Blood Clot Prevention-B

Warfarin and Nutrients: Can They Work Together?

Warfarin was originally isolated in 1939 from sweet clover. Interestingly, warfarin is the active ingredient found in many commercial rat poisons and insecticides, which work by encouraging bleeding. Warfarin is used to prevent heart attacks, arterial blood clots, and deep vein thrombosis. It is also used in patients who have prosthetic heart valves to prevent blood clots.

Bleeding is the primary side effect of warfarin therapy. Minor bleeding from warfarin usually begins with ecchymoses (purple patches on the skin). Then the mucous membranes are affected, causing nosebleed and bleeding under the mucous membranes that cover the eyes and inner eyelids. Hematuria (blood in the urine) may also occur. Major complications usually involve gastrointestinal bleeding and intracranial bleeding (bleeding within the brain).

Warfarin has an extremely long list of contraindications and drug interactions. Of particular concern is its use in elderly patients because they have an increased risk of hemorrhage. Several common drugs negatively interact with warfarin, including aspirin, cimetidine, lovastatin, thyroid hormones, and estrogens and oral contraceptives.

There is much debate and confusion about the interactions between dietary nutrients and warfarin. Patients who take warfarin are regularly warned about taking dietary antiplatelet agents, including Ginkgo biloba, green tea, vitamin E, garlic, and fish oil (Heck AM et al 2000). Other nutrients that may increase the risk of bleeding include angelica root, arnica flower, anise, asafetida, bogbean, borage seed oil, bromelain, capsicum, celery, chamomile, clove, fenugreek, feverfew, ginger, horse chestnut, licorice root, lovage root, meadowsweet, onion, parsley, passionflower, poplar, quassia, red clover, rue, sweet clover, turmeric, and willow bark (Heck AM et al 2000).

One nutrient, however, may have been unfairly swept up in this long list of contraindications. A few animal studies and case histories have claimed that coenzyme Q10 (CoQ10), a powerful antioxidant, is contraindicated in patients taking warfarin. However, a study of 24 patients (who were undergoing stable, long-term warfarin treatment) examined the effect of taking 100 mg of Ginkgo biloba and 100 mg of CoQ10 along with warfarin. Researchers found no change in the effects of warfarin therapy after a 1-month treatment period (Engelsen J et al 2003).

By following an ultra cautious approach regarding warfarin and nutrients, patients may be denying themselves the possibility of designing a personalized approach that relies on both warfarin and antiplatelet nutrient therapy. Major medical publications confirm the importance of lowering the risk of cerebrovascular stroke and heart attack by taking both antiplatelets and anticoagulants (Fasey N et al 2002; Hurlen M et al 2002).

Patients who wish to take this approach will need to work closely with their physicians and undergo regular blood testing. The test most often used to monitor warfarin therapy is prothrombin. This test measures the activity of various factors involved in the clotting process. It is expressed as the international normalized ratio (INR), which is a mathematical calculation that corrects for variability in prothrombin test results based on different laboratory testing agents used. Desired INR ranges vary, depending on underlying conditions. A target INR range of 2.0 to 3.0 is recommended for most conditions, while 2.5 to 3.5 INR is recommended for prosthetic heart valves.

Because the prothrombin test does not reveal antiplatelet activity, however, it’s also necessary for patients on combination warfarin/antiplatelet therapy to undergo regular bleeding time tests. In this test, a small prick is made in the skin, and the physician measures how long it takes for a clot to form and for bleeding to stop. The normal time range is 1 to 9 minutes.

By using these two tests in concert, it may be possible to develop a balanced program of anticoagulant and antiplatelet therapy that is uniquely suited to an individual, reduces the risk of blood clots, and cuts down on adverse effects associated with anticoagulant therapy.

Ximelagatran: A Possible Blockbuster
Already approved in Europe for certain conditions, ximelagatran is the most exciting anticoagulant news in the last 30 years. Developed under the trade name Exanta®, ximelagatran is a direct thrombin inhibitor.

