb Res. 2015; 135: 231- 242.

CrossrefCASPubMedWeb of Science®Google Scholar

13Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008; 336: 924- 926.

CrossrefPubMedWeb of Science®Google Scholar

14Novikova N, Hofmeyr GJ, Cluver C. Tranexamic acid for preventing postpartum haemorrhage. Cochrane Database Syst Rev. 2015; 1- 62.

Web of Science®Google Scholar

15Myles PS, Smith JA, Forbes A, et al. Tranexamic acid in patients undergoing coronary-artery surgery. N Engl J Med. 2017; 376: 136- 148.

CrossrefCASPubMedWeb of Science®Google Scholar

16 Collaborators C-3 trial. Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial. Lancet. 2019; 394: 1713- 1723.

CrossrefPubMedWeb of Science®Google Scholar

17Ac B, Lethaby A, Farquhar C, Hickey M. Antifibrinolytics for heavy menstrual bleeding (Review). Cochrane Database Syst Rev. 2018; 1- 76.

Web of Science®Google Scholar

18La S, Warner GT, Cope E. Treatment of menorrhagia with tranexamic acid. a double-blind trial summary: a double-blind trial. Br Med J. 1970; 4: 214- 216.

CrossrefPubMedGoogle Scholar

19Lukes A, Moore K, Muse K, Gersten J. Tranexamic acid treatment for heavy menstrual bleeding. J Obstet Gynecol. 2010; 116: 865- 867.

CrossrefGoogle Scholar

20Sprigg N, Flaherty K, Appleton JP, et al. Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage (TICH-2): an international randomised, placebo-controlled, phase 3 superiority trial. The Lancet. 2018; 391: 2107- 2115. https://doi.org/10.1016/S0140-6736(18)31033-X

CrossrefCASPubMedWeb of Science®Google Scholar

21Wand O, Guber E, Guber A, Epstein Shochet G, Israeli-Shani L, Shitrit D. Inhaled tranexamic acid for hemoptysis treatment. Chest. 2018; 154: 1379- 1384. https://doi.org/10.1016/j.chest.2018.09.026

CrossrefPubMedWeb of Science®Google Scholar

22Calvo GS, De Granda-Orive I, Padilla DL. Inhaled tranexamic acid as an alternative for hemoptysis treatment. Chest. 2016; 149: 604. https://doi.org/10.1016/j.chest.2015.10.016

CrossrefPubMedWeb of Science®Google Scholar

23Kagoma YK, Crowther MA, Douketis J, Bhandari M, Eikelboom J, Lim W. Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic surgery: a systematic review of randomized trials. Thromb Res. 2009; 123: 687- 696.

CrossrefCASPubMedWeb of Science®Google Scholar

24Wang Z, Zhang H. Comparative effectiveness and safety of tranexamic acid plus diluted epinephrine to control blood loss during total hip arthroplasty: a meta-analysis. J Orthop Surg Res. 2018; 13: 1- 11.

CrossrefPubMedWeb of Science®Google Scholar

25Morimoto Y, Yoshioka A, Sugimoto M, Imai Y, Kirita T. Haemostatic management of intraoral bleeding in patients with von Willebrand disease. Oral Dis. 2005; 11: 243- 248.

Wiley Online LibraryCASPubMedWeb of Science®Google Scholar

26Eghbali A, Melikof L, Taherahmadi H, Bagheri B. Efficacy of tranexamic acid for the prevention of bleeding in patients with von Willebrand disease and Glanzmann thrombasthenia: a controlled, before and after trial. Haemophilia. 2016; 22: e423- e426.

Wiley Online LibraryCASPubMedWeb of Science®Google Scholar

27Montroy J, Hutton B, Moodley P, et al. The efficacy and safety of topical tranexamic acid: a systematic review and meta-analysis. Transfus Med Rev. 2018; 32: 165- 178.

CrossrefWeb of Science®Google Scholar

28Zahed R, Mousavi Jazayeri MH, Naderi A, Naderpour Z, Saeedi M. Topical tranexamic acid compared with anterior nasal packing for treatment of epistaxis in patients taking antiplatelet drugs: randomized controlled trial. Acad Emerg Med. 2018; 25: 261- 266.

Wiley Online LibraryPubMedWeb of Science®Google Scholar

29Joseph J, Martinez-Devesa P, Bellorini J, Burton MJ. Tranexamic acid for patients with nasal haemorrhage (epistaxis). Cochrane Database Syst Rev. 2018; 2018: 1- 38.

