The following is the final in a 3-part series on the history and contemporary use of sclerotherapy. Read parts one and two or download the full 3-part series in PDF format online at PracticalDermatology.com.
1989 was not a particularly opportune time for an American dermatologist / phlebologist (we’ll call him Dr. A), to write an enthusiastic article describing his use and satisfaction with polidocanol (POL), an agent which would remain illegal to use for another 21 years. The FDA had essentially paralyzed Dr. A with fear when they investigated his use of this “illegal” drug. In a state of panic, he asked an experienced phlebologist (Dr. B) to mollify the FDA by providing him with a character reference. When Dr. B was interviewed by an FDA investigator, after being assured that he was not being investigated, he naively confessed that he considered polidocanol the treatment of choice for small vessels, confessing that he used it himself on a daily basis. This turned out to be a big mistake. About a year later, a series of increasingly threatening letters began to arrive at his office. The FDA advised him that it intended to impose draconian sanctions unless he signed an agreement to stop using or advocating the use of this agent. Logic didn’t seem to help. A careful review of the world literature, which confirmed the safety, patient comfort, and freedom from extravasation necrosis (I’ve injected 0.5cc of 3% polidocanol mid-dermally into my arm without developing tissue necrosis), as well as its widespread employment internationally (enough has been sold to treat several million people) was dispatched to the FDA. They replied with a form letter. A Washington, DC attorney, who routinely handled FDA cases, was retained. He was depressingly pessimistic about the prospects of wringing any concessions from the FDA.
A few weeks later, providentially, two events occurred that dramatically changed the trajectory, frequency, and menace of subsequent interactions. The first involved a letter from a phlebologist in Minnesota describing to Dr. B the death of a patient some 15 minutes after the employment of a 0.5cc test dose of 0.5% sodium Sotradecol sulfate (STS). At that time, this was the only sclerosant specifically approved for the treatment of lower extremity venous disease, although other highly toxic sclerosants could be legally employed. The patient who died was a healthy woman with no risk factors other than a reported allergy to diazepam. Tryptase studies, which at that time were considered experimental, rose precipitously to a level consistent with the occurrence of anaphylaxis. Even more providentially, one of Dr. B’s patients, the fiancé of a well-known television talk show host who, after reading the letter that described the circumstances of the fatality, arranged with her fiancé to have Dr. B share an appearance on his show with an FDA representative in a kind of point counterpoint colloquium. After receiving this information, Dr. B’s attorney informed him that the FDA had decided to terminate the investigation.
Hippocratic dissonance: The circumstances of the time
Robert Weiss summarized the moral ambiguities vis-a-vis the use of approved and non-approved sclerosants in the United States. In his 2001 text he noted, “Paradoxically, routine use of what are widely regarded as safer, more efficacious agents has become the usual standard of care today, despite the fact they have not been approved for this purpose by the FDA…POL, intensely studied and in many ways more advantageous than other sclerosants, is taught and recommended at a number of major universities and in nearly every medical textbook…Malpractice carriers provided explicit waivers to cover its use.”
In one survey carried out in 1990, physicians using POL outnumbered those who used sodium sotradecol sulfate, hypertonic saline, or the extraordinarily toxic sodium morrhuate by a considerable margin. The notion that the legality of using certain types of sclerosants was essentially unrelated to the risks they presented would have made Hippocrates curse. In all fairness, the FDA faces a zero sum game. If they approve a drug and things go wrong, there will be no end of investigations, breast-beating, finger pointing, scapegoating, and head rolling. Conversely, if they didn’t approve a useful drug, which was widely and legally employed in counties with respectable scientific infrastructures, they face the same circumstances. Fortunately, for all concerned, by 2010, polidocanol was finally approved and was comfortably ensconced under the name Asclera.
Insights from the phlebologic community
The opinions of “The ad hoc” advisors, who were kind enough to contribute their ideas and experiences solicited in a detailed survey (mentioned above), reflect an unexpected degree of unanimity. Their ranks included general and vascular surgeons, dermatologists, and practitioners from different countries, cultures, training backgrounds, and treatment approaches.
An attempt was also made to balance the opinions of acknowledged phlebological experts whose CVs resemble the Guttenberg Bible, with front line phlebologists, surgeons, and non-surgeons. A brief synopsis of their observations is reported here.
