Blood Clot Prevention-A

Battling a Dangerous Condition

Thrombi (blood clots) are a leading cause of death and disability in the United States (American Heart Association 2004). Blood clots are responsible for a grim litany of health problems, including stroke, heart attack, pulmonary embolism, and complications of cancer. Because of this intense danger, conventional physicians prescribe a number of powerful drugs to prevent blood clots. But these drugs have dangers of their own; if their use is not closely monitored, they may cause serious bleeding and even death.

Blood clots are a natural part of the healing process; blood thickens around an injured area, forms a protective scab, and eventually dissolves on its own. However, clots become dangerous when they interfere with the circulatory system.

The best way to manage blood clots is to prevent them from forming in the first place. By the time a patient has had a stroke or heart attack, there has already been a failure of preventive medicine. These patients may end up taking anticlotting medication for the rest of their lives. The Life Extension Foundation believes that people should lower their risk of debilitating injury from a blood clot by using dietary nutrients that have been shown to modulate the blood’s ability to clot and to enhance the effectiveness of a prescription anticlotting medication.

Blood clots can block any of the blood vessels in our bodies, stopping the flow of blood. Or they may break off and travel through the circulatory system until they become lodged in a smaller artery or vein, causing tissue damage.

If this happens in an artery, any tissue that is downstream from the blockage will quickly become starved of oxygen and start to die. If it occurs in the coronary arteries that feed the heart, a heart attack may result. If this takes place in the arteries that feed the brain, an ischemic stroke or transient ischemic attack (TIA, also known as a ministroke) may result. Atrial emboli (blood clots that form in the heart chambers) can travel to the lungs, causing a potentially fatal blockage called a pulmonary embolism. In other instances, the clots can travel to the brain, causing a stroke. The US Centers for Disease Control and Prevention estimates that, if all forms of major cardiovascular disease were eliminated, life expectancy in the United States would rise by 7 percent (US Decennial for Life Tables for 1989-1991 1999).

Blood clots can also occur in the veins, which transport oxygen-poor blood from the body back to the heart. Blood clots may be caused by sluggish blood flow due to disease, injury to the vein, or even long periods of immobility. Sometimes these venous blood clots pose relatively little threat beyond cosmetic injury, such as in the case of varicose veins. However, if a blood clot forms in the deep veins of the legs (called deep vein thrombosis), there is a significant risk the clot will break off and travel to the lungs. Up to 90 percent of cases of acute pulmonary embolism are caused by blood clots that have traveled to the lungs from the legs. Pulmonary embolism is the cause of death or is a major contributing factor to death in up to 12 percent of patients who die in the hospital (Anderson FA Jr et al 1991).

Cancer is also associated with the risk of blood clots. Patients who have cancer often have hypercoagulable blood due to multiple disturbances in their metabolism and circulation. Patients with cancer are also more susceptible to infections. The ability of cancer to metastasize (spread) is determined at least in part by blood clotting factors that allow malignant cells to become fixed in capillaries (Hejna M et al 1999).

Blood clot treatment and prevention is a major focus of conventional medicine. Patients are advised to lower their risk through lifestyle modifications, such as exercising more and eating a healthful diet, and these patients may be prescribed medications that interfere with the blood’s ability to clot. The most common of these is simple, over-the-counter, low-dose aspirin, which is widely recommended to prevent heart attacks and strokes. More powerful prescription anticoagulants are also routinely prescribed, including heparin and warfarin (Coumadin®). It is notoriously difficult to find the correct dosages for these drugs. Frequent blood testing is required to make sure patients are not being put at increased risk of bleeding from the medications. Newer, more controllable anticoagulants are on the horizon, but they have not yet been approved in the United States.

Dealing with an existing blood clot may be a true medical emergency. Physicians may have to perform emergency open-heart surgeries to reestablish blood flow. Angioplasty, a procedure in which a balloon-tipped catheter is used to open a blocked vessel, is becoming increasingly common in the treatment of heart attacks and other emboli. In the case of a stroke, powerful medications called thrombolytics may be prescribed. If given quickly enough, these medications may be able to dissolve a blood clot and limit permanent damage to the brain or heart.

The Life Extension Foundation recommends taking active steps to reduce the risk of serious injury from a blood clot. This means regular blood testing to keep track of levels of cholesterol, homocysteine, fibrinogen, and other substances that are closely tied to blood clot risk. For patients at risk of blood clots, it means testing blood to track clotting risk. (These special tests are explained in more detail later in this chapter.) It also means exercising and eating healthy and using dietary supplements that have been shown to lower the risk of blood clot formation.

