Thrombosis Prevention

Thrombosis: from the Greek word thrombos, meaning clot
An abnormal blood clot inside a blood vessel is called thrombosis. Thrombosis has been described as coagulation occurring in the wrong place or at the wrong time. The end result of thrombosis is an obstruction of the blood flow. Since the leading cause of death in the Western world is the formation of an abnormal blood clot inside a blood vessel, it is important for healthy people to take steps to prevent thrombosis. For those with risk factors for developing thrombosis, aggressive actions must be taken to protect against stroke, heart attack, kidney failure, pulmonary embolus, etc.

As noted above, thrombi are clots that form in a blood vessel or in the wrong place: in an artery, a vein, or in the chambers of the heart. Thrombi in the arteries form under high pressure and flow conditions and are composed of platelet aggregates bound together by intrinsic fibrin protein strands. Clots in veins form under low flow conditions, are composed predominantly of red cells with few platelets, and contain a large amount of interspersed fibrin strands.

These thrombi may remain static in the vessel. However, clots can also become mobile or embolize. If a clot travels from a lower extremity vein to the lungs, the result is a pulmonary embolism and/or a pulmonary infarction (lung cell death). Similarly, if a clot moves from the heart or the carotid artery to the brain, it causes a stroke. If a clot travels to a position that occludes, or blocks, the coronary artery, it can develop into a heart attack (myocardial infarction, or MI). Certain conditions such as irregular heart rhythms (e.g., atrial fibrillation) and valvular diseases (e.g., mitral stenosis) cause atrial chamber enlargement and inefficient atrial chamber contractions. This increases the risk of clots forming in the atria that can mobilize to the brain and cause a stroke.

The prevention of thrombosis is essential in order to significantly reduce heart disease, cancer, and stroke mortality. Cardiovascular disease remains the leading cause of death at approximately 1 million deaths yearly. This is about twice the incidence of yearly cancer deaths. Of these cardiovascular deaths, coronary artery disease represents approximately 51%, while strokes represent 16%. These diseases involve thrombosis in their evolution and make up a significant percentage of all cardiovascular deaths (American Heart Association 1997). In addition, thrombosis is a common killer of cancer patients. Therefore, it becomes paramount to optimize the prevention of thrombosis in order to reduce the high incidence of death from cardiovascular as well as other diseases.

SYMPTOMS

The symptoms of thrombosis depend on where the clot forms. During a heart attack, which sometimes occurs because a clot lodges in a coronary artery, the onset of associated symptoms is usually sudden in nature. If the coronary artery involved is a minor vessel and the vessel is occluded (blocked) by the clot at its terminal end, the heart attack may be without any symptoms at all. However, when the clot is large and suddenly occludes the left main coronary artery, the entire blood supply to the left ventricle is suddenly cut off and the heart attack is massive and abruptly fatal. Branches of the left or right main coronary arteries can be occluded by embolisms or, more commonly, by small clots that form on the wall of a coronary artery and mix with oxidized LDL and fibrinogen to occlude the vessel, forming what is called an atheroma, and narrowing the lumen of the involved coronary artery.

This occlusion often causes the classic symptoms of a sudden heart attack: angina-related chest pain, shortness of breath, cold and clammy perspiration, cold extremities, overwhelming anxiety, nausea, profound weakness, dizziness, difficulty concentrating, chest fluttering, and palpitations or other irregular heart beats. The classic chest pain felt during a heart attack resembles a heavy, crushing, constricting sensation. This pain can originate in the chest, the left or right arm, the shoulders, or even the jaw. The pain often extends from the chest down the left arm. However, the extension of pain can move from the chest to the right arm or even to the jaw. When associated with an on-going heart attack, the pain tends to last 10-15 minutes rather than 1-3 minutes prior to the heart attack.

In cases where the occlusion is less severe or in cases of impaired nerve supply (e.g., as in diabetic neuropathy), a heart attack can occur without any symptoms and even present to the emergency room with a normal EKG. In this situation, the heart attack is diagnosed by identifying positive cardiac enzymes in the blood. If classic heart attack symptoms manifest, the most important initial step the victim can take is to chew on 1 whole aspirin tablet. The antiplatelet actions of aspirin can sometimes forestall a full-blown heart attack.

The symptoms associated with a thrombotic stroke are varied, depending on whether the stroke occurs from a sudden embolism or gradual clot formation. In a cerebral embolic stroke, the symptoms are rapid in onset and often peak within a few seconds. Victims may experience seizures and a headache on the affected side due to the sudden onset of symptoms. In a cerebral thrombotic stroke, the onset is over minutes or hours and occasionally the stroke progresses in stages over days or weeks.

The symptoms that occur during a stroke depend upon the region of the brain that is injured. For example, when the region supplying the eyes (the retinal region) is involved, patients experience transient blackouts and the sense that a shade is being pulled over their eyes. When the cerebrum is involved, contralateral monoparesis, hemiparesis, localized tingling, numbness, hemianopic visual loss, aphasia, and (rare) losses of consciousness can occur. When the vertebrobasilar region is involved, patients experience bilateral visual disturbances (dim, gray, blurred vision, or temporary total blindness called diplopia). Vertebrobasilar episodes cause symptoms to be induced by abrupt position changes while carotid episodes do not. When the labyrinth or medulla is involved, vertigo, unsteadiness, nausea, and vomiting occur. When the brainstem is involved, patients experience slurred speech, dysarthria, dysphagia, numbness, weakness, and all four-limb paresthesia. "Drop" attacks from sudden loss of postural tone are symptoms of a stroke that is basilar in origin.

The symptoms associated with the onset of a pulmonary embolism or infarction can be nonspecific and often vary in frequency and intensity. This depends upon the extent of pulmonary vascular occlusion, the functional strength of the heart before the embolism occurred, and the size of the emboli. Small emboli, or microemboli, may be asymptomatic. However, if symptoms occur, they tend to develop abruptly over a few minutes, including sudden shortness of breath or breathlessness with or without a cough or wheezing, rapid breathing, anxiety, and restlessness. Often at the time of pulmonary embolism, high blood pressure exists within the pulmonary arterial vasculature. If this is the case, when the embolism occurs, dull chest pain may occur. In a massive pulmonary embolism, right heart failure may develop with fluid in the abdominal and lower extremities. There may be lightheadedness, unconsciousness, and seizures due to a drop in cardiac output from the failing heart. The face often turns white and bluish (cyanosis).

SILENT STROKES

Several studies have shown that the incidence of "silent" strokes in the elderly is very high. Over time, these "silent" strokes lead to memory loss and other neurological problems, of particular concern for people who are at risk for stroke.

An article in the journal Neurology found that 28% of the 3324 older participants in the Cardiovascular Health Study had evidence of silent infarcts discovered on cranial magnetic resonance imaging (MRI). The authors also found that high blood pressure, thickness of common and internal carotid walls, and the presence of atrial fibrillation were associated with an increased risk of stroke in those with silent infarcts (Bernick et al. 2001).

THE BLOOD CLOTTING SYSTEM

The blood clotting system is activated when blood vessels are damaged, exposing collagen, the major protein that connective tissue is made from. Platelets circulating in the blood adhere to exposed collagen on the cell wall of the blood vessel and secrete chemicals that start the clotting process as follows:

1. Platelet aggregators cause platelets to clump together (aggregate). They also cause the blood vessels to contract (vasoconstrict), which reduces blood loss. Platelet aggregators include adenosine diphosphate (ADP), thromboxane A2, and serotonin (5-HT).
2. Coagulants such as fibrin then bind the platelets together to form a permanent plug (clot) that seals the leak.

Fibrin is formed from fibrinogen in a complex series of reactions called the coagulation cascade. The enzymes that comprise the coagulation system are called coagulation factors, which are numbered in the order in which they were discovered. They include factor XII, factor XI, factor IX, factor X, factor VII, and factor V. The activation of the coagulation factors results in the formation of thrombin, which acts as a cofactor for the conversion of fibrinogen into fibrin.