Where did you receive your training?
Only one of the respondents received training in a formal program. All of them gratefully identified their mentors and role models whose names, unfortunately, I do not have space to include.
What were the most important advances in phlebology?
Advances in sclerotherapy included “Safe and effective detergent solutions,” and FDA approval for polidocanol. Foam sclerotherapy was considered to be a major advance as were endoluminal therapies, specifically EVLT (endovenous laser therapy), and radiofrequency ablation. For the treatment of telangiectasia, the usefulness of compression and a clearer understanding of the relationship of telangiectasia to reticular veins and venous hypertension were cited as major advances. None of the respondents regarded the use of lasers for lower extremity telangiectasia and reticular veins to be worthy of comment.
Surgical advances included refinements in vein ligation and stripping and better surgical techniques “Except in the US, where surgery is fading.” Propagation of ambulatory phlebectomy by an eminent Swiss dermatologist, R. Muller, and the substitution of tumescent anesthesia for general anesthesia for its employment were also cited.
Innovations and refinements
Good quality, accessible venous duplex scanning was considered to be, “By far the most important advance.” “Magnetic resonance venography”, “Thrombolysis for ilieofemoral DVTs”, and “The recognition of iliac obstructions”, are cited. Good quality, graduated, compression stockings, low molecular weight heparin, and novel anticoagulants were also part of the list.
Will phlebology become a bona fide subspecialty? What practitioners should be included?
Members of the European Union are “establishing a register of phlebologists to achieve this goal.” “Phlebology will gain acceptance as a bonafide subspecialty because of work by phlebologic organizations.” “Phlebologists should be recruited from any physicians interested in venous and lymphatic diseases who have completed appropriate training, including diagnostic ultrasound,” regardless of their primary specialty.
Practicing phlebological physicians “Are already a part of an existing sub-specialty, and must be given ‘grandfathered’ sub specialty phlebology status. Newcomers to phlebology have to go through an accredited training scheme.”
What are your concerns?
“Cost and profit.”The many great advances in phlebology are being counterbalanced on the downside by the pursuit of money, especially in the west.” “We are developing more and more expensive venous treatments which other countries cannot afford.” “Vested interest exists in each country for and against each sub specialty.” “Dishonest phlebologists are going toward fraudulent misrepresentation that endovenous ablation will cure telangiectasia.” “It will achieve the status of a recognized sub specialty once we work through all the unnecessary endovenous procedures being performed.”
Phlebologic monopolies, are they real?
“Depends on individual countries.” “Invasive radiologists see this as a profitable opportunity; they have the most 3-D duplex knowledge.” “The interventional cardiologists and radiologists want to take over the world and all of medicine.” “Great technicians, but they know nothing about venous disease so they may gather the revenue for the procedures, but a long-term phlebologist is needed.” “Fight between interventional radiologists, vascular surgeons, and hucksters.” “Now the surgeons are learning endovenous treatments, I think it may swing back to surgeons filling this phlebology role.”
Phlebological organizations, how do you rate them?
ACP, AVF, and UIP are rated different ways. “UIP, the most importantly globally, ACP, the most clinical members, AVF, is the most academic.” “The American board of venous and lymphatic medicine is the only organization in the world that provides anything near a comprehensive certification process in venous disease.” “ACP is truly inclusive, great educational opportunities, has fostered investment in the field by healthcare professionals and industry.” “AVF, principle academic venous society, numerous important contributions such as the CEAP classification, guideline and consensus documents, and an emphasis on evidence based medicine.” “French Society of Phlebology, the mother of all others, still the only society having sponsored / published clinical trials.” “ACP biggest, most energetic.” “There are some, made for truly developing phlebology, and some that are made just to promote some individuals.”
