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A natural anticoagulant regimen: originally published in allergy research group focus.

This interview offers an introduction to Dr. Philip Miller's natural anticoagulant regimen. For a more detailed and comprehensive four-part tutorial on this subject of prevention of heart attacks and strokes (with numerous visually enhanced diagrams), please visit his website at www.antiaging.com, with accompanying blog posts at blog. antiaging.com.

Focus: On the website for your clinic, you offer a four-part, very detailed and fascinating description of a regimen you have developed to help prevent heart disease and stroke. What inspired you to craft this regimen?

Miller: About 1.5 million heart attacks and strokes occur every year in the United States, and one in every three deaths is due to cardiovascular disease. (1) Cardiovascular disease is the number one cause of death globally. (2) Everybody worries about a heart attack or stroke, especially if they're over sixty. People worry that they're at risk. I developed this comprehensive approach over many years, and it is empirically derived, based on a good, fundamental knowledge of all the pathways in the body that contribute to a catastrophic vascular event. My approach relies on a novel combination of anti-fibrin and anti-platelet modalities. It is a rational approach that addresses the entire coagulation cascade, from beginning to end. This includes platelet aggregation, fibrin deposition, markers of inflammation, and even the properties of red blood cells and why and how they stick together.

My one emphatic caveat is that this regimen must be carried out under the care of a skilled and knowledgeable physician. You cannot self-treat, and nobody should abruptly stop a conventional anticoagulant routine. And let me emphasize, this proprietary anticoagulation routine is prescribed only after starting our core program of select micro-nutrients and nutritional advice. We use CoQ10, taurine, d-ribose, and carnitine in high doses to support heart and brain function. It's all part of an integrative approach.

During the twenty years I've offered this regimen, I can't remember more than eight to ten patients who have suffered a major stroke or heart attack. This is out of thousands of patients, many of them older, with significant cardiovascular risk factors.

I monitor my patients regularly, and adjust the protocol when indicated. I also follow this approach myself, because I do not want to ever have a stroke.

Focus: What is your opinion of the conventional approach to coagulation?

Miller: It is certainly an interesting time in the treatment of stroke and heart attack. In the last few years, the FDA has a new class of oral anticoagulant drugs. Although their safety profile appears better than the old standby--Coumadin (warfarin)--all three of the new medicines are blood thinners that can cause excessive bleeding and are to be used with caution in patients with kidney disease. Two of these new medicines lack an antidote in the event of a severe bleeding episode, which is of concern. (3) An antidote has recently been approved for the third (dabigatran etexilate). (4)

Even with these advances in anticoagulant treatment, I still find the conventional, mainstream approach to stroke and heart attack to be too guideline driven. Some guidelines emphasize the prevention of platelet aggregation. Other guidelines emphasize the long-term use of antifibrin drugs. What is the best strategy? In this scenario, it depends on the guidelines. These evolving guidelines are determined by age, associated risk factors, and preceding conditions. The guidelines were originally developed to make decision-making simple, uniform, and coherent. But guidelines eventually become bloated and incoherent. They can read much like IRS tax code. (5)

Focus: Give us a quick precis of the conventional approach to preventing hypercoagulation.

Miller: The conventional approach to stroke and heart attack prevention starts by preventing platelets from clumping. Both aspirin and clopidogrel (Plavix) are drugs of choice. Aspirin is probably the safest conventional drug to help prevent heart attack and stroke. Clopidogrel is the second line of defense in antiplatelet therapy. It works by breaking down into metabolites, one of which binds irreversibly to a receptor on platelets. This prevents the platelets from aggregating and lasts the entire 7- to 10-day life of a platelet.