What You Have Learned So Far
To sum up:

A blood clot is called a thrombus. Blood clots are a normal part of the healing process of wounds, but may be very dangerous if they occur abnormally within the circulation.
Heart attacks, strokes, and pulmonary embolism can be caused by blood clots. Blood clots that trigger heart attack and stroke are the leading cause of death and disability in the United States.
Blood clots are a major complication of cancer, which interferes with the body’s natural coagulation system.
Conventional medications to treat blood clots usually focus on prevention or on interfering with the blood’s ability to clot. Low-dose aspirin is widely prescribed to help prevent blood clots. In an emergency situation, surgery may be necessary.
Everyone at risk of a blood clot should have his or her blood tested regularly for such risk markers as cholesterol, fibrinogen, and homocysteine levels and prothrombin time. Many nutrients and supplements have been shown to lower the risk of blood clots.


Thrombosis and Coronary Artery Disease
Coronary artery disease (CAD) is the single deadliest disease in the United States. An estimated 13.2 million people have CAD, or 6.4 percent of the population (American Heart Association 2004). An estimated 700,000 people in the United States will have their first heart attack this year. Another half a million will have another heart attack (American Heart Association 2004).

CAD occurs when the arteries feeding the heart become brittle and calcified. This process is called atherosclerosis and results in blockage of an artery. Atherosclerosis is often a lifelong process that begins in childhood and gradually worsens. Symptoms of atherosclerosis include angina (chest pain), shortness of breath, fatigue, leg pain, or other symptoms of poor circulation.

Researchers have made a great deal of progress unraveling the biochemical and physiologic cascade involved in atherosclerosis. The process often begins with mechanical damage from changes in blood pressure and the turbulent blood flow that exists at arterial branches. This stresses the intima layers (internal lining) of the arteries, which causes tiny tears that stimulate a combined healing and inflammatory response (Alexander RW 1995; Lee RT et al 2000; Massy ZA et al 1996).

These lesions attract blood platelets, which adhere to the vessel wall and cause smooth muscle cells on the walls of arteries to multiply. The smooth muscle cells have an increased permeability to platelets and lipids, especially low-density lipoprotein (LDL) cholesterol. As LDL increases at the site of the injury, it penetrates further into the arterial wall. This may occur very slowly at first, but the process speeds up under certain conditions or as part of normal aging. Even the arteries of children have been shown to have increased thickness in the presence of conditions such as obesity, diabetes, and high cholesterol (Aggoun Y et al 2005).

Over time, plaque begins to form on the interior arterial wall. The condition is aggravated by age as our endothelial cells gradually lose their ability to dissolve blood clots. Ultimately, the plaque deposit may become brittle and unstable and finally rupture. When the plaque ruptures, pieces of calcified plaque shower downstream into the artery, blocking it. Alternatively, a blood clot may rapidly form at the site of the injury. In either case, blood flow is restricted to a portion of the heart muscle, causing heart tissue damage.

Thrombosis and Stroke
Similar to the risk that thrombosis poses in the heart, thrombosis in the brain can be a life-threatening situation. Blood clots that form in the carotid arteries may potentially detach and block blood flow to brain tissue beyond the blockage (causing an embolic stroke), or they may grow large enough to block blood flow within their native artery (a thrombotic stroke). Embolic strokes also occur when blood clots travel from elsewhere in the body into the arteries of the brain. This happens sometimes as a result of atrial fibrillation, a condition in which the upper chambers of the heart beat abnormally quickly, causing incomplete emptying of the atria and allowing the blood inside the chambers to form clots that are then pumped into the circulation.

While researchers used to distinguish between full-blown strokes and TIAs, there is a growing recognition that these are similar events differing only in magnitude. The damage to the brain from many TIAs can occur insidiously and lead to dementia that resembles Alzheimer’s disease. According to one study, by the time people reach their 70s, one in three has had a silent stroke (Leary MC et al 2003). In a follow-up study, one in four survivors of a stroke had at least one silent stroke in the 2 years after his or her initial stroke (Corea F et al 2002). Among people who haven’t had a major stroke, TIAs are considered warning signs of an impending stroke.

Thrombosis and Cancer
Blood clots are also closely associated with cancer because of the way cancer interferes with the natural circulatory process. About 50 percent of all patients with cancer, and up to 95 percent of the patients with cancer who also have metastatic disease, show some abnormality in their coagulation system. Up to 11 percent of all patients with cancer have blood clots; hemorrhage occurs in about 10 percent. Thromboembolism and hemorrhage, as a whole, are the second most common cause of death among patients who have cancer (Lip GY et al 2002).