Google Scholar

30Geisthoff UW, Seyfert UT, Kübler M, Bieg B, Plinkert PK, König J. Treatment of epistaxis in hereditary hemorrhagic telangiectasia with tranexamic acid - a double-blind placebo-controlled cross-over phase IIIB study. Thromb Res. 2014; 134: 565- 571.

CrossrefCASPubMedWeb of Science®Google Scholar

31Shpilberg O, Blumenthal R, Sofer O, et al. A controlled trial of tranexamic acid therapy for the reduction of bleeding during treatment of acute myeloid leukemia. Leuk Lymphoma. 1995; 19: 141- 144.

CrossrefCASPubMedWeb of Science®Google Scholar

32Avvisati G, Büller HR, Ten CJW, Mandelli F. Tranexamic acid for control of haemorrhage in acute promyelocytic leukaemia. Lancet. 1989; 334: 122- 124.

CrossrefGoogle Scholar

33Kim HJ, Moon SH, Cho SH, Lee JD, Kim HS. Efficacy and safety of tranexamic acid in melasma: a meta-analysis and systematic review. Acta Derm Venereol. 2017; 97: 776- 781.

CrossrefCASPubMedWeb of Science®Google Scholar

34Compels MM, Lock RJ. C1 inhibitor deficiency: management. Clin Exp Dermatol. 2005; 30: 737- 740.

Wiley Online LibraryPubMedWeb of Science®Google Scholar

35Sentilhes L, Winer N, Azria E, et al. Tranexamic acid for the prevention of blood loss after vaginal delivery. N Engl J Med. 2018; 379: 731- 742.

CrossrefCASPubMedWeb of Science®Google Scholar

36Sentilhes L, Daniel V, Deneux-Tharaux C. TRAAP2-TRAnexamic Acid for Preventing postpartum hemorrhage after cesarean delivery: a multicenter randomized, doubleblind, placebo-controlled trial-a study protocol. BMC Pregnancy Childbirth. 2020; 20: 1- 11.

CrossrefWeb of Science®Google Scholar

37Ker K, Roberts I, Chaudhri R, et al. Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: study protocol for an international, randomised, double-blind, placebo-controlled trial. Trials. 2018; 19: 1- 19.

CrossrefPubMedWeb of Science®Google Scholar

38 Pfizer Canada. Product Monograph: Cyklokapron [Internet]; 2018. https://www.pfizer.ca/cyklokapron-tranexamic-acid (accessed December 16, 2020).

Google Scholar

39 Tranexamic acid. FDA. [Internet]; 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212020lbl.pdf (accessed January 25, 2021).

Google Scholar

40Muse K, Lukes AS, Gersten J, Waldbaum A, Mabey RG, Trott E. Long-term evaluation of safety and health-related quality of life in women with heavy menstrual bleeding treated with oral tranexamic acid. Women’s Heal. 2011; 7: 699- 707.

CrossrefCASPubMedGoogle Scholar

41Lecker I, Wang DS, Whissell PD, Avramescu S, Mazer CD, Orser BA. Tranexamic acid-associated seizures: causes and treatment. Ann Neurol. 2016; 79: 18- 26.

Wiley Online LibraryCASPubMedWeb of Science®Google Scholar

42Gofton TE, Chu MWA, Norton L, et al. A prospective observational study of seizures after cardiac surgery using continuous EEG monitoring. Neurocrit Care. 2014; 21: 220- 227.

CrossrefPubMedWeb of Science®Google Scholar

43Manji RA, Grocott HP, Leake J, et al. Seizures following cardiac surgery: the impact of tranexamic acid and other risk factors. Can J Anesth. 2012; 59: 6- 13.

CrossrefPubMedWeb of Science®Google Scholar

44Kalavrouziotis D, Voisine P, Mohammadi S, Dionne S, Dagenais F. High-dose tranexamic acid is an independent predictor of early seizure after cardiopulmonary bypass. Ann Thorac Surg [Internet]. 2012; 93: 148- 154. https://doi.org/10.1016/j.athoracsur.2011.07.085

CrossrefPubMedWeb of Science®Google Scholar

45Lin Z, Xiaoyi Z. Tranexamic acid-associated seizures: a meta-analysis. Seizure [Internet]. 2016; 36: 70- 73. https://doi.org/10.1016/j.seizure.2016.02.011

CrossrefPubMedWeb of Science®Google Scholar

46Baharoglu MI, Germans MR, Rinkel GJE, et al. Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev. 2013; 2013.

Google Scholar

47Imbesi S, Nettis E, Minciullo PL, et al. Hypersensitivity to tranexamic acid: a wide spectrum of adverse reactions. Pharm World Sci. 2010; 32: 416- 419.

