Blood Clot Prevention

Blood Clot Prevention

1 Overview

Summary and Quick Facts

  • If you are over 50, the greatest threat to your continued existence is the formation of abnormal blood clots in your arteries and veins.
  • This protocol first discusses some technical details about thrombosis, the conventional drugs that doctors prescribe, and important blood tests to consider. It then reveals little-known methods of inhibiting a multitude of thrombotic risk factors that mainstream doctors overlook.
  • Measures to lower the risk of blood clots include decreasing chronic inflammation, maintaining healthy body weight, reducing cholesterol, suppressing homocysteine levels and lowering blood pressure. Additionally, the use of scientifically studied nutrients to target abnormal platelet aggregation can intervene in the thrombotic process before it causes a life-threatening medical emergency.

What are Blood Clots?

Normal clots are an essential part of the healing process, both inside blood vessels and at external injury sites. However, if a blood clot blocks blood flow to organs or tissues, it can be very dangerous. Abnormal blood clots (thrombosis) are the most common cause of heart attacks and strokes.

High-risk individuals are generally treated with antiplatelet drugs or anticoagulants. While these drugs can reduce risk of developing a clot, they fail to address many underlying risk factors and can have serious side effects.

Natural interventions like olive oil/olive leaf extract and quercetin may help prevent thrombosis and the related complications.

What are Risk Factors for Blood Clots?

  • High LDL cholesterol/low HDL cholesterol
  • Hypertension
  • Elevated glucose/insulin levels
  • Obesity, especially excess abdominal fat
  • History of stroke, heart attack, atrial fibrillation, or coronary artery disease
  • Sedentary lifestyle
  • Surgery
  • Thyroid disorders
  • Pregnancy
  • Cancer
  • Smoking

What are Conventional Medical Treatments for Blood Clots?

  • Antiplatelet drugs (eg, aspirin and clopidogrel)
  • Anticoagulants (eg, warfarin and heparin)

What are Emerging Therapies for Blood Clots?

  • New anticoagulants: dabigatran, rivaroxaban, and apixaban
  • Metformin

What Dietary and Lifestyle Changes Can Be Beneficial for Blood Clots?

  • Eat a balanced diet rich in fruits, vegetables, and unsaturated fats (Mediterranean style diets can be beneficial)
  • Exercise regularly
  • Quit smoking

What Natural Interventions Can Help Prevent Blood Clots?

  • Olive. Olives (and olive oil and olive leaf extract) have been used to combat high blood pressure and high cholesterol for many years. Various olive preparations have been shown to have antithrombotic effects.
  • Green and black tea. Tea consumption has been linked to increased cardiovascular health. Subjects who consumed black tea had reduced platelet aggregation.
  • Quercetin. Quercetin, a flavonoid naturally found in many plants, has demonstrated success in preventing platelet aggregation.
  • Salvia. Salvia is a diverse group of plants with many species. Red sage and chia are two examples shown to have antithrombotic effects.
  • Resveratrol. In vitro and animal studies have demonstrated resveratrol’s ability to inhibit platelet adhesion and aggregation. A human study also showed resveratrol (from wine) inhibited platelet activation.
  • Tomatoes. Tomatoes contain several compounds associated with cardiovascular health, lycopene being the most well-known. Tomato extracts have been shown to reduce platelet aggregation and lower cholesterol.
  • Garlic. Garlic has been shown to promote cardiovascular health in many human studies. One of the benefits observed in several cases was garlic’s ability to reduce platelet aggregation.
  • Fish oil. Fish oil, which is a good source of omega-3 fatty acids, has demonstrated the ability to lower triglyceride levels, blood pressure, and risk of cardiovascular mortality. It also has antithrombotic activity.
  • Curcumin. Curcumin has many protective roles in cardiovascular health. It can reduce oxidative stress and inflammation, and also has antiplatelet activity.
  • Pycnogenol. Pycnogenol (French maritime pine bark extract) was effective at decreasing incidence of thrombosis in travelers on long flights, people who previously experienced deep vein thrombosis, and cancer patients.
  • Ethanol. Consuming ethanol (drinking alcohol)in low doses can reduce thrombotic risk by modifying platelet function and reducing platelet aggregation. Exceeding the daily recommended amount (two drinks or less for men and one drink or less for women), however, increases clot risk.
  • Other natural interventions that can help prevent blood clots and improve cardiovascular health include niacin, vitamin C, nattokinase, grape seed extract, pomegranate, capsaicinoids, and ginger.

2 Introduction

You may not know it, but if you are over 50 the greatest threat to your continued existence is the formation of abnormal blood clots in your arteries and veins.

The most common form of heart attack occurs when a blood clot (thrombus) blocks a coronary artery that feeds your heart muscle. The leading cause of stroke occurs when a blood clot occludes, or obstructs, an artery supplying blood to your brain. Formation of vascular blood clots is also a leading cause of death in cancer patients because cancer cells create conditions that favor clotting.

While normal blood clots are a natural part of healing, abnormal arterial and venous blood clots are a significant cause of death and disability.1

The good news is that health-conscious individuals already take a wide variety of nutrients through their diet and supplement program that drastically reduce their risk of developing thrombosis, which is the medical term for an abnormal vascular blood clot.

Certain individuals, however, have underlying medical conditions that predispose them to developing thrombotic events. These include atherosclerosis, mechanical heart valves, atrial fibrillation, venostasis, blood clotting disorders, and cancer. These individuals must take special precautions to protect against thrombosis.

Conventional medicine offers drugs proven to reduce thrombotic risk via specific mechanisms. These drugs fail, however, to neutralize the broad array of mechanisms that can induce a thrombotic event, which is why a comprehensive thrombosis prevention program is so critically important to those at high risk.

This protocol first discusses some technical details about thrombosis, the conventional drugs that doctors prescribe, and important blood tests to consider. It then reveals little-known methods of inhibiting a multitude of thrombotic risk factors that mainstream doctors overlook.

Life Extension believes patients succumb to thrombotic events, even when taking powerful anti-coagulation drugs such as warfarin, because their doctors failed to suppress the many other underlying risk factors that cause abnormal clots to form inside a blood vessel.

3 The Flaws of Mainstream Therapies

The most effective means of blood clot management is prevention. For high-risk patients, mainstream prophylaxis against thrombosis and its complications often includes powerful anti-clotting medications. These require careful monitoring and inconvenient dietary restrictions.

Conventional medications used to prevent blood clots, such as warfarin (Coumadin), increase the potential for serious bleeding as well as the risk of mortality from traumatic injuries.2 Moreover, warfarin may lead to significant long-term side effects, such as increased risk of atherosclerosis and osteoporosis.

Life Extension has identified a strategy to reduce the detriments of long-term warfarin therapy. Judicious use of vitamin K2 has been shown in peer-reviewed studies to reduce the fluctuation in coagulation status associated with warfarin therapy. This notion runs contrary to that of conventional medicine, whose best advice is to totally eliminate vitamin K from the diet during warfarin therapy, an outdated guideline that compromises vascular and skeletal health.

Next-generation anticoagulant medications that overcome these vascular and skeletal risks are emerging, yet they still lack sufficient data from clinical trials to solidify them as first-line treatments. The most promising of these new drugs is dabigatran (Pradaxa); however, early trials indicate that dabigatran may be more effective for reducing stroke risk in patients with atrial fibrillation.3,4

Life Extension emphasizes that optimal thrombosis risk reduction can never be viewed in isolation, but must encompass a global strategy. Measures to reduce the risk of blood clots include reducing chronic inflammation, maintaining healthy body weight, reducing cholesterol, suppressing homocysteine levels, and lowering blood pressure. Additionally, the use of scientifically studied nutrients to target abnormal platelet aggregation can intervene in the thrombotic process before it causes a life-threatening medical emergency.

4 What is a Blood Clot?

A normal blood clot consists of a "clump" of blood-born particles that have become "stuck" together inside a blood vessel; this usually occurs at the site of a blood vessel injury and is part of the normal healing process. However, clotting also can occur in areas where blood flow is slow or stagnant, such as in a blood vessel occluded, or obstructed, by atherosclerotic plaque. A blood clot that develops in a blood vessel or the heart and remains there is called a thrombus, while a blood clot that has broken loose and floats freely through the circulatory system is called an embolus.

Blood clots are made up of:

Platelets: Small fragments of larger cells called megakaryocytes, platelets circulate through the blood and carry important substances such as proteins and other cellular signaling molecules. A platelet has a lifespan of about 7–10 days.

Red blood cells: The most common type of blood cell, red blood cells transport oxygen from the lungs and distribute it to all the tissues of the body.

White blood cells: The cells of the immune system, white blood cells originate in the bone marrow as stem cells that differentiate into various types of immune cells.

Fibrin: A web-like proteinaceous gel, fibrin binds the other components of the clot together.

5 Thrombotic Disease

A clot formation can be especially dangerous if it blocks blood flow to organs or tissues. For example, blockage of the coronary arteries (the blood vessels that directly supply oxygen to the heart muscle itself) can result in myocardial infarction (a heart attack), and death of heart muscle tissue.

An unstable thrombus can break away from the vessel wall and cascade freely through the bloodstream. This thrombus can become problematic if it becomes wedged in a blood vessel too small to allow its passage, obstructing blood flow and impairing oxygen delivery to tissue. This blockage is called an embolism. Cerebral embolism is one such example—an embolism in the small arteries of the brain can cause an embolic stroke.

Arterial thrombosis is associated with several life-threatening complications. Clots in the veins (venous thrombosis) of the legs are relatively common, and pose a significant risk of forming emboli that can travel to the lungs, causing a potentially fatal pulmonary embolism.

Complications of Thrombosis

Conditions caused by arterial thrombosis (blockage of arteries that carry oxygen-rich blood from the heart to other tissues):

  • Stroke: either slow-developing caused by thrombi, or rapid-onset caused by embolism.
  • Transient ischemic attack (TIA): a "mini-stroke" without tissue death.
  • Myocardial infarction (heart attack): blockage of the coronary arteries that supply oxygen to the heart muscle.
  • Pulmonary embolism: life-threatening blockage of arteries in the lungs, starving the body of oxygen. Some estimates place the incidence of pulmonary embolism at more than 180,000 new cases per year, making it the third most common life-threatening cardiovascular disease in the United States.5 A blood clot that leads to pulmonary embolism often forms in the legs as deep vein thrombosis (DVT), but can also form in the atrium in those with atrial fibrillation. In about 40% of cases, the origin of the emboli is unknown.6
  • Angina pectoris: reduction of blood supply to the heart, typically resulting in severe chest pain.

Conditions caused by venous thrombosis (blockage of veins that carry oxygen-poor blood back to the heart):

  • Deep vein thrombosis (DVT): a clot formed in a deep vein, usually in the legs. Quite common; data suggest the lifetime risk of DVT is about 5%.7 Unstable clots formed from DVT have the potential to break free and travel to the artery that supplies deoxygenated blood to the lungs, where they can cause a potentially fatal pulmonary embolism. Damage from DVT can also lead to post-thrombotic syndrome, a condition typified by leg pain, heaviness, swelling, or ulceration. More than one-third of women with DVT develop post-thrombotic syndrome.8
  • Portal vein thrombosis: a rare blockage of the vein that carries blood from the abdomen to the liver. Portal vein thrombosis is relatively uncommon and usually associated with liver disease.9
  • Renal vein thrombosis: a blockage of the vein that drains blood from kidney. This type of thrombosis is relatively uncommon and often associated with trauma to the abdomen.

6 Risk Factors for Thrombosis

The risk factors for thrombosis are believed to increase clotting through one or more of these three mechanisms: 1) altering or damaging the blood vessel lining (endothelium); 2) impairing or slowing the flow of blood; or 3) promoting a state that favors excess coagulation (hypercoagulation).

Alteration of the blood vessel lining (endothelium). Alteration of the endothelium produces areas of disturbance that are not necessarily tears, but may nonetheless mimic the physiology of vascular injury, thus encouraging the recruitment of platelets and the clotting process. Factors that pose a risk to endothelial cell health include:

  • Abnormal blood lipids. Abnormal blood lipids, particularly elevated total cholesterol, LDL (low-density lipoprotein) cholesterol, triglycerides, and low HDL (high-density lipoprotein) cholesterol, pose a risk to endothelial cell health. Blood lipid values outside of optimal ranges (see Table 2) are one of the risk factors for atherosclerosis, which causes arterial plaques on blood vessel walls. Clots can form on or near the lipid-rich arterial plaques in vessel walls, disrupting blood flow and increasing heart attack or stroke risk. Scientific strategies for cholesterol risk reduction are available in Life Extension's “Cholesterol Management” protocol.
  • Elevated high-sensitivity C-reactive protein (hs-CRP). hs-CRP is an indicator of inflammation and blood vessel injury; high levels are predictive of future risk of heart attack or stroke.10 CRP also exerts several pro-thrombotic activities, and may be associated with risk of venous thrombosis.11
  • Hypertension. Sustained high blood pressure compromises the integrity of the endothelium, and can cause endothelial activation and initiation of clotting.12 For optimal endothelial protection and blood clot prevention, a target blood pressure of 115/75 mmHg is suggested. Those with blood pressure higher than the optimal range are encouraged to read Life Extension's “High Blood Pressure” protocol.
  • Elevated glucose. Elevated blood glucose levels, even those that remain in the lab-normal range, may significantly increase the risk of developing a blood clot. In fact, a clinical study involving patients with coronary artery disease (CAD), found that patients with fasting glucose levels above 88 mg/dL had greater platelet dependent thrombosis than those with levels below 88 mg/dL. The authors of this study remarked: "The relationship is evident even in the range of blood glucose levels considered normal, indicating that the risk associated with blood glucose may be continuous and graded. These findings suggest that the increased CAD risk associated with elevated blood glucose may be, in part, related to enhanced platelet-mediated thrombogenesis."13 Life Extension suggests fasting glucose levels be kept between 70–85 mg/dL to limit glucose-induced platelet aggregation and promote optimal overall health.
  • Excess abdominal body fat. Abdominal obesity, also known as android obesity, consists of excessive deposition of fat tissue around the trunk of the body (eg, the belly). The fatty tissue around the trunk is prone to secrete inflammatory chemicals and cause high blood sugar and hypertension, all factors that pose dire risk to the health of the endothelial cells. Maintaining an ideal body weight is critical to reducing thrombosis risk.
  • Elevated homocysteine. Elevated homocysteine has been associated with a 60% increase in venous thrombosis risk for each 5 µmol/L increase in concentration.14 Homocysteine damages the endothelium, increases endothelial cell and platelet activation, and lowers fibrinolytic (clot breakdown) activity.15 Life Extension recommends keeping homocysteine levels below 7‒8 µmol/L for optimal health (Table 2); guidelines for doing so are discussed in the “Homocysteine Reduction” protocol.
  • History of stroke, transient ischemic attack, heart attack, or coronary artery disease. These all indicate a susceptibility to arterial thrombosis and are among the strongest predictors of future thrombotic events.

