Turkiye Klinikleri Journal of Medical Sciences

.: ORIGINAL RESEARCH
Course of Treatment of Chronic Bleeding and Anemia with Systemic Bevacizumab Treatment in Hereditary Hemorrhagic Telangiectasia: A Retrospective Cohort
Herediter Hemorajik Telenjiyektazide Sistemik Bevasizumab Tedavisiyle Kronik Kanama ve Anemi Tedavisinin Seyri: Bir Retrospektif Kohort
Emine DURAKa , Mehmet Can UĞURb , Füsun GEDİZc
aDepartment of Hematology, Abant İzzet Baysal University İzzet Baysal Training and Research Hospital, Bolu, Türkiye
bDepartment of Hematology, İzmir Bakırçay University Çiğli Training and Research Hospital, İzmir, Türkiye
cDepartment of Internal Medicine, İzmir University of Economics Medicalpoint Hospital, İzmir, Türkiye
Turkiye Klinikleri J Med Sci. 2023;43(3):281-6
doi: 10.5336/medsci.2023-96203
Article Language: EN
Full Text
ABSTRACT
 Objective: Hereditary hemorrhagic telangiectasia (HHT), is an autosomal dominant disorder that causes abnormal angiogenesis. Interest in targeted therapies has been increasing in recent years, especially for the treatment of severe forms of HHT. One of these treatment options is the vascular endothelial growth factor inhibitor bevacizumab. Purpose of this study is to investigate the effect of systemic bevacizumab use on the treatment of chronic bleeding course and anemia in patients diagnosed with HHT. Material and Methods: The treatment response and adverse events of patients with bevacizumab were evaluated retrospectively. Results: The mean age was 51,5. Mean duration of treatment was 15.4 (4-25 months) months. The first 4 doses of 5 mg/kg intravenous bevacizumab were administered at 2-week intervals in all patients. Bevacizumab maintenance continued at a dose of 5 mg/kg in monthly periods. With bevacizumab treatment, an increase in hemoglobin values, a decrease in epistaxis severity score, parenteral iron and erythrocyte transfusion requirement were achieved. Side effects observed were allergic rash in one patient and arthralgia in one patient. None of the patients required discontinuation of treatment due to side effects. Conclusion: Bevacizumab is a promising treatment option in HHT, which can be mortal if not controlled. However, there remains a need for more comprehensive studies in order to achieve a global consensus on treatment protocols and management of adverse events.

Keywords: Bevacizumab; hereditary hemorrhagic telangiectasia; epistaxis
ÖZET
 Amaç: Kalıtsal hemorajik telenjiyektazi (HHT), anormal anjiyogeneze neden olan otozomal dominant bir hastalıktır. Son yıllarda, özellikle şiddetli HHT formlarının tedavisi için hedefe yönelik tedavilere olan ilgi artmaktadır. Bu tedavi seçeneklerinden biri de vasküler endotelyal büyüme faktörü inhibitörü bevasizumabtır. Bu çalışmanın amacı, HHT tanısı alan hastalarda sistemik bevasizumab kullanımının kronik kanama seyri ve anemi tedavisindeki etkisini araştırmaktır. Gereç ve Yöntemler: Bevasizumab kullanan hastaların tedavi yanıtı ve yan etkileri retrospektif olarak değerlendirildi. Bulgular: Hastaların yaş ortalaması 51,5 yıl idi. Ortalama tedavi süresi 15,4 (4-25 ay) aydı. Tüm hastalara 2 hafta arayla ilk 4 doz 5 mg/kg intravenöz bevasizumab uygulandı. Bevasizumab idamesi 5 mg/kg dozunda aylık periyotlarla devam etti. Bevasizumab tedavisi ile hemoglobin değerlerinde artış, epistaksis şiddet skorunda parenteral demir ve eritrosit transfüzyon gereksiniminde azalma sağlandı. Gözlenen yan etkiler, 1 hastada alerjik döküntü ve 1 hastada artralji idi. Yan etkiler nedeniyle hiçbir hastada tedavinin kesilmesi gerekmedi. Sonuç: Bevasizumab, kontrol edilmediği takdirde ölümcül olabilen HHT'de umut verici bir tedavi seçeneğidir. Bununla birlikte, tedavi protokolleri ve advers olayların yönetimi konusunda global konsensus sağlamak için daha kapsamlı çalışmalara ihtiyaç vardır.