After the leak has been sealed with a blood clot, the body responds with another set of chemical messengers that oppose the actions of these chemicals. These include:

• Platelet aggregation inhibitors and vasodilators, such as nitric oxide and prostacyclin, which is also known as prostaglandin I2 (PGI2)
• Plasminogen activators that promote the breakdown of fibrin, such as tissue plasminogen activator (t-PA)
• Anticoagulants that inhibit enzymes in the coagulation cascade, such as antithrombin III (activated by heparin) and proteins C and S

As you can see, the blood clotting system is quite complex. In the healthy body, a balance is created between the opposing chemicals--for example, coagulants versus anticoagulants; vasodilators versus vasoconstrictors; and platelet aggregators versus platelet aggregator inhibitors. The beauty of nutritional supplements is that they support the natural mechanisms of the body and allow the body to maintain its own equilibrium (homeostasis).

THROMBOSIS RELATED TO ATHEROSCLEROSIS (HARDENING OF ARTERIES)

It is generally accepted that platelet adherence to plaques on the linings of arteries is part of the atherosclerosis cascade. Platelet adherence is worsened by excess fibrin. Platelets release a platelet-derived growth factor, causing the smooth muscle cells on the walls of arteries to proliferate. The resultant smooth muscle cells have an increased permeability to platelets and lipids, especially LDL-cholesterol. As LDL increases, it penetrates further into the arterial wall. Plaque forms in the arterial wall as a benign neoplastic growth (a monoclonal mutation). Excess fibrin, free radicals, chronic inflammation, homocysteine, oxidized LDL, and environmental hydrocarbons, etc. aggravate this mutation.

In the free radical hypothesis, lipid peroxides damage the arterial walls, further enhancing wall permeability, as well as additionally increasing the oxidation of lipids, especially LDL. These free radicals invade the arterial wall and activate cell proliferation and abnormal cell duplication. The newly mutated cells migrate into the arterial wall and induce plaque formation. This cell proliferation increases the surrounding clot growth or thrombus formation. T-cell antibodies regulate this process. The resulting lesions are atheromatous plaque. The surrounding thrombi form primarily from modified smooth muscle cells, LDL, and fibrin.

Naturally occurring thrombolytic enzymes that dissolve clots are generated in the endothelial cells of blood vessels. As people age, production of these enzymes slows and the blood is more prone to coagulation. This results in clotting. However, clots can form at any age.

CAUSES

Thrombosis can be caused by one or more of the following events:

• Injury to the cells that line the heart, arteries, and veins (endothelium)
• Sluggish blood flow, thatcontributes to venous thrombosis, usually affects the veins of the lower extremities. Venous thrombi may cause one-sided edema of the ankle and foot, but often are asymptomatic until they embolize.
• Alterations in arterial blood flow that give rise to arterial thrombosis
• Hypercoagulability (thick blood) which can also cause thrombosis
• Excess fibrinogen
• Excess platelet aggregation, adhesiveness, and/or activity

Although anticoagulants (such as Coumadin and heparin) are the conventional treatment of choice for thrombosis prevention, thrombi which arise solely from hypercoagulability are considered to be uncommon. There are quite a few risk factors for hypercoagulable states: myocardial infarction, prolonged bed rest or immobilization, tissue damage (e.g., burns, surgery, fractures), cardiac failure, cancer, acute leukemia, myeloproliferative disorders, heart valve replacement, disseminated intravascular coagulation, thrombotic thrombocytopenia, homocysteinuria, smoking, hypercholesterolemia, atrial fibrillation, cardiomyopathy, nephrotic syndrome, late pregnancy post-delivery, oral contraceptives, hyperlipidemia, lupus anticoagulant, sickle cell anemia, and thrombocytosis.

Blood stasis and endothelial injury, however, may be a common underlying mechanism for many of these risk factors (Table 1).

Cancer Patients
In cancer patients, disorders related to blood clotting are frequently observed. The biological processes leading to coagulation are probably involved in the mechanisms of metastasis. About 50% of all cancer patients, and up to 95% of those with metastatic disease, show some abnormalities (a prethrombotic state) in the coagulation-fibrinolytic system. Thromboembolic complications are seen in up to 11% of cancer patients, and hemorrhage occurs in about 10%. Thromboembolism and hemorrhage, as a whole, are the second most common cause of death after infection (Ambrus et al. 1975; Lip et al. 2002).

In one study, subclinical changes in the coagulation-fibrinolytic system were frequently detected in lung cancer patients. Five conventional tests and a new standard of blood coagulation were prospectively recorded in a series of 286 patients with new primary lung cancer: platelet count (P); prothrombin time (PT); partial thromboplastin time (PTT); fibrinogen (F); and d-dimer of fibrin (DD). A prethrombotic state--depicted by a prolongation of PT, PTT, and increase of d-dimer of fibrin--was significantly associated with an adverse outcome (van Wersch et al. 1991; Gabazza et al. 1993; Buccheri et al. 1997).

Anticoagulant treatment of cancer patients, particularly those with lung cancer, has been reported to improve survival. These interesting, although preliminary, results of controlled trials lend some support to the argument that activation of blood coagulation plays a role in the natural history of tumor growth. Studies compared the effectiveness of standard heparin with low molecular weight heparin (LMWH) in the treatment of deep vein thrombosis (DVT). In both studies, mortality rates were lower in the patients randomized to LMWH. The analysis of these deaths reveals a striking difference in cancer-related mortality (Green et al. 1992; Hull et al. 1992; Prandoni et al. 1992; Sciumbata et al. 1996; Hejna et al. 1999).

Cancer-related mortality with standard heparin was 31% versus 11% with low molecular weight heparin. This difference cannot solely be attributed to thrombotic or bleeding events. Because large numbers of cancer patients were included in the studies, it seems unlikely that there were more patients with advanced tumors in the standard heparin group than in the low molecular weight heparin group. Although it also is possible that standard heparin increases cancer mortality, such an adverse effect has not been previously reported. These considerations suggest that low molecular weight heparin might exert an inhibitory effect on tumor growth (Collen et al. 2000; von Tempelhoff et al. 2000; Mismetti et al. 2001; Prandoni 2001).

If your oncologist does not or will not test for thrombotic risk factors, contact the Life Extension Foundation at (800) 544-4440.

CONVENTIONAL PREVENTION AND TREATMENT

Preventing thrombosis is essential. Inside a healthy circulatory system, the body constantly prevents clotting. Coagulation/anticoagulation is a "mechanism" that the body must maintain in perfect balance. If this process fails, our lives can be in danger in a matter of minutes.

To function optimally, the body must keep blood flowing well in all vessels, regardless of size. When a leak (or damage) occurs in an artery or vein, the body must encourage the coagulation aspect of this balance to seal the leak. However, when there is a significant disturbance or a clot in the blood flow, the consequences are often lethal.

Because so many factors can contribute to coagulation and therefore should be considered for prevention, it is difficult for conventional medicine to control them all. Mainstream medicine can exert control on some crucial steps in the coagulation cascade, but it may often fail to influence them all.

PRESCRIPTION DRUGS

Several prescription drugs address different parts of the coagulation/anticoagulation system:

• Coumadin (warfarin) inhibits the synthesis of vitamin K-dependent coagulation factors such as Factors II, VII, IX and X and anticoagulant proteins C and S.
• Aspirin inhibits platelet aggregation by interfering with thromboxane synthesis.
• Ticlopidine (Ticlid) inhibits platelet aggregation by interfering with the binding of fibrinogen to the platelet membrane. Ticlopidine is a prescription drug that may be of particular value as an alternative to aspirin. Ticlopidine is often considered in patients that have a high risk of thrombotic stroke and are intolerant to aspirin.
• Heparin (administered intravenously) increases the activity of antithrombin III, which prevents the conversion of fibrinogen to fibrin. Heparin is not absorbed by the gastrointestinal (GI) tract and must be administered intravenously. It is usually only used in emergency situations (e.g., after a stroke).
• Tissue plasminogen factor (t-PA) activates plasmin which breaks apart fibrin. t-PA is used in emergency situations to dissolve blood clots. Streptokinase is another tissue plasminogen factor drug. Both of these drugs are administered intravenously in emergency thrombotic situations (e.g., ischemic stroke or MI).