Note: In addition to these factors listed above, additional discussion of risk factors that compromise endothelial health (and therefore increase risk for thrombosis) can be found in the Life Extension Magazine article entitled "How to Circumvent 17 Independent Heart Attack Risk Factors."

Interrupted blood flow. Interrupted blood flow stimulates thrombosis by allowing the localized accumulation of circulating platelets and clotting factors and by increasing the probability of clotting reactions. Risk factors include:

  • Sedentary behavior. Sedentary behavior, either as inactive lifestyle or due to extended immobilization such as during hospitalization or long-distance travel,16 increase thrombosis risk. According to the CDC, adults aged 18+ should engage in at least 2.5 hours of moderate intensity aerobic exercise each week, and full-body strength training at least twice a week. Even greater health benefits are available through five hours of moderate-intensity aerobic exercise each week combined with full-body strength training two or more days a week.
  • Surgeries of the lower extremities (hip, knee, ankle). Surgeries of the lower extremities increase thrombosis risk either due to trauma to the veins during surgical manipulation, or immobilization during recovery.17 Without treatment, the incidence of DVT following total hip or total knee replacement surgery is as high as 40­–60%.18
  • Atrial fibrillation. Atrial fibrillation, the most common type of abnormal heart rhythm, can lead to blood pooling in the heart and subsequent clot formation in the left atrium, increasing stroke risk 5-fold.19

Hypercoagulable states. Hypercoagulable states (sometimes called thrombophilias) are conditions in which the nature or composition of the blood encourages coagulation. Some hypercoagulable states are inherited disorders that increase the activity of clotting factors or reduce the activity of natural anticoagulants. Some of the more common non-genetic hypercoagulable states include:

  • Thyroid disorders. Thyroid disorders, which alter the balance of clotting factors and anticoagulants, can increase the risk of thrombosis. Hyperthyroidism (high thyroid function) increases the risk of thrombosis due to disruption of the clotting process, such as increased production of clotting factors, increased thrombin activity, and reduced rate of fibrinolysis (clot breakdown).20 Hyperthyroidism also can increase blood volume, which can lead to high blood pressure and cardiac arrhythmias, both of which are risk factors for thrombosis.21 In hyperthyroid patients, the incidence of arterial thrombosis, especially cerebral thrombosis, is between 8% and 10%.22 Hypothyroidism (low thyroid function) also increases the risk of thrombosis. Hypothyroid patients cannot clear clotting factors from the blood as quickly, have elevated levels of fibrinogen, and have reduced rates of fibrinolysis.23
  • Elevated plasma fibrinogen. Elevated plasma fibrinogen, the main coagulation protein, may result from a variety of conditions such as smoking, thyroid disorders, or infection. A comprehensive review of observational studies estimated that a 98 mg/dL reduction in fibrinogen concentration would lead to a relative risk reduction of 80% in coronary heart disease.24
  • Pregnancy. Pregnancy shifts the balance of hemostatic factors towards coagulation and enhances the activation of platelets, especially in pre-eclampsia (pregnancy-associated hypertension), which may affect 2–4% of pregnancies.25
  • Cancer. Cancer can increase risk of venous thrombosis 4- to 7-fold, especially in metastatic cancers or those where the infiltration of tumors or compression of blood vessels disrupt blood flow.26 Pancreatic, brain, and gastric cancers especially increase the risk of thrombosis.26

Blood clots may be predictive of cancer risk as well. In a case-control study involving nearly 60,000 patients, the likelihood of developing any cancer within six months of diagnosis of venous thromboembolism (VTE) was 420% higher than that of the general population.27 Particularly, cancer of the ovary was more than 700% more likely, while non-Hodgkin’s lymphoma and Hodgkin’s disease were 500–600% more likely within a year of VTE.

Tumors exert a number of pro-thrombotic effects on the blood, as does chemotherapy itself.28 Unfortunately, once cancer has progressed sufficiently to cause a blood clot, it is usually in an advanced stage, and the survival rate of patients diagnosed with cancer within one year of VTE is poor.29

Alarmingly, the close link between cancer and thrombogenesis appears to be underappreciated by conventional physicians. A small survey of oncologists revealed that 27% believed cancer patients were not at increased risk for clotting.28 Similarly, another survey found that the majority of oncologists utilize thromboprophylaxis in cancer patients very rarely, despite the fact that VTE is a leading cause of death in this population.30

Additional risk factors include age, female sex, smoking, and obesity; additionally, surgery can increase thrombosis risk.

Table 1 shows the standard reference ranges and optimal levels recommended by Life Extension for blood parameters associated with risk of thrombosis or its complications.

Table 1. Recommended Blood Values and Pressure to Reduce Thrombosis Risk*

Blood Test

Standard Reference Range


Total cholesterol

100‒199 mg/dL

160‒180 mg/dL

LDL cholesterol

0‒99 mg/dL

under 70‒100 mg/dL

HDL cholesterol

over 39 mg/dL

over 50‒60 mg/dL

Fasting Triglycerides

0‒149 mg/dL

under 80 mg/dL

Fasting Glucose

65‒99 mg/dL

70‒85 mg/dL


0‒15 µmol/L

under 7‒8 µmol/L


150‒450 mg/dL

295‒369 mg/dL


0.45‒4.5 μIU/mL

1.0‒2.0 μIU/mL


0‒3.0 mg/L

Men: under 0.55 mg/L
Women: under 1.0 mg/L

Blood Pressure

Hypertension: over 139/89 mmHg

115 /75 mmHg31

*TSH=thyroid-stimulating hormone; LDL=low-density lipoprotein; HDL=high-density lipoprotein; CRP=C-reactive protein; μU/dL=microunits per deciliter; mg/dL=milligrams per deciliter; µmol/L=micromoles per liter; mg/L=milligrams per liter; mmHg: millimeters of mercury.

7 Blood Clotting Mechanisms

Hemostasis, a process that maintains the blood in a free-flowing state and helps stop bleeding during injury, is critical for survival. Blood clotting or coagulation is necessary to repair not only large injuries to blood vessels, but also the thousands of microscopic internal tears that happen daily under normal circumstances. Without a proper hemostatic response, the smallest of vessel injuries would lead to fatal hemorrhage (bleeding).

However, if the intricate balance among hemostatic mechanisms is disturbed, the tendency for a clot to become pathologic dramatically increases. The steps below briefly outline key aspects of the clotting process. This list also highlights points at which some drugs and natural compounds can combat derangement of the clotting system and offset thrombosis risk.

Normal blood clotting is a complex process, consisting of three major phases: 1) vasoconstriction, 2) temporary blockage of a break by a platelet plug, and 3) blood coagulation, or formation of a clot that seals the hole until tissue repair occurs.

The following four steps summarize clot formation, and also highlight key areas that pharmaceutical drugs and some natural compounds target in order to impede clotting:

  1. Vasoconstriction: Endothelial damage occurs, leading to neurogenic vessel constriction and decreased blood flow near the site of injury. This creates a local environment that favors clotting. Examples of injuries that may initiate the clotting process include rupture of an atherosclerotic plaque, or homocysteine-induced endothelial damage.
    1. Damage to the endothelium liberates sub-endothelial collagen and tissue factor (factor III), which initiate the intrinsic and extrinsic clotting pathways, respectively, in the immediate area (details in section titled "secondary hemostasis").
      • Intervention: Polyphenolic antioxidants, such as punicalagins from pomegranate, oligomeric procyanidins from grape seed, and trans-resveratrol, protect endothelial cells against injury and help maintain flexibility of blood vessels.

Primary Hemostasis

  1. Platelet adhesion and activation
    1. As circulating platelets pass by the site of vessel wall injury, receptors on their surfaces bind to exposed collagen and membrane proteins on activated endothelial cells, causing adhesion of platelets at and around the site of injury. This adhesion is mediated by von Willebrand factor and P-selectin.
      • Intervention: Curcumin, a bioactive compound derived from the spice turmeric, acts to suppress P-selectin expression and limits platelet adhesion by this mechanism.32
    2. Binding of the surface receptors leads to several molecular events that "activate" the platelets, causing release of adenosine diphosphate (ADP) from secretory granules within the platelet.
      • Intervention: Bioactive compounds in garlic work to suppress platelet granule release.33
    3. ADP binds to surface receptors called P2Y1 and P2Y12 on nearby platelets. This binding causes increased synthesis of thromboxane A2 (TXA2) via conversion of the inflammatory omega-6 fatty acid arachidonic acid by the enzyme cyclooxygenase-1 (COX-1).
      • Intervention: Aspirin inhibits the activity of COX-1 for the entire lifespan of the platelet, which is about 7–10 days.
      • Intervention: The omega-3 fatty acids EPA and DHA from fish oil counteract the synthesis of TXA2 by competing with omega-6 fatty acids as substrates for the COX enzyme.34
    4. Binding of P2Y1 and P2Y12 by ADP also causes the expression of another surface receptor, called glycoprotein IIb/IIIa (GPIIb/IIIa). The significance of GPIIb/IIIa will be examined in the "platelet aggregation" section.
      • Intervention: The "blood thinning" drugs Plavix (clopidogrel) and Ticlid (ticlopidine) block ADP from binding to the P2Y12 receptor for the entire lifespan of the platelet, which is about 7–10 days. The drug Effient (prasugrel) is a reversible inhibitor of P2Y12; its effects last about 5–9 days.
    5. Additional factors, including newly synthesized thromboxane A2, increase expression of the surface receptor GPIIb/IIIa as well.
    6. This process of platelet activation is self-propagating among platelets that happen to be near each other, and near the site of blood vessel wall injury.
  2. Platelet aggregation
    1. Following the activation of platelets as described above, the expressed GPIIb/IIIa surface receptors bind a circulating protein called fibrinogen, which comprises about 4% of total blood protein.
      • Intervention: The B-vitamin niacin, which is well known for being heart-healthy, exerts some of its cardioprotective actions by lowering plasma fibrinogen levels, thus attenuating the proclivity for platelets to aggregate and form a clot.35,36
      • Intervention: Vitamin C also appears to lower plasma fibrinogen levels, as suggested by some clinical trials and epidemiological studies.37,38
    2. Fibrinogen can bind GPIIb/IIIa receptors on adjacent platelets, linking them together in a process known as platelet aggregation.
      • Intervention: Tomato bioactives inhibit the function of GPIIb/IIIa, thereby blocking platelets from 1) binding circulating fibrinogen, and 2) binding to each other.39
    3. In a matter of seconds after vessel wall damage, platelet adhesion, activation, and aggregation culminate in the formation of a platelet plug, temporarily sealing off the injury.

Secondary Hemostasis

  1. Coagulation: Simultaneously to the formation of the platelet plug, tissue factor and collagen that were liberated upon vessel wall injury initiate two separate but related coagulation pathways.
    1. Collagen interacts with factor XII to initiate the intrinsic coagulation cascade.
    2. Concurrently, tissue factor interacts with factor VII to initiate the extrinsic coagulation cascade.
    3. Both the intrinsic and extrinsic pathways converge into the common pathway, which, through a complex series of interactions, converts prothrombin (factor II) into an enzyme called thrombin. This process is locally self-propagating via a process known as amplification, in which thrombin feeds back into the intrinsic pathway to drive further conversion of prothrombin.
    4. Thrombin then acts upon circulating fibrinogen to convert it into fibrin.
      • Intervention: Heparin is a naturally occurring anticoagulant that enhances the action of antithrombin, a glycoprotein that suppresses the ability of thrombin to convert fibrinogen to fibrin, thus slowing the coagulation process. Heparin is helpful when administered during medical emergencies involving atrial fibrillation and DVT.

    Rarely, some individuals develop a condition called heparin-induced thrombycytopenia (HIT) after receiving heparin. This is due to genetic differences in the immune response of these patients. Patients who develop HIT can be treated more safely with a new heparin alternative called fondaparinux.

