Beverly Cosgrove, Version 4, 5-7-2023

Thrombosis. A scary word. This is the term for a formation of a blood clot, and is the ONE remaining significant risk of MTF hormone treatment with modern forms of estradiol. Blood clots have been known to travel to the heart, lung, or brain, causing damage in the form of Ischemia – reduced blood flow, which can be crippling or lethal. In the past, the risk of thrombosis was heavily linked to “conjugated estrogens” – also known as the trademarked drug Premarin, a mix of horse estrogen metabolites obtained from pregnant mares, or forms of Ethinyl Estradiol, a synthetic estrogen. Additional minor risks have been associated with taking estradiol or estradiol valerate in pill form. But even if Premarin and Estinyl are avoided, and estradiol in pill form is avoided, there is still a theoretical risk of thrombosis, because estradiol always has at least a slight effect on clotting time. Many have advised (your doctor, perhaps, or a friend) taking baby aspirin daily to assist you with reducing that risk. There is reason to believe that strategy may have some limited benefit for transsexual HRT. But in this article I will outline use of RUTIN for that purpose — quite possibly a superior method.

The discovery dates from May of 2012. [Ref. 1] The Harvard researchers knew that clotting was moderated by Protein disulfide isomerase (PDI), so they began a search for inhibitors of that substance. They knew that PDI inhibitors would do two things – reduce platelet based clotting (clots in arteries are mostly platelet-based), and also reduce fibrinogen based clotting (clotting in veins is dependent more on Fibrinogen than platelets). That’s better than Aspirin, which does only ONE of these – increasing the platelet-based clotting time. Aspirin is useful in preventing some types of heart attacks. But aspirin does little for Deep Vein Thrombosis (DVT), the killer of some transsexual women on HRT.

The researchers designed a test which checked thousands of substances for their ability to inhibit the Protein Disulfide Isomerase (PDI). Several interesting substances were identified, but it was Rutin, a simple plant based extract, that was most interesting of the PDI inhibiting substances. Flavonols similar to or containing Rutin had already been shown to confer protection against myocardial infarction and stroke, proportional to their dosage, and many other benefits as well. (4) One, Kaempferol, in addition to its antithrombotic activity, even seemed to offer some protection against cancers, diabetes, and other disorders (5) but Rutin exceeded all previously known substances as a PDI inhibitor. Harvard lead investigator Robert Flaumenhaft said, “It’s not always fully appreciated that the majority of Americans will die as the result of a blood clot in either their heart or their brain. Approximately half of all morbidity and mortality in the United States can be attributed to heart attack or stroke… Rutin proved to be the most potently anti-thrombotic compound that we ever tested.” (1) Their game-changing article is entitled, “Protein Disulfide Isomerase Inhibitors Constitute a New Class of Antithrombotic Agents.” published in Journal of Clinical Investigation. (4)

How about tests in vivo? (In living animals.) Even though tests in vitro (tissues outside the body) were successful, the question remained, but new research in 2022 gave the answer. Test mice were subjected to electrically induced thrombosis in their common carotid artery, which normally causes a deadly clot. Giving the animals a dose of specially prepared Rutin called Nano-R greatly extended the clotting time of the animals compared to controls, even saving the lives of many of them. This led researchers to believe results would probably be duplicated in humans, where the biochemistry is identical. “…it is rational to assume that oral delivery of NanoR with a rutin dose of 50 mg/kg is sufficient to exert a strong antithrombotic effect via PDI inhibition. In vivo results verified our deduction, and were consistent with the results of in vitro.” (21) Additional work done in 2023 with Rutin-zinc combinations are showing even stronger anti-thrombotic results. (22)

Transsexual women have suffered weak and compromised HRT for decades based on their doctors belief that estrogen-caused thrombosis was the overriding risk (and that all estrogens are alike)(19), forcing them to administer a low estradiol dose, aided by antiandrogens such as Spironolactone. However, there is evidence today that antiandrogens such as Spironolactone contribute to anxiety, depression, and cognitive impairment in trans women, and may indirectly cause an increase in self harm, suicide, and addictive behavior in this highly stressed patient population. (18) Also, antiandrogens have been shown to sabotage success in full feminization, fat mobilization, and breast development, the key goals of HRT. From studies of male prostate patients we know that HRT with higher levels of estradiol, but without any antiandrogen, is highly effective in suppressing testosterone and producing feminizing effects, but of course, some doctors still feared that high estradiol levels would outweigh their benefits. But now, with easy access to a potent anti-thrombotic treatment, it is to be hoped that more patients can experience the benefits of HRT using parenteral estradiol alone, at levels which are highly effective at feminization.