“We’re still pretty far away from understanding the genetic and pathogenetic basis of the most common forms of varicose syndromes.” “Many of the clinical contradictions and controversies will be laid to rest as the mechanisms underlying their occurrence are understood at the molecular level.” Replies include “Molecular scientists and geneticists, and basic researchers were predicted to be the people, who in the future, will lead the evolution of phlebology”, “It will not be frontline phlebologists”. “Only textbooks and electronic formats like iBook’s will be used.”, “Tissue manipulation, and genetic engineering” are cited as important issues. “Enhanced visualization, less invasive saphenous vein closure techniques”, and “Control and even prevention with medication” are predicted. “Diagnostic tools beyond duplex ultrasound”and“More endovenous thermal devices, sclerotherapy, and possibly glue, which may even replace RF and internal laser devices”. “Stripping will no longer be a standard”. Further predictions include “Sonography will develop toward 3-dimensional scanning”, “DVT treatment may become more invasive, “and “Compression will change toward new devices with more indication related design.” “Stenting and stents with valves for PTS (post thrombotic syndrome) along with the accelerated development of some pharmacologic treatment and or prevention” will eventuate. Thermals and glue will come and go, “The use of glue may increase, however, it is effective, but still too expensive”. “The expansion of sclerotherapy into for a wide range of cosmetic concerns may represent a new era and application for this versatile technique.” “The development of procedures that do not require anesthesia” holds promise for the simplification and accessibility of phlebological procedures.
Novel future treatment modalities
“FALOS, Laser assisted foam sclerotherapy combines a holmium laser with sclerotherapy. Laser energy is concentrated in the media and not on adventitia or on tunica intima…perivascular damage is zero.” Photochemical cross linking of main wall collagen in which riboflavin and blue light are used for formation of new covalent links among collagen fiber in the vein wall. This provokes shrinkage of the vein without endothelial damage.
Current phlebological practices can be viewed as the latest links in a 3,500-year old chain of theoretical and therapeutic advances, mishaps, discoveries, technologies and innovations. The addition of each new link cannot occur without the knowledge and experience embedded in the preceding link. The first links were forged by ancient empiricists. The last, will be hammered out worldwide in the laboratories of geneticists, molecular biologists, pharmacologic, and biomaterials researchers. It is also quite possible that ethical issues, and political and legal concerns will result in a few kinks in the newest links. n
This series is adapted from a chapter originally written by Dr. Duffy at the request of friend and colleague Stuart Maddin, MD, who long considered to be the godfather of Canadian dermatology. He was until his recent death a Professor Emeritus at the University of British Columbia. He unfortunately passed away before the book could be published.
Dedications and acknowledgements
This treatise is dedicated to John Bergan, whose willingness to share his expertise with interested specialists regardless of their backgrounds motivated an entire generation of phlebologists, and to Stuart Maddin whose extraordinary contributions to medical advances in a number of fields has provided guidance for over five decades. Sincere thanks must be given to A. Frullini, Mitchel Goldman, Jean-Jerome Guex, Nick Morrison, Milos Pavolvic, Eberhard Rabe, Neil Sadick, Margaret and Robert Weiss, and Steven Zimmet, whose wisdom has enriched this publication. I must personally acknowledge the debt I have to Donald Alderman at Yale who instructed me in sclerotherapy in 1978. Recognition for their discoveries and the clarity of their publications are also in order for H.I. Biegeleisen, Andre Davy, C.M. Hamel-Desnos, Craig Feid, Larry Fields, William Foley, Arnost and Helene Froneck, Mihael Georgiev, David Green, W.P. De Groot, Mary Lupo, Pauline Raymond-Martimbeau and A.N. Nicolaides. Certain individuals have provided me with enthusiastic encouragement; they include Jay Barnett, Gene Bodian, Anton Butie, Al and Jean Carruthers, William Coleman, Mitch Goldman, Neil Sadick, Margaret Weiss, Robert Weiss and the late Larry Tretbar. Some of my most inspirational colleagues are also no longer with us. They include the brilliant Sam Stegman, Ted Tromovich and Murray Zimmerman. Organizations which have been particularly supportive include The American Society for Dermatologic Surgery, and The American College of Phlebology, along with the unfortunately defunct American Society of Cosmetic Dermatology and Aesthetic Surgery. Last, but not least, Mitchel Goldman, Robert and Margaret Weiss, and Neil Sadick deserve credit for being the tireless phlebological apostles who have almost single handedly reanimated a longstanding moribund American interest in phlebology. Finally, this paper could never have been written without the patience and extraordinary efforts of Peggy Goodwin, my industrious and invaluable helpmate.
Apologies are also in order for the omission of the names and accomplishments of many individuals and organizations in the United States and abroad, who have steadfastly advanced the development of phlebology worldwide, both currently, and in times past.