Platelet Aggregation Inhibitors (Platelet Anti-Aggregation Drugs)

Aspirin
More than any other medication, aspirin is used alone for the prevention of recurrent strokes and transient ischemic attacks (TIAs). Aspirin acts to inhibit blood clotting by reducing platelet aggregation (clumping), thereby preventing the formation of platelet plugs. Aspirin inhibits cyclooxygenase, which facilitates the production of thromboxane A2 (TA2). TA2 is a potent inducer of platelet aggregation and vasoconstriction. In humans, platelet cyclooxygenase can be completely inhibited with aspirin at doses as low as 30 mg daily. A study compared the use of aspirin with warfarin in the prevention of recurrent ischemic strokes: over a 2-year period, it was found that aspirin, as well as warfarin, protected against stroke recurrence and death (Mohr et al. 2001). Warfarin is prescribed for stroke recurrence prevention in many patients who have had an ischemic stroke. Therefore, aspirin is a reasonable, equally effective approach for some people, but for persons with artificial heart valves and certain types of atrial fibrillation, Coumadin has been shown to be more effective than aspirin in preventing stroke (Hurlen et al. 2002).

Other Conventional Platelet Aggregation Inhibition Drugs
There are a number of other drugs that act as platelet aggregation inhibitors, including dipyridamole, ticlopidine, and clopidogrel. As noted above, aspirin can provide comparable platelet aggregation inhibition and related risk reduction.

Anticoagulants

Coumarin Derivatives
Derivatives of Coumarin (e.g., generics warfarin and dicumarol) interfere with the rate of synthesis of blood clotting factors II (prothrombin), VII, IX, and X. As a result, prothrombin and partial thromboplastin times are significantly altered by anticoagulants, but are not altered by antiplatelet agents such as aspirin. Patients taking Coumarin derivatives are monitored for PT and PTT times to optimize dosing and avoid excessive bleeding.

Coumadin (warfarin) is the most frequently prescribed drug for thrombosis prophylaxis (prevention). It is an anticoagulant drug that was originally isolated in 1939 from sweet clover. Interestingly, Coumadin is the active ingredient found in many commercial rat poisons and insecticides. It works by interfering with the synthesis of vitamin K-dependent coagulation factors. Coumadin is used as a prophylaxis for myocardial infarction, stroke, arterial thromboembolism, and deep venous thrombosis. It is also used in patients with prosthetic heart valves.

Coumadin prolongs both PT and APTT, but PT is the one used to guide treatment. However, the new standard is the International Normalization Ratio (INR) which is described below. Bleeding is the primary adverse effect of Coumadin therapy. Bleeding is related to the intensity of anticoagulation, length of therapy, the patient's underlying clinical state, and the use of other drugs that can affect blood coagulation or interfere with Coumadin metabolism.

Minor bleeding from Coumadin therapy usually begins with ecchymoses (purple patches on the skin). Then the mucous membranes are affected, causing epistaxis (nosebleed) and subconjunctival hemorrhage (bleeding under the mucous membranes covering the eyes and inner eyelids). Purple toe syndrome is also associated with Coumadin therapy. Hematuria (blood in the urine) may also occur. Major bleeding complications usually involve gastrointestinal (GI) and intracranial bleeding.

Coumadin has an extremely long list of contraindications and drug interactions (see the Cerebral Vascular Disease/Thrombotic Stroke protocol for a complete list). Of particular concern is its use in elderly patients because they are more susceptible to the effects of anticoagulants and have an increased risk of hemorrhage. Several common drugs interact with Coumadin, including acetominaphen, cimetidine, lovastatin, thyroid hormones, and estrogens and oral contraceptives.

Caution: Do not take aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen (e.g., Motrin, Advil, Nuprin, etc.), ketop (e.g., Orudis, Orudis KT, Oruvail), naproxen (e.g., Naprosyn, Aleve, Anaprox), or other over-the-counter products while taking Coumadin, except under the supervision of your doctor. Over-the-counter NSAIDs increase the risk of bleeding. Consult your physician before taking any new prescription or over-the-counter product. Always take Coumadin in the evening, preferably between 5 p.m.-7 p.m.

Combining Coumadin with Antiplatelet Agents
As has been previously described, Coumadin interferes with specific coagulation factors that can induce a thrombotic event. Coumadin is classified as an "anticoagulant" agent.

Aspirin, fish oil, vitamin E, and garlic inhibit platelet adhesion and platelet aggregation and are classified as "antiplatelet" agents. The inhibition of blood platelets' ability to adhere and/or aggregate also decreases the likelihood of thrombosis.

In a perfect world, an individualized program would be designed to deliver the optimal combination of anticoagulation and antiplatelet agents to provide the broadest protection against thrombosis without inducing hemorrhage.

There is much debate and confusion about the interactions between dietary nutrients and prescription antithrombotic medications regarding clot formation. The concern expressed in some studies involves potential interactions between Coumadin and antiplatelet agents such as ginkgo biloba, green tea, vitamin E, garlic, and fish oil (Heck et al. 2000). There has been apprehension that certain supplements put the patient at risk for bleeding problems by adding to the overall effects of Coumadin.

As a result of this concern, some doctors advise patients who are taking Coumadin to avoid any dietary supplement that could possibly cause increased bleeding. A problem with this ultra-cautious approach is that it deprives the patient of nutrients they may need to sustain life. It also prevents the use of antiplatelet agents that act on hemostatic mechanisms, separate from those of Coumadin, to reduce more effectively the risk of thrombosis. There are major medical publications that confirm the importance of lowering the incidence of cerebrovascular stroke and heart attack by such a two-pronged approach using an agent with antiplatelet activity, for example, Coumadin (Fasey et al. 2002; Hurlen et al. 2002).

A patient taking Coumadin has to be concerned that any food, drug, nutrient, or other substance they put into their body may not only increase the bleeding time, but also affect Coumadin metabolism, which may either increase or decrease the effect of Coumadin on the International Normalized Ratio (INR). The inherent variability that occurs in each individual taking Coumadin makes it difficult to provide general guidance. For instance, the underlying medical condition determines the degree of desired anticoagulation. No studies have correlated optimal anticoagulant doses of Coumadin, as measured by the INR reference range, with optimal doses of multiple antiplatelet agents, as measured by the template bleeding time (TBT).

The template bleeding time is done in a physician's office where a template device nicks the skin and the number of minutes it takes for blood flow to stop is assessed by a nurse or lab technician. The "normal" template bleeding time is up to 9 minutes. A bleeding time (BT) of 4-5 minutes might indicate increased thrombotic risk, although a BT over 9 minutes may indicate an increased hemorrhagic risk. However, what is really important in this setting is the patient context, as discussed below.

As it relates to antiplatelet agents like fish oil and garlic, a BT of 4-5 minutes could suggest a benefit of taking higher amounts of these agents, whereas a BT over 9 minutes in a patient already on an antiplatelet agent might indicate that antiplatelet agent doses are having a biological effect and further dose increases should be avoided. The problem patients face today is that there are no standards that document the ideal balance between Coumadin and antiplatelet agents such as fish oil, garlic, vitamin E, etc. Too much Coumadin and/or antiplatelet agents can cause hemorrhage, whereas too little Coumadin and/or antiplatelet agent(s) can cause thrombosis. In this setting or context, as with many medical issues, balance is the key concept. The approach that the meticulous physician uses to achieve this balance is called "titration." There is an art to titrating doses to where the "happy medium" is reached. This is embraced in the key medical concept of therapeutic index which relates to the equation:

TI (Therapeutic Index) = Therapeutic Benefits ÷ SideEffects of Therapy.

In an ideal setting, a physician would carefully monitor the INR and the TBT to measure precisely the optimal level of anticoagulant and antiplatelet agents, respectively, in an individual patient. For instance, a patient with a heart valve replacement may have a desired INR range of 2.5-3.0, while an optimal template bleeding time may be between 7-9 minutes. If these tests were routinely conducted, a more scientific determination of the ideal intake of Coumadin, fish oil, garlic, vitamin E, etc. could be made.

Some early reports indicated that CoQ10 may reduce the anti-coagulant efficacy of Coumadin (Spigset 1994). These reports have been contradicted by a more recent study showing that CoQ10 does not affect Coumadin’s anticoagulation mechanisms (Engelsen et al. 2003).