Is it possible that this inexpensive supplement works as well or better in preventing thrombosis than high priced drugs such as Xarelto, which costs at least 100 times as much? It would certainly be premature to suggest it… but the nature of profit-driven drug development means that one-to-one comparisons of these two anticlotting compounds are NOT likely to happen soon. But with 60 tablets of Rutin selling for about $7 (On Amazon) and 60 20mg tablets of Xarelto selling for over $700 (GoodRx cash discount price) we have a hundred to one difference in price. Meanwhile, the profit incentive is already causing researchers to search for patentable synthetic look-alike drugs that work like Rutin. (6,7) We can expect this to end up a lot like the story of estradiol substitutes — first, they do as little research as possible on the natural substance, only enough to understand how it works, and then they do as much expensive testing as possible on the patented drug — and then they sell the patented drug at very high cost to doctors, because “We don’t have enough research to show that Rutin is as safe and effective as our drug.” The profit motive of drug design looks ugly indeed, when potentially safe natural drugs are pushed aside for riskier, expensive patented ones.  However, a counter argument exists: due to its quick elimination, the duration of action of Rutin may be too short for practical therapeutic use. In that case, it may be necessary to consume Rutin multiple times a day in small amounts for best effect. [Note, speculation follows.] One might speculate that one of the foods containing significant amounts of Rutin, black tea, offers a natural way for nearly continuous consumption of Rutin throughout the day, and indeed some of the health benefits of drinking black tea all day may derive from the constant, small dosing with Rutin and similar compounds.  If there were a pill with the statistically proven heart benefits of black tea, the company making that pill would probably tout it as a major breakthrough drug. (20)

We as HRT recipients, have the power to choose to take Rutin on our own behalf, until the unlikely studies are done, and benefit from some, and perhaps a lot, of clot risk reduction. By word of mouth, Rutin seems destined to become a widespread adjunct in HRT. It can be bought at local vitamin stores or online. It is FDA recognized as a safe herbal supplement. Rutin occurs naturally in buckwheat seeds, teas, many fruits and fruit rinds. (3) Doses of 200-600mg daily, taken once or twice a day, are appropriate for anti-thrombotic uses. (3) I take it every day — perhaps you should too. Many online vitamin distributors offer Rutin, but be sure you rely on reputable vitamin manufacturers. And, why not tell your friends. Even for men, and women not taking added estrogens, Rutin may offer life-saving benefits.

Group knowledge is scanty so far. We know of one person who reported that they regularly donated blood, and often had a problem with clotting in the blood line as they donated, but after taking 500-600mg a day of Rutin, their blood donation went smoothly without clotting. In our HRT group, we’re watching for instances of bruising, but nothing especially noteworthy so far has been seen.

Is Rutin safe?  A 5-year study of Rutin, for vein health, showed that “No side effects or cases of intolerance were observed.” (17) Rutin is an old, and long used flavonoid nutrition supplement. Rutin is nothing new. It is GRAS – Generally Recognized as Safe – a designation given by the FDA to a substance that has been widely used already for many years and is not known to have any health dangers, or has undergone the full gauntlet of medical testing required for a food additive.(12) Rutin affects clotting, and you should remember, blood is supposed to clot, eventually. Blood which cannot clot, can cause bleeding which is out of control. Stomach bleeding is especially a problem such as can occur when aspirin is taken, irritating the stomach lining — Xarelto has become involved in numerous lawsuits where excessive bleeding has occurred. One consumer drug safety group called Xarelto currently the “Most Dangerous Drug in the United States.” (10) It’s comforting that we are not aware of any bleeding problems associated with Rutin use, and in fact, Rutin is routinely used to improve hemorrhoids and relieve chronic venous insufficiency.

What dose should we take? One medical treatment for osteoarthritis and multiple sclerosis, Phlogenzym, contains Rutin and has been studied at 200mg a day (of Rutin) and deemed safe.(11) A five year study of a group of patients (including diabetic ones) taking 2000mg a day of Rutin reported “no side effects” and significant benefits in improving vein function and even reducing cholesterol. (17) So, it seems reasonable to believe that Rutin is unlikely to cause excessive bleeding, like Xarelto and similar pharmaceutical drugs, and that’s our main concern. Based on available information, it seems wise to not exceed 2000mg a day. The Harvard article mentioned up to 600mg a day as a possible dose. (1) I personally take 500mg a day. Anecdotal information from a large discussion group seems to show that the anti-clotting action works at about this dose. This is all the information we have. [Disclaimer: if you are a patient taking Xarelto or other anticlotting medication, get your doctor’s approval before you stop or add Rutin.]

Rutin has long been used medicinally. “Rutin has been prescribed for the treatment of vascular disorders characterized by abnormally fragile or permeable capillaries. Correction by Rutin of increased capillary fragility results in a decreased incidence of vascular complications such as retinal hemorrhage, apoplexy, and coronary occlusion.” (13) Extensive testing in rats, mice, hamsters, and rabbits shows a variety of cardioprotective, neuroprotective, anti-cancer, anti-inflammatory, and other health benefits, some from Rutin’s clotting inhibition, and others from its strong anti-oxidant effects.(15) Rutin, like a few other flavonoids, also has a very mild sedating, tranquilizing effect, which does not depend on the usual GABA mechanism like benzodiazepines.(16)

The two common foods with the highest concentration of rutin are raw black olives and whole grain Buckwheat flower. (14) It makes one think… there are two locations in the world famous for longevity — the Mediterranean, and Japan. In one, raw black olives are a widely used food, and in the other, buckwheat grain is a daily part of the diet. In a world where vascular disease due to thrombosis is a major cause of death, as the Harvard researchers said, Rutin may be a key to health and ultimately, longer life.