David M. Duffy, MD is Clinical Professor of Medicine (Dermatology), University of Southern California.
Abdelsaid M, Kaczmarek, J, Coucha, M, Ergul A. Dual endothelin receptor antagonism with bosentan reverses established vascular remodeling and dysfunctional angiogenesis in diabetic rats: Relevance to glycemic control. Life Sci (2014), http://dx.doi.org/10,1016/j.lfs.2014.01.008.
ACP History & Timeline. www.phlebology.org/aboutus/history.html
Adrian RM, Treatment of leg telangiectasias using a long-pulse frequency-doubled neodymium:YAG laser at 532 nm. Dermatol Surg 1998;24:19-23.
Allegra C, Bernbach, H., Blattler W., Blazek V., et al. Ed. F. Mariani. Compression – Consensus document based on scientific evidence and clinical experiences. Edizioni Minerva medica Torino 2009.
Almeida JI, Javier JJ, Mackay E. et al. First human use of cyanoacrylate adhesive for treatment of saphenous vein incompetence. Published online 20 Dec. 2012. http://www.jvsvenous.org/article/PIIS2213333X1200030. Accessed 12/15/2014.
Avgerinos ED1; European Vascular Surgeons in Training (EVST) Writing Committee. Vascular training profiles across Europe. Eur J Vasc Endovasc Surg. 2013 Dec;46(6):719-25. doi: 10.1016/j.ejvs.2013.08.003. Epub 2013 Oct 2.
Bergan JJ. Editor. The Vein Book 2007 Elsevier, Inc.
Biegeleisen HI. Telangiectasia associated with varicose veins: Treatment by micro-injection technique. JAMA 1934;102:2092-4.
Biegeleisen HI. Varicose veins, related diseases, and sclerotherapy: A guide for practitioners. 1984. Eden Press, Canada and London.
Biron, L. http://theweek.com/article/index/261812/doctors-close-in-on-vaccinations-against-heroin-cocaine-and-meth May 2014. Accessed 1/2/15.
Bishawi M, Bernstein R, Boter M, et al. Mechanochemical ablation in patients with chronic venous disease: A prospective multicenter report. Phlebology 2014. Vol 29(6);397-400.
Bjordal RI. Circulation patterns in incompetent perforating veins in the calf and in the saphenous system in primary varicose veins. Acta Chir Scand. 1972; 138:251-261.
Bowes LE, Goldman MP. Sclerotherapy of reticular and telangiectatic veins of face, hands, and chest. Dermatol Surg 2002;28:46-51.
Bull P. The Harley Street Vein Clinic. London, UK. History of varicose vein surgery. Http://dr-bull.com/history%20of%20varicose%20vein%20surgery.htm. Accessed 12/15/2014.
Caggiati A, Allegra C. The Vein Book. Chapter I, Historical Introduction. 2006, Elsevier, Inc.
Calatayud J, Gonzalez A. History of the development and evolution of local anesthesia since the coca leaf. Anesth. June 2003 – Vol. 98, Issue 6. Pp 1503-1508.
Cockett FB, Jones DEE. The ankle blow-out syndrome; a new approach to the varicose ulcer problem. Lancet. 1953 Jan 3;1(6749):17–23.
Compton BG, Lewis JA. 3D-printing of lightweight cellular composites. Adv. Mater 2014, DOI: 10.1002/adma.201408104.
Conrad P, Malouf GM, Stacey MC. The Australian Polidocanol (Aethoxysklerol) Study. Dermatol Surg 1995;21:334-336.
Couchair M, Phillips TJ. Compression Therapy. Dermatol Surg 1998;24:141-148.
Cryotherapy. Cryo-S Classic® http://www.metrum.com.pl/en/products/cryosurgery-devices/cryo-s-classic. Accessed 12/15/2014.
Cyborg. Wikipedia. www.http://en.wikipedia.org/wiki/Cyborg Accessed 12/09/14.
Díaz-Ley B, Grillo E, Ríos-Buceta L, Paoli J, Moreno C, Vano-Galván S. and Jaén-Olasolo P. Classic Kaposi’s sarcoma treated with topical rapamycin. Dermatol Ther. 2014 Oct 14. doi: 10.1111/dth.12182. [Epub ahead of print].