Then there are the standard anticoagulant drugs. Coumadin is the best known. Bleeding is the major adverse effect of warfarin. Hemorrhage may occur at virtually any site in the body. (6-7) My biggest concern with warfarin is its mechanism of action. It depletes vitamin K reserves. There are seven vitamin K-dependent blood clotting ('coagulation') factors, and they are each important in the coagulation cascade that helps form a clot. (8) Patients on warfarin are advised not to ingest any extra vitamin K and maintain a moderate, constant level of intake. (9)

Vitamin K is important for building bone. (10-12) It helps regulate cellular growth, cell division, and both the developing and aging nervous system. (13,14) Vitamin K is essential for matrix GLA protein activity, which prevents reverse calcium flow from bones into your arteries and heart valves.

Warfarin, by blocking vitamin K, can accelerate osteoporosis and arterial calcification. (15-17) Healthy doses of vitamin K are vital to many functions. So, to me, the risk-benefit ratio seems questionable, especially if there are other, safer options.

Finally, there is a new class of anticoagulant drugs, called factor Xa drugs, which target the thrombin cascade. Thrombin is an enzyme that helps clots form. One molecule of factor XZa can cleave over 1000 molecules of prothrombin to thrombin. (18) By cleaving prothrombin, factor Xa drugs can slow conversion to thrombin and reduce clots.

These newer drugs do not need frequent monitoring. They do not block vitamin K. Excessive bleeding is still their big risk, and one downside to direct factor Xa inhibitors is that, in most cases, there are no antidotes to unintentional overdose and a bleed. Taking vitamin K is a simple antidote to warfarin.

In addition, because these drugs are so new, eventually discover other long-term consequences that are not apparent yet.

Focus: What causes a stroke or heart attack?

Miller: It all starts with the blood clot, which is essentially the eye of the hurricane. The blood clot is our body's universal mechanism for healing injury, and it usually results from injury. In the case of stroke or heart attack, it is an injury to the wall of a vein or artery. Take atherosclerosis, a condition where plaque builds up in the arteries over many years. Eventually, an area of plaque can rupture inside of an artery. The body attempts to repair that injury by forming a blood clot on the plaque's surface. If the clot becomes large enough, it can mostly or completely block blood flow, depriving tissues of oxygen (ischemia) and leading to stroke (cerebral infarction) or heart attack (myocardial infarction).

Atrial fibrillation, a heart arrhythmia, can also lead to a clot. In this case, the abnormal firing of electrical impulses causes the atria (the top chambers in the heart) to quiver. Blood flow slows down, and there is turbulence, (19) which may lead to the formation of a clot. This type of arrhythmia is the most common type of irregular heartbeat and is found in 5% of those over the age of 65 and 10% of those over 80. (20) Untreated atrial fibrillation increases the risk of a stroke by five-fold. (21) Or alternatively, other research shows about 2% stroke incidence annually, in untreated atrial fibrillation. (22)

In both atherosclerosis and atrial fibrillation, the 'healing' clot may prove to be a problem.

Focus: So, the body's effort to heal an injury can sometimes backfire. What pathways and what cascade of reactions and interactions leads up to the clot?

Miller: Picture the blood vessel --a flexible tube through which your lifeblood is rushing at the astounding speed of three feet a minute the moment it leaves the heart. (23) Every blood vessel is lined with endothelial cells, which form a protective lining called the endothelium. The endothelium secretes substances that stop those cascading blood cells from sticking to it.

But when it is injured or damaged, the endothelium sends out distress signals. Those distress signals are picked up by platelets, tiny blood cells that help your body form clots. The platelets rush to the site of damage, ready to clump together (aggregate) and stick to the exposed wound and help form a clot. During and after aggregation, platelets continue to release substances that trigger further platelet accumulation and activation, as well as constrict veins and help form clots. Platelets are also involved in the inflammatory response and produce proinflammatory chemicals. (24)

Platelets are significant in both atherosclerosis and in the development of stroke and heart attack. Aggregating platelets form the center of the growing clot. (25,26) The clot in individuals who have died of a heart attack has a layered appearance, suggesting it has grown episodically over time. (27)

Once the initial platelet plug has formed, a second important pathway is initiated. This pathway involves the body's fibrin cascade. At first, thrombin is released. Thrombin is an enzyme in blood plasma that causes the clotting of blood. Thrombin converts fibrinogen, a soluble protein, to strong and insoluble fibrin molecules at the place of the wound. Shaped like long threads, the fibrin molecules interlace and crosslink with each other to form a kind of polymer mesh over the clot and stabilize it. It is a remarkable feat.