      • Intervention: Dabigatran (Pradaxa) is a direct thrombin inhibitor. Dabigatran directly inhibits the action of thrombin, preventing it from converting fibrinogen to fibrin.
    1. Individual fibrin particles associate with one another to form polymers, which themselves associate into a web-like gel that traps circulating white blood cells, red blood cells, and additional platelets.
      • The widely used anticoagulant drug warfarin (Coumadin) interferes in several steps along both the intrinsic and extrinsic coagulation pathways by inhibiting the activity of vitamin K.
      • Vitamin K is required for activation of a number of factors (II, VII, IX, X, protein C, and protein S) involved in coagulation. Vitamin K facilitates carboxylation reactions required to activate these coagulation factors. After vitamin K successfully "carboxylates" a coagulation factor, it transitions to a less active form. In order for vitamin K to carboxylate additional coagulation factors, it must be recycled into its active form; this is accomplished by an enzyme called vitamin K epoxide reductase.Warfarin inhibits vitamin K epoxide reductase and impairs the recycling of vitamin K, thus slowing activation of factors required for coagulation.
    2. The fibrin gel and included blood cells and platelets then fuse with the platelet plug to reinforce the injury and completely seal it off until tissue repair can begin.


After clotting and coagulation is complete (usually between 3–6 minutes after injury), the trapped platelets within the clot begin to retract. This causes the clot to shrink, and pulls the edges of the injury closer together, squeezing out any excess clotting factors. Then the process of vessel repair can begin. Once healing is complete, the unneeded clot is dissolved and removed by a process called fibrinolysis.

Fibrinolysis involves the cleavage ("cutting") of the fibrin mesh by the enzyme plasmin to release the trapped blood cells and platelets, allowing the clot to "dissolve."

    1. An enzyme called tissue plasminogen activator (TPA) converts the inactive protein plasminogen into the active plasmin, which then cleaves the fibrin web.
      • Intervention: In some medical emergencies involving an embolic event, such as embolic stroke, pulmonary embolism, and myocardial infarction (heart attack), TPA can be administered intravenously to dissolve the blood clot and improve clinical outcome. TPA should be administered as soon as possible after an embolic event for maximum benefit.
      • Intervention: Nattokinase, a fermentation product from soy, is an enzyme that has been shown to increase the fibrinolytic activity of plasma in laboratory studies.40

In the absence of a blood vessel injury, platelet activation and coagulation cascades must be kept in check or the risk for thrombotic disease increases. Several factors disable blood clotting when it is not needed:

Protein C and protein S. These proteins associate with another protein called thrombomodulin, produced by healthy endothelial cells, to form a complex that blocks the activation of factor V and hence the conversion of prothrombin to thrombin.

  • Interestingly, the action of the protein C/S complex depends upon vitamin K. Therefore, vitamin K is not only critical for optimal coagulation when blood vessel injury has occurred, but it is also needed to limit the formation of thrombi during healthy conditions. Adequate vitamin K intake is paramount in ensuring hemostatic balance at all times.

Antithrombin. The liver produces this small protein and it is found in relatively high concentrations in blood plasma. It inhibits the activation of several coagulation factors and remains constantly active to limit thrombotic disease risk. When clotting is needed to repair an injury, the coagulation cascade initiated by the exposure of collagen and tissue factor overwhelms antithrombin and clotting is able to proceed.

As noted above, the anticoagulant heparin dramatically increases antithrombin activity. When administered intravenously, heparin can cause the anticoagulatory tendency of antithrombin to inhibit the clotting cascade, thus slowing clot formation.

Tissue factor pathway inhibitor. This polypeptide blunts the ability of the extrinsic pathway to activate thrombin under healthy conditions. However, as with antithrombin, vessel wall injury overwhelms this coagulation inhibitor by liberating large amounts of tissue factor, allowing coagulation to proceed.

Plasmin. Healthy endothelial cells secrete tissue plasminogen activator, an enzyme that converts plasminogen into plasmin. Plasmin breaks down the fibrin web that holds clots together. Therefore, plasmin is constantly contributing to fibrinolysis by breaking down any clots that are not needed.

Prostacyclin (PGI2). This fatty acid derivative is produced by healthy endothelial cells and by platelets via the action of the cyclooxygenase-2 enzyme. PGI2 counteracts the action of thromboxane A2, thereby suppressing platelet activation during healthy conditions. PGI2 also acts as a vasodilator to help maintain free blood flow during healthy conditions.

Nitric oxide (NO). NO is a signaling molecule involved in a vast array of biochemical functions. During healthy conditions, the endothelium produces NO via an enzyme called endothelial nitric oxide synthase (eNOS). eNOS contributes to vasodilation, thus reducing the risk of thrombosis.

8 Conventional Therapies for Blood Clots and Thrombosis Risk Reduction

Two classes of pharmaceutical drugs reduce the risk of thrombosis and its complications, antiplatelet drugs and anticoagulants. Reserved for emergency situations, a third class called thrombolytics/fibrinolytics break up blood clots and limit tissue damage; tissue plasminogen activator (Activase) and urokinase (Abbokinase) are two examples.

Antiplatelet Drugs

Antiplatelet drugs inhibit platelet activation and aggregation, an early step in the clotting process. Several classes of antiplatelet drugs inhibit platelet aggregation and activation at a different point in platelet metabolism.

The most common antiplatelet drug is aspirin. It inhibits the enzyme cyclooxygenase (COX), which is responsible for synthesizing thromboxane A2.41 Thromboxane A2 is a factor secreted by platelets to recruit other platelets to the site of injury during the initial stages of the clotting process. The cyclooxygenase inhibitory effect of aspirin is permanent for the life of the platelet (about 7–10 days). Aspirin has been shown effective in preventing complications of several disorders, including hypertension, heart attack, and stroke.42 Importantly, ibuprofen can attenuate the COX inhibitory action of aspirin in platelets; therefore, if low-dose aspirin is being taken preventatively, ibuprofen for pain relief should be taken at least eight hours apart from aspirin to ensure maximum effectiveness.

Interestingly, aspirin also inhibits the COX enzyme in endothelial cells, but does not exert an irreversible action here. Unlike platelets, endothelial cells contain DNA and RNA and can therefore synthesize new COX enzymes even after aspirin has bound to existing COX enzymes. This dichotomy of aspirin action in platelets versus endothelial cells is significant because the COX enzyme is critical for the synthesis of the anti-platelet, vasodilatory compound prostacyclin (PGI2). Healthy endothelial cells secrete prostacyclin to counteract the action of TXA2 and ensure that a clot does not continue to grow and occlude the blood vessel.

The difference between endothelial cell biology and platelet biology also explains why low-dose aspirin is cardioprotective. Low-dose aspirin does not impair endothelial secretion of prostacyclin because these cells quickly synthesize new COX enzymes and overwhelm low concentrations of aspirin. However, platelets do not synthesize new COX so that aspirin, even in low concentrations, suppresses platelet-derived TXA2 until new platelets arise from the bone marrow. Thus, low-dose aspirin is effective for reducing the risk of pathologic clot formation while maintaining optimal endothelial function.

Aspirin's inhibition of COX also helps explain its potential in cancer reduction as observed in several studies.43-46 Several types of cancers (particularly breast, prostate, and colon) overproduce the pro-inflammatory enzyme COX-2, which appears to play a role in increasing the proliferation of mutated cells, tumor formation, tumor invasion, and metastasis.47,48 COX-2 may also contribute to drug resistance in some cancers, and its expression in cancer has been correlated with a poor prognosis.48

A second group of commonly prescribed antiplatelet drugs, including clopidogrel (Plavix), prasugrel (Effient), and ticagrelor (Brilinta), are characterized by their ability to bind to the surface of platelets and block the P2Y12 ADP receptor, inhibiting the platelet from becoming activated. Clopidogrel, the most widely prescribed antiplatelet, is more effective than aspirin in its ability to reduce the aggregation of platelets.49 Clopidogrel activity can be enhanced when combined with aspirin,50 and this combination has been tested for its efficacy, safety, and cost effectiveness for a variety of clinical applications. In some cases, the combination represents a significant improvement over clopidogrel alone.

In patients with acute coronary syndrome, the CURE (Clopidogrel in Unstable angina to prevent Recurrent Events) trial demonstrated that combining clopidogrel and aspirin resulted in a 20% reduction in risk of cardiovascular death, heart attack, or stroke, as compared to aspirin alone after a one-year follow up. However, those in the clopidogrel group had an increased risk of bleeding.51 Similar results were also observed in the COMMIT (Clopidogrel and Metoprolol in Myocardial Infarction Trial) trial, in which short-term combination therapy (four weeks) lowered risk of heart attack, stroke, and death in patients with a previous heart attack (9% risk reduction).52 In both trials the benefits of the combination therapy outweighed the moderate cost increase in treatment. However, for other applications, such as prevention of heart attack in high-risk individuals without established cardiovascular disease, or in the treatment of stable coronary artery disease, treatment with aspirin alone has proven safer and more cost effective than combination therapy.53,54

Other clinically important oral antiplatelets include dipyridamole (Persatine) and cilostazol (Pletal), which are platelet phosphodiesterase inhibitors. These drugs are used less frequently as large-scale clinical trials have not proved them to be more effective than aspirin and Plavix.


Anticoagulants inhibit the transformation of fibrinogen into fibrin, one of the last steps in the clotting process that stabilizes a thrombus.

Warfarin has a lengthy list of interactions that can increase the risk of bleeding (hemorrhage). More than 205 pharmaceutical, nutritional, and herbal medicine interactions have been identified for warfarin. Some medications that can potentially interact with warfarin include aspirin, cimetidine, lovastatin, thyroid hormones, and oral contraceptives. Foods and nutritional ingredients such as onions, garlic, ginger, coenzyme Q10 (CoQ10), fatty fish, and vitamin E have been reported to increase the risk of bleeding when combined with warfarin; however, many of these reports are anecdotal and may not represent significant concerns.55,56 Many nutritional ingredients that "thin the blood" do so by different mechanisms than warfarin. For instance, rather than interfering with coagulation they may inhibit platelet aggregation, a different step in blood clot formation.

While it is prudent to follow a conservative approach regarding warfarin's potential for interaction with a variety of pharmaceutical and nutritional agents, being overly cautious may cause potential cardiovascular health benefits to go unrealized.

In fact, warfarin combined with conventional antiplatelet drugs has been studied already in patients at high-risk for thrombosis.57 Additional evidence suggests warfarin can be combined safely with antiplatelet nutrients, such as garlic,58 as long as one takes these nutrients responsibly. The most important considerations for individuals who wish to take this approach are monitoring and awareness; patients must work closely with their healthcare practitioner and undergo regular blood testing to measure coagulant activity (see section titled "Testing Clotting Function").

For over 50 years, vitamin K antagonists like warfarin (Coumadin) were the only orally bioavailable anticoagulant drugs; aspirin is not an anticoagulant drug, but rather reduces the ability of platelets to stick together in primary hemostasis. However, use of vitamin K antagonists like warfarin in patients has been plagued by problems.

Warfarin treatment risks multiple medication (and food) interactions, the problem of variable pharmacologic effect, a narrow, brittle therapeutic index, and a relatively slow onset of action, all of which serve to place patients at risk. 

For example, an underappreciated analysis showed that 44% of bleeding complications with warfarin occurred in patients anticoagulated excessively with the drug, and 48% of clotting events (thromboembolic) occurred in patients anticoagulated inadequately with the drug.59

However, over the past several years, many novel, orally bioavailable anticoagulant drugs have become available in the United States.

These new medications target critical anticoagulant factors like factor X and thrombin (factor IIa). These novel, oral anticoagulant drugs include dabigatran (Pradaxa), rivaroxaban (Xarelto), and apixaban (Eliquis).


Dabigatran (Pradaxa), a direct thrombin inhibitor, is approved in the United States for use in the prevention of stroke and systemic embolism in adult patients with non-valvular atrial fibrillation, treatment of deep venous thrombosis and pulmonary embolism, and to reduce the risk of recurrence of deep venous thrombosis and pulmonary embolism.

  • The RE-COVER study in patients with acute venous thromboembolism showed60:
    • The 6-month incidence of recurrent symptomatic venous thromboembolism and related deaths was similar, 2.4% (2.3% venous thromboembolism; 0.1% deaths) in patients treated with dabigatran versus 2.1% (1.9% venous thromboembolism; 0.2% deaths) in those treated with warfarin;
    • The rates of major bleeding episodes were similar in the dabigatran and warfarin groups (1.6% vs. 1.9%, respectively). However, the incidence of all bleeding events was lower with dabigatran (16.1%) than warfarin (21.9%).
  • The RE-LY ([Randomized Evaluation of Long-term Anticoagulant Therapy]; warfarin compared with dabigatran) study in patients with non-valvular atrial fibrillation and at risk of thromboembolism showed61:
    • Stroke (including hemorrhagic stroke) rate per year was lower with a 150 mg dabigatran dose (1.11%) and statistically equivalent with a 110 mg dabigatran dose (1.53%) compared with warfarin (1.69%);
    • The rate of major bleeding with a 150 mg dabigatran dose was not different (3.11%; P=0.31) compared with warfarin (3.36%) but was lower with a 110 mg dose (2.71%; P=0.003); the rates of hemorrhagic stroke with the 110 and 150 mg dabigatran doses were lower than with warfarin (0.12% and 0.10% vs. 0.38%; P<0.001), as were the rates of intracranial hemorrhage (0.23% and 0.30% vs. 0.74%; P<0.001).
  • An analysis of seven trials involving over 30,000 patients, including two studies of stroke prophylaxis in atrial fibrillation, one in acute venous thromboembolism, one in acute coronary syndrome, and three of short-term prophylaxis of deep venous thrombosis showed62:
    • Dabigatran was significantly associated with a higher risk of myocardial infarction or acute coronary syndrome (dabigatran [1.19%] vs. control [0.79%]; P=0.03);
    • The risk of myocardial infarction or acute coronary syndrome was similar when using revised criteria to include exclusion of short-term trials and was consistent using different methods and measures of association.