So far, in early clinical studies, ximelagatran has shown great promise. Whereas warfarin requires frequent blood testing and dosage adjustment, ximelagatran may be given at a fixed dose. It also has fewer side effects and drug interactions than warfarin, and can be administered orally.

Ximelagatran has been tested against a wide variety of diseases and disorders, including atrial fibrillation (O’Brien CL et al 2005) and deep vein thrombosis (Feissinger JN et al 2005). It may be as effective as warfarin. However, it is more expensive.

As of this time, ximelagatran has not been approved for use in the United States because of concerns about liver toxicity. In some early studies, ximelagatran raised liver enzyme levels of some patients (Brinker A et al 2005).

A Balanced Approach to Reducing Blood Clot Risk
Many of the nutrients that have been shown to lower the risk of blood clots work by acting on underlying conditions, and they often have overlapping functions with other nutrients. For instance, an elevated homocysteine level is one of the risk factors for blood clots because homocysteine has been linked to CAD. So, there is overlap between the nutrients the Life Extension Foundation recommends to reduce homocysteine levels and those recommended to reduce the risk of blood clots. The same is true for nutrients recommended to treat certain cancers, stroke, and many other conditions.

It is important to remember that good health is truly a lifestyle decision, requiring a balanced, comprehensive approach to diet and nutrient supplementation. The Life Extension Foundation believes in promoting optimal health (not just in treating single diseases), because good health will enable us to live longer, happier, and more productive lives. Almost nowhere is this approach more important than in lowering the risk for blood clots. Contrary to excessive use of medications, supplying the body with what it needs to heal reduces adverse effects and causes less stress on the body.

Following are some of the nutrients that have been shown to reduce the risk of blood clotting:

Catechin and quercetin—Catechin and quercetin are antioxidants that reduce the adhesion of blood platelets, possibly by decreasing the production of hydrogen peroxide (Pignatelli P et al 2000).
Curcumin—Curcumin, a dietary spice derived from turmeric, is known to be anti-inflammatory, anticarcinogenic, and antithrombotic (Shah BH et al 1999).
Dehydroepiandrosterone (DHEA)—Among its many anti-aging properties, DHEA has been shown to reduce inflammation by inhibiting cytokines, or chemicals that promote inflammation within blood vessels (Straub RH et al 2000). With reduced inflammation, less platelet aggregation and LDL migration into the vessel walls occurs. This can lead to less blood clot formation and atherosclerosis.
Essential fatty acids—Essential fatty acids are found in healthy oils, such as flax, borage, perilla, and fish oils. Essential fatty acids, including docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are known to inhibit platelet aggregation and reduce the risk of blood clots. Several studies have found that essential fatty acids exhibit antiplatelet activity. Essential fatty acids were shown to inhibit collagen-induced and arachidonic acid–induced platelet aggregation. No effects were seen in thrombin-induced aggregation (Akiba S et al 2000; Ikeda I et al 1998). An Australian study found that omega-3 fatty acids (those rich in alpha-linolenic acid, such as flaxseed and perilla oils) were more effective at platelet inhibition than omega-6 fatty acids (those rich in linoleic acid, such as sunflower oil) (Allman MA et al 1995). A German study reported the same result; an omega-3 to omega-6 ratio of 15:1 caused a significant decrease of collagen-induced platelet aggregation (Stroh S et al 1991).

Folic acid—Because of the danger of homocysteine and its close association with prothrombotic diseases such as CAD, the Life Extension Foundation recommends keeping homocysteine levels between 7 and 8 mmol/L. Folic acid and folate are critical elements in any homocysteine-lowering program, as both have been shown to reduce plasma homocysteine levels (Durand P et al 2001).

Garlic extract—Aged garlic extract is a well-known supplement for lowering cholesterol and improving the cardiovascular system. It has a number of beneficial effects. Garlic increases the synthesis of nitric oxide, which inhibits platelet aggregation and vasodilates blood vessels (Das I et al 1995; Dirsch VM et al 1998; Kim KM et al 2001; Kim-Park S et al 2000). It inhibits platelet aggregation (Rahman K et al 2000; Steiner M et al 1998) and lowers cholesterol by as much as 20 percent (Ali M et al 1990; Ali M et al 1995). Garlic also reduces atherosclerotic plaque volume while lowering blood pressure and increasing HDL cholesterol (Siegel G et al 1999).