Dickens C, Browne HK. (1951). The life and adventures of Martin Chuzzlewit. London: Oxford University Press.
Duffy DM, Techniques of small vessel sclerotherapy. In: Goldman M, Weiss R, Bergan J (Eds.) Varicose veins and telangiectasia: diagnosis and treatment. 2nd edition 1999. Quality Medical Publishing, St. Louis, MO.
Duffy DM. Procedures in Cosmetic Dermatology Series.. Hsu JTS. Ed. Alam M, Nguyen TH. Elsevier 2006.
Duffy DM, Garcia C, Clark R. The Role of Sclerotherapy in Abnormal Varicose Hand Veins. Journal of Plastic & Reconstructive Surgery, Revised May 28, 1999.
Duffy DM. What’s new in phlebology? DermQuest available at: https://www.dermquest.com/expert-opinions/surgery-and-cosmetics/2012/what%E2%80%99s-new-in-phlebology.html. Accessed 12/10/14.
Duffy DM. Prevention of excessive endothelin-1 release in sclerotherapy: in vitro and in vivo studies. Editorial. Dermatol Surg. 2014 Dec;40(12):1306-8.
Duffy DM, Torok H, Keeling J, Rendon M. Surveying cosmetic procedural residency training: are we short-changing tomorrow’s dermatologists? A preliminary report. Cosmetic Dermatology. September 2008, Vol. 21, No. 9.
Duffy DM. Cosmetic applications of sclerotherapy. G Ital Dermatol Venereol 2011;146:45-63.
Duffy DM. Sclerosants: A Comparative Review. Dermatol Surg 2010:36:1010-1025.
Duffy DM. Sclerotherapy induced vascular remodeling/neovascularization. Scripta Phlebologica Vol. 6, November 1998.
Duffy DM. Small vessel sclerotherapy: An overview. Advances in Dermatology, Vol. 3, Dec. 1987.
Eklof B. Modern treatment of varicose veins. Br J Surg. 1988;75:297-298.
Epstein A. Which op is best for YOUR varicose veins? From lasers to glue, our experts reveal the pros and cons. The Daily Mail, UK. PUBLISHED: 15:21 EST, 16 July 2012 | UPDATED: 01:35 EST, 17 July 2012.
Evans CJ, Fowkes FGR, Ruckley CV, Lee AJ. Prevalence of varicose veins and chronic venous insufficiency in men and women in the general population: Edinburgh Vein Study. J Epid. Community Health 1999;53:149-153.
Ferrara F. A history of sclerotherapy. Veins and Lymphatics. http://www.pagepressjournals.org/index.php/vl/article/view/AncestCorner.2012.1/html Accessed 12/15/2014.
Frullini A, Da Pozzo E, Felice F, Burchielli S, Martini C, Di Stefano R. Prevention of excessive endothelin-1 release in sclerotherapy: in vitro and in vivo studies. Dermatol Surg. 2014 Jul;40(7):769-75.
Gao L. Topical Rapamycin systemically suppresses Lasers in Surgery and Medicine Vol 46, No 9, Nov. 2014.
Garde C. Utilisation d’un laser Nd-YAH multipulse dans le traitement des telangiectasies: à propos de 100 cas représentant 430 zones de traitement. Suivi pendant trois mois. Phlebology 2014;29:66-70.
Goldman MP, Weiss RA, Bergan J. Editors. Second edition. Varicose veins and telangiectasias: diagnosis and treatment. 1999 Quality Medical Pub., Inc. Duffy D. Chap.24:518-547.
Goldman MP, Guex JJ, Weiss, R. Sclerotherapy Treatment of Varicose and Telangiectatic Leg Veins. Fifth Ed. Saunders Elsevier 2011.
Goldman MP. The history and present state of phlebology. Vein Magazine. Summer 2012.
Goldman MP, Sadick, NS, Weiss, RA. The history of dermatology in American phlebology. Dermatol Surg 2000;26:616-621.
Grandi L, Granda RA, Tomasi CD, et al. Acute and chronic consequences of polidocanol foam injection in the lung in experimental animals. Phlebology 2013;28:441-444.
Green D. Reticular veins, incompetent reticular veins, and their relationship to telangiectases. Dermatol Surg 1998;24:1129-1141.