Various studies have shown the close connection between cancer and blood clots. In one pair of studies, two anticoagulants used to prevent blood clots (heparin versus low molecular weight heparin [LMWH]) were compared in the treatment of deep vein thrombosis. A significant number of patients with cancer were included in the pool of study subjects. In both studies, mortality rates were lower in the patients randomized to LMWH, but analysis of the death rates yielded a striking difference among the cancer patients (Green D et al 1992; Hejna M et al 1999; Hull RD et al 1992; Prandoni P et al 1992; Sciumbata T et al 1996). Cancer-related mortality with standard heparin was 31 percent versus 11 percent with LMWH. This suggests that LMWH might interfere with cancer’s reliance on the blood coagulation system to grow and metastasize (Collen A et al 2000; Mismetti P et al 2001; Prandoni P 2001; von Tempelhoff GF et al 2000).

The Clotting Process
The vastly complex blood clotting system begins when blood vessels are damaged. This damage may occur externally, as in the case of a cut, or the damage may be from within, as in the case of atherosclerosis caused by elevated homocysteine or high LDL cholesterol levels.

In response to vessel damage, collagen in the blood vessel tissue is exposed to the bloodstream. Within seconds, platelets circulating in the blood adhere to exposed collagen and secrete chemicals that start the following steps in the clotting process:

Platelet aggregators cause platelets to aggregate (clump together) and vasoconstrict (contract) blood vessels, which reduces blood loss. (Adenosine diphosphate (ADP), thromboxane A2, and serotonin are examples of some vasoconstrictors.)
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 series of reactions as part of 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. Some coagulation factors are responsible for accelerating the coagulation process (factor V, factor VIII, factor X, factor Xa, and factor IXa), while other blood factors (protein C, protein S, and thrombomodulin) are responsible for slowing and stopping the coagulation cascade. When it works correctly, this system results in the formation of thrombin, which helps convert fibrinogen into fibrin to plug the wound, and stop the growth of the blood clot at the appropriate time.

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. Nutrient supplements can be used to maintain this balance.


Risk Factors for Thrombosis
The best way to avoid damage from a blood clot is to take preventive action. A person with multiple risk factors for blood clots may consider taking active steps to reduce his or her risk. Risk factors for a blood clot include:

Elevated homocysteine levels—Homocysteine is an intermediary amino acid that is formed from the conversion of methionine into glutathione. High levels in the body indicate impaired homocysteine metabolism (via depressed methylation) or oxidative stress. Elevated homocysteine levels have been linked to increased risk of arterial blood clots (Ebbesen LS 2004). The Life Extension Foundation recommends keeping homocysteine levels between 7 and 8 millimoles per liter (mmol/L
History of heart attack or CAD—Atherosclerosis rarely occurs in isolation. Rather, it tends to be widespread throughout the body, so a history of atherosclerosis or heart attack translates into increased risk of blood clots.
History of stroke or TIA—One of the strongest predictors of stroke risk is a history of previous stroke or TIA. All patients who have had an ischemic brain event should take steps to lower their risk of future (and possibly more serious) events.
Inflammation—Chronic inflammation is associated with a variety of chronic diseases, including cardiovascular disease. C-reactive protein (CRP) is a sensitive indicator of inflammation throughout the body. A feature article in the May 2002 issue of Scientific American emphasized the link between chronic inflammation and the evolution of CAD (Libby P 2002). The Life Extension Foundation highly recommends measuring CRP levels using a high-sensitivity CRP blood test.
Elevated fibrinogen—Fibrinogen has a number of effects in the blood coagulation process. It reacts with thrombin to produce fibrin, it promotes platelet aggregation (which can lead to diminished blood flow), and it can cause platelets to bind together. An article in the journal Neurology found that prior stroke and elevated fibrinogen levels predicted new brain events in patients who have had a stroke (Beamer NB et al 1998).
Abnormal blood lipids—
Cholesterol’s role in atherosclerosis and blood clotting is well documented. LDL cholesterol molecules, which are large and unstable, contribute to plaque formation on arterial walls. When plaque ruptures, the resulting blood clot may cause a heart attack or stroke. Elevated levels of triglycerides, another kind of blood lipid, are also associated with heart disease, while depressed high-density lipoprotein (HDL) cholesterol levels are associated with elevated risk of heart attacks and strokes.
Hypothyroidism—A deficiency in thyroid hormone is associated with elevated levels of several clotting factors (Chadarevian R et al 2001; Muller B et al 2001) and with elevated homocysteine and depressed folate levels (Lien EA et al 2000; Nedrebo BG et al 2003). Supplemental thyroid hormone returns homocysteine levels to normal (Diekman MJ et al 2001; Hussein WI et al 1999). Furthermore, thyroid hormone inhibits LDL oxidation (Diekman MJ et al 2000). Hypothyroidism, even at levels detected only by an elevation of thyroid-stimulating hormone (TSH) level in the blood, is also a known risk factor for the development of atherosclerosis (Carantoni M et al 1997; Hak AE et al 2000).
If you are worried about developing blood clots, monitor your blood levels of these substances. Blood tests may be scheduled through your physician. These tests are also available through the Life Extension Foundation.
Table 1 shows the standard reference ranges and ideal levels recommended by the Life Extension Foundation.