Under normal circumstances, your body has highly sensitive feedback systems to balance bleeding and clotting. Your body produces plasmin, an enzyme that degrades fibrin clots. And, to balance that dissolving process, you also produce inhibitors of plasmin.

So, to sum it up: injury or stasis, platelet plug, fibrin mesh, successful clot--but over time, potential infarction.

Focus: You've compiled a natural anticoagulation regimen that addresses all these pathways. Which natural molecules do you use and why?

Miller: I combine four simple but powerful constituents. They are nattokinase, Ginkgo biloba, high-dose fish oils, and vitamin E isomers. And, I emphasize adequate hydration--which means many glasses of pure water daily. Studies have shown that water can actually stop red blood cells from clumping as aggressively.

All of the above, when combined in proper doses by a physician, can be both gentle and potent. Every surgeon is now medically and legally required to ask, "What vitamins and herbs are you taking?" Every surgeon knowns that each and all of these agents I have discussed clearly have anticoagulant effects, but via different mechanisms.

Nattokinase

Nattokinase is a well-known fibrinolytic agent. (28) As you may recall our goal is to prevent fibrinogen from converting to fibrin. A 2009, open label study involved three groups of patients: healthy volunteers, patients at risk for cardiovascular disease, and patients undergoing dialysis. Two months of nattokinase reduced fibrinogen, as well as two clotting factors known as factor VII and factor VIII. (41) And a 2014 study in Nature found that a single oral dose of nattokinase improved fibrinolysis and blood flow. (29)

Studies have consistently shown that nattokinase possesses strong fibrinolytic activity. (30,31) Nattokinase reduces plasminogen activator inhibitor I (PAI-1), which as you may recall, is important in the clotting cascade. (32) Nattokinase also stimulates the conversion of plasminogen to plasmin. (33) Nattokinase shows thrombolytic (clot dissolving) activity. (45) The thrombolytic power of nattokinase may be stronger than plasmin. (43)

I have treated thousands of cases with nattokinase to help prevent recurrent thrombophlebitis, strokes, and heart attacks. It is essential that you source NSK-SD[R] nattolinase, which is proven highly effective and standardized.

There are alternatives to nattokinase. Lumbrokinase is a similar fibrinolytic derived from the earthworm. By the manufacturer's claims, it is even more potent. Serrapeptase, an enzyme derived from silkworms, has similar but not identical properties and is often used to combat inflammation and swelling. (34-35) I do use serrapeptase to treat arterial plaques.

Gingko biloba

Ginkgo biloba is a time-honored and venerated Chinese herb with many potent constituents, including flavonol and flavone glycosides, lactone derivatives (ginkgolides), and bilobalide. (36,37) I use a standardized 26% ginkgo extract.

Ginkgo biloba exerts its action primarily as an anti-platelet and anticoagulant. It inhibits platelet aggregating factor. (38) Ginkgo has many other uses. It is an antioxidant, may have vasodilatory effects, and has been used for cognitive enhancement. I find it much more effective as a cardiac protective herb.

Ginkgo is potent. A high dose can cause excess blood thinning and bleeding. Because of its action, Ginkgo biloba should not be combined with aspirin or non-steroidal anti-inflammatory drugs (NSAIDs). It will have an unwanted synergistic effect.

High Potency Fish Oils

High-dose fish oils have a "rheological" effect. That is, they prevent aggregation of red blood cells, which as you may recall, is part of the coagulation cascade. (39,40) An image I find effective in describing fish oils to my patients is that they act like Teflon to prevent this aggregating effect. The dose that I recommend in my protocol is aggressive: one tablespoon daily. You will rarely achieve these doses with oral capsules. I rely on fish oils in liquid form.