A factor Xa inhibitor, rivaroxaban (Xarelto) is approved in the United States for reducing stroke risk in non-valvular atrial fibrillation, treatment of deep venous thrombosis and pulmonary embolism as well as reduction in risk of recurrence of deep venous thrombosis and pulmonary embolism, and prophylaxis of deep venous thrombosis after knee replacement and hip replacement surgery.

  • The Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study evaluated rivaroxaban for prevention of stroke or embolization in patients with non-valvular atrial fibrillation at risk of stroke, and showed63,64:
    • Rivaroxaban was similar to warfarin for risk of stroke and embolism (2.1% vs. 2.4% per year);
    • Similar rates were observed between patients taking rivaroxaban and those taking warfarin in terms of all bleeding events (14.9% vs. 14.5% per 100 patient-years) and major bleeding events (3.6% vs. 3.4% per 100 patient-years).
      • In addition, the rates of intracranial hemorrhage and fatal bleeding were less with rivaroxaban therapy (0.4% vs. 0.8%, P=0.003 and 0.5% vs. 0.7%, P=0.02, respectively).
  • The EINSTEIN study compared oral rivaroxaban to traditional therapy with low molecular weight heparin (enoxaparin) and a vitamin K antagonist in patients with acute, symptomatic deep venous thrombosis65 and showed:
    • Rivaroxaban therapy was similar (non-inferiority test) to enoxaparin/vitamin K antagonist therapy with respect to recurrent venous thromboembolism (2.1% vs. 3.0%; P<.001)
    • The principal safety outcome of major or clinically relevant non-major bleeding occurred at similar rates in both treatment arms (dabigatran vs. enoxaparin/vitamin K antagonist).


Apixaban (Eliquis), an inhibitor of free and clot-bound factor Xa as well as prothrombinase activity, is approved in the United States for the treatment of deep venous thrombosis and pulmonary embolism; reduction in risk of recurrent deep venous thrombosis and pulmonary embolism following initial therapy; reduction in risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation; and prophylaxis of deep venous thrombosis, which may lead to pulmonary embolism, in patients who have undergone hip or knee replacement surgery.

  • The Apixaban after the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy-Extended Treatment (AMPLIFY-EXT) trial evaluated the efficacy and safety of different doses of apixaban compared with placebo in patients with a recent venous thromboembolism who completed prior anticoagulation therapy and showed66:
    • The incidence of recurrent venous thromboembolism and venous thromboembolism-related mortality was 1.7% in both apixaban dose groups compared with 8.8% in the placebo group (P<0.001);
    • The rates of major bleeding were similar across the treatment groups (2.5 mg of apixaban: 0.2%; 5 mg of apixaban: 0.1%; placebo: 0.5%).
  • The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial compared apixaban with the vitamin K antagonist warfarin in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke and showed67:
    • Compared with warfarin, apixaban therapy was better in preventing stroke or embolism (1.27% vs. 1.60% per year; P<0.001 for non-inferiority and P=0.01 for superiority);
    • The rate of major bleeding per year with apixaban was better (2.1%) than with warfarin (3.1%) (P<0.001).

At the time of this writing, a fourth oral anticoagulant, edoxaban (Savaysa), has been submitted for regulatory approval, and although in October 2014 the Food and Drug Administration (FDA) advisory panel voted overwhelmingly in favor of this oral anticoagulant for the treatment of patients with atrial fibrillation,68 this drug is not yet approved for this indication in the United States.

Be aware that although there appear to be a variety of advantages associated with the new oral anticoagulants in comparison with warfarin, there is also controversy.

For example, many of the studies submitted for FDA approval with the new oral anticoagulants utilized so-called non-inferiority designs and statistical tests in order to show that the newer drugs are at least as good as the vitamin K antagonist warfarin in reducing the risk of thromboembolic events as well as supporting safety, in particular in the context of major bleeding like intracranial hemorrhage. However, one criticism of non-inferiority test suggests that the relative benefits of these newer drugs versus warfarin has been overstated (given the limitations of the trial designs).

Also, although some outcomes may “appear” better (or safer) with specific new anticoagulants, the patient populations are similar, but not the same (nor are the trial designs), and the idea that one agent is necessarily better than another at the current time is not supportable. However, one (dabigatran) of the new oral agents has a potential safety signal—though very controversial at the current time, some data suggest an increase in heart attack and acute coronary syndrome in some patients with the use of this new drug.68

General advantages of the new oral anticoagulants (compared with warfarin)

  • More rapid onset of action
  • No need for frequent blood test monitoring
  • Far more predictable, consistent pharmacologic effects
  • Dramatically reduced drug-drug and drug-food interactions
  • Similar (or better) short-term efficacy for reduction of clotting events (thromboembolism)
  • Similar (or improved) short-term safety (eg, major bleeding risk)

General disadvantages of the new oral anticoagulants

  • High(er) cost relative to warfarin
  • No specific antidote to counteract bleeding (in contrast to high-dose vitamin K to reverse warfarin’s effects), though protein C concentrate has been used
  • Lack of long-term safety data and adequate data to support use in pregnancy, patients with mechanical heart valves, and patients with severe kidney disease
  • Potential safety signal observed with at least one of the new drugs (dabigatran), suggesting an increase in heart attack and acute coronary syndrome risk in at least some vulnerable patients62

Metformin and Blood Clot Prevention

Blood clots in atherosclerotic vessels are the leading cause of death in people with diabetes.69 Metformin, a medication used to treat diabetes, has been demonstrated to reduce diabetes-related cardiovascular changes and disease, as well as deaths related to diabetes and to all causes.70-74

Emerging research indicates that metformin’s cardiovascular benefits may be related to an antithrombotic action. In a study in experimentally-activated platelets, treatment with metformin preserved mitochondrial function, decreased free radical production, and reduced platelet activation and aggregation. This effect was confirmed in normal and diabetic laboratory animals, in which metformin treatment prevented platelet-induced blood clots in arteries and veins. Importantly, metformin was not associated with any increase in bleeding time, spontaneous bleeding, or gastric ulcer.75

Early research in humans supports a role for metformin in improving platelet function and preventing blood clots. A study that compared diabetic subjects taking metformin to medically similar individuals not using metformin found metformin use was associated with a lower risk of DVT.74 Metformin use has been associated with a lower mortality rate in patients with diabetes and related tendency to thrombosis.76 In patients with polycystic ovarian syndrome and related insulin resistance, metformin use was associated with improved mitochondrial function and reduced platelet reactivity.77 Another study found diabetic patients treated with metformin had lower platelet production of a free radical called superoxide anion than those treated with other glucose-lowering medications, and their platelet superoxide production was similar to that seen in healthy subjects.78

Vitamin K and Warfarin

Besides its dualistic role in coagulation (recall that the coagulation factors II, VII, IX, and X are vitamin K-dependent, but so are the anti-thrombotic factors protein C and S), vitamin K is central to bone and vascular health as well. Just as several coagulation factors must undergo vitamin K-dependent carboxylation before they become active, a number of proteins involved in bone formation and stability require this same activation; warfarin can disable these proteins too, leading to compromised bone integrity. Moreover, a protein in blood vessels, matrix GLA protein, works to keep blood vessels flexible by inhibiting calcification of vascular cells (eg, "hardening" of the arteries). Matrix GLA protein must also be carboxylated by vitamin K to function properly; thus, vitamin K epoxide reductase inhibition can compromise vascular elasticity.

Tragically, there is poor appreciation within mainstream medicine for enhanced risk of conditions associated with vitamin K antagonist treatment, including vascular calcification,79 lower bone mineral density,80 and osteoporotic fracture.81

Many conventional physicians have been reluctant to supplement a warfarin regimen with low dose vitamin K in order to stabilize coagulation time and guard against long-term detriments associated with vitamin K antagonist therapy. Peer-reviewed scientific literature indicates that this strategy can decrease dangerous fluctuations in coagulant status during warfarin treatment (as measured by wide variations in prothrombin time [PT] standardized for the international normalized ratio [INR]).82,83

There are several potential reasons for fluctuating INR values during warfarin treatment, including genetic polymorphisms in vitamin K-related genes, interactions with other drugs, and dietary vitamin K intake.84 Unstable anticoagulation has been associated with diets low in vitamin K,82 and a strong association between variations in INR and highly variable vitamin K intake exist.83 Consistent intake of a low dose of vitamin K, with appropriate adjustment of warfarin dosage, has been shown in several studies to stabilize INR values. This is likely due to maintenance of constant body stores of the vitamin and minimizing the effects of dietary fluctuations.85

In a small, open-label crossover study, nine patients (average age 50 years old) with a history of unstable INR received 500 mcg/day of vitamin K for eight weeks. In five of the nine patients, variability in INR decreased (as measured by the reduction in viability between INR measurements at several time-points) and achieved a therapeutic range within an average of 14 days. On average, warfarin doses were increased by 50% to achieve a stable INR value during the vitamin K supplementation.86

The amount of time that INR stays within a therapeutic range (called the TTR) is another measurement of INR variability. On average, patients on coumarin anticoagulant therapy only maintain their INR within the therapeutic range 50–60% of the time, despite careful monitoring.87 Three studies have shown that combination therapy of vitamin K and coumarin anticoagulants can significantly increase TTR, especially in patients with unstable coagulation control. A small study compared two groups of 35 patients on warfarin therapy with fluctuating INR values receiving 150 mg vitamin K1 or a placebo daily for six months. Variability in the test group decreased at the end of the study compared to the control group, and the amount of time patients maintained their INR in the therapeutic range increased by 13%.85

In a second study, two groups of 100 patients on a coumarin anticoagulant were assigned to receive either 100 mcg vitamin K1 or placebo. Unlike previous studies, however, this study was not limited to patients with unstable control of anticoagulation. Compared with the control group, patients receiving vitamin K showed a 3.6% increase in TTR.88

A larger study of 400 patients from two anticoagulation clinics were randomized to receive either a placebo or 100, 150, or 200 mcg of vitamin K once daily with their coumarin anticoagulant for a period between six and 12 months. Although this study also was not limited to patients with a history of unstable INR, the results showed that doses of 100 mcg or 150 mcg increased the amount of time patients had an INR within the therapeutic range (by 2.1% and 2.7%, respectively), compared to the control group. Moreover, these patients had twice the chance of maintaining their INR within the therapeutic range for extended periods of time.89

Vitamin K supplementation in those taking warfarin should be conducted under careful supervision by a healthcare practitioner.

Heparin is a natural anticoagulant that stimulates the activity of antithrombin III and prevents the assembly of fibrinogen molecules into fibrin. Several heparin derivatives, including low-molecular-weight heparin, unfractionated heparin, and fondaparinux (a synthetic heparin derivative) are also clinically important. Heparin and its derivatives are given by injection.1

Other potential therapies currently being investigated make use of thrombolytic (clot-dissolving) agents. These include: the co-administration of a clot-dissolving thrombolytic drug and an anticoagulant (warfarin) for DVT treatment; directly infusing the thrombolytic drug tissue plasminogen activator (tPA) into clots in the brain (through a minimally invasive surgical technique) or clots in the leg (by injection)90,91; and the administration of red blood cells coated with tPA to patients, which increases the lifetime of the drug and reduces the likelihood that it will cause excess bleeding.92

Testing Clotting Function93,94

Several different lab tests assess clotting function. The appropriateness of each test depends on several variables (ie, which type of "blood-thinning" medication the person is taking, if the person has any genetic predispositions to clotting dysfunction, etc.). A healthcare practitioner should help determine the test most appropriate in each situation.

Clot-based assays test the time it takes for a sample of blood plasma to clot. They are used to test the function of the latter stages of clotting (fibrin formation). Different types of clot-based assays exist to test for deficiencies in different parts of the coagulation cascade. (Recall there are three "pathways" involved in secondary hemostasis: intrinsic, extrinsic, and common pathways.)

Prothrombin time (PT test or PT/INR) measures the time (in seconds) it takes for a blood sample to clot after the addition of a platelet activator inhibitor and a clotting factor (tissue factor). The PT test is most often used to monitor coagulation status during warfarin therapy. This test is useful for assessing factor VII activity.

Due to variation in laboratory methodology, the results of this test are reported as the international normalized ratio (INR), which can correct for this variability. Conditions that affect coagulation (like vitamin K deficiency or warfarin use) prolong clotting time, while those that affect platelet activity (like taking aspirin) have no effect on the test.

A target INR range of 2.0 to 3.0 is typically recommended for individuals being treated with anticoagulant medication.

Because the PT test does not reveal antiplatelet activity, patients on combination warfarin/antiplatelet therapy with either antiplatelet drugs and/or antiplatelet nutrients should undergo regular bleeding time tests and PT tests. By using these two tests in concert, a balanced program of conventional anticoagulant therapy plus antiplatelet drugs and/ or antiplatelet nutrients can be uniquely tailored to an individual.