Ginkgo biloba—Ginkgo biloba is a natural antiplatelet. An article in the journal Thrombosis Research described a study of the effects of Ginkgo biloba in combination with ticlopidine when used to treat rats with experimentally induced thrombosis. The combination of Ginkgo biloba (40 mg/kg daily) and a small dose of ticlopidine (50 mg/kg daily) was shown to be comparable to a large dose of ticlopidine (200 mg/kg daily). The combination also significantly prolonged bleeding time and consistently decreased the thrombus weight (Kim et al 1998).
Grape seed extract—Grape seed and skin have been shown to inhibit platelet aggregation (Keevil JG et al 2000).

Green tea—Green tea catechins, which include epigallocatechin gallate, have an antiplatelet effect (Son DJ et al 2004). Green tea also inhibits fibrinogen (Kang WS et al 1999; Kang WS et al 2001; Sagesaka-Mitane Y et al 1990).
N-acetyl-L-cysteine—N-acetyl-L-cysteine enhances the effect of L-arginine, which promotes creation of nitric oxide (Anfossi G et al 1999; Anfossi G et al 2001). An adverse effect of this is the creation of free radicals. It may be helpful to take N-acetyl-L-cysteine with gamma tocopherol and L-arginine to minimize free radical damage.

Nattokinase—This enzyme, which was isolated from a traditional Japanese soy food called natto, has been shown to reduce fibrin levels (Chang CT et al 2000).

Nettle leaf—In Germany, nettle leaf is an herb (Urtica dioica) with a long tradition as an adjuvant remedy in the treatment of arthritis. Like DHEA, nettle leaf has anti-inflammatory effects that work by inhibiting chemicals that cause inflammation within blood vessel walls (cytokines) (Obertreis B et al 1996; Obertreis B et al 1996; Teucher T et al 1996). Reduced inflammation lowers the risk of blood clot formation.

Niacin—Niacin favorably modifies fibrinogen and LDL cholesterol (Chesney CM et al 2000; Johansson JO et al 1997; Philipp CS et al 1998) and is the recommended agent for lowering lipoprotein(a) (Batiste MC et al 2002).
Policosanol—Isolated from sugar cane wax, policosanol has demonstrated a powerful cholesterol-lowering ability. Policosanol is at least as effective as aspirin in reducing platelet aggregation (Arruzazabala ML et al 1997; Carbajal D et al 1998). Policosanol also improves cholesterol metabolism, in one study increasing HDL cholesterol by 18.4 percent and reducing triglycerides by 14.1 percent (Castano G et al 1999). In a study of heart disease patients with myocardial ischemia, policosanol improved exercise electrocardiogram responses, an effect that was augmented by aspirin (Stusser R et al 1998).

Tomatoes—Tomatoes contain lycopene, a well-known and powerful antioxidant that may be particularly effective in blocking the oxidation of LDL cholesterol. Among all fruits tested for their antiplatelet property, tomatoes had the highest activity (Dutta-Roy AK et al 2001).

Vitamins C and E—Vitamin E inhibits collagen-induced platelet activation by blunting hydrogen peroxide formation (Pignatelli P et al 1999). Vitamins C and E together are associated with an enzyme (paraoxonase) that improves cholesterol levels (Jarvik GP et al 2002).
For More Information
Blood clots are usually caused by an underlying disorder or condition, which means that successful management of the underlying condition can reduce the risk of getting a debilitating blood clot. Other chapters that may be of interest include:

Hyperhomocysteinemia

Life Extension Foundation Recommendations

If you have risk factors for blood clots, we recommend that you take an active role in lowering your risk—through blood tests, dietary nutrients, and positive lifestyle changes. Exercise is an excellent method to reduce the risk of blood clots because of its proven ability to decrease the level of blood fibrinogen (El Sayed MS et al 1999; Imhof A et al 2001; Koenig W et al 2000; Verissimo MT et al 2001). Any exercise program should be launched only under the supervision of a physician.