CrossrefCASPubMedWeb of Science®Google Scholar

48Li PH, Trigg C, Rutkowski R, Rutkowski K. Anaphylaxis to tranexamic acid—a rare reaction to a common drug. J Allergy Clin Immunol Pract [Internet]. 2017; 5: 839- 841. https://doi.org/10.1016/j.jaip.2016.12.014

CrossrefPubMedWeb of Science®Google Scholar

49Connolly ES, Rabinstein AA, Carhuapoma JR, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2012; 43: 1711- 1737.

CrossrefPubMedWeb of Science®Google Scholar

50Post R, Germans MR, Tjerkstra MA, et al. Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial. Lancet. 2020; 6736: 1- 7.

Google Scholar

51Hallberg L, Högdahl AM, Nilsson L, Rybo G. Menstrual blood loss—a population study. Variation at different ages and attempts to define normality. Obstet Gynecol Surv. 1967; 22: 653- 654.

CrossrefGoogle Scholar

52 Heavy menstrual bleeding clinical guideline 2007. National Collaborating Centre for Women’s and Children’s Health. NICE; 2007.

Google Scholar

53Connell NT, Flood VH, Brignardello-Petersen R, et al. ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease. Blood Adv. 2021; 5: 301- 325.

CrossrefCASPubMedWeb of Science®Google Scholar

54Kouides PA, Byams VR, Philipp CS, et al. Multisite management study of menorrhagia with abnormal laboratory haemostasis: a prospective crossover study of intranasal desmopressin and oral tranexamic acid. Br J Haematol. 2009; 145: 212- 220.

Wiley Online LibraryCASPubMedWeb of Science®Google Scholar

55Roberts I, Shakur-Still H, Afolabi A, et al. Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial. Lancet. 2020; 395: 1927- 1936.

CrossrefPubMedWeb of Science®Google Scholar

56Roberts LN. Tranexamic acid in acute gastrointestinal bleeding – a cautionary tale. J Thromb Haemost. 2020; 18: 2440- 2443.

Wiley Online LibraryCASPubMedWeb of Science®Google Scholar

57Blasi A, Patel VC, Adelmeijer J, et al. Mixed fibrinolytic phenotypes in decompensated cirrhosis and acute-on-chronic liver failure with hypofibrinolysis in those with complications and poor survival. Hepatology. 2020; 71: 1381- 1390.

Wiley Online LibraryCASPubMedWeb of Science®Google Scholar

58Lisman T, De Groot PG, Meijers JCM, Rosendaal FR. Reduced plasma fibrinolytic potential is a risk factor for venous thrombosis. Blood. 2005; 105: 1102- 1105.

CrossrefCASPubMedWeb of Science®Google Scholar

59Gernsheimer T, Brown SP, Triulzi DJ, et al. Effects of tranexamic acid prophylaxis on bleeding outcomes in hematologic malignancy: the a-TREAT trial. Blood. 2020; 136: 1- 2.

CrossrefPubMedWeb of Science®Google Scholar

60Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981; 47: 207- 214.

Wiley Online LibraryCASPubMedWeb of Science®Google Scholar

61Chornenki NLJ, Um KJ, Mendoza PA, et al. Risk of venous and arterial thrombosis in non-surgical patients receiving systemic tranexamic acid: a systematic review and meta-analysis. Thromb Res [Internet]. 2019; 179: 81- 86. https://doi.org/10.1016/j.thromres.2019.05.003

CrossrefCASPubMedWeb of Science®Google Scholar

62Taeuber I, Weibel S, Herrmann E, et al. Association of intravenous tranexamic acid with thromboembolic events and mortality. A systematic review, meta-analysis, and meta-regression . JAMA Surg. 2021; 156; 1- 14.

CrossrefWeb of Science®Google Scholar

63Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis. BMJ. 2012; 344: 1- 13.

CrossrefGoogle Scholar

64Ker K, Prieto-Merino D, Roberts I. Systematic review, meta-analysis and meta-regression of the effect of tranexamic acid on surgical blood loss. Br J Surg. 2013; 100: 1271- 1279.

Wiley Online LibraryCASPubMedWeb of Science®Google Scholar

65Thorne JG, James PD, Reid RL. Heavy menstrual bleeding: is tranexamic acid a safe adjunct to combined hormonal contraception? Contraception [Internet]. 2018; 98: 1- 3. https://doi.org/10.1016/j.contraception.2018.02.008

CrossrefCASPubMedWeb of Science®Google Scholar

66Heinemann LAJ, Dinger JC. Range of published estimates of venous thromboembolism incidence in young women. Contraception. 2007; 75: 328- 336.