Table 1. Laboratory Tests and Procedures*

1)Blood Test:TSH
Standard Reference Range-0.4-5.0 ?U/dL
Ideal Levels-0.2-2.0 ?U/dL


2)Blood Test:Total cholesterol
Standard Reference Range:100-199 mg/dL
Ideal Levels:180-200 mg/dL

3)Blood Test:LDL cholesterol
Standard Reference Range:0-129 mg/dL
Ideal Levels:Under 100 mg/dL

4)Blood Test:HDL cholesterol
Standard Reference Range:35-150 mg/dL
Ideal Levels:55-150 mg/dL

5)Blood Test:Triglyceride
Standard Reference Range:0-199 mg/dL
Ideal Levels:40-100 mg/dL

6)Blood Test:Homocysteine
Standard Reference Range:5-15 mmol/L
Ideal Levels:7-8 mmol/L

7)Blood Test:Fibrinogen
Standard Reference Range:200-400 mg/dL
Ideal Levels:200-300 mg/dL

8)Blood Test:CRP
Standard Reference Range:Up to 4.9 mg/L
Ideal Levels:Under 2 mg/L

9)Blood Test:DHEA
Standard Reference Range:Men: 280-640 mcg/dL
Ideal Levels:Men: 500-640 mcg/dL
Standard Reference Range:Women: 65-380 mcg/dL
Ideal Levels:Women: 250-380 mcg/dL

*TSH=thyroid-stimulating hormone; LDL=low-density lipoprotein; HDL=high-density lipoprotein; CRP=C-reactive protein; DHEA=dehydroepiandrosterone; ?U/dL=microunits per deciliter; mg/dL=milligrams per deciliter; mmol/L=millimoles per liter; mg/L=milligrams per liter; mcg/dL=micrograms per deciliter.


Conventional Treatment of Blood Clots: Anticoagulants, Antiplatelets, and Thrombolytics
In general, the following three classes of prescription drugs are used to treat or prevent blood clots:

Anticoagulants
Anticoagulants are drugs that interfere with the blood’s ability to clot. They are very powerful prescription medications whose dosages are monitored carefully. The effects of anticoagulants are known to be highly variable within each individual, so it is essential that a physician regularly monitor dosages by having the patient take frequent blood tests. A side effect of anticoagulants is increased risk of bleeding.

Some anticoagulant drugs used to prevent blood clots are:

Warfarin®—Warfarin® inhibits the synthesis of coagulation factors such as factors II, VII, IX, and X and anticoagulant proteins C and S. (Warfarin® is discussed in greater detail later in this chapter.)

Heparin—Heparin increases the activity of antithrombin III, which prevents the conversion of fibrinogen to fibrin. Heparin is not absorbed by the gastrointestinal tract and must be administered intravenously. It is usually used only in emergency situations (e.g., after a stroke).

Ximelagatran—Ximelagatran belongs to a new class of anticoagulants. Instead of interfering with the blood coagulation factors, ximelagatran is a direct thrombin inhibitor. It appears to offer several major advantages over other anticoagulants. Although clinical studies are still ongoing, early results of the effectiveness of ximelagatran have been promising. (Ximelagatran is discussed in greater detail later in this chapter.)

Antiplatelets
Antiplatelets interfere with the ability of blood platelets to clump. The most common antiplatelet is aspirin, which is prescribed for millions of patients at risk of blood clots.

Studies show that aspirin can prevent heart attacks; however, more recent research have caused some confusion. While aspirin’s effectiveness in heart attack prevention in men is well documented, a very recent study showed that aspirin is not as effective in preventing heart attacks in women. Based on these results, the authors of the study recommended that women younger than 65 years should avoid taking aspirin to prevent heart attacks because of the increased risk of bleeding. However, this type of aspirin therapy may be warranted in women older than 65 (Ridker PM et al 2005).

Other prescription antiplatelets include dipyridamole, clopidogrel (Plavix®), and ticlopidine (Ticlid™). Ticlopidine inhibits platelet aggregation by interfering with the binding of fibrinogen to the platelet membrane. It is a prescription drug that may be of particular value as an alternative to aspirin. Clopidogrel, meanwhile, is gaining popularity as an effective treatment for patients who have CAD and who have had a heart attack. It has been shown, in some cases, to enhance the effectiveness of aspirin (Doggrell SA 2005).

Thrombolytics
Thrombolytics break up existing blood clots in emergency situations such as a stroke or acute heart attack. The most commonly used thrombolytic is tissue plasminogen activator (TPA), which activates plasmin to break apart fibrin. Streptokinase is another TPA drug. In the case of stroke, rapid treatment with a thrombolytic has been shown to limit the amount of permanent brain damage.