Patients already taking anticoagulants may also consider adding antiplatelet dietary nutrients under the supervision of their physician. In this case, the Life Extension Foundation recommends frequent blood testing for prothrombin test time and bleeding time to make sure there is no enhanced risk of bleeding.

The Life Extension Foundation’s recommended protocol to reduce the risk of blood clots includes:

Cholesterol-lowering nutrients:
Policosanol—10 mg in the evening
Garlic—500 to 1000 mg daily
No-flush niacin—1600 to 2400 mg daily
Antiplatelet nutrients:
Low-dose aspirin—81 mg daily
Ginkgo extract—120 mg daily
Fish oil (essential fatty acids)—1400 mg of EPA and 1000 mg of DHA
Nattokinase—430 mg daily
Vitamin E—400 international units (IU) daily of alpha-tocopherol succinate
Gamma tocopherol—350 to 400 mg
N-acetyl-L-cysteine—250 mg three times daily, with 200 to 400 mg of gamma tocopherol and 1800 to 3600 mg of L-arginine two to four times daily
Homocysteine-lowering nutrients:
Folic acid—800 to 2400 micrograms (mcg) daily, with vitamin B12
Vitamin B12—1000 m2cg
Vitamin B6—250 to 750 mg daily
Anti-inflammatory nutrients:
Curcumin—800 to 1600 mg daily
DHEA—25 to 50 mg daily
Nettle leaf—1000 mg daily
Antioxidants:
Vitamin C—2.5 to 6 grams daily
Lycopene—15 to 30 mg daily
Quercetin—500 mg daily
Grape seed extract—300 mg daily
Standardized green tea extract—725 mg capsules daily

Blood Clot Prevention Safety Caveats

An aggressive program of dietary supplementation should not be launched without the supervision of a qualified physician. Several of the nutrients suggested in this protocol may have adverse effects. These include:

Curcumin
Do not take curcumin if you have a bile duct obstruction or a history of gallstones. Taking curcumin can stimulate bile production.
Consult your doctor before taking curcumin if you have gastroesophageal reflux disease (GERD) or a history of peptic ulcer disease.
Consult your doctor before taking curcumin if you take warfarin or antiplatelet drugs. Curcumin can have antithrombotic activity.
Always take curcumin with food. Curcumin may cause gastric irritation, ulceration, gastritis, and peptic ulcer disease if taken on an empty stomach.
Curcumin can cause gastrointestinal symptoms such as nausea and diarrhea.

DHEA
Do not take DHEA if you could be pregnant, are breastfeeding, or could have prostate, breast, uterine, or ovarian cancer.
EPA/DHA

Consult your doctor before taking EPA/DHA if you take warfarin (Coumadin). Taking EPA/DHA with warfarin may increase the risk of bleeding.
Discontinue using EPA/DHA 2 weeks before any surgical procedure.

Folic acid
Consult your doctor before taking folic acid if you have a vitamin B12 deficiency.
Daily doses of more than 1 milligram of folic acid can precipitate or exacerbate the neurological damage caused by a vitamin B12 deficiency.

Garlic
Garlic has blood-thinning, anticlotting properties.
Discontinue using garlic before any surgical procedure.
Garlic can cause headache, muscle pain, fatigue, vertigo, watery eyes, asthma, and gastrointestinal symptoms such as nausea and diarrhea.
Ingesting large amounts of garlic can cause bad breath and body odor.
Ginkgo biloba

Individuals with a known risk factor for intracranial hemorrhage, systematic arterial hypertension, diabetes, or seizures should avoid ginkgo.
Do not use prior to or after surgery.
Avoid concomitant use of ginkgo with NSAIDS, blood thinners, diuretics, or SSRI’s.
Gastrointestinal symptoms (nausea and diarrhea) may occur.
Allergic skin reactions may occur.
Elevations in blood pressure may occur.