Activated partial thromboplastin time (aPTT) is a related test that measures clotting in response to different clotting factors; specifically, the aPTT test does not measure factor VII activity (ie, this test focuses on the intrinsic pathway). This test is typically used to measure the efficacy of heparin on clotting (heparin prolongs the aPTT time) but other anticoagulants can increase aPTT clotting time as well.

Platelet function assays test the ability of platelets to become activated or aggregate, which occurs in the initial stages of the clotting process. They are less sensitive to the effects of coagulation factors. In other words, platelet function assays test primary hemostasis, while coagulation assays test secondary hemostasis.

The bleeding time test is a simple test in which blood pressure is maintained by use of a blood pressure cuff while small cuts or "pricks" are made on the fingertip or lower arm. The time for bleeding to stop (a measurement of platelet plug formation) is measured. A normal result is 1 to 9 minutes, depending on which method is used.

Light transmittance aggregometry (LTA) is a standard technique in which platelet-rich plasma is exposed to an aggregating agent (like collagen or ADP), and the clumping of platelets is measured by their ability to block the transmission of light. This technique can be used to monitor the efficacy of antiplatelet drugs, or can detect genetic platelet defects such as von Willebrand disease.

The platelet function analyzer (PFA) is a relatively new instrument that measures the effect of an aggregating agent (collagen, ADP, or others) on platelet aggregation in conditions simulating arterial blood flow. As platelets flow through the instrument, they are forced through a small opening (simulating a vessel tear), and the time for a thrombus to form over the opening (called closure time) is reported. Some local labs typically offer this test, and those interested in having the PFA test should discuss it with their physicians.

Platelet count determines whether blood platelets fall within a healthy range, (about 150,000 to 400,000 platelets per μL) although it does not determine whether the platelets are functioning properly.

9 Dietary Approaches to Reduce Thrombosis Risk

The successful nutritional approach to reduce thrombosis risk does not depend solely on a set of "antithrombotic nutrients." Rather, Life Extension supports a multifactorial approach that includes nutrition and lifestyle interventions to reduce the risk of thrombosis. These include abnormal blood lipids, chronic inflammation, hypertension, elevated plasma homocysteine, and obesity.

Reducing Platelet Activation and Aggregation

Platelet activation and aggregation occurs via a complex, multifactorial process. Several natural ingredients can target varying steps involved in clot formation, and a diversified regimen can provide multiple defenses against aberrant clotting.

Olive. Olive (Olea europaea) has a history of use against high blood pressure, atherosclerosis, and diabetes.95 The leaves contain the active iridoid compounds oleuropein and oleacein,96 which are thought to be responsible for its blood pressure-lowering and cholesterol-lowering properties demonstrated in recent human trials.97

In laboratory tests, olive leaf extract also demonstrated antiplatelet activity in blood isolated from healthy male volunteers.98 High-oleuropein extracts from olive tree wood also inhibit aggregation of human platelets in laboratory tests, especially those from type 2 diabetic patients.99 Hydroxytyrosol and hydroxytyrol acetate, two metabolites of oleuropein that are found in olive fruit and oil, have well-established anti-inflammatory and antiplatelet activities in laboratory tests and in animal models.100

Phenolic-rich olive oil preparations have demonstrated decreases in the production of proinflammatory and prothrombotic factors in human studies as well.101,102 Hydroxytyrosol acetate inhibits platelet aggregation with an efficacy similar to aspirin in vitro using whole blood samples from healthy volunteers.103 Hydroxytyrosol-rich extracts (25 mg/day) for four days reduced production of the prothrombotic factor thromboxane A2 in a pilot trial of five diabetic adults.104 High-fat diets rich in olive oil lowered the plasma levels of several clotting factors in a larger study of 20 healthy young adults.105

Tea. Tea consumption has established protective effects on cardiovascular health; reductions in risk of coronary heart disease and stroke from tea consumption have been confirmed through the analyses of several population studies.106 Purified green tea polyphenols, such as EGCG, increase clotting time in rats and reduce platelet aggregation in isolated human platelets.107

Human trials of tea consumption and thrombosis risk have had mixed results. While short-term consumption (two weeks) of green tea showed no measurable effect of platelet activity,108 longer-term studies showed modest improvements in platelet function.109 The most promising results have been observed in a randomized blinded trial of tea consumption; six weeks of black tea consumption (four cups/day) in 37 healthy volunteers significantly reduced platelet activation, as measured by the presence of platelet aggregates.110 Tea catechins and the flavonoid quercetin have demonstrated synergistic reductions in platelet adhesion, activation, and aggregation in vitro.111

Quercetin. Quercetin has demonstrated success inhibiting platelet aggregation. Single doses of quercetin glucosides, the naturally occurring form of quercetin (150 mg or 300 mg), from food sources and higher quality dietary supplements, were able to significantly inhibit collagen-induced platelet aggregation in one small human study.112 However, long-term supplementation with 1 gram/day of quercetin aglycone (the form typically found in lower quality dietary supplements) for 28 days had no significant effect on platelet aggregation in healthy human volunteers.113 It should be noted that the plasma concentrations of quercetin in the former study (successful) were significantly higher than in the latter at the time of aggregation measurements, suggesting that quercetin glucosides are absorbed more efficiently than quercetin aglycone. Quercetin from food sources (onions) have shown positive trends on platelet aggregation.114

Salvia. Salvia is a diverse genus of plants encompassing hundreds of species, many with ornamental, culinary, or medicinal importance. Salvia miltiorrhiza (red sage or danshen) is one of the most versatile Chinese herbal drugs, used for hundreds of years in the treatment of cardiovascular diseases115 and still widely used as standard thrombolytic treatment in Chinese hospitals.116 Salvianolic acids A and B, water soluble polyphenols from S. miltiorrhiza root, are responsible for its observed antiplatelet activity in animal models117 and in blood samples from healthy human volunteers.118

The seeds of Salvia hispanica (chia) are rich in protein and the omega-3 fatty acid α-linolenic acid. In a small study of 27 patients with type 2 diabetes, whole chia seed (15 grams/1,000 kcal of intake) for 12 weeks showed significant reductions in plasma fibrinogen and the platelet adhesion protein von Willebrand factor (vWF). Small reductions in additional cardiovascular risk factors (systolic blood pressure and hs-CRP) were also observed.119

Resveratrol. Resveratrol has several effects on blood platelets as determined in vitro (using human platelets) and in animal models, including inhibition of platelet adhesion and aggregation, reduction in secretion of clotting factors from platelets, and inhibition of cyclooxygenase, the proinflammatory enzyme involved in platelet activation.120,121 Plasma resveratrol from consumption of red or white wine increases the release of nitric oxide from platelets in healthy volunteers, inhibiting their activation.122 In an experimental study, resveratrol was able to suppress the detrimental effects of homocysteine on platelet aggregation and free radical generation.123

Grape seed extract. Grape seed extract contains oligomeric procyanidins that support cardiovascular health through vasodilation and an increase in nitric oxide production.124 They have significantly reduced blood pressure in human trials.125 Grape seed extract also exhibits antithrombotic activity in animals126 and in platelets isolated from healthy human volunteers.127 This may be related to an anti-inflammatory effect.128

In a small, 8-week study of 17 post-menopausal women taking 400 mg of flavonoid-rich grape seed extract/day, a significant (23%) lengthening of clotting time compared to the control was observed on day 1 of the study. (Increased clotting time indicates reduced platelet activation and aggregation.) After eight weeks, the difference in clotting time was not as significant, but trended higher in the test group.129 Similar short-term reductions in platelet activity also were observed in a study of 23 male smokers.130 When combined with grape skin polyphenols, grape seed extracts demonstrated better antiplatelet properties than either extract alone in animal models as well as human platelets.131

Tomatoes. Tomatoes contain several nutrients with established protective effects on the cardiovascular system. Lycopene has demonstrated hypotensive activity in humans,132 and several human trials indicate a cholesterol-lowering effect.133 One mechanism by which lycopene may limit platelet aggregation is by activating cyclic-GMP, a signaling molecule involved in vessel dilation.

Tomatoes also exert potent antiplatelet activity in laboratory tests.134 The antithrombotic compounds of tomato are small molecules found within its water-soluble fractions, which are also high in soluble sugar content. Removal of these sugars increases the concentration of tomato actives and stimulates their inhibition of platelet aggregation by up to 50 times.135

Two studies examined the effects of these standardized tomato extracts on platelet function in healthy human volunteers: High dose (18 grams, equivalent to six whole tomatoes) and low dose (equivalent to two tomatoes) standardized tomato extracts both exhibited significant reductions in platelet aggregation up to six hours after ingestion. Standardized bioactives from tomato suppress platelet adhesion and aggregation by reversibly inhibiting P-selectin and GPIIb/IIIa, two receptors necessary for clot formation.135

Pomegranate. Pomegranate contains several bioactive antioxidant polyphenols, including the unique tannins punicaligins. Pomegranate juice consumption has been associated with significant decreases in blood pressure in hypertensive subjects136,137 and decreases in LDL cholesterol oxidation.138 Pomegranate juice polyphenols also function as vasodilators by supporting endothelial function, and as inhibitors of angiotensin-converting enzyme, an enzyme associated with high blood pressure. Two weeks of pomegranate juice consumption (50 mL/day) reduced platelet aggregation by 11% in a small study of 13 healthy individuals.139 In a human clinical trial, pomegranate juice consumption was shown to prolong clotting time as little as six hours after consumption.140

Garlic. Garlic's (Allium sativum) promotion of cardiovascular health has been substantiated by several human trials, particularly its blood pressure-lowering activity141 and its ability to induce favorable blood lipid profiles.142 In cell models, garlic extracts inhibit platelet aggregation by reducing ion signaling involved in platelet activation, and by increasing synthesis of c-GMP, a vasodilator. Garlic bioactives also promote endothelial nitric oxide release and enhance fibrinolysis.143,144 Moreover, garlic inhibits the COX-1 and COX-2 enzymes, which suppress TXA2 levels.145

The antithrombotic activity of garlic has also been the subject of several human trials in both healthy subjects and patients with cardiovascular disease, using aged extracts,146 water extracts,147 or garlic oil.148 Garlic demonstrated reductions in platelet aggregation in each of the studies.

Fish oil. Fish oil is a source of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are essential for several metabolic processes. Studies of tens of thousands of moderate- and high-risk cardiovascular disease patients demonstrated the ability of fish oil to reduce plasma triglycerides, blood pressure, and the risk of cardiovascular mortality.149 Several human studies observed the antithrombotic activities of fish oil,150 due in part to its ability to reduce the production of the platelet aggregator thromboxane A2, a metabolite of the inflammatory omega-6 fatty acid arachidonic acid.

Fish oil consumption decreases platelet activation151 and aggregation,152 and plasma fibrinogen levels.153 In type 2 diabetic patients, the pooled data from three human trials of 159 participants demonstrated a reduction in plasma fibrinogen by 32 mg/dL, and platelet aggregation by more than 10%.154

Capsaicinoids. Capsaicinoids (capsaicin and dihydrocapsaicin) are the major pungent constituents of chili peppers from the genus Capsicum. Regular intake of chili peppers delays oxidation of serum lipids, and lowers and improves insulin and glucose profiles following a meal, both of which contribute to reducing the risk of cardiovascular disease.155 In animal models, capsaicin reduces platelet aggregation.156 An early study attributed the reduced plasma fibrinogen and increased fibrinolytic activity of native Thai individuals, compared to Americans living in Thailand, to the amounts of capsaicin in their diets.157 In laboratory tests, both capsaicin and dihydrocapsaicin reduced platelet aggregation and reduced the activity of clotting proteins in blood samples from six healthy patients.158

Ginger. Ginger has been shown to inhibit platelet aggregation and to decrease platelet thromboxane production in laboratory tests.159 Both raw and powdered preparations reduced platelet aggregation in small human trials.160 Five grams/day of fresh ginger for seven days inhibited thromboxane production in seven healthy volunteers,161 while two additional studies (a single dose of 2.5 grams dried powder in 10 healthy volunteers and 10 grams dried powder/day for three months in 30 patients with coronary artery disease) demonstrated inhibition of platelet aggregation.162,163 Doses lower than 2.5 grams had no effect in human trials.164

Curcumin. Curcumin has a variety of protective roles in cardiovascular health, reducing oxidative stress, inflammation, and the proliferation of vascular smooth muscle cells and monocytes (immune cells that contribute to atherosclerosis in the presence of oxidized LDL cholesterol). Human trials revealed the effects of curcumin on reducing lipid peroxidation165,166 and plasma fibrinogen,167 both factors in the progression of atherosclerosis.168 Another mechanism by which curcumin inhibits platelet aggregation is through dampening expression of P-selectin, an adhesion molecule expressed on both activated endothelial cells and platelets that mediates aggregation between these two cell types.32 P-selectin also recruits leukocytes to the forming thrombus.