---

REFERENCES
(1) “Flavonoid compound can prevent blood clots”, Harvard Gazette 5-9-2012, http://news.harvard.edu/gazette/story/2012/05/flavonoid-compound-can-prevent-blood-clots/
(2) “Anti-thrombotic effect of rutin isolated from Dendropanax morbifera Leveille”, Choi et al, j.jbiosc.2014.12.012, http://www.sciencedirect.com/science/article/pii/S1389172314004915
(3) “Rutin- potent natural thrombolytic agent”, Dar and Tabassum, International Current Pharmaceutical Journal 2012, 1(12): 431-435, http://www.icpjonline.com/documents/Vol1Issue12/07.pdf
(4) “Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents”, Jasuja et al, 10.1172/JCI61228. http://www.jci.org/articles/view/61228
(5) “Kaempferol inhibits thrombosis and platelet activation”, Choi et al, j.biochi.2015.06.001
(6) “Therapeutic implications of protein disulfide isomerase inhibition in thrombotic disease”, Arterioscler Thromb Vasc Biol. 2015 Jan;35(1):16-23. doi: 10.1161/ATVBAHA.114.303410. Epub 2014 Aug 7
(7)”Thiol isomerases in thrombus formation”, Circ Res. 2014 Mar 28;114(7):1162-73. doi: 10.1161/CIRCRESAHA.114.301808.
(8) “Protein disulfide isomerase as an antithrombotic target”, Trends Cardiovasc Med. 2013 Oct;23(7):264-8. doi: 10.1016/j.tcm.2013.03.001. Epub 2013 Mar 27
(9) “Comparative Function-structural Analysis Of Antiplatelet And Antiradical Activities Of Flavonoid Phytochemicals”, Guo C, The Journal of Animal & Plant Sciences, 24(3): 2014, Page: 926-935 ISSN: 1018-7081, http://www.thejaps.org.pk/docs/v-24-3/37.pdf
(10) “Rivaroxaban (XARELTO), an oral anticoagulant, accounted for the largest number of reported cases of domestic, serious injury among regularly monitored drugs, a total of 10,674 reports, including 1,121 patient deaths and 4,508 injuries requiring hospitalization.”, ISMP Quarter Watch June 29, 2016.
(11) “Effect of phlogenzym in long-term treatment of patients with multiple sclerosis”, Lik Sprava. 2003 Apr-Jun;(3-4):109-13. PMID: 12889375
(12) “Under sections 201(s) and 409 of the Act, and FDA’s implementing regulations in 21 CFR 170.3 and 21 CFR 170.30, the use of a food substance may be GRAS either through scientific procedures or, for a substance used in food before 1958, through experience based on common use in food Under 21 CFR 170.30(b), general recognition of safety through scientific procedures requires the same quantity and quality of scientific evidence as is required to obtain approval of the substance as a food additive. General recognition of safety through scientific procedures is based upon the application of generally available and accepted scientific data, information, or methods, which ordinarily are published, as well as the application of scientific principles, and may be corroborated by the application of unpublished scientific data, information, or methods.” https://www.fda.gov/food/ingredientspackaginglabeling/gras/
(13) Effects of Agronomic Factors on the Rutin Content of Buckwheat, Naghski J, US Department of Agriculture Technical Bulletin No. 1132, 10-55.
(14) http://phenol-explorer.eu/contents/polyphenol/296
(15) “The Pharmacological Potential of Rutin“, Saudi Pharmaceutical Journal, Volume 25, Issue 2, February 2017, Pages 149-164.
(16) “Central nervous system depressant action of flavonoid glycosides”, Fernández S, European Journal of Pharmacology 539 (2006) 168–176
(17) “Five-year treatment of chronic venous insufficiency with O-(β-hydroxyethyl)-rutosides: Safety aspects”, Stuard S, Int J Angiol. 2008 Autumn; 17(3): 143–148.
(18) “The Case Against Spironolactone“, Cosgrove B.
(19) “What Went Wrong With MTF Hormonal Therapy?“, Cosgrove B.
(20) “10 Evidence-Based Health Benefits of Black Tea“, Autumn Enloe, MS, RD, LD, May 16, 2018
(21) “Orally delivered rutin in lipid-based nano-formulation exerts strong antithrombotic effects by protein disulfide isomerase inhibition“, Dan Chen et al, Drug Delivery, 2022, v29 no. 1, https://doi.org/10.1080/10717544.2022.2083726
(22) “Enhanced inhibition of protein disulfide isomerase and anti-thrombotic activity of a rutin derivative: rutin:Zn complex“, Xinyuan Liao et al, RSC Adv., 2023, 13, 11464-11471. DOI: 10.1039/D3RA01135F