Anahtar Kelimeler: Bevasizumab; herediter hemorajik telenjiyektazi; epistaksis
REFERENCES:
  1. Marchuk DA. Genetic abnormalities in hereditary hemorrhagic telangiectasia. Curr Opin Hematol. 1998;5(5):332-8. [Crossref]  [PubMed] 
  2. Westermann CJ, Rosina AF, De Vries V, de Coteau PA. The prevalence and manifestations of hereditary hemorrhagic telangiectasia in the Afro-Caribbean population of the Netherlands Antilles: a family screening. Am J Med Genet A. 2003;116A(4):324-8. [Crossref]  [PubMed] 
  3. Kritharis A, Al-Samkari H, Kuter DJ. Hereditary hemorrhagic telangiectasia: diagnosis and management from the hematologist's perspective. Haematologica. 2018;103(9):1433-43. [Crossref]  [PubMed]  [PMC] 
  4. Richards-Yutz J, Grant K, Chao EC, Walther SE, Ganguly A. Update on molecular diagnosis of hereditary hemorrhagic telangiectasia. Hum Genet. 2010;128(1):61-77. [Crossref]  [PubMed] 
  5. Kühnel T, Wirsching K, Wohlgemuth W, Chavan A, Evert K, Vielsmeier V. Hereditary Hemorrhagic Telangiectasia. Otolaryngol Clin North Am. 2018;51(1):237-54. [Crossref]  [PubMed] 
  6. Brydon HL, Akinwunmi J, Selway R, Ul-Haq I. Brain abscesses associated with pulmonary arteriovenous malformations. Br J Neurosurg. 1999;13(3):265-9. [Crossref]  [PubMed] 
  7. Cho D, Kim S, Kim M, Seo YH, Kim W, Kang SH, et al. Two cases of high output heart failure caused by hereditary hemorrhagic telangiectasia. Korean Circ J. 2012;42(12):861-5. [Crossref]  [PubMed]  [PMC] 
  8. Jessurun GA, Kamphuis DJ, van der Zande FH, Nossent JC. Cerebral arteriovenous malformations in The Netherlands Antilles. High prevalence of hereditary hemorrhagic telangiectasia-related single and multiple cerebral arteriovenous malformations. Clin Neurol Neurosurg. 1993;95(3):193-8. [Crossref]  [PubMed] 
  9. AAssar OS, Friedman CM, White RI Jr. The natural history of epistaxis in hereditary hemorrhagic telangiectasia. Laryngoscope. 1991;101(9):977-80. [Crossref]  [PubMed] 
  10. Shovlin CL, Guttmacher AE, Buscarini E, Faughnan ME, Hyland RH, Westermann CJ, et al. Diagnostic criteria for hereditary hemorrhagic telangiectasia (Rendu-Osler-Weber syndrome). Am J Med Genet. 2000;91(1):66-7. [Crossref]  [PubMed] 
  11. Iyer VN, Apala DR, Pannu BS, Kotecha A, Brinjikji W, Leise MD, et al. Intravenous bevacizumab for refractory hereditary hemorrhagic telangiectasia-related epistaxis and gastrointestinal bleeding. Mayo Clin Proc. 2018;93(2):155-66. Erratum in: Mayo Clin Proc. 2018;93(3):396. [Crossref]  [PubMed] 
  12. Kjeldsen Jens, Fialla Annette D, Tine Rosenberg ADK. Bevacizumab as treatment of bleeding in patients with hereditary haemorrhagic telangiectasia (HHT). Gastroenterology. 2018;154:S701-2. [Crossref] 
  13. Yin LX, Reh DD, Hoag JB, Mitchell SE, Mathai SC, Robinson GM, et al. The minimal important difference of the epistaxis severity score in hereditary hemorrhagic telangiectasia. Laryngoscope. 2016;126(5):1029-32. [Crossref]  [PubMed] 
  14. Lesca G, Olivieri C, Burnichon N, Pagella F, Carette MF, Gilbert-Dussardier B, et al; French-Italian-Rendu-Osler Network. Genotype-phenotype correlations in hereditary hemorrhagic telangiectasia: data from the French-Italian HHT network. Genet Med. 2007;9(1):14-22. [Crossref]  [PubMed] 
  15. Shovlin CL, Simeoni I, Downes K, Frazer ZC, Megy K, Bernabeu-Herrero ME, et al. Mutational and phenotypic characterization of hereditary hemorrhagic telangiectasia. Blood. 2020;136(17):1907-18. [Crossref]  [PubMed]  [PMC] 
  16. Jelsig AM, Kjeldsen A, Christensen LL, Bertelsen B, Karstensen JG, Brusgaard K, et al. Hereditary haemorrhagic telangiectasia in Danish patients with pathogenic variants in SMAD4: a nationwide study. J Med Genet. 2023;60(5):464-8. [Crossref]  [PubMed] 
  17. Guilhem A, Fargeton AE, Simon AC, Duffau P, Harle JR, Lavigne C, et al. Intra-venous bevacizumab in hereditary hemorrhagic telangiectasia (HHT): a retrospective study of 46 patients. PLoS One. 2017;12(11):e0188943. [Crossref]  [PubMed]  [PMC] 
  18. Gaillard S, Dupuis-Girod S, Boutitie F, Rivière S, Morinière S, Hatron PY, et al; ATERO Study Group. Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease. J Thromb Haemost. 2014;12(9):1494-502. [Crossref]  [PubMed] 
  19. Vase P. Estrogen treatment of hereditary hemorrhagic telangiectasia. A double-blind controlled clinical trial. Acta Med Scand. 1981;209(5):393-6. [Crossref]  [PubMed] 
  20. Whitehead KJ, Sautter NB, McWilliams JP, Chakinala MM, Merlo CA, Johnson MH, et al. Effect of topical intranasal therapy on epistaxis frequency in patients with hereditary hemorrhagic telangiectasia: a randomized clinical trial. JAMA. 2016;316(9):943-51. [Crossref]  [PubMed] 
  21. Dupuis-Girod S, Pitiot V, Bergerot C, Fargeton AE, Beaudoin M, Decullier E, et al. Efficacy of TIMOLOL nasal spray as a treatment for epistaxis in hereditary hemorrhagic telangiectasia. A double-blind, randomized, placebo-controlled trial. Sci Rep. 2019;9(1):11986. [Crossref]  [PubMed]  [PMC] 
  22. Cirulli A, Liso A, D'Ovidio F, Mestice A, Pasculli G, Gallitelli M, et al. Vascular endothelial growth factor serum levels are elevated in patients with hereditary hemorrhagic telangiectasia. Acta Haematol. 2003;110(1):29-32. [Crossref]  [PubMed] 
  23. Michels S, Rosenfeld PJ, Puliafito CA, Marcus EN, Venkatraman AS. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration twelve-week results of an uncontrolled open-label clinical study. Ophthalmology. 2005;112(6):1035-47. [Crossref]  [PubMed] 
  24. Bose P, Holter JL, Selby GB. Bevacizumab in hereditary hemorrhagic telangiectasia. N Engl J Med. 2009;360(20):2143-4. [Crossref]  [PubMed] 
  25. Dupuis-Girod S, Ambrun A, Decullier E, Fargeton AE, Roux A, Bréant V, et al. Effect of bevacizumab nasal spray on epistaxis duration in hereditary hemorrhagic telangectasia: a randomized clinical trial. JAMA. 2016;316(9):934-42. [Crossref]  [PubMed] 
  26. Al-Samkari H, Kasthuri RS, Parambil JG, Albitar HA, Almodallal YA, Vázquez C, et al. An international, multicenter study of intravenous bevacizumab for bleeding in hereditary hemorrhagic telangiectasia: the InHIBIT-Bleed study. Haematologica. 2021;106(8):2161-9. [Crossref]  [PubMed]  [PMC] 