In eight subjects with abnormally high plasma fibrinogen, 20 mg of curcumin for 15 days reduced fibrinogen levels by nearly 50%.167 Experiments using human platelets or whole blood have demonstrated curcumin's ability to inhibit platelet aggregation.169

French maritime pine bark extract. French maritime pink bark extract (commercially known as Pycnogenol), which has strong anti-inflammatory and free radical-scavenging effects, has been found to stabilize vascular collagen and prevent blood clots.170 In in vitro research, an extract from New Zealand pine bark reduced cytokine-related expression of adhesion molecules by endothelial cells, thereby reducing the likelihood of blood cell aggregation, in response to inflammatory signaling.171

Pine bark extract may help travelers avoid blood clots during and after long flights. One study compared the effect of pine bark extract to placebo in 198 long-haul air travelers with a high risk of blood clots. Travelers received 200 mg pine bark extract or placebo two to three hours before flight time and six hours later, and 100 mg the next day. Flights averaged 8.25 hours. No thrombotic events occurred in those given pine bark extract, but five occurred in the placebo group.172 In another trial, 186 travelers on 7‒8 hour flights received two tablets containing 150 mg of a proprietary blend of pine bark extract plus nattokinase or placebo two hours before travel and six hours later, and completed pre- and post-flight monitoring of edema and blood clots. No thrombotic events occurred in the treated group, but seven flight-related thrombotic events occurred in the placebo group. In addition, edema scores based on measurements taken before treatment and after air travel decreased by 15% in the pine bark-nattokinase combination group and increased 12% in those receiving placebo, with a significant difference between the two.173

One trial examined the effect of pine bark extract in 156 participants who experienced a single episode of DVT. Participants were assigned to one of three treatments: pine bark extract, compression stockings, or both. After one year, two new episodes of DVT occurred in participants using compression stockings versus none in either of the groups receiving pine bark extract. In addition, pine bark extract was more effective than compression stockings in reducing edema and as effective in improving microcirculation, while the combination of both was the most effective. This may be especially significant because compression stockings are historically associated with low compliance due to discomfort.174

Findings from a clinical trial suggest pine bark extract may help prevent thrombosis and other side effects in cancer patients undergoing chemotherapy and radiation therapy. The study included 46 cancer patients who began supplementing with three 50 mg pine bark extract or placebo after meals (total of 150 mg daily) after completing their first course of chemotherapy or radiation. After two months, the patients receiving pine bark extract had decreased frequencies of all investigated side effects, including thrombotic events, compared with those receiving placebo.175

Suppressing Fibrinogen Levels

Niacin/nicotinic acid. Niacin/nicotinic acid (vitamin B3) is an essential nutrient with important effects throughout human metabolism. At dosages substantially above the Recommended Dietary Intake (RDI), niacin reduces risk factors for cardiovascular disease, and reduces cardiovascular events and mortality.176 Some of this risk reduction is due to niacin's ability to significantly raise HDL cholesterol by up to 35%,177 and reduce the amount of small, dense low-density lipoprotein (LDL) particles, a risk factor for atherosclerosis.178

Niacin also lowers plasma fibrinogen levels, a risk factor for cardiovascular disease. In the multi-center Arterial Disease Multiple Intervention Trial (ADMIT), patients with peripheral arterial disease (PAD) who were randomized to niacin (initially 100 mg a day, raised to 3,000 mg/day over the 12-month study) saw an average reduction of fibrinogen by 48 mg/dL (~13.5%), as well as a reduction in prothrombin time, a measure of blood clotting.35 Similar reductions in plasma fibrinogen (-54 mg/dL, ~15%) were observed in a 6-week study of men with elevated triglycerides.36

Vitamin C. Vitamin C may possibly suppress fibrinogen levels, as suggested by some association studies. A study involving more than 3,200 men in the United Kingdom found those with the higher plasma levels of vitamin C also had lower levels of fibrinogen and superior endothelial function.38 Likewise, a study of 96 aging men and women found that an increase of dietary vitamin C of 60 mg daily, or the equivalent of about one orange, was associated with a reduction in fibrinogen that was estimated to cause a 10% reduction in risk of ischemic heart disease.37

In an animal model, vitamin C was shown to reduce levels of von Willebrand factor and fibrinogen, suggesting inhibition of platelet adhesion and aggregation. Moreover, vitamin C was able to reduce blood pressure in this study.179

An experimental study found that incubation of fibrinogen molecules with vitamin C in vitro caused functional changes to fibrinogen, which may be associated with an impaired capacity for binding the surface of platelets.180

Promoting Fibrinolysis (Clot Breakdown)

Nattokinase. Nattokinase is a fibrinolytic enzyme (an enzyme that breaks down fibrin clots) found in natto, a soy fermented by the bacteria Bacillus subtillis. The bacteria produce the enzyme—nattokinase is not a metabolite of soy. In laboratory tests it reduces platelet aggregation and blood viscosity,181 and enhances the fibrinolytic activity of plasma in animal models.40

At a dose of 4,000 fibrinolysis units (FUs) per day, nattokinase has been shown to reduce circulating fibrinogen and clotting factors (which are independent risk factors for cardiovascular disease) in patients undergoing dialysis or with cardiovascular disease, and in healthy volunteers.182 It was also able to reduce the frequency of DVT in 94 high-risk individuals on extended airline flights when combined with pine bark extract, or pycnogenol.173 Nattokinase also has been shown to reduce blood pressure in hypertensive individuals, which may be attributed to its ability to lower blood viscosity.183

Ethanol. Ethanol (drinking alcohol), in low doses, reduces thrombotic risk by modifying platelet function and reducing platelet aggregation. As little as a half glass of red wine daily provides enough ethanol to reduce thrombotic risk. However, higher doses of ethanol increase the risk for clotting substantially.184 All types of ethanol consumed in moderation (two drinks or less daily for men and one drink or less daily for women) should reduce thrombotic risk, but red wine also provides beneficial polyphenols such as quercetin.