Fish oils contain EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). One tablespoon of high potency fish oil will yield this high dose of 4300 mg EPA, approximately 3000 mg of DHA, and 1000 mg of other omega-3s. You will not achieve these doses with fish oil capsules.

Fish oils, in addition to their anticoagulant effect, may have multiple ancillary benefits:

* Enhance brain function--cognitive enhancement, (41)

* Prevent cardiovascular events, (42)

* Antidepressant, (43)

* Improve skin elasticity, (44)

* Lower blood pressure. (45)

Vitamin E Isomers

Like fish oil, vitamin E has rheological properties. It prevents red blood cell aggregation and lowers blood viscosity, or stickiness. (46) Vitamin E exists as a family of tocopherols and tocotrienols, and I recommend mixed tocopherols, an isomeric mix of natural tocopherols including the alpha, beta, gamma and delta forms of vitamin E. There is a difference between "natural" vitamin E and "synthetic" natural vitamin E. Synthetic vitamin E is a tocopheryl nottocopherol.

Fibrin synthesis cascade

Water, Elixir of Life

And last but not least, hydration. Keep well hydrated. Hydration will also prevent red blood cell and platelet aggregation. (47) It will improve skin elasticity. I recommend filtered water in glass bottles, not plastic bottles. We all should avoid plasticizers. The softer the plastic bottle, the higher the plasticizer content.

Focus: When a patient comes to you seeking an anticoagulation protocol, what do you do?

Miller: I run a series of tests. First, I look at typical lab work - a complete blood count (CBC), chemistries (liver and kidney function), lipids, vitamin D, thyroid and adrenal. I also look at inflammatory markers such as C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fibrinogen levels. With more sophisticated testing, we can test arachidonic acid/EPA ratios. These are obtained through one of a number of specialty labs.

I routinely measure fibrinogen levels on every one of my patients. I am aggressive about reducing fibrinogen levels. If levels are above 350 mg/dl, I recommend nattokinase, despite most labs using an upper level for high fibrinogen >450 mg/dl. I look at the patient's clinical picture: age, risk factors such as hypertension, cardiovascular issues, and family history. It's always a combination of lab values, family history, and the clinical picture.

I find that my recommended regimen, when fully implemented, treats all pathways of coagulation. Empirically and rationally, there is good evidence this approach has the ability to effectively prevent heart attacks, strokes, and recurrent thrombophlebitis. It is a comprehensive approach to anticoagulant therapy that, for my patients and me, has stood the test of time.

References

(1.) https://millionhearts.hhs.gov/learn-prevent/costconsequences.html

(2.) Grove EL. Antiplatelet effect of aspirin in patients with coronary artery disease. Dan Med J. 2012;59(9):B4506.

(3.) http://www.medscape.com/viewarticle/828669

(4.) https://www.boehringer-ingelheim.us/press-release/ fda-approves-praxbind-idarucizumab-specific-reversal-agent-pradaxa-dabigatran

(5.) http://www.aafp.org/afp/2013/0415/p556.html

(6.) Gomes T, et al. Rates of hemorrhage during warfarin therapy for atrial fibrillation. CMAJ. 2013 Feb 5;185(2):E121-7.

(7.) Palareti G, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet. 1996; 348(9025):423-8.

(8.) http://www.nutri-facts.Org/en_US/nutrients/vitamins/k/ health-functions.html

(9.) Booth SL, et al. Vitamin K: a practical guide to the dietary management of patients on warfarin. Nutr.Rev. 1999 Sep;57(9 Pt l):288-90.

(10.) Shearer MJ. The roles of vitamins D and K in bone health and osteoporosis prevention. Proc NutrSoc. 1997; 56(3): 915-37.

(11.) Booth SL. Skeletal functions of vitamin K-dependent proteins: not just for clotting anymore. NutrRev. 1997; 55(7): 282-284.