Green Tea
Consult your doctor before taking green tea extract if you take aspirin or warfarin (Coumadin). Taking green tea extract and aspirin or warfarin can increase the risk of bleeding.
Discontinue using green tea extract 2 weeks before any surgical procedure. Green tea extract may decrease platelet aggregation.
Green tea extract contains caffeine, which may produce a variety of symptoms including restlessness, nausea, headache, muscle tension, sleep disturbances, and rapid heartbeat.

NAC
NAC clearance is reduced in people who have chronic liver disease.
Do not take NAC if you have a history of kidney stones (particularly cystine stones).
NAC can produce a false-positive result in the nitroprusside test for ketone bodies used to detect diabetes.
Consult your doctor before taking NAC if you have a history of peptic ulcer disease. Mucolytic agents may disrupt the gastric mucosal barrier.
NAC can cause headache (especially when used along with nitrates) and gastrointestinal symptoms such as nausea and diarrhea.

Nattokinase
Do not take nattokinase if you have a blood coagulation disorder.
Niacin (nicotinic acid)

Do not take high doses of nicotinic acid (1.5 to 5 grams daily or more) if you have liver dysfunction, an unexplained elevation in your serum aminotransferase (transaminase) level, active peptic ulcer disease, arterial bleeding, or if you consume large amounts of alcohol.
Consult your doctor before taking high doses of nicotinic acid if you have a history of jaundice, peptic ulcer disease, gastritis, disease of the liver or bile ducts, gout, kidney dysfunction, or cardiovascular disease (especially acute myocardial infarction or unstable angina).
Consult your doctor before taking high doses of nicotinic acid if you have diabetes. High doses of nicotinic acid can negatively affect glucose tolerance. Monitor your serum glucose level frequently if you take nicotinic acid and have diabetes.
Have your doctor monitor your serum aminotransferase level if you take high-doses of nicotinic acid.
Nicotinic acid may cause flushing, principally of the face, neck, and chest. This flushing is thought to be prostaglandin-prostacyclin mediated. Histamine may also play a role in the flushing.
Nicotinic acid can cause dizziness, palpitations, rapid heartbeat, shortness of breath, sweating, chills, insomnia, nausea, vomiting, abdominal pain, and muscle pain.
High doses of nicotinic acid can cause blurred vision, macular edema, toxic amblyopia, and cystic maculopathy.
Policosanol

Consult your doctor before taking policosanol if you take aspirin or warfarin (Coumadin) or if you have hemophilia. Policosanol can have antithrombotic activity, and policosanol may enhance the antithrombotic properties of aspirin.
Discontinue using policosanol before any surgical procedure.
Policosanol can cause rash, headache, insomnia, weight loss, and gastrointestinal symptoms such as nausea and diarrhea.

Quercetin

Quercetin can cause headache, mild tingling of the extremities, and gastrointestinal symptoms such as nausea.

Vitamin B6
Do not take 5 milligrams or more of vitamin B6 daily if you are being treated with levodopa, unless you are taking carbidopa at the same time.
Vitamin B12 (cyanocobalamin)

Do not take cyanocobalamin if you have Leber's optic atrophy.

Vitamin C
Do not take vitamin C if you have a history of kidney stones or of kidney insufficiency (defined as having a serum creatine level greater than 2 milligrams per deciliter and/or a creatinine clearance less than 30 milliliters per minute.
Consult your doctor before taking large amounts of vitamin C if you have hemochromatosis, thalassemia, sideroblastic anemia, sickle cell anemia, or erythrocyte glucose-6-phosphate dehydrogenase (G6PD) deficiency. You can experience iron overload if you have one of these conditions and use large amounts of vitamin C.

Vitamin E
Consult your doctor before taking vitamin E if you take warfarin (Coumadin).
Consult your doctor before taking high doses of vitamin E if you have a vitamin K deficiency or a history of liver failure.
Consult your doctor before taking vitamin E if you have a history of any bleeding disorder such as peptic ulcers, hemorrhagic stroke, or hemophilia.
Discontinue using vitamin E 1 month before any surgical procedure.