  1. Mannucci PM, Franchini M. Old and new anticoagulant drugs: a minireview. Ann Med. 2011;43(2):116–123.
  2. Dossett LA, Riesel JN, Griffin MR, Cotton BA. Prevalence and implications of preinjury warfarin use: an analysis of the National Trauma Databank. Arch Surg. 2011;146(5):565–570.
  3. Peetz D et al. Dabigatran versus warfarin for venous thromboembolism. N Engl J Med. 2010 Mar 18;362(11):1050; author reply 1050-1.
  4. Houston DS et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009 Dec 31;361(27):2671; author reply 2674-5.
  5. Cushman M, Tsai A, White R. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. The American journal of Medicine 2004;117(1):19-25.
  6. Flegel KM et al. When atrial fibrillation occurs with pulmonary embolism, is it the chicken or the egg? CMAJ. 1999 Apr 20;160(8):1181-2.
  7. Silverstein MD, Heit JA, Mohr DN, et al. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med. 1998;158(6):585–593.
  8. Kahn SR. The post thrombotic syndrome. Thromb. Res. 2011;127 Suppl3:S89–92.
  9. Rajani R, Björnsson E, Bergquist A, et al. The epidemiology and clinical features of portal vein thrombosis: a multicentre study. Aliment. Pharmacol. Ther. 2010;32(9):1154–1162.
  10. Ridker PM, Silvertown JD. Inflammation, C-reactive protein, and atherothrombosis. J. Periodontol. 2008;79(8 Suppl):1544–1551.
  11. Lippi G, FavaloroEJ, Montagnana M, Franchini M. C-reactive protein and venous thromboembolism: causal or casual association? Clin. Chem. Lab. Med. 2010;48(12):1693–1701.
  12. Schmieder, Roland E. "End Organ Damage in Hypertension." DeutschesÄrzteblatt International 2010; 107(49) : 866–873.
  13. Shechter M et al. Blood glucose and platelet-dependent thrombosis in patients with coronary artery disease. J Am CollCardiol. 2000 Feb;35(2):300-7.
  14. den Heijer M, Lewington S, Clarke R. Homocysteine, MTHFR and risk of venous thrombosis: a meta-analysis of published epidemiological studies. J Thromb Haemost 2005; 3:292–299.
  15. Di Minno MND, Tremoli E, Coppola A, Lupoli R, Di Minno G. Homocysteine and arterial thrombosis: Challenge and opportunity. Thromb. Haemost. 2010;103(5):942–961.
  16. Lippi G, Maffulli N. Biological influence of physical exercise on hemostasis. Semin. Thromb. Hemost. 2009;35(3):269–276.
  17. Stamatakis JD, Kakkar VV, Sagar S, et al. Femoral vein thrombosis and total hip replacement. British Medical Journal. 1977;2:223-5.
  18. Baser O. Prevalence and economic burden of venous thromboembolism after total hip arthroplasty or total knee arthroplasty. Am J Manag Care. 2011;17(1 Suppl):S6–8.
  19. XueYZ, Wang LX. Contemporary management of atrial fibrillation: a brief review. Adv Med Sci. 2010;55(2):130–136.
  20. Erem C. Thyroid disorders and hypercoagulability. Semin. Thromb. Hemost. 2011;37(1):17–26.
  21. Franchini M. Hemostatic changes in thyroid diseases: haemostasis and thrombosis. Hematology 2006;11(3): 203–208.
  22. Burggraaf J, Lalezari S, EmeisJJ, et al. Endothelial function in patients with hyperthyroidism before and after treatment with propranolol and thiamazole. Thyroid 2001;11(2): 153–160
  23. Erem C, Kavgaci H, Ersooz H. Blood coagulation and fibrinolytic activity in hypothyroidism. Int J ClinPract2003;57(2):78–81.
  24. Folsom AR. Epidemiology of fibrinogen. Eur Heart J. 1995;16(suppl A):21-24
  25. de Maat MPM, de Groot CJM. Thrombophilia and pre-eclampsia. Semin. Thromb. Hemost. 2011;37(2):106–110.
  26. Streiff MB. Anticoagulation in the management of venous thromboembolism in the cancer patient. J Thromb Thrombolysis. 2011;31(3):282–294.
  27. Murchison JT et al. Excess risk of cancer in patients with primary venousthromboembolism: a national, population-based cohort study. Br J Cancer. 2004 Jul 5;91(1):92-5.
  28. Kirwan CC et al. Prophylaxis for venous thromboembolism during treatment for cancer: questionnaire survey. BMJ 327 : 597 doi: 10.1136/bmj.327.7415.597 (Published 11 September 2003).
  29. Sørensen HT, Mellemkjaer L, Steffensen FH, e al. [Incidence of cancer after primary deep venous thrombosis or pulmonary embolism]. Lakartidningen. 2000;97(16):1961-4.
  30. Kakkar AK et al. Venous thrombosis in cancer patients: insights from the FRONTLINE survey. Oncologist. 2003;8(4):381-8.
  31. Chobanian, Aram V et al. "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 Report." JAMA : the Journal of the American Medical Association 2003; 2560–2572.
  32. Vachharajani V et al. Curcumin modulates leukocyte and platelet adhesion in murine sepsis. Microcirculation. 2010 Aug;17(6):407-16.
  33. Mousa SA. Antithrombotic effects of naturally derived products on coagulation and platelet function. Methods Mol Biol. 2010;663:229-40.
  34. Tapiero H et al. Polyunsaturated fatty acids (PUFA) and eicosanoids in human health and pathologies. Biomed Pharmacother. 2002 Jul;56(5):215-22.
  35. Philipp CS, Cisar LA, Saidi P, Kostis JB. Effect of niacin supplementation on fibrinogen levels in patients with peripheral vascular disease. Am J Cardiol. 1998;82(5):697–9, A9.
  36. Johansson JO, Egberg N, Asplund-Carlson A, Carlson LA. Nicotinic acid treatment shifts the fibrinolytic balance favourably and decreases plasma fibrinogen in hypertriglyceridaemic men. J Cardiovasc Risk. 1997;4(3):165–171.
  37. Khaw T et al. Interrelation of vitamin C, infection, haemostatic factors, and cardiovascular disease. BMJ. 1995 Jun 17;310(6994):1559-63.
  38. WannametheeSG et al. Associations of vitamin C status, fruit and vegetable intakes, and markers of inflammation and hemostasis. Am J ClinNutr. 2006 Mar;83(3):567-74; quiz 726-7.
  39. O'Kennedy N, Crosbie L, Whelan S, et al. Effects of tomato extract on platelet function: a double-blinded crossover study in healthy humans. Am J Clin Nutr. 2006 Sep;84(3):561-9.
  40. Fujita M, Hong K, Ito Y, et al. Thrombolytic effect of nattokinase on a chemically induced thrombosis model in rat. Biol. Pharm. Bull. 1995;18(10):1387–139.
  41. Hall R, Mazer CD. Antiplatelet drugs: a review of their pharmacology and management in the perioperative period. Anesth. Analg. 2011;112(2):292–318.
  42. Patrono C, Baigent C, Hirsh J, Roth G. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133: 199S–233S
  43. Rothwell PM, FowkesFG, Belch JF, Ogawa H, WarlowCP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011; 377(9759):31-41.
  44. Rothwell PM, Wilson M, Elwin CE, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010; 376(9754):1741-50.
  45. Salinas CA, Kwon EM, FitzGerald LM, et al. Use of aspirin and other nonsteroidalantiinflammatory medications in relation to prostate cancer risk. Am J Epidemiol. 2010;172(5):578-90.
  46. Flossmann E, Rothwell PM. Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies. Lancet. 2007; 369(9573):1603-13.
  47. Cerella C, Sobolewski C, Dicato M, Diederich M. Targeting COX-2 expression by natural compounds: a promising alternative strategy to synthetic COX-2 inhibitors for cancer chemoprevention and therapy. Biochem. Pharmacol. 2010;80(12):1801–1815.
  48. Sobolewski C, Cerella C, Dicato M, et al. The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. Int J Cell Biol. 2010;2010:215158.
  49. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329–39.
  50. Becker RC, Meade TW, Berger PB, et al. The primary and secondary prevention of coronary artery disease: American College of Chest Physicians Evidence- Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:776S– 814S
  51. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 2001;345(7):494–502.
  52. Chen ZM, Jiang LX, Chen YP, Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomized placebo-controlled trial. Lancet 2005;366 (9497)L 1607-21
  53. Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16):1706–1717.
  54. Arnold SV, Cohen DJ, Magnuson EA. Cost-effectiveness of oral antiplatelet agents—current and future perspectives. Nat Rev Cardiol. 2011;8(10):580-91.
  55. Ulbricht C, Chao W, Costa D, et al. Clinical evidence of herb-drug interactions: a systematic review by the natural standard research collaboration. Curr Drug Metab. 2008;9(10):1063–1120.
  56. Shalansky S et al. Risk of warfarin-related bleeding events and supratherapeutic international normalized ratios associated with complementary and alternative medicine: a longitudinal analysis. Pharmacotherapy. 2007 Sep;27(9):1237-47.
  57. Vedovati MC, Becattini C, Agnelli G. Combined oral anticoagulants and antiplatelets: benefits and risks. Intern Emerg Med. 2010;5(4):281–290.
  58. Macan H, Uykimpang R, Alconcel M, et al. Aged garlic extract may be safe for patients on warfarin therapy. J Nutr. 2006;136(3 Suppl):793S–795S.
  59. Oake N, Fergusson DA, Forster AJ, van Walraven C. Frequency of adverse events in patients with poor anticoagulation: a metaanalysis. CMAJ. 2007;176(11):1589-1594.
  60. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-52.
  61. Wallentin L, Yusuf S, Ezekowitz MD, et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet. 2010; 376(9745):975-983.
  62. Uchino K, Hernandez AV. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomized controlled trials. Arch Intern Med. 2012 Mar 12;172(5):397-402.
  63. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011; 365(10):883-891.
  64. Fox KA, Piccini JP, Wojdyla D, et al. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J. 2011;32(19):2387-2394.
  65. Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363(26):2499-2510.
  66. Agnelli G, Buller HR, Cohen A, et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013; 368(8):699-708.
  67. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011; 365(11):981-992.
  68. Daiichi Sankyo. US FDA Cardiovascular and Renal Drugs Advisory Committee makes recommendation on Daiichi Sankyo's once-daily Savaysa (edoxaban) for the reduction in risk of stroke and systemic embolic events in patients with non-valvular atrial fibrillation [press release]. October 31, 2014.
  69. Hess K, Grant PJ. Inflammation and thrombosis in diabetes. Thrombosis and haemostasis. May 2011;105 Suppl 1:S43-54.
  70. Batchuluun B, Sonoda N, Takayanagi R, Inoguchi T. The Cardiovascular Effects of Metformin: Conventional and New Insights. J Endocrinol Diabetes Obes. 2014;2(2):1035.
  71. Triggle CR, Ding H. Cardiovascular impact of drugs used in the treatment of diabetes. Therapeutic advances in chronic disease. 2014;5(6):245-268.
  72. Fung CSC, Wan EYF, Wong CKH, Jiao F, Chan AKC. Effect of metformin monotherapy on cardiovascular diseases and mortality: a retrospective cohort study on Chinese type 2 diabetes mellitus patients. Cardiovascular diabetology. 2015;14(1):137.
  73. Anfossi G, Russo I, Bonomo K, Trovati M. The cardiovascular effects of metformin: further reasons to consider an old drug as a cornerstone in the therapy of type 2 diabetes mellitus. Current vascular pharmacology. May 2010;8(3):327-337.
  74. Lu DY, Huang CC, Huang PH, et al. Metformin use in patients with type 2 diabetes mellitus is associated with reduced risk of deep vein thrombosis: a non-randomized, pair-matched cohort study. BMC cardiovascular disorders. Dec 15 2014;14:187.
  75. Xin G, Wei Z, Ji C, et al. Metformin Uniquely Prevents Thrombosis by Inhibiting Platelet Activation and mtDNA Release. Scientific reports. Nov 02 2016;6:36222.
  76. Roussel R, Travert F, Pasquet B, et al. Metformin use and mortality among patients with diabetes and atherothrombosis. Archives of internal medicine. Nov 22 2010;170(21):1892-1899.
  77. Randriamboavonjy V, Mann WA, Elgheznawy A, et al. Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity. Thrombosis and haemostasis. Aug 31 2015;114(3):569-578.
  78. Gargiulo P, Caccese D, Pignatelli P, et al. Metformin decreases platelet superoxide anion production in diabetic patients. Diabetes/metabolism research and reviews. Mar-Apr 2002;18(2):156-159.
  79. SchurgersLJ, Aebert H, Vermeer C, Bultmann B, Janzen J. Oral anticoagulant treatment: friend or foe in cardiovascular disease? Blood. 2004;104(10):3231-2.
  80. Rezaieyazdi Z, Falsoleiman H, Khajehdaluee M, Saghafi M, Mokhtari-Amirmajdi E. Reduced bone density in patients on long-term warfarin. Int J Rheum Dis. 2009;12(2):130–135.
  81. Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF. Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med. 2006 Jan 23;166(2):241-6.
  82. Sconce E, Khan T, Mason J, et al. Patients with unstable control have a poorer dietary intake of vitamin K compared to patients with stable control of anticoagulation. Thromb. Haemost. 2005;93(5):872–875.
  83. Couris R, Tataronis G, McCloskey W, et al. Dietary vitamin K variability affects International Normalized Ratio (INR) coagulation indices. Int J VitamNutr Res. 2006;76(2):65–74.
  84. Lurie Y, Loebstein R, Kurnik D, Almog S, Halkin H. Warfarin and vitamin K intake in the era of pharmacogenetics. Br J ClinPharmacol. 2010;70(2):164–170.
  85. Sconce E, Avery P, Wynne H, Kamali F. Vitamin K supplementation can improve stability of anticoagulation for patients with unexplained variability in response to warfarin. Blood. 2007;109(6):2419–2423.
  86. Ford SK, Misita CP, Shilliday BB, et al. Prospective study of supplemental vitamin K therapy in patients on oral anticoagulants with unstable international normalized ratios. J Thromb Thrombolysis. 2007;24(1):23–27.
  87. Reynolds MW, Fahrbach K, Hauch O, et al. Warfarin anticoagulation and outcomes in patients with atrial fibrillation: a systematic review and metaanalysis. Chest. 2004;126(6):1938–1945.
  88. Rombouts EK, Rosendaal FR, Van Der Meer FJM. Daily vitamin K supplementation improves anticoagulant stability. J. Thromb. Haemost. 2007;5(10):2043–2048.
  89. Gebuis EP, Rosendaal FR, van Meegen E, van der Meer FJ. Vitamin K1 supplementation to improve the stability of anticoagulation therapy with vitamin K antagonists: a dose-finding study. Haematologica. 2011;96(4):583–589.
  90. Johnson W and Bouz PA Use of IntralesionaltPA in Spontaneous Intracerebral Hemorrhage: Retrospective Analysis. Intracerebral Hemorrhage Research. 2011;111(6):425-428.
  91. Chang R, Horne MK, Shawker TH, et al. Low-dose, once-daily, intraclot injections of alteplase for treatment of acute deep venous thrombosis. J VascIntervRadiol. 2011;22(8):1107–1116.
  92. Murciano J, Medinilla S, Eslin D. et al. Prophylactic fibrinolysis through selective dissolution of nascent clots by tPA-carrying erythrocytes. Nature Biotech. 2003;21(8):891-896
  93. Samama MM, Guinet C. Laboratory assessment of new anticoagulants. Clin Chem Lab Med. 2011;49(5):761-72.
  94. Rechner AR. Platelet function testing in clinical diagnostics. Hamostaseologie. 2011;31(2):79–87.
  95. Jänicke, C., Grünwald, J., Brendler, T., 2003. HandbuchPhytotherapie. WissenschaftlicheVerlagsgesellschaft, Stuttgart.
  96. Somova LI, Shode FO, Ramnanan P, Nadar A. Antihypertensive, antiatherosclerotic and antioxidant activity of triterpenoids isolated from Oleaeuropaea, subspecies africana leaves. J Ethnopharmacol 2003 Feb.;84(2-3):299–305.
  97. Perrinjaquet-Moccetti T, Busjahn A, Schmidlin C, Schmidt A, Bradl B, Aydogan C. Food supplementation with an olive (Oleaeuropaea L.) leaf extract reduces blood pressure in borderline hypertensive monozygotic twins. Phytother Res 2008 Sep.;22(9):1239–1242.
  98. Singh I, Mok M, Christensen A-M, Turner AH, Hawley JA. The effects of polyphenols in olive leaves on platelet function. NutrMetabCardiovasc Dis. 2008;18(2):127–132.
  99. Zbidi H, Salido S, Altarejos J, et al. Olive tree wood phenolic compounds with human platelet antiaggregant properties. Blood Cells Mol. Dis. 2009;42(3):279–285.