(12.) O'Donnell CJ, et al. Matrix GLA Protein Is Associated with Risk Factors for Atherosclerosis but not with Coronary Artery Calcification. Atheroscler Thromb Vase Biol. 2006;26:2769-2774.

(13.) Ferland G. Vitamin K. In: Bowman BA, Russell RM, eds. Present Knowledge in Nutrition. 9th ed. Volume 1. Washington, DC: ILSI Press; 2006: 220-230.

(14.) Tsaioun Kl. Vitamin K-dependent proteins in the developing and aging nervous system. NutrRev. 1999;57(8):231-40.

(15.) Jiang X, et al. Vitamin K2 regression aortic calcification induced by warfarin via Gas6/Axl survival pathway in rats. Eur J Pharmacol. 2016;786:10-18.

(16.) Namba S, et al. Long-term warfarin therapy and biomarkers for osteoporosis and atherosclerosis. BBA Clin. 2015;4:7680.

(17.) Bennis Y, et al. Vascular calcifications, the hidden side effects of vitamin K antagonists. Therapie. 2016;71(4):355-363.

(18.) Laux V, et al. Direct inhibitors of coagulation proteins - the end of the heparin and low-molecular-weight heparin era for anticoagulant therapy? Thromb Haemost. 2009;102(5):8929.

(19.) Kaski JC, et al. Inflammation and thrombosis in atrial fibrillation. Rev Esp Cardio. 2011;64(7): 551-3.

(20.) http://www.afibmatters.org/About-atrial-fibrillation

(21.) http://www.heart.org/HEARTORG/Conditions/Arrhythmia/ About Arrhythmia/What-are-the-Symptoms-of-Atria-Fibrillation-AFib-or-AF_UCM_423777_Article.jsp

(22.) http://stroke.ahajournals.org/content/ strokeaha/41/ll/2705.full.pdf.

(23.) http://www.thenakedscientists.com/HTML/questions/ question/3418/

(24.) Kirchhofer D, et al. Specific accumulation of circulating monocytes and polymorphonuclear leukocytes on platelet thrombi in a vascular injury model. Blood. 1997 89:1270-1278.

(25.) Ueda Y, et al. Intracoronary morphology of culprit lesions after reperfusion in acute myocardial infarction: serial angioscopic observations. J Am Coll Cardiol. 1996;27: 606-610.

(26.) Hoak JC. Platelets and atherosclerosis. Semin Thromb Hemost. 1988;14:202.

(27.) Falk A. Unstable angina with fatal outcome: dynamic coronary thrombosis leading to infarction and/or sudden death. Autopsy evidence of recurrent mural thrombosis with peripheral embolization culminating in total vascular occlusion. Circulation. 1985;71(4):699.

(28.) Hsia CH, et al. Nattokinase decreases plasma levels of fibrinogen factor VII and factor VIII in human subjects. Nutr Res. 2009;29(3):190-6.

(29.) Kurosawa Y, et al. A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles. Sci Rep. 2015;25(5): 11601.

(30.) Suzuki Y, et al. Dietary supplementation with fermented soybeans suppresses intimal thickening. Nutrition. 2003;19:261-4.

(31.) Fujita M, et al. Thrombolytic effect of nattokinase on a chemically induced thrombosis model in a rat. Biol Pharm Bull. 1995;18:1387-91.

(32.) Urano T, et al. The Profibrinolytic Enzyme Subtilisin NAT Purified from Bacillus subtilis Cleaves and Inactivates Plasminogen Activator Inhibitor Type 1. J Biol Chem. 2001;276:24690-6.

(33.) Tai MW, Sweet BV. Nattokinase for prevention of thrombosis. Am J Health Syst Pharm. 2006;63(12):1121-1123.

(34.) Kotb E. The biotechnological potential of fibrinolytic enzymes in the dissolution of endogenous blood thrombi. Biotechnol Prog. 2014;30(3):656-72.