Heparin
Heparin inhibits thrombosis (clotting) via inactivating factor X and by inhibiting the conversion of prothrombin to thrombin. Activation of factor X is the major rate-limiting step in the coagulation cascade. By inhibiting the activation of the fibrin-stabilizing factor by thrombin, heparin prevents formation of a stable fibrin clot. Heparin also decreases the levels of triglycerides by releasing lipoprotein lipase from tissues. The resultant hydrolysis of triglycerides causes increased blood levels of free fatty acids.

Exanta® -- A Novel Drug on the Horizon
A new drug application for Exanta was filed with the FDA in the fourth quarter of 2003. Exanta (ximelagatran) is a novel drug with potential to revolutionize anticoagulant management. It is the first oral anticoagulant drug in over 50 years—since warfarin (Coumadin) — to reach late-stage clinical development. Current clinical trials are investigating the efficacy ximelagatran for treatment of venous thromboembolism and atrial fibrillation to prevent stroke. Ximelagatran is a specific, reversible, direct inhibitor of the clotting factor thrombin. It inhibits free and clot-bound thrombin and has a half-life of 1.7 to 2.5 hours (Samama et al. 2002). Ximelagatran has significant advantages: oral administration; minimal monitoring; active immediately; a short half-life; and no known pharmacokinetic food or drug interactions (Petersen et al. 2003). Because it has a predictable blood-thinning effect, the frequent monitoring and dose adjustments required for warfarin are not needed for ximelagatran. Its short half-life allows ximelagatran to be discontinued a few hours before surgery. Bleeding events are also low. Studies report impressive results:

• • ESTEEM II (Efficacy and Safety of the Oral Thrombin Inhibitor Ximelagatran in Combination with Aspirin, in PatiEnts with REcent Myocardial Damage): ESTEEM II is a placebo-controlled, double-blind, multicenter (191 hospitals), multinational (18 countries) study that assessed 1883 patients with recent MI for 6 months. Study participants were given oral ximelagatran (24, 36, 48, or 60 mg) or placebo twice daily. All participants received aspirin (160 mg) daily. All-cause deaths, non-fatal MIs, and severe recurrent ischemia for ximelagatran and placebo were compared. After 6 months, oral ximelagatran combined with aspirin significantly reduced the risk of major cardiovascular events (24% compared to aspirin alone) with rare major bleeding events and no serious, clinically adverse outcomes related to the drug (Brown 2003; Wallentin et al. 2003).
• • SPORTIF III (Stroke Prevention by ORal Thrombin Inhibitor in Atrial Fibrillation): SPORTIF III is a randomized, open-label, parallel-group study (3407 patients; 259 sites; 23 countries) to investigate ximelagatran as an alternative to warfarin to prevent thromboembolism and stroke in subjects with non-valvular atrial fibrillation (NVAF). In addition to NVAF, subjects had at least one additional stroke risk factor: previous MI, TIA, systemic embolism, hypertension, left ventricular dysfunction, age 75, or age 65 with coronary artery disease or diabetes mellitus. The objective was to establish the non-inferiority (as good as, no compromise) of ximelagatran compared to warfarin. Endpoints were incidence of stroke and systemic embolic events (death, MI, TIA, bleeding with treatment ended). Fixed-dose ximelagatran (36 mg) was given twice daily. Patients were treated for an average of 17 months. Twice-daily fixed-dose ximelagatran compared favorably with dose-adjusted warfarin in preventing stroke and systemic embolism events in AF. Despite lack of coagulation monitoring and the fixed-dose regimen, bleeding events were lower for ximelagatran than for warfarin, and there was no significant difference in all-cause mortality between the two treatment groups. The results of SPORTIF III suggest that ximelagatran can offer an alternative to warfarin and its complications without compromising patient safety or efficacy (Halperin et al. 2003; Saunders 2003).
• • THRIVE III (THrombin Inhibitor in Venous Thromboembolism). THRIVE III is a double-blind, multicenter, randomized trial that enrolled 1233 patients who had received anticoagulant therapy for 6 months for venous thromboembolism. The patients were randomly assigned to receive extended secondary prevention of venous thromboembolism with 24 mg of oral ximelagatran (612) or placebo (611), twice daily for 18 months, with no monitoring of coagulation. Symptomatic recurrent venous thromboembolism occurred in 12 subjects in the ximelagatran group and in 71 subjects in the placebo group (all-cause death, 6 vs. 7; bleeding, 134 vs. 111; major hemorrhage, 6 vs. 5 with no fatalities). For individuals who discontinue anticoagulant treatment with warfarin after 6 months because the risk of bleeding outweighs the risk of recurrence, long-term treatment with ximelagatran offers clinically significant reduction of recurrent venous thromboembolism without coagulation monitoring and dose adjustments (Barclay 2003; Schulman et al. 2003).

Compared to warfarin, ESTEEM II, SPORTIF III, and THRIVE III studies all reported an increased incidence of elevated liver enzymes in the early months of ximelagatran treatment. The lowest dose of ximelagatran (24 mg) elevated liver enzymes in 6.5% of patients compared to placebo (1.2%). Elevations were seen in 12 to 13% of patients at higher doses (36, 48, 60 mg). Elevated enzyme levels were not associated with specific clinical symptoms and they decreased toward baseline levels as treatment continued or when it was discontinued (Brown 2003; Saunders 2003).

Arixtra® (fondaparinum, fondaparinux sodium) is another synthetic antithrombotic drug with a defined mechanism of action, specifically to inhibit factor FXa (a mediating factor in thrombin formation, the final factor in the blood clotting process). It has a half-life of about 17 hours. Fondaparinux inhibits free FXa, but not FXa bound to prothrombinase (Samama et al. 2002). Because Arixtra binds exclusively to only factor Xa which is essential to the clotting process, it ensures a highly predictable antithrombotic effect (Organon/Sanofi-Synthelabo 2002). Arixtra is the first synthetic antithrombotic drug used during hip fracture, hip replacement, or knee replacement surgery to reduce the risk of a pulmonary embolism (received FDA approval for hip fracture and hip and knee replacement surgery on December 7, 2001).

Laboratory Tests for Patient Response to Anticoagulants
It is extremely important to regularly evaluate a patient's response to Coumadin (or any other anticoagulant). This ensures that excess bleeding does not occur due to improper dosing of the medication. The standard blood test to assess coagulation status is the PT test using the INR as a standard unit of measurement. This blood test enables your physician to adjust the dose of Coumadin to provide optimal anticoagulation benefits without inducing serious bleeding.

The target INR for a person taking Coumadin varies depending on the type of disorder that puts the patient at risk for thrombosis. For some disorders, the ranges are between 1.6-2.5, although others may extend up to 3.5. Although test results can vary considerably between individuals, the INR becomes a very important number to evaluate. If, for instance, you significantly overcoagulate and your INR levels significantly exceed 4.5, your physician can prescribe vitamin K to bring your INR levels into a safe range. Some physicians fail to prescribe vitamin K and just tell the overcoagulated patient to stop the Coumadin. Failing to prescribe vitamin K during an acute overcoagulation state (INR over 4.5) puts a patient in serious jeopardy.

Additionally, as noted earlier, if you are taking an anticoagulant drug such as Coumadin or heparin, you must be very careful about what you eat and what medicines you take as well as being diligent about having your blood checked regularly. This is even more essential if you take a combination of drugs for other conditions or take over-the-counter medications such as aspirin. With the concomitant use of natural therapies and aspirin, the need for weekly or biweekly blood monitoring increases even more. The two most important markers or references to monitor for those taking other drugs and/or antiplatelet agents with Coumadin are the INR reference range and the TBT test.

For those taking Coumadin, prothrombin blood tests using the INR reference ranges are recommended weekly or biweekly. For those with serious diseases such as cancer, in addition to using INR reference ranges, the following supplementary blood tests might be considered every 30-90 days to measure thrombotic risk more precisely:

• PTT
• Fibrinogen
• D-dimer of fibrin

How PTs and INRs Are Calculated
When a fibrin clot forms, the time measured in seconds is referred to as the prothrombin time (PT). Thromboplastin agents used for testing come from various sources with varying degrees of sensitivity. This is important information because the result can have a detrimental effect on the management of the anticoagulant therapy.