  100. Granados-Principal S, Quiles JL, et al. Hydroxytyrosol: from laboratory investigations to future clinical trials. Nutr Rev. 2010;68(4):191–206.
  101. Bogani, P., Galli, C., Villa, M., and Visioli, F. (2007). Postprandial anti- inflammatory and antioxidant effects of extra virgin olive oil. Atherosclerosis, 190:181–186.
  102. Visioli, F., Caruso, D., Grande, S., et al. Virgin Olive Oil Study (VOLOS): vasoprotective potential of extra virgin olive oil in mildly dyslipidemic patients. European Journal of Nutrition, 2005;44:121–127.
  103. Correa JAG, López-Villodres JA, Asensi R, et al. Virgin olive oil polyphenol hydroxytyrosol acetate inhibits in vitro platelet aggregation in human whole blood: comparison with hydroxytyrosol and acetylsalicylic acid. Br J Nutr. 2009;101(8):1157–1164.
  104. Léger CL, Carbonneau MA, Michel F, et al. A thromboxane effect of a hydroxytyrosol-rich olive oil wastewater extract in patients with uncomplicated type I diabetes. Eur J ClinNutr. 2005;59(5):727–730.
  105. Junker R, Kratz M, Neufeld M, et al. Effects of diets containing olive oil, sunflower oil, or rapeseed oil on the hemostatic system. Thromb. Haemost. 2001;85(2):280–286.
  106. Peters U, Poole C, Arab L. Does tea affect cardiovascular disease? A meta-analysis. Am. J. Epidemiol. 2001;154(6):495–503.
  107. Kang WS, Lim IH, Yuk DY, et al. Antithrombotic activities of green tea catechins and (-)-epigallocatechingallate. Thromb. Res. 1999;96(3):229–237.
  108. Hirano-Ohmori R, Takahashi R, Momiyama Y, et al. Green tea consumption and serum malondialdehyde-modified LDL concentrations in healthy subjects. J Am CollNutr. 2005;24(5):342–346.
  109. Wolfram RM, Oguogho A, Efthimiou Y, Budinsky AC, Sinzinger H. Effect of black tea on (iso-)prostaglandins and platelet aggregation in healthy volunteers. Prostaglandins Leukot. Essent. Fatty Acids. 2002;66(5-6):529–533.
  110. Steptoe A, Gibson EL, Vuononvirta R, et al. The effects of chronic tea intake on platelet activation and inflammation: a double-blind placebo controlled trial. Atherosclerosis. 2007;193(2):277–282.
  111. Pignatelli P, Pulcinelli FM, Celestini A, et al. The flavonoids quercetin and catechin synergistically inhibit platelet function by antagonizing the intracellular production of hydrogen peroxide. Am J ClinNutr. 2000;72(5):1150–1155.
  112. Hubbard GP, Wolffram S, Lovegrove JA, Gibbins JM. Ingestion of quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in humans. J. Thromb. Haemost. 2004;2(12):2138–2145.
  113. Conquer JA, Maiani G, Azzini E, Raguzzini A, Holub BJ. Supplementation with quercetin markedly increases plasma quercetin concentration without effect on selected risk factors for heart disease in healthy subjects. J Nutr. 1998;128(3):593–597.
  114. Hubbard GP, Wolffram S, de Vos R, et al. Ingestion of onion soup high in quercetin inhibits platelet aggregation and essential components of the collagen-stimulated platelet activation pathway in man: a pilot study. Br J Nutr. 2006;96(3):482–488.
  115. Cheng TO. Cardiovascular effects of Danshen. Int. J. Cardiol. 2007;121(1):9–22.
  116. Wu B, Liu M, Zhang S. Dan Shen agents for acute ischaemic stroke. Cochrane Database Syst Rev. 2007;(2):CD004295.
  117. Fan HY, Fu FH, Yang MY, et al. Antiplatelet and antithrombotic activities of salvianolic acid A. Thromb. Res. 2010;126(1):e17–22.
  118. Huang ZS, Zeng CL, Zhu LJ, et al. Salvianolic acid A inhibits platelet activation and arterial thrombosis via inhibition of phosphoinositide 3-kinase. J. Thromb. Haemost. 2010;8(6):1383–1393.
  119. Vuksan V, Whitham D, SievenpiperJL, et al. Supplementation of conventional therapy with the novel grain Salba (Salvia hispanica L.) improves major and emerging cardiovascular risk factors in type 2 diabetes: results of a randomized controlled trial. Diabetes Care. 2007;30(11):2804–2810.
  120. Olas B, Wachowicz B. Resveratrol, a phenolic antioxidant with effects on blood platelet functions. Platelets. 2005;16(5):251–260.
  121. Yang Y et al. Inhibitory effects of resveratrol on platelet activation induced by thromboxane a(2) receptor agonist in human platelets. Am J Chin Med. 2011;39(1):145-59.
  122. Gresele P, Pignatelli P, Guglielmini G, et al. Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. Journal of Nutrition. 2008;138(9):1602–1608.
  123. Malinowska J et al. Response of blood platelets to resveratrol during a model of hyperhomocysteinemia. Platelets. 2011;22(4):277-83.
  124. Clouatre, D., Kandaswami, C and Connolly, KM. Grape Seed Extract. In Encyclopedia of Dietary Supplements, 2nd Edition. P. M. Coates, J. M. Betz, M. R. Blackman et al. New York, NY, Informa Healthcare: 2010; 916.
  125. Siva B, Edirisinghe I, Randolph J, Steinberg F. Effect of polyphenolics extracts of grape seeds (GSE) on blood pressure (BP) in patients with metabolic syndrome (MetS). FASEB J 2006;20:A305.
  126. Sano T, Oda E, Yamashita T, et al. Anti-thrombotic effect of proanthocyanidin, a purified ingredient of grape seed. Thromb. Res. 2005;115(1-2):115–12.
  127. Vitseva O, Varghese S, Chakrabarti S, Folts JD, Freedman JE. Grape seed and skin extracts inhibit platelet function and release of reactive oxygen intermediates. J. Cardiovasc. Pharmacol. 2005;46(4):445–451.
  128. Zhang Y et al. Antithrombotic effect of grape seed proanthocyanidins extract in a rat model of deep vein thrombosis. J Vasc Surg. 2011 Mar;53(3):743-53. Epub 2010 Nov 20.
  129. Shenoy SF, Keen CL, Kalgaonkar S, Polagruto JA. Effects of grape seed extract consumption on platelet function in postmenopausal women. Thromb. Res. 2007;121(3):431–432.
  130. Polagruto JA, Gross HB, Kamangar F, et al. Platelet reactivity in male smokers following the acute consumption of a flavanol-rich grapeseed extract. J Med Food. 2007;10(4):725–730.
  131. Shanmuganayagam D, BeahmMR, Osman HE, et al. Grape seed and grape skin extracts elicit a greater antiplatelet effect when used in combination than when used individually in dogs and humans. J Nutr. 2002;132(12):3592–3598.
  132. Engelhard YN, Gazer B, Paran E. Natural antioxidants from tomato extract reduce blood pressure in patients with grade-1 hypertension: a double-blind, placebo-controlled pilot study. Am. Heart J. 2006 Jan.;151(1):100.
  133. Ried K, Fakler P. Protective effect of lycopene on serum cholesterol and blood pressure: Meta-analyses of intervention trials. Maturitas 2011 Apr.;68(4):299-310.
  134. Dutta-Roy AK, Crosbie L, Gordon MJ. Effects of tomato extract on human platelet aggregation in vitro. Platelets. 2001;12(4):218–227.
  135. O'Kennedy N, Crosbie L, van Lieshout M, et al. Effects of antiplatelet components of tomato extract on platelet function in vitro and ex vivo: a time-course cannulation study in healthy humans. Am J ClinNutr. 2006a;84(3):570–579.
  136. Aviram M, Dornfeld L. Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure. Atherosclerosis 2001 Sep.;158(1):195–198.
  137. Sumner MD, Elliott-Eller M, Weidner G, DaubenmierJJ, Chew MH, Marlin R, Raisin CJ, Ornish D. Effects of pomegranate juice consumption on myocardial perfusion in patients with coronary heart disease. Am J Cardiol 2005 Sep.;96(6):810–814.
  138. Aviram M, Rosenblat M, Gaitini D, et al. Pomegranate juice consumption for 3 years by patients with carotid artery stenosis reduces common carotid intima-media thickness, blood pressure and LDL oxidation. ClinNutr 2004 Jun.;23(3):423–433.
  139. Aviram M, Dornfeld L, Rosenblat M, et al. Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and in atherosclerotic apolipoprotein E-deficient mice. Am J ClinNutr. 2000;71(5):1062–1076.
  140. Polagruto JA et al. Effects of flavonoid-rich beverages on prostacyclin synthesis in humans and human aortic endothelial cells: association with ex vivo platelet function. J Med Food. 2003 Winter;6(4):301-8.
  141. Ried K, Frank OR, Stocks NP, Fakler P, Sullivan T. Effect of garlic on blood pressure: a systematic review and meta-analysis. BMC CardiovascDisord 2008;8:13.
  142. Reinhart KM, Talati R, White CM, Coleman CI. The impact of garlic on lipid parameters: a systematic review and meta-analysis. Nutr Res Rev 2009 Jun.;22(1):39-48.
  143. Rahman K, Lowe GM. Garlic and cardiovascular disease: a critical review. J Nutr. 2006;136(3 Suppl):736S–740S.
  144. Rahman K. Effects of garlic on platelet biochemistry and physiology. MolNutr Food Res. 2007 Nov;51(11):1335-44.
  145. Park JB et al. Effects of typheramide and alfrutamide found in Allium species on cyclooxygenases and lipoxygenases. J Med Food. 2011 Mar;14(3):226-31.
  146. Steiner M, Lin RS. Changes in platelet function and susceptibility of lipoproteins to oxidation associated with administration of aged garlic extract. J. Cardiovasc. Pharmacol. 1998;31(6):904–908.
  147. Bordia A, Verma SK, Srivastava KC. Effect of garlic (Allium sativum) on blood lipids, blood sugar, fibrinogen and fibrinolytic activity in patients with coronary artery disease. Prostaglandins Leukot. Essent. Fatty Acids. 1998;58(4):257–263.
  148. Wojcikowski K, Myers S, Brooks L. Effects of garlic oil on platelet aggregation: a double-blind placebo-controlled crossover study. Platelets. 2007;18(1):29–34.
  149. Marik PE, Varon J. Omega-3 dietary supplements and the risk of cardiovascular events: a systematic review. ClinCardiol 2009 Jul.;32(7):365-372.
  150. McEwen B, Morel-Kopp M-C, Tofler G, Ward C. Effect of omega-3 fish oil on cardiovascular risk in diabetes. Diabetes Educ. 2010;36(4):565–584.
  151. Nomura S, Kanazawa S, Fukuhara S. Effects of eicosapentaenoic acid on platelet activation markers and cell adhesion molecules in hyperlipidemic patients with type 2 diabetes mellitus. J Diabetes Complications. 2003;17:153-159.
  152. Mori TA, BeilinLJ, Burke V, Morris J, Ritchie J. Interactions between dietary fat, fish, and fish oils and their effects on platelet function in men at risk of cardiovascular disease. ArteriosclerThrombVasc Biol. 1997;17:279-286.
  153. Vanschoonbeek K, Feijge MA, Paquay M, et al. Variable hypocoagulant effect of fish oil intake in humans: modulation of fibrinogen level and thrombin generation. ArteriosclerThrombVasc Biol. 2004;24:1734-1740.
  154. Hartweg J, Farmer AJ, Holman RR, Neil A. Potential impact of omega-3 treatment on cardiovascular disease in type 2 diabetes. Curr. Opin. Lipidol. 2009;20(1):30–38.
  155. Ahuja KD, Ball MJ. Effects of daily ingestion of chilli on serum lipoprotein oxidation in adult men and women. Br J Nutr 2006;96:239–42.
  156. Wang JP, Hsu MF, Teng CM. Antiplatelet effect of capsaicin. Thromb. Res. 1984;36(6):497–507.
  157. Visudhiphan S, Poolsuppasit S, Piboonnukarintr O, Tumliang S. The relationship between high fibrinolytic activity and daily capsicum ingestion in Thais. Am J ClinNutr. 1982;35(6):1452–1458.
  158. Adams MJ, Ahuja KDK, Geraghty DP. Effect of capsaicin and dihydrocapsaicin on in vitro blood coagulation and platelet aggregation. Thromb. Res. 2009;124(6):721–723.
  159. Srivas KC. Effects of aqueous extracts of onion, garlic and ginger on platelet aggregation and metabolism of arachidonic acid in the blood vascular system: in vitro study. Prostaglandins Leukot Med. 1984;13(2):227–235.
  160. Chrubasik S, Pittler MH, Roufogalis BD. Zingiberisrhizoma: a comprehensive review on the ginger effect and efficacy profiles. Phytomedicine. 2005;12(9):684–701.
  161. Srivastava KC. Effect of onion and ginger consumption on platelet thromboxane production in humans. Prostaglandins Leukot. Essent. Fatty Acids. 1989;35(3):183–185.
  162. Verma SK, Singh J, Khamesra R, Bordia A. Effect of ginger on platelet aggregation in man. Indian J. Med. Res. 1993;98:240–242.
  163. Bordia A, Verma SK, Srivastava KC. Effect of ginger (ZingiberofficinaleRosc.) and fenugreek (Trigonellafoenumgraecum L.) on blood lipids, blood sugar and platelet aggregation in patients with coronary artery disease. Prostaglandins Leukot. Essent. Fatty Acids. 1997;56(5):379–384.
  164. Lumb AB. Effect of dried ginger on human platelet function. Thromb. Haemost. 1994;71(1):110–111.
  165. Ramirez Boscá A, Soler A, Gutierrez MC. Antioxidant curcuma extracts decrease the blood lipid peroxide levels of human subjects. Age 1995;
  166. Ramirez Boscá A, Carrión-Gutiérrez MA, et al. Effects of the antioxidant turmeric on lipoprotein peroxides: Implications for the prevention of atherosclerosis. Age 1997 Jul.;20(3):165-168.
  167. Ramirez Boscá A, Soler A, Carrión-Gutiérrez MA, et al. An hydroalcoholic extract of Curcuma longa lowers the abnormally high values of human-plasma fibrinogen. Mech Ageing Dev 2000 Apr.;114(3):207-210.
  168. Wongcharoen W, Phrommintikul A. The protective role of curcumin in cardiovascular diseases. Int. J. Cardiol. 2009 Apr.;133(2):145-151.
  169. Jantan I, Raweh SM, Sirat HM, et al. Inhibitory effect of compounds from Zingiberaceae species on human platelet aggregation. Phytomedicine. 2008;15(4):306–309.
  170. Gulati OP. Pycnogenol® in chronic venous insufficiency and related venous disorders. Phytotherapy research: PTR.Mar 2014;28(3):348-362.
  171. Kim DS, Kim MS, Kang SW, Sung HY, Kang YH. Pine bark extract enzogenol attenuated tumor necrosis factor-alpha-induced endothelial cell adhesion and monocyte transmigration. Journal of agricultural and food chemistry. Jun 09 2010;58(11):7088-7095.
  172. Belcaro G, Cesarone MR, Rohdewald P, et al. Prevention of venous thrombosis and thrombophlebitis in long-haul flights with pycnogenol. Clinical and applied thrombosis/hemostasis: official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis. Oct 2004;10(4):373-377.
  173. Cesarone MR, Belcaro G, Nicolaides AN, et al. Prevention of venous thrombosis in long-haul flights with Flite Tabs: the LONFLIT-FLITE randomized, controlled trial. Angiology 2003 Aug.;54(5):531–539.
  174. Errichi BM, Belcaro G, Hosoi M, et al. Prevention of post thrombotic syndrome with Pycnogenol(R) in a twelve month study. Panminerva medica.Sep 2011;53(3 Suppl 1):21-27.
  175. Belcaro G, Cesarone MR, Genovesi D, et al. Pycnogenol may alleviate adverse effects in oncologic treatment. Panminerva medica.Sep 2008;50(3):227-234.
  176. Duggal JK, Singh M, Attri N, et al. Effect of niacin therapy on cardiovascular outcomes in patients with coronary artery disease. J. Cardiovasc. Pharmacol. Ther. 2010 Jun.;15(2):158-166.
  177. Morgan JM, Capuzzi DM, Baksh RI, et al. Effects of extended-release niacin on lipoprotein subclass distribution. Am J Cardiol 2003 Jun.;91(12):1432-1436.
  178. Florentin M, Tselepis AD, Elisaf MS, et al. Effect of non-statin lipid lowering and anti-obesity drugs on LDLsubfractions in patients with mixed dyslipidaemia. CurrVascPharmacol 2010 Nov.;8(6):820-830.
  179. Haidara MA et al. Impact of alpha-tocopherol and vitamin C on endothelial markers in rats with streptozotocin-induced diabetes. Med SciMonit. 2004 Feb;10(2):BR41-6.
  180. Sharma CP et al. Influence of L-ascorbic acid, blood cells and components on protein adsorption/desorption on polycarbonate. Haemostasis. 1987;17(1-2):70-8.
  181. Pais E, Alexy T, Holsworth RE, Meiselman HJ. Effects of nattokinase, a pro-fibrinolytic enzyme, on red blood cell aggregation and whole blood viscosity. Clin. Hemorheol. Microcirc. 2006;35(1-2):139–142.
  182. Hsia CH, Shen MC, Lin JS, Wen YK, Hwang KL, Cham TM, Yang NC. Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects. Nutr Res 2009 Mar.;29(3):190–196.
  183. Kim JY, Gum SN, Paik JK, et al. Effects of nattokinase on blood pressure: a randomized, controlled trial. Hypertens. Res. 2008 Aug.;31(8):1583–1588.
  184. Salem RO, Laposata M. Effects of alcohol on hemostasis. Am J Clin Path. 2005;12 Suppl:S96-105.