.: Up To Date

Login

 Forgot your password?

 New Registration  

Contact

Ortadoğu Reklam Tanıtım Yayıncılık Turizm Eğitim İnşaat Sanayi ve Ticaret A.Ş.

.: Address

Turkocagi Caddesi No:30 06520 Balgat / ANKARA
Phone: +90 312 286 56 56
Fax: +90 312 220 04 70
E-mail: info@turkiyeklinikleri.com

.: Manuscript Editing Department

Phone: +90 312 286 56 56/ 2
E-mail: yaziisleri@turkiyeklinikleri.com

.: English Language Redaction

Phone: +90 312 286 56 56/ 145
E-mail: tkyayindestek@turkiyeklinikleri.com

.: Marketing Sales-Project Department

Phone: +90 312 286 56 56/ 142
E-mail: reklam@turkiyeklinikleri.com

.: Subscription and Public Relations Department

Phone: +90 312 286 56 56/ 118
E-mail: abone@turkiyeklinikleri.com

.: Customer Services

Phone: +90 312 286 56 56/ 118
E-mail: satisdestek@turkiyeklinikleri.com

1. TERMS OF USE

1.1. To use the web pages with http://www.turkiyeklinikleri.com domain name or the websites reached through the sub domain names attached to the domain name (They will be collectively referred as "SITE"), please read the conditions below. If you do not accept these terms, please cease to use the "SITE." "SITE" owner reserves the right to change the information on the website, forms, contents, the "SITE," "SITE" terms of use anytime they want.