To standardize potential differences in sensitivity between reagents, manufacturers assign an International Sensitivity Index (ISI) to each batch of reagent. The ISI is then compared to a working reference reagent preparation. The INR is a mathematical calculation that corrects for the variability of PT results due to the variable sensitivities of the thromboplastin agents used by various laboratories.

INR = (patient PT/control PT) × ISI (International Sensitivity Index)

THROMBOTIC RISK FACTORS

Homocysteine
Homocysteine is a toxic compound formed in the body from the amino acid methionine. Several studies have shown that homocysteine increases blood coagulation by inhibiting tissue fibrinogen activators. The result is increased levels of fibrinogen and fibrin (de Jong et al. 1998; Selhub et al. 1998; Coppola et al. 2000; Durand et al. 2001; Kuch et al. 2001).

In order to reduce blood homocysteine levels, adequate amounts of folic acid, vitamin B12, and vitamin B6 are usually required. High homocysteine levels have been shown to be a risk factor for cardiovascular disease, including atherosclerosis, heart attack, and stroke. Ideal levels of homocysteine are under 7 micromoles/L of blood.

For more information about homocysteine, see the Cardiovascular Disease protocol.

Fibrinogen
Fibrinogen is the precursor to fibrin, a coagulant protein that binds platelets together to form a blood clot. It has a role in normal and abnormal clot formation (coagulation) in the body. During coagulation, fibrinogen reacts with thrombin, releasing four small fibrinopeptides that produce fibrin, which in turn creates an insoluble fibrin network generally referred to as a scab.

Fibrinogen also participates in the cellular phase of coagulation. Fibrinogen promotes platelet aggregation, which can lead to diminished blood flow and reduced delivery of oxygen to the body. Fibrinogen can also cause blood platelets to bind together, initiating abnormal arterial blood clots.

An article in the journal Neurology described a study of cardiovascular laboratory tests in 136 patients with acute stroke, 76 patients with comparable risk factors for stroke, and 48 healthy controls. Statistical analysis found that prior stroke and fibrinogen levels predicted new events in stroke patients. After 1 year, fibrinogen levels remained elevated in stroke survivors. The researchers concluded that fibrinogen levels are associated with increased risk of recurrent vascular events (Beamer et al. 1998).

The Life Extension Foundation recommends the measurement of fibrinogen as part of a cardiovascular risk assessment. The normal reference range for fibrinogen is 200-400 mg/dL. Optimally, fibrinogen should be 200-300 mg/dL.

Atherosclerosis
Once symptomatic atherosclerosis has developed, a person is at significant risk for stroke, heart attack, and peripheral arterial occlusion. The occlusive event (stroke, MI, etc.) tends to develop at sites of preexisting narrowing (stenosis). Atherosclerotic plaques can rupture and expose tissue factor-rich plaque contents to the blood, initiating thrombus formation.

Inflammation
Chronic inflammation is associated with a variety of chronic diseases, including cardiovascular disease. C-reactive protein (CRP) is a sensitive indicator of inflammation that rises before the erythrocyte sedimentation rate. CRP is a marker of systemic inflammation and unstable arterial plaque, both of which are indictors of increased thrombotic risk. Certain pro-inflammatory immune cytokines cause elevated CRP. These cytokines may be suppressed by taking supplements such as the DHA fraction of fish oil, the hormone DHEA, vitamin K, and nettle leaf extract.

An article in the journal Thrombosis Research described a study of patients with acute thrombotic stroke prior to treatment. The patients with elevated CRP also had significantly elevated plasma levels of thrombin-antithrombin complex, plasmin-antiplasmin complex, and d-dimer of fibrin. When compared to those with normal levels, platelet aggregation induced by ADP was also significantly higher in patients with elevated CRP. The authors hypothesized that the activation of the blood coagulation and platelet aggregation system may be related to elevated CRP levels in stroke patients (Tohgi et al. 2000). A feature article in the May 2002 issue of Scientific American further emphasized the link between chronic inflammation and the evolution of atherosclerosis and coronary artery disease (Libby 2002).

Measuring CRP levels (using a high-sensitivity C-reactive protein blood test) is highly recommended by the Life Extension Foundation (see Table 2 for the normal and optimal range of CRP).

Lipoprotein(a)
Lipoprotein(a) is an altered form of LDL cholesterol that has a structure nearly identical to plasminogen, a protein that forms plasmin. Plasmin dissolves fibrin. Unfortunately, lipoprotein(a) inhibits the breakdown of fibrin by competing with plasminogen. Lipoprotein(a) was found to be a key component in blood clots, plaque formation and coronary heart disease (CHD) (Rath et al. 1989; Beisiegel et al. 1990).

Linus Pauling's theory of heart disease focused on the adverse effects of lipoprotein(a) on the cardiovascular system. Pauling and Rath proposed that lipoprotein(a) acted as a surrogate (replacement) for vitamin C (Rath et al. 1990a). They also proposed that a deficiency of vitamin C resulted in the increased production of lipoprotein(a), which both hardened the arteries and caused blood clots (Rath et al. 1990b). Linus Pauling recommended the use of high doses of pure vitamin C and lysine to both prevent and treat cardiovascular disease. Niacin, CoQ10, serine, and regular aerobic exercise have also been shown to lower lipoprotein(a) (Cohn 1998; Singh et al. 1999; Batiste et al. 2002).

Hypothyroidism
The endocrine system is a complex mechanism in which each organ impacts the function of other organs. A low-functioning thyroid (hypothyroidism) would therefore impact other systems, including the cardiovascular system. Hypothyroidism is associated with increased cholesterol levels, atherosclerosis, and increased homocysteine (Carantoni et al. 1997; Diekman et al. 1998; Nedrebo et al. 1998; Hussein et al. 1999; Hak et al. 2000; Kahaly 2000; Diekman et al. 2001). The effect of hypothyroidism on the blood clotting system is currently controversial and is the focus of several studies (Chadarevian et al. 1998; Muller et al. 2001).

For additional information about hypothyroidism, see the Thyroid Replacement Therapy protocol.

COMPREHENSIVE LABORATORY TESTING FOR CARDIOVASCULAR RISK

The Life Extension Foundation recommends that all of its members be checked for cardiovascular risk with both conventional laboratory tests and new markers such as CRP.

Furthermore, optimal ranges of these laboratory tests are much narrower than the standard reference ranges used in conventional medicine. It is important to emphasize that the "average" person has a high risk of developing a thrombotic-related disease. For health-conscious people, this dismal fate is unacceptable.

CONSULTING YOUR PHYSICIAN

When over-the-counter supplements, such as aspirin, vitamins, herbs, and oils are used as primary antithrombotic therapy, the risk of undesirable side effects is reduced significantly. However, although over-the-counter medications such as aspirin and natural therapies come with a lower risk of hemorrhaging, they should not be substituted for prescription medication if you are at a high risk for thrombosis. Some common conditions that cause a high risk of thrombosis include atrial fibrillation, valvular replacement, recurrent or chronic deep venous thrombosis, pulmonary embolism, and cancer.

Because appropriate therapeutic dosing is crucial and the associated risks can be life-threatening in all circumstances that require anticoagulation therapy or antiplatelet therapy, your physician must be consulted if you desire to make any substitutions to your medication. Because medications, such as Coumadin and heparin, have very narrow therapeutic ranges, anyone on these medications should have his or her blood tested frequently for prothrombin using the INR as a reference range. Once the effective dose is achieved, blood testing is recommended every 1-2 weeks to monitor the medication blood levels and to avoid overdosing, which could lead to hemorrhaging. In addition to the INR values, template bleeding time should also be closely monitored if any over-the-counter drugs or natural supplements that affect the clotting cascade are added to the regimen. Some of these supplements include vitamin E, ginkgo biloba, CoQ10, garlic, ginseng, green tea, vitamin C, vitamin A, policosanol, Dong Quai, white willow, ipriflavone, and vinpocetine (periwinkle).