CrossrefPubMedWeb of Science®Google Scholar

67Reid RL, Westhoff C, Mansour D, et al. Oral contraceptives and venous thromboembolism: consensus opinion from an international workshop held in Berlin, Germany in December 2009. J Fam Plan Reprod Heal Care. 2010; 36: 117- 122.

CrossrefPubMedWeb of Science®Google Scholar

68Iacobellis G, Iacobellis G. Combined treatment with tranexamic acid and oral contraceptive pill causes coronary ulcerated plaque and acute myocardial infarction. Cardiovasc Drugs Ther. 2004; 18: 239- 240.

CrossrefCASPubMedWeb of Science®Google Scholar

69Klok FA, Schreiber K, Stach K, et al. Oral contraception and menstrual bleeding during treatment of venous thromboembolism: expert opinion versus current practice. Thromb Res. 2017; 153: 101- 107.

CrossrefCASPubMedWeb of Science®Google Scholar

70Meschino D, Sholzberg M. Evaluating the combined effect of anti-fibrinolytics and estrogen on the risk of thromboembolism: a scoping review. Available from: osf.io/edj28

Google Scholar

71Vujkovac B, Sabovic M. A successful treatment of life-threatening bleeding from polycystic kidneys with antifibrinolytic agent tranexamic acid. Blood Coagul Fibrinolysis. 2006; 17: 589- 591.

CrossrefPubMedWeb of Science®Google Scholar

72AlAmeel T, West M. Tranexamic acid treatment of life-threatening hematuria in polycystic kidney disease. Int J Nephrol. 2011; 2011: 1- 3.

CrossrefGoogle Scholar

73Peces R, Aguilar A, Vega C. Medical therapy with tranexamic acid in autosomal dominant polycystic kidney disease patients with severe haematuria. Nefrologia. 2012; 32: 160- 165.

PubMedWeb of Science®Google Scholar

74Lee S, Fralick M, Sholzberg M, et al. Systematic-review of Hematuria and Acute Renal-failure with cycloKapron (SHARK); 2020.

Google Scholar

Citing Literature

Number of times cited according to CrossRef: 3

Stephanie G. Lee, John Fralick, Christopher J. D. Wallis, Monica Boctor, Michelle Sholzberg, Michael Fralick, Systematic review of hematuria and acute renal failure with tranexamic acid, European Journal of Haematology, 10.1111/ejh.13762, 108, 6, (510-517), (2022).

Wiley Online Library

Sarah Nersesian, Michelle Sholzberg, Mary Cushman, Alisa S. Wolberg, The Journey to a Successful Illustrated Review, Research and Practice in Thrombosis and Haemostasis, 10.1002/rth2.12721, 6, 4, (2022).

Wiley Online Library

Giuliana D’Aulerio, Nagendra N. Dudi‐Venkata, Chris Varghese, Uyen G. Vo, Peter Pockney, Toby Richards, David I. Watson, Deborah Wright, Doug Robb, Liam Ferguson, Jana‐Lee Moss, William Xu, Bridget Hwang, Laure Taher Mansour, Warren Seow, Scott Gelzinnis, Joel Seto, Cameron I. Wells, José Antonio García‐Erce, James Glasbey, Sivesh K. Kamarajah, Kenneth McLean, Ane Abad Motos, Francesco Pata, Gianluca Pellino, Javier Ripolles, Postoperative variations in anaemia treatment and transfusions (POSTVenTT): protocol for a prospective multicentre observational cohort study of anaemia after major abdominal surgery, Colorectal Disease, 10.1111/codi.15902, 24, 2, (228-234), (2021).

Wiley Online Library

You could be interested TXA en el campo: usos, protocolos y por qué debe considerarse para pacientes con shock y trauma / TXA in the field: Uses, protocols and why it should be considered for shock, trauma patients

Dr Ramon REYES, MD,
Por favor compartir nuestras REDES SOCIALES @DrRamonReyesMD, así podremos llegar a mas personas y estos se beneficiarán de la disponibilidad de estos documentos, pdf, e-book, gratuitos y legales..

Grupo Biblioteca/PDFs gratis en Facebook

https://www.facebook.com/groups/PDFgratisMedicina #DrRamonReyesMD

Facebook
https://www.facebook.com/DrRamonReyesMD

Instagram
https://www.instagram.com/drramonreyesmd/

Pinterest
https://www.pinterest.es/DrRamonReyesMD/

LinkedIn
https://www.linkedin.com/in/drramonreyes/

Twitter
https://twitter.com/eeiispain

Blog
http://emssolutionsint.blogspot.com/2016/12/dr-ramon-reyes-diaz-md-emt-t-dmo.html

TELEGRAM
Group https://t.me/joinchat/GRsTvEHYjNLP8yc6gPXQ9Q