Hakansson G, Gesslein B, Gustafsson L, Englund-Johansson U, Malmsjo M. Hypoxia-inducible factor and vascular endothelial growth factor in the neuroretina and retinal blood vessels after retinal ischemia. J Ocul Biol Dis Infor Mar 2010;3(1):20-29.
Hanke CW, Moy RL, Roenigk RK, Et al. Current status of surgery in dermatology. J Am Acad Dermatol 2013;69:972-1001.
Harley Street Vein Clinic. History of Venous Surgery, phlebolymphology No. 72.
Historical Aspects of Treatment http://www.expertconsultbook.com/expertconsult/ob/book.do?method=display&type=bookPage&decorator=none&eid=4-u1.0-B978-0-323-07367-7.00022-4--f0015&isbn=978-0-323-07367-7 Accessed 12/10/14.
History of Sclerotherapy. Williamette Vein Center, Salem, OR http://www.lovelylegs.com/historys.php Accessed 12/15/2014.
Hypodermic Needle. http://en.wikipedia.org/wiki/Hypodermic_needle Accessed 12/10/14.
Jeanneret C, Karatolois K. Varicose veins- A critical review of the definition and the therapeutical options. Vasa. 2011 Sep;40(5):344-58. doi: 10.1024/0301-1526/a000131.
Kolesky DB, Truby RL, Gladman AS, Busbee, TA, Homan KA, Lewis JA. 3D Bioprinting of vascularized, heterogenous cell-laden tissue constructs. Advanced Materials 2014, DOI: 10.1002/adma.20130556. Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Wileyonlinelibrary.com Accessed online Nov. 24, 2014.
Krock Bl, Skuli N, Simon MC. Hypoxia-induced angiogenesis – good and evil. Genes Cancer. Dec 2011;2(12)1117-1133.
Lost-wax castin. Wikipedia. www.http://en.wikipedia.org/wiki/Lost-wax_casting. Accessed 12/09/14.
Malas MB, Qazi U, Lazarus G, et. al. Comparative effectiveness of surgical interventions aimed at treating underlying venous pathology in patients with chronic venous ulcer. J Vasc. Surg: Venous and Lym Dis 2014;2:212-25.
Marston A. Treatment of varicose veins. Lancet 1975;2:453.
Miller JS. The Billion Cell Construct: Will Three-Dimensional Printing Get Us There? PLoS Biol 2014. 12(6): e1001882. doi:10.1371/journal.pbio.1001882.
Milleret R, Le Pivert P. Cryosclerosis of the saphenous veins in varicose reflux in the obese and elderly. Phlebologie. 1981;34:601-5.
Mlosek RK, Woźniak W, Gruszecki L, Stapa RZ. The use of a novel method of endovenous steam ablation in treatment of great saphenous vein insufficiency: own experiences. Phlebology. 2014 Feb;29(1):58-65.
Moul DK, L Housman, S Romine, H Greenway. Endovenous laser ablation of the great and short saphenous veins with a 1320-nm neodymium:yttrium-aluminum-garnte laser: Retrospective case series of 1171 procedures. J Am Acad Dermatol 2014;70:326-31.
National Enquirer May 1990 Beware! Many varicose vein clinics are run by quacks.
Nelson JS, Jia W, Phung TL, Mihm MC, Jr. Observations on enhanced port wine stain blanching induced by combined pulsed dye laser and rapamycin administration. Lasers Surg Med 2011;43:939-942.
Nicolaides AN. Investigation of chronic venous insufficiency: A consensus statement. Circulation. 2000;102:e126-e163.
Pang XD, Yi Zhengfang, Zhang J, Lu Binbin, Sung Bokyung, Qu Weijing, Aggarawal BB, Liu M. Celastrol suppresses angiogenesis-mediated tumor growth through inhibition of AKT/Mammalian target of rapamycin pathway. Cancer Res. Mar 1, 2010;70(5):1951-1959.
Pennisi E. In the battle for fitness, being smart doesn’t always pay. Science. August 8, 2014. Vol. 345, Issue 6197. Pp. 609-10.
Perrin M. History of venous surgery. Part 2. Vascular surgery, Lyon, France Phlebolymphology. Vol. 18, No. 3, 2011.