1.2. The owner of the "SITE" is Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. (From now on it is going to be referred as "Turkiye Klinikleri", shortly) and it resides at Turkocagi cad. No:30, 06520 Balgat Ankara. The services in the "SITE" are provided by "Turkiye Klinikleri."

1.3. Anyone accessing the "SITE" with or without a fee whether they are a natural person or a legal identity is considered to agree these terms of use. In this contract hereby, "Turkiye Klinikleri" may change the stated terms anytime. These changes will be published in the "SITE" periodically and they will be valid when they are published. Any natural person or legal identity benefiting from and reaching to the "SITE" are considered to be agreed to any change on hereby contract terms done by "Turkiye Klinikleri."

1.4. The "Terms of Use" hereby is published in the website with the last change on March 30th 2014 and the "SITE" is activated by enabling the access to everyone. The "Terms of Use" hereby is also a part of the any "USER Contract" was and/or will be done with the users using "Turkiye Klinikleri" services with or without a fee an inseparable.

2. DEFINITIONS

2.1. "SITE": A website offering different kind of services and context with a certain frame determined by "Turkiye Klinikleri" and it is accessible on-line on http://www.turkiyeklinikleri.com domain name and/or subdomains connected to the domain name.

2.2. USER: A natural person or a legal identity accessing to the "SITE" through online settings.

2.3. LINK: A link enabling to access to another website through the "SITE", the files, the context or through another website to the "SITE", the files and the context.

2.4. CONTEXT: Any visual, literary and auditory images published in the "Turkiye Klinikleri", "SITE" and/or any website or any accessible information, file, picture, number/figures, price, etc.

2.5. "USER CONTRACT": An electronically signed contract between a natural or a legal identity benefiting from special services "Turkiye Klinikleri" will provide and "Turkiye Klinikleri".

3. SCOPE OF THE SERVICES

3.1. "Turkiye Klinikleri" is completely free to determine the scope and quality of the services via the "SITE".

3.2. To benefit the services of "Turkiye Klinikleri" "SITE", the "USER" must deliver the features that will be specified by "Turkiye Klinikleri". "Turkiye Klinikleri" may change this necessity any time single-sided.

3.3. Not for a limited number, the services "Turkiye Klinikleri" will provide through the "SITE" for a certain price or for free are;

- Providing scientific articles, books and informative publications for health industry.

- Providing structural, statistical and editorial support to article preparation stage for scientific journals.

4. GENERAL PROVISIONS

4.1. "Turkiye Klinikleri" is completely free to determine which of the services and contents provided in the "SITE" will be charged.

4.2. People benefiting from the services provided by "Turkiye Klinikleri" and using the website can use the "SITE" only according to the law and only for personal reasons. Users have the criminal and civil liability for every process and action they take in the "SITE". Every USER agrees, declares and undertakes that they will not proceed by any function or action infringement of rights of "Turkiye Klinikleri"s and/or other third parties', they are the exclusive right holder on usage, processing, storage, made public and revealing any written, visual or auditory information reported to Turkiye Klinikleri" and/or "SITE" to the third parties. "USER" agrees and undertakes that s/he will not duplicate, copy, distribute, process, the pictures, text, visual and auditory images, video clips, files, databases, catalogs and lists within the "SITE", s/he will not be using these actions or with other ways to compete with "Turkiye Klinikleri", directly or indirectly.

4.3. The services provided and the context published within the "SITE" by third parties is not under the responsibility of "Turkiye Klinikleri", institutions collaborated with "Turkiye Klinikleri", "Turkiye Klinikleri" employee and directors, "Turkiye Klinikleri" authorized salespeople. Commitment to accuracy and legality of the published information, context, visual and auditory images provided by any third party are under the full responsibility of the third party. "Turkiye Klinikleri" does not promise and guarantee the safety, accuracy and legality of the services and context provided by a third party.

4.4. "USER"s cannot act against "Turkiye Klinikleri", other "USER"s and third parties by using the "SITE". "Turkiye Klinikleri" has no direct and/or indirect responsibility for any damage a third party suffered or will suffer regarding "USER"s actions on the "SITE" against the rules of the hereby "Terms of Use" and the law.

4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com