NUTRITIONAL SUPPLEMENTS

The nutritional supplements listed below have been scientifically studied specifically for their ability to reduce the risk of thrombosis. The bulk of the research focuses on inhibiting platelet aggregation. The supplements are divided into several broad categories based on their primary actions:

• Cholesterol-lowering supplements
• Natural platelet aggregation inhibitors
• Homocysteine-lowering supplements
• Anti-inflammatories
• Antioxidants
• Sulfur-containing compounds

Note: The supplements in the natural blood thinners category could easily have been put into other categories. Ginkgo and vitamin E, for instance, are very powerful antioxidants. Essential fatty acids are also known for their anti-inflammatory actions. However, their blood-thinning effects are much more important in the prevention of thrombosis.

Other protocols contain further information on specific topics. (For research on supplements that increase fibrinolysis, see the Fibrinogen section of the Cardiovascular Disease protocol.)

Cholesterol-Lowering Supplements

Policosanol
Policosanol is a cholesterol-lowering agent derived from sugar cane wax. In some cases, it can normalize cholesterol, as well as prescription drugs, doing so without side effects.

The efficacy and safety of policosanol has been shown in numerous clinical trials. It has been used by millions of people in other countries. Policosanol can lower LDL cholesterol as much as 20% and raise protective HDL cholesterol by 10%. This compares favorably with some cholesterol-lowering drugs that can cause side effects such as liver dysfunction and muscle atrophy (Mas et al. 1999).

Policosanol works by blocking the synthesis of cholesterol. It may not inhibit the HMG-CoA enzyme like the "statin" cholesterol-lowering drugs. Instead, it may inhibit a different enzyme involved in cholesterol synthesis. However, its exact mechanism is not known. Like statin drugs, policosanol helps stop the formation of atherosclerotic lesions, which was proven in studies using rabbits fed a diet designed to create high cholesterol (Noa et al. 1995).

Policosanol inhibits the formation of clots and may work synergistically with aspirin in this respect. In a comparison of aspirin and policosanol, aspirin was better at reducing one type of platelet aggregation (clumping together of blood cells) and policosanol was better at inhibiting another type. Together, policosanol and aspirin worked better than either one alone (Arruzazabala et al. 1997; Stusser et al. 1998).

An article in the journal Pharmacology Research described a randomized, double-blind, placebo-controlled study of policosanal and aspirin. Participants received either policosanol (20 mg daily), aspirin (100 mg daily), a combination of both, or placebo for 7 days. The effects on platelet aggregation are summarized above (Arruzazabala et al. 1997). A related effect is that significant reductions in the level of thromboxane (a blood vessel-constricting eicosanoid produced by platelets) occur in humans after 2 weeks of policosanol (Carbajal et al. 1998).

The normal dose of policosanol is 10-20 mg taken at bedtime. Cholesterol levels should be measured regularly because both high and low cholesterol levels are considered unhealthy. Consider using aspirin (81 mg daily) in combination with policosanol.

Aged Garlic
Aged garlic has become a well-known, popular supplement for the cardiovascular system. Garlic has been found to increase the synthesis of nitric oxide, a chemical messenger that inhibits platelet aggregation and vasodilates blood vessels (Das et al. 1995; Dirsch et al. 1998; Kim-Park et al. 2000; Kim et al. 2001).

An article in the journal Nutrition described a randomized, double-blind study of aged garlic on normal, healthy individuals. The researchers found that aged garlic inhibited platelet adherence and aggregation. Higher doses (7.2 grams daily) had a more profound effect than lower doses (2.4 grams daily) (Steiner et al. 2001).

The specific effects of aged garlic have been the subject of several studies. Aged garlic has been shown to inhibit platelet aggregation by ADP, epinephrine, and collagen, although one study found that it did not affect ADP-induced aggregation (Steiner et al. 1998; Rahman et al. 2000).

Another study examined the effects of consuming one fresh clove of garlic every day on men. After 26 weeks of garlic consumption, there was an approximate 20% reduction of serum cholesterol and about 80% reduction in serum thromboxane B2, a stable metabolite of thromboxane A2. Recall that thromboxane A2 is a platelet aggregator and vasoconstrictor secreted by platelets (Ali et al. 1990, 1995).

Niacin
Niacin (vitamin B3) causes peripheral vasodilation (flushing) within about 20 minutes. Large doses of niacin (up to 6 grams daily) have been found to lower cholesterol, raise HDL, and lower LDL and VLDL lipids. The safest form of niacin is inositol hexa-nicotinate in the dose of 1600-2400 mg daily. Individuals taking continuous high-dose niacin therapy need to have their blood levels monitored for elevations in liver enzymes and uric acid.

An article in the American Heart Journal described the Arterial Disease Multiple Intervention Trial (ADMIT), a multicenter, randomized, placebo-controlled trial to assess the feasibility of an antioxidant therapy on coagulation. Patients with peripheral artery disease randomly received low-dose Coumadin, niacin, an antioxidant vitamin cocktail, or placebo. Unexpectedly, the niacin treatment resulted in a significant decrease in fibrinogen (Chesney et al. 2000).

Natural Platelet Aggregation Inhibitors

Ginkgo Biloba
Ginkgo biloba extract is made from the leaves of the oldest living tree. Ginkgo biloba has a long history of medicinal use. It has become a very popular herb to help improve memory, particularly in the elderly.

Ginkgo biloba has been shown to inhibit platelet aggregation induced by platelet-activating factor (PAF), but not by oxidative stress (Akiba et al. 1998).

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 only ticlopidine (200 mg/kg daily). The combination also prolonged bleeding time by 150% and consistently decreased the thrombus weight (Kim et al. 1998).

Essential Fatty Acids
Essential fatty acids are found in healthy oils, such as flax, borage, perilla, and fish oils. Essential fatty acids are termed "essential" because they are necessary for life. Essential fatty acids, including DHA (docosahexaenoic acid) and EPA (eicosapentaenoic acid), are known to inhibit platelet aggregation and are included as potential contraindications for use with anticoagulant (warfarin) therapy. The contraindication is actually more of a strong caution to avoid thinning the blood too much. What this means is that if a patient on Coumadin does take fish oil supplements, the TBT test should be done in addition to checking the INR reference range.

Several studies examined the antiplatelet mechanisms of essential fatty acids like EPA and DHA and showed they inhibited collagen- and arachidonic acid-induced platelet aggregation. No effects were seen in thrombin-induced aggregation. The mechanism was related to the ability of these fatty acids to suppress thromboxane A2 formation by inhibiting cyclooxygenase-1 (Ikeda et al. 1998; Akiba et al. 2000).

An Australian study found that omega-3 fatty acids (those rich in alpha-linolenic acid, such as flaxseed and perilla oils) were more effective than omega-6 fatty acids (those rich in linoleic acid, such as sunflower oil) (Allman et al. 1995). This same result was also reported in a German study which found that an omega-3 to omega-6 ratio of 15:1 caused a significant decrease of collagen-induced platelet aggregation (Stroh et al. 1991).

Vitamin E
Vitamin E (tocopherol) is a potent antioxidant that has been shown to increase prostaglandin I2 synthesis, one of the platelet aggregation inhibitors and vasodilators. Vitamin E is depleted by estrogen, birth control pills, and chlorine.

A study found that vitamin E was able to inhibit collagen-induced platelet aggregation at concentrations achievable in blood after supplementation. The researchers also isolated a mechanism by which vitamin E blunts hydrogen peroxide formation, which then mediates arachidonic acid metabolism and phospholipase C activation in platelet aggregation induced by collagen (Pignatelli et al. 1999).

Caution: If vitamin E is used with Coumadin, the template bleeding time test should be done by the physician to guard against risk of hemorrhage.

Vitamin K
Vitamin K plays a unique role in the clotting system by contributing to both coagulation and anticoagulation. Vitamin K is a precursor of coagulation factors II, VII, IX, and X. Vitamin K is also a cofactor for the synthesis of proteins C and S. Protein C is a proteolytic enzyme that acts as an anticoagulant by inactivating clotting factors V and VIII and by increasing production of tissue plasminogen activator.

An article in the journal Lancet recommended that asymptomatic patients on Coumadin should consider low-dose vitamin K if blood-clotting time, as measured by the INR, is 4.5-10.0. The article described a multicenter, double-blind, placebo-controlled, randomized trial in which patients received either a placebo or 1 mg of vitamin K orally. Patients given vitamin K had a more rapid decrease in the INR than those given placebo, and fewer of them had bleeding episodes during the follow-up period. The authors concluded that low-dose vitamin K therapy rapidly lowers INR values in patients taking Coumadin and may be effective in preventing hemorrhage (one of the common side effects of Coumadin therapy) (Crowther et al. 1998, 2000).