Phlebology International Vein Magazine. 3 of Vol 1-6/20/28 2008.
Pocard M. Varicose veins and methods used to cut them: from the Ebers papyrus to Trendelenburg. Ann Chir. 1997;51(7):710-2.
Puch CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 2003;9:677-684.
Rabe E, Schliephake D, Otto J. Sclerotherapy of telangiectasias and reticular veins: a double-blind, randomized, comparative clinical trial of polidocanol, sodium tetradecyl sulphate and isotonic saline (EASI study). Phlebology 2010;25:124-131.
Rao J, Wildemore JK, Goldman MP. Dermatol Surg. 2005 Jun;31(6):631-5; discussion 635.
Ravey CA. Injection treatment of varicose veins. Vermont State Medical Society. NEJM. Jan. 23, 1939.
Rooke TW, Felty CL. A different way to look at varicose veins. Jnl of Vasc Surg: Venous and Lymphatic Disorders, Vol 2, No. 2;207-11.
Rosenhek J. Needle Trade. http://www.doctorsreview.com/history/needle-trade Accessed 12/17/14.
Sadick N. Manual of Sclerotherapy. Lippincott Williams & Wilkins 2000.
Sadick NS, et al. (eds.), Practical Approach to the Management and Treatment of Venous Disorders. © Springer-Verlag, London 2013.
Schou C. Phlebology International. Vein Magazine. Issue 3:Vol1;6/20/2008. www.veindirectory.org/magazine/article/phlebology_international.
Scott C. 3D printed organs, blood vessels and all, takes a big step toward reality. Longevity, May 05, 2014. http://singularityhub.com/2014/05/05/new-method-to-produce-blood-vessels-in-lab-grown-organs/. Accessed online Nov. 24, 2014.
Sekiguchi Y, Zhang J, Patterson S, Liu L, Hamada C. Tomino Y, et al. Rapamycin inhibits transforming growth factor beta-induced peritoneal angiogenesis by blocking the secondary hypoxic response. J Cell Mol Med 2012;16:1934-1945.
Sella A. Lüer’s syringe. Chemistryworld. http://www.rsc.org/chemistryworld/2012/08/luer-syringe. Accessed 12/15/2014.
Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell 2012;148:399-408.
Seokjong L, Wonchae L, Yoonseok C, et al. Gene Expression profiles in varicose veins using complementary DNA microarray. Dermatol Surg 2005;31:391-395.
Sigg K. Varizen, Ulcus cruris, und Thrombose, Berlin, 1976, Springer-Verlag.
Spruiell SS. Is it time? Phlebology as a recognized specialty in the U.S. Vein Magazine. Summer 2009.
Toops KA, Hagemann TL, Messing A, Nickells RW. The effect of lial fibrillary acidic protein expression on neurite outgrowth from retinal explants in a permissive environment. BMC Research Notes 2012, 5:693.
Trendelenburg test. http://en.Wikipedia.org/wiki/Trendelenburg_test. Accessed 12/15/2014.
Van der Molen HR. The development of phlebology in the last 30 years. Phlebologie, 1981 Jul-Sep;34(3):313-32.
Vandendriessche M, Hobbs JT. The evolution of ultrasound guided foam sclerotherapy. Acta Chir Belg, 2008, 108, 660-665.
Vein Magazine Winter 2014. Vein Industry Spotlight. What you may already know about Varithena™.
Vein Magazine. The History and Present State of Phlebology in the USA: A Personal Perspective. Issue 3, Vol. 5, 8/31/2012
Weiss RA, Feied CF, Weiss MA, Editors. Vein Diagnosis & treatment: A comprehensive Approach. 2001 McGraw-Hill Inc.
Weiss MA, Hsu JT, Neuhaus I, Sadick NS, Duffy DM. Consensus for Sclerotherapy. Dermatologic Surgery: December 2014 - Volume 40 - Issue 12 - p 1309–1318.
http://en.wikipedia.org/wiki/Cocaine Accessed 12/17/2014.
Wollmann JC. History and today practice in sclerosant foam preparation. Kreussler & Co. GmbH. Wiesbaden, Germany. Presentation 19th Annual Congress ACP, San Francisco, November 2005.
Wollmann JC. The History of Sclerosing Foams. Dermatol Surg 2004;30:694-703.