(35.) Tachibana M, et al. A multi-centre, double-blind study of serrapeptase versus placebo in post-antrotomy buccal swelling. Pharmatherapeutica. 1984;3(8):526-30.

(36.) Blumenthal M, ed. Herbal Medicine: Expanded Commission E Monographs. Integrative Medicine Communications. Feb. 15, 2000.

(37.) http://www.sigmaaldrich.com/life-science/nutrition-research/ learning-center/plant-profiler/ginkgo-biloba.html

(38.) Ryu KH, et al. Ginkgo biloba extract enhances antiplatelet and antithrombotic effects of cilostazol without prolongation of bleeding time. Thromb Res. 2009 Jul;124(3):328-34.

(39.) Urakaze M, et al. Infusion of fish oil emulsion: effects on platelet aggregation and fatty acid composition in phospholipids of plasma, platelets, and red blood cell membranes in rabbits. Am J Clin Nutr. 1987;46(6):936-40.

(40.) Sanders TA, et al. The influence of a fish oil high in docosahexaenoic acid on plasma lipoprotein and vitamin E concentrations and haemostatic function in healthy male volunteers. Br J Nutr. 1992;68(l):163-73.

(41.) Chiu CC, et al. The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: A preliminary randomized double-blind placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32(6): 1538-44.

(42.) Gebauer SK, et al. n-3 fatty acid dietary recommendations and food sources to achieve essentially and cardiovascular benefits. Am J Clin Nutr. 2006: 83(6 Suppl):1526S-1535S.

(43.) Su KP, et al. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 2003;13(4):267-71.

(44.) Angelo G. Essential Fatty Acids and Skin Health. Linus Pauling Institute. 2012.

(45.) Hoshi T, et al. Omega-3 fatty acids lower blood pressure by directly activating large-conductance [Ca.sup.2+]-dependent [K.sup.+] channels. Proc Natl Acad Sci USA. 2013 Mar 19;110(12):4816-21.

(46.) Cuzzocrea M, et al. Changes in blood viscosity after administration of vitamin E in the rabbit. Boll Soc Ital Biol Sper. 1983 May 30;59(5):679-85.

(47.) Waltz X, et al. Effects of hydration level and heat stress on thermoregulatory responses, hematological and blood reheological properties in growing pigs. PLos One. 2014;9(7):el02537.

Dr. Miller's Caveats

A major caveat: I never advocate abruptly stopping conventional anticoagulant routines. You need experienced medical supervision to start and monitor your progress. This anticoagulant routine requires special knowledge of potency, dosing and the value of these natural sources. Dosages will vary depending on your laboratory tests. I have treated thousands of cases over the past 20 years. This is time- tested. It is effective. But this regimen has not been "validated" through conventional guidelines or task force committees. It is not the "standard of care." For this reason, your internist, cardiologist or family practitioner will have little understanding of the rationale or efficacy of this routine. Do not self-treat.

Philip Lee Miller, MD

Dr. Philip Lee Miller, MD is the Founder, Medical Director, and CEO of California Age Management Institute, located in Monterey, CA. He has been in medical practice for over 45 years. He graduated from UC Berkeley in 1968 (Centennial) with a degree in biochemistry. In 1972, he graduated from the School of Medicine at UC San Diego with an MD degree -- the school's first (charter) graduating class. There was further training in neurology at UC Davis. He was ABEM Board Certified in Emergency and is currently a Diplomat of the American Board on AntiAging Medicine (ABAAM).

Caption: Dr. Miller is an internationally recognized leader in anti-aging, age management and integrative medicine. This started with a past association with Dr. Julian Whitaker of the Whitaker Wellness Institute in Newport Beach, California. Dr. Miller is the lead co-author of one of the classics in the anti-aging medicine literature: The LEF Revolution: The New Science of Growing Older Without Aging, first released on May 17, 2005. He regularly pens topical blogs at blog.antiaging.com on subjects with a critical view and additional blogs on Huffington Post. You can easily find him on www.antiaging.com.
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Date:May 1, 2017
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