Vitamin K counteracts the action of Coumadin and is strictly contraindicated in patients on anticoagulant drug therapy. The Life Extension Foundation recommends the use of 10 mg daily of vitamin K in healthy individuals.

Lowering Homocysteine
Homocysteine has slowly become accepted in conventional medicine as a risk factor for cardiovascular disease. Clinical research has shown that some vitamins (folic acid and vitamins B6 and B12) are very effective at lowering homocysteine levels. It has been proposed that homocysteine activates the blood clotting system by damaging endothelial cells.

An article in Thrombosis Research described a study of 11 persons with high homocysteine levels who had atherosclerosis. After an 8-week treatment with folic acid (5 mg daily, orally), vitamin B6 (300 mg daily, orally), and vitamin B12 (1000 mcg weekly, intramuscularly), homocysteine levels dropped from an average of 20 to 10. Vitamin treatment was also associated with a significant decrease in the markers of thrombin formation, including thrombin-antithrombin III complexes and prothrombin fragment 1+2 concentrations in peripheral venous blood. Bleeding time became prolonged by about 60 seconds (Undas et al. 1999).

The Life Extension Foundation strongly recommends that homocysteine levels be measured. Supplementation with vitamins B6 and B12 and folic acid are recommended to lower homocysteine levels.

Anti-Inflammatories

Curcumin
Curcumin is the Latin name for the common yellow spice known as turmeric. Curcumin is commonly used for its anti-inflammatory effects. Curcumin has also been shown to lower cholesterol.

Research has examined the mechanism of the antiplatelet action of curcumin (turmeric). Curcumin was shown to inhibit platelet aggregation induced by ephedrine, ADP, platelet-activating factor (PAF), collagen, and arachidonic acid. Curcumin acted most strongly against aggregation by PAF and arachidonic acid. The mechanism appeared to be related to curcumin's inhibition of thromboxane A2 (Shah et al. 1999). Curcumin should be taken with meals to avoid the possibility of gastric irritation. The daily dose for most people is 900 mg with 5 mg of bioperine to enhance assimilation.

DHEA
DHEA has been shown to inhibit inflammatory cytokines (Straub et al. 2000). With reduced inflammation, less platelet aggregation and LDL migration into the vessel walls occurs. This can lead to less thrombus formation and atherosclerosis. DHEA also competitively inhibits cortisol, the other main adrenal steroid (Boudarene et al. 2002). If cortisol levels are high, DHEA may be depleted leading to immune deficiencies and reduced muscle mass. High cortisol also worsens responses to stress.

Nettle Leaf (Urtica Dioica)
In Germany, nettle leaf is an herb with a long tradition of use as an adjuvant remedy in the treatment of arthritis. It has also been used extensively in the treatment of allergies. Nettle leaf extract has been found to contain a variety of active compounds, such as cyclooxygenase and lipoxygenase inhibitors, and substances that affect cytokine secretion (Obertreis et al. 1996a; 1996b; Teucher et al. 1996).

Cytokines are proteins that carry messages between cells and regulate immunity and inflammation. Two cytokines, tumor necrosis factor alpha (TNF-a) and interleukin-one-beta (IL-1b), are examples of pro-inflammatory cytokines (Pinto et al. 1999). These cytokines have been found to be elevated in patients with allergies and arthritis. In animal models, it was shown that inhibition of TNF-a results in decreased inflammation, while inhibition of IL-1b effectively prevents cartilage destruction (Probert et al. 1995).

Nettle leaf reduces TNF-a levels by potently inhibiting the genetic transcription factor that activates IL-lb and TNF-a. This pro-inflammatory transcription factor, nuclear factor kappa beta ( NF-kb), is known to be elevated in chronic inflammatory diseases and is essential to activation of TNF-a. Nettle leaf is also thought to work by preventing degradation of the natural inhibitor of NF-kb in the body (Riehemann et al. 1999). In vessels, reduction of inflammatory cytokines (such as TNF-a) also reduces platelet aggregation and the tendencies toward thrombus formation.

Antioxidants

Quercetin and Catechin
Quercetin and catechin (from green tea) are bioflavonoids with strong antioxidant properties. Quercetin is primarily used for its beneficial effects on allergies.

An article in the American Journal of Clinical Nutrition found that catechin and quercetin inhibited collagen-induced platelet adhesion. The authors proposed that the effects may be due to the ability of catechin and quercetin to decrease hydrogen peroxide production (Pignatelli et al. 2000). Quercetin may also inhibit platelet aggregation by its antioxidant properties (Xie et al. 1996).

Another study examined the inhibition of thrombin-induced platelet aggregation by a semisynthetic derivative of quercetin. The authors found that quercetin inhibited platelet aggregation by reducing calcium mobilization and influx (Liu et al. 1999, 2000).

Green Tea
Green tea has become very popular for the prevention and treatment of a wide range of diseases. Green tea protects the cardiovascular system and might prevent cancer.

A study in the journal Thrombosis Research examined the effects of green tea tannins and epigallocatechin on platelet aggregation. Both substances inhibited platelet aggregation induced by ADP and collagen in rats. They also inhibited platelet aggregation induced by ADP, collagen, and epinephrine in human blood samples (Kang et al. 1999).

In rabbits, Japanese researchers found that green tea inhibited aggregation of platelets. The researchers noted that epigallocatechin suppressed collagen-induced platelet aggregation. Epigallocatechin also inhibited platelet aggregation induced by thrombin and platelet-activating factor (PAF) (Sagesaka-Mitane et al. 1990).

Tomatoes
Lycopene, found in tomatoes, has been shown to have strong antioxidant properties. Lycopene may be particularly effective in blocking the oxidation of LDL cholesterol.

An article in the journal Platelets described a study of fruits and their effect on human platelet aggregation in vitro. Researchers found that tomato extract inhibited both ADP- and collagen-induced aggregation by up to 70%. The antiplatelet components were found to be concentrated in the yellow fluid around the seeds in tomatoes. Grapefruit, melon, and strawberry were also found to have antiplatelet activity, but to a lesser extent (Dutta-Roy et al. 2001).

Grape Juice
Grapes have gained popularity as a result of several studies that found that consuming 1 cup of red wine daily had beneficial effects on the cardiovascular system. Grapes contain proanthrocyanadins, which are concentrated in the seeds and skin and impart the blue color. Studies have shown that the antioxidant power of grape seed-skin extract is 50 times greater than vitamin E and 20 times greater than vitamin C.

An article in the journal Circulation described a study that examined the effects of purple grape juice on platelets. Laboratory tests (in vitro) found that purple grape juice inhibited platelet aggregation, increased nitric oxide production, and decreased superoxide formation. The researchers then conducted a study with 20 healthy subjects who consumed 7 mL/kg daily of purple grape juice for 14 days. Purple grape juice supplementation inhibited platelet aggregation, increased platelet nitric oxide production, and decreased superoxide formation. The authors proposed that purple grape juice may have beneficial effects in cardiovascular disease (Freedman et al. 2001).

An article in the journal Nutrition described a study in which 10 healthy subjects drank 5-7.5 mL/kg daily of purple grape juice, grapefruit juice, or orange juice for 1 week. Drinking purple grape juice reduced platelet aggregation by 77%. Orange and grapefruit juice had no effect. The authors proposed that the flavonoids in grape juice may decrease the risk of thrombosis (Keevil et al. 2000).

Sulfur-Containing Compounds

N-Acetyl-L-Cysteine
The amino acid N-acetyl-L-cysteine (NAC) inhibits platelet aggregation by several mechanisms, including:

• Increasing the antiplatelet aggregating effects of L-arginine, which promotes endogenous synthesis of nitric oxide (Anfossi et al. 1999, 2001). Increases in nitric oxide cause arterial vasodilation increasing blood flow to the heart and brain in coronary artery disease or cerebral ischemia. However, in doing so, nitric oxide generates the free radical nitric peroxide, which is best quenched by gamma tocopherol, a fraction of vitamin E. A recommended protocol for arterial vasodilation includes the use of gamma tocopherol (200-400 IU) in combination with L-arginine (1800-3600 mg) 2-4 times daily, and NAC (250 mg) 3 times daily. This combination may lower blood pressure as well.
• Affecting platelet-derived growth factor, a key player in fibrosis (Durante et al. 1999; Okuyama et al. 2001).

