~Thrombosis Prevention

~Thrombosis Prevention
Reprinted with permission of Life Extension®.

  • Symptoms
  • Silent Strokes
  • Blood Clotting System
  • Thrombosis Related To Atherosclerosis
  • Causes
  • Conventional Prevention And Treatment
  • Precription Drugs
  • Risk Factors
  • Comprehensive Laboratory Testing
  • Consulting Your Physician
  • Nutritional Supplements
  • Summary


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.

Underlying Causes of Thrombosis
Endothelial injury

Trauma from accidents, surgery, etc.

From toxins in cigarette smoke

High cholesterol

Homocysteine

Bacterial toxins or endotoxins

Immune complex deposition

Presence of inflammatory mediators: cytokines, macrophages

Viral infections

Drugs

Sluggish venous blood flow

Prolonged bed rest, immobilization, or reduced physical activity (movement is required to pump the blood through the veins back to the heart)

Cardiac failure resulting in decreased cardiac output, particularly right-sided heart failure

Nephrotic syndrome

Disseminated cancer

Oral contraceptives

Alterations in arterial blood flow

Myocardial infarction

Rheumatic heart disease, which leads to blocking of the mitral valve Cardiac arrhythmias, including atrial fibrillation with related atrial chamber enlargement

Atherosclerosis (lipid deposits with smooth muscle cell proliferation and inflammatory mediators that clog the arteries)

Aneurysms (abnormal dilations of arteries)

Hypercoagulability (thick blood)

Genetic disorders, including deficiencies of antithrombin III, protein C, or protein S, and fibrinolysis defects

Oral contraceptives, causing an increase in plasma fibrinogen, prothrombin, and clotting factors VII, VIII, and X

Disseminated intravascular coagulation due to secretion of factors that activate coagulation

Factor X

Systemic lupus due to an antibody known as lupus anticoagulant Autoantibodies against anionic phospholipids (cardiolipin)
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).

Continued . . .


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