NAC is an antioxidant that is helpful in breaking up pulmonary and bronchial mucus. NAC is also a precursor of glutathione.

Onions
Onion juice has been shown to reduce in vitro human platelet aggregation. To retain their health benefits, onions should be eaten raw or lightly steamed because high heat deactivates the active ingredients.

The antiplatelet aggregation action of onions is attributed to sulfur compounds called thiosulfonates. The strongest thiosulfonates are allicin, propyl propane thiosulfonate, and ethyl ethane thiosulfonate. All three of these thiosulfonate compounds were shown to be significantly more potent platelet aggregators than aspirin at nearly equivalent doses (Briggs et al. 2000).

In a study using 9-week-old rats, the antithrombotic effects of Welsh onion juice was examined. Two days after treatment (2 g/kg daily), the raw Welsh onion juice consumption significantly lowered systolic blood pressure, prolonged bleeding time, and diminished platelet adhesion as compared to controls. The authors also found that boiled onion juice had no effect (Chen et al. 2000).

An article in the journal Nutrition described a study in dogs in which onion juice was administered 20 minutes after the coronary arteries were mechanically damaged (narrowed). Treatment with onion juice reversed the induced cyclic flow reduction within 2.5-3 hours in all five of the treated dogs. The authors concluded that onion juice might help prevent platelet-mediated cardiovascular disorders, but also noted that the effects might be greater in dogs than in humans (Briggs et al. 2001).

Exercise
The effects of exercise on fibrinogen levels have been extensively studied. Several studies demonstrate that regular exercise lowers fibrinogen levels and reduces the risk of thrombosis (El-Sayed et al. 1999; 2000; Koenig et al. 2000; Imhof et al. 2001; Verissimo et al. 2001).

Regular exercise is also well known to provide a host of other health benefits, particularly for the cardiovascular system.

Prevention of blood clots is a complex task involving maintenance of a fine balance between the process of coagulation and anticoagulation. Patients on prescription medications (e.g., Coumadin), as well as those who combine Coumadin with over-the-counter anti-inflammatories or aspirin, need close monitoring, in particular weekly or biweekly testing of their prothrombin using the INR and the TBT test. Patients taking supplements (such as vitamins, herbs, or oils) should also have their thrombotic risk factors evaluated in the same way. However, close monitoring of coagulation balance is usually not necessary in people who are otherwise healthy.

Caution: Never change an anticoagulation medication without physician approval: thrombosis, bleeding, and sudden death can occur.

The Life Extension Foundation recommends a comprehensive approach to preventing thrombosis with a full assessment of cardiovascular health (including the presence of hypertension and atherosclerosis) and levels of homocysteine, fibrinogen, and cholesterol. A thrombosis prevention protocol fits well with an overall approach to wellness including a healthy diet and regular exercise. Smoking is a well-known risk factor for chronic disease and should be avoided.

Thrombosis prevention involves several diverse mechanisms. Several laboratory tests are recommended to assess the cardiovascular system and guide appropriate treatment, including cholesterol and triglyceride levels, homocysteine, template bleeding time, fibrinogen, and CRP (see the protocols on Medical Testing, Cardiovascular Disease, Stroke, and Diabetes for specific recommendations).

The following supplements have demonstrated antithrombotic action by lowering cholesterol, fibrinogen, and homocysteine; suppressing inflammation; and by inhibiting platelet aggregation.

1. Low-dose aspirin is widely recommended to help prevent abnormal platelet aggregation, thus reducing heart attack and stroke risk. The Life Extension Foundation recommends Healthprin, which contains 81 mg of enterically coated aspirin. One tablet daily is recommended for its anticlotting and anti-inflammatory effects. Some people may require more than 81 mg of aspirin daily, which can be determined by a TBT.
2. Garlic inhibits thrombosis by multiple mechanisms. Garlic is available in supplement form as Kyolic one-per-day caplets that supply 1000 mg of odorless garlic. One to two caplets daily is suggested. Another form of garlic is Pure-Gar Caps (900 mg garlic powder) or Pure-Gar with EDTA (a chelating agent). Two to four of these garlic capsules are recommended daily.
3. Essential fatty acids GLA (from borage oil), DHA and EPA (from fish oil). The most efficient way of obtaining all three of these antithrombotic fatty acids is to take 6 capsules a day of a supplement called Super GLA/DHA.
4. Vitamin E is an antioxidant and platelet aggregation inhibitor. The recommended dose for most people is 400 IU of alpha tocopheryl succinate, 200 mg of gamma tocopherol, and at least 50 mg of tocotrienols. Vitamin E with gamma tocopherol is essential when taking arginine, nitroglycerin, iso-sorbide mononitrate, or other nitrate medications.
5. Homocysteine can also be lowered by vitamins B6 and B12 and folic acid. For vitamin B6, 100-750 mg daily is recommended. Folic acid should only be taken in the dose of 800-2400 mcg with at least 1000 mcg of vitamin B12 to prevent masking a B12 deficiency. Trimethylglycine also lowers homocysteine levels (see the Cardiovascular Disease protocol for more information). TMG tablets contain 500 mg of trimethylglycine. One to five tablets daily are recommended. TMG Powder is also available. One scoop contains 500 mg of trimethylglycine. Two to five scoops daily are recommended.
6. Fibrinogen levels may be lowered by taking at least 2000 mg of vitamin C; 1000 mg of niacin; and 2000 mg of bromelain or by using a fish oil supplement that provides 5600 mg of EPA and 3200 mg of DHA.
7. Curcumin is well known for its anti-inflammatory action. It has also been shown to inhibit platelet aggregation. One 900-mg capsule with 5 mg of bioperine daily is recommended for healthy people. Curcumin should be used with caution in patients with biliary tract obstruction because it stimulates secretion of cholesterol bile acids from the liver through the bile duct into the intestines. High doses of curcumin on an empty stomach may contribute to stomach ulcers or gastric irritation.
8. DHEA has been shown to suppress certain inflammatory cytokines that cause elevated levels of CRP. Typical dosing for men and women is 25-50 mg daily. Refer to DHEA Replacement Therapy protocol for information and precautions.
9. Nettle leaf extract reduces inflammatory cyto-kines, which increase platelet aggregation that can lead to thrombosis. A dose of at least 1000 mg daily is suggested.
10. Quercetin is an antiplatelet agent. About 100-500 mg daily of highly absorbable water-soluble quercetin is suggested.
11. Green tea inhibits several factors involved in abnormal platelet aggregation. Green tea extract is available in 350-mg capsules and in 300-mg decaffeinated capsules for persons who are sensitive to caffeine. Two to four capsules daily is recommended for healthy people. Higher amounts may be taken to further reduce thrombotic risk. Green tea is best taken with meals. Green tea is also available in bulk leaf or in tea bags for those who want to brew and drink the tea.
12. Tomatoes have been shown to inhibit platelet aggregation. Lycopene, the main constituent of tomatoes, is a powerful antioxidant. Lycopene is available in supplement form: 10-30 mg a day is suggested.
13. Policosanol has been shown to lower cholesterol, inhibit platelet aggregation, and prevent thrombosis. Policosanol Tabs usually contain 10 mg of policosanol. To achieve optimal cholesterol levels, the normal dose is usually 10-20 mg taken daily at bedtime. Monitor cholesterol levels regularly because levels below 150-180 can be dangerous.

PRODUCT AVAILABILITY

Policosanol, Super Ginkgo Extract, Vitamin E, Gamma E Tocopherol/Tocotrienols, Essential Fatty Acids (Super GLA/DHA, perilla oil, flaxseed oil), DHEA, trimethylglycine, methylcobalamin (B12), folic acid, vitamin B6, vitamin C, bromelain, Kyolic Garlic, Pure-Gar, Super K, Healthprin (low-dose aspirin), quercetin, curcumin, green tea extract, Super Lycopene, grape seed-skin extract, and Life Extension Mix are available by calling (800) 544-4440 or by ordering online.