What are Blood Clots?

Normal blood 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 “blood thinner” drugs including antiplatelet drugs like aspirin and clopidogrel or anticoagulants like heparin, warfarin, and dabigatran. While these drugs can reduce the risk of developing a clot, they fail to address many underlying risk factors and can have serious side effects.

Nutrients like fish oil, ginkgo, garlic, and cocoa flavanols may help prevent thrombosis and related complications.

What Dietary and Lifestyle Changes Can Help Prevent Blood Clots?

• Eat a plant-based unprocessed diet rich in fruits, vegetables, and unsaturated fats, such as a Mediterranean style or DASH diet
• Exercise regularly
• Manage stress

What Nutrients May Help Prevent Blood Clots?

• Fish oil. Fish oil and its omega-3 fatty acids lower the risk of thrombotic events such as heart attack and stroke, as well as deep vein thrombosis.
• Ginkgo. Ginkgo may improve platelet and blood vessel function, and has been shown in preclinical studies to inhibit platelet activation and aggregation and promote the breakdown of blood clots.
• Garlic. Garlic has been shown to promote cardiovascular health in many human studies. One of the observed benefits is garlic’s ability to reduce platelet aggregation, which may help protect against excessive blood clotting.
• Cocoa flavanols. Cocoa intake is correlated with cardiovascular health and lower risk of conditions that raise thrombosis risk. Clinical trials show cocoa flavanols can reduce platelet aggregation.
• Coenzyme Q10. Clinical trials have shown coenzyme Q10 supplementation can lower levels of markers of thrombotic risk, improve blood vessel function, and reduce cardiovascular risk.
• Pycnogenol. Pycnogenol, extracted from French maritime pine bark, has been shown to reduce fluid build-up and blood clots in people with a history of venous thrombosis.
• Probiotics. Certain probiotic bacteria, especially the Lactobacillus reuteri NCIMB 30242 strain, have been found to improve markers of thrombosis risk.
• Nattokinase. Nattokinase has demonstrated the ability to increase the breakdown of blood clots. Together with pycnogenol, nattokinase was found to reduce leg edema and venous blood clots in long-haul air travelers.
• B vitamins. Vitamin B12 and folic acid deficiencies cause high homocysteine levels, which have been associated with increased atherosclerosis, stroke, arterial clots, and venous thrombosis risk. Vitamin B3 (niacin) may also reduce thrombosis risk by inhibiting platelet aggregation and supporting blood clot breakdown.
• Other natural interventions that may help prevent blood clots and improve cardiovascular health include green tea extract, pomegranate, saffron, quercetin, ginger, and guavirova.

What are Some Risk Factors and Conditions Associated with Blood Clots?

• Older age
• History of a previous thrombotic event
• Smoking
• Chronic venous disease
• Atherosclerosis
• Abnormal lipid levels
• Hypertension
• Type 2 diabetes
• Obesity
• Sleep apnea
• Prolonged inactivity
• Hospitalization or surgery
• Infection, transplant, and transfusion reactions
• Pregnancy
• Cancer
• Use of high-dose oral estrogens (eg, hormone replacement therapy or a high-dose birth control pill)  

How are Blood Clots Treated?

• Emergency thrombolytic (“clot buster”) agents and sonothrombolysis (clot-breaking ultrasound)
• Some cases may be amenable to emergency surgery to remove a clot (thrombectomy)
• Blood thinners, including antiplatelet drugs (eg, aspirin and clopidogrel), mainly for arterial thrombosis, and anticoagulants (eg, heparin, warfarin, and dabigatran)

What are Some Emerging Therapies for Blood Clots?

• New methods of sonothrombolysis
• Canakinumab
• Repurposed drugs: statins, colchicine, and metformin

Blood clotting is an important part of hemostasis, the balance of anti-coagulation and pro-coagulation mechanisms that preserves normal blood flow throughout the body. In healthy conditions, blood clots, which includes venous and arterial clots, form to prevent blood loss after an injury to a blood vessel. However, in some circumstances, hemostatic signaling becomes dysregulated and excessive blood clotting or abnormal clots that obstruct blood flow can form.^1,2 Depending on where these clots occur, they can cause dangerous or even life-threatening complications.³

Blood clots can form in veins (venous clots), interfering with the return of blood from tissues to the heart, or arteries (arterial clots), interfering with movement of oxygenated blood from the heart to tissues and organs throughout the body. A blood clot attached to a vessel wall is known as a thrombus and one that breaks free and travels in the blood is called an embolus. Pulmonary embolism, venous thromboembolism (VTE), and post-thrombotic syndrome are dangerous complications of venous blood clots, while serious complications of arterial blood clots include heart attack and stroke. Complications of blood clots are the most common cause of death in developed countries and are responsible for one of every four deaths worldwide.^3,4

Smoking, older age, obesity and metabolic syndrome, family history, a sedentary lifestyle, infection, and certain health conditions and medications increase the risk of developing an abnormal blood clot.^3,5 Injury to a vessel, such as due to surgery or trauma, can also trigger thrombosis while immobility during recovery can also be a provoking factor. In addition, the risk of venous thrombosis or VTE is higher in women during pregnancy and in those using oral birth control pills or oral estrogen-containing postmenopausal hormone replacement therapy.³

Blood clots are diagnosed using imaging such as specialized ultrasound, venography (an x-ray taken after a dye is injected into the vein), magnetic resonance imaging (MRI), or computed tomography (CT) techniques.^6,7 Blood tests may be helpful in determining if a clot exists and for monitoring the blood’s propensity to form clots.² Once a blood clot is found, it may require immediate treatment with thrombolytic medication or clot busters, mechanical destruction using ultrasound, or surgical removal.^8,9 Individuals with a high risk of arterial clots may be treated with one or more long-term antiplatelet blood thinner medications like aspirin and clopidogrel (Plavix). Those at high risk of recurrent venous thrombosis or VTE may receive long-term anticoagulant therapy using warfarin or a direct oral anticoagulant (DOAC). While effective for reducing blood clots, these medications can all cause serious bleeding side effects.³ Importantly, they also do nothing to address the underlying conditions that contribute to thrombosis risk.

Because of the potentially devastating consequences of blood clots, it is critical to reduce their risk using dietary, lifestyle, and nutrient strategies. In addition to addressing modifiable risk factors, a plant-based, minimally processed diet, regular exercise, and stress management are the cornerstones of blood clot prevention and should be considered primary interventions. In addition, a number of nutrients, including ginseng, ginkgo, garlic, and cocoa have been found in clinical trials to reduce the likelihood of thrombosis.

Hemostasis and Blood Clots

Figure 1: The Blood Clotting Cascade. Credit: OpenStax College CC 4.0.¹⁰

Hemostasis is an intricate process by which blood flow is maintained while both bleeding and excessive blood clotting are avoided. It involves balanced interactions between red and white blood cells, platelets, endothelial cells (the cells that form the inner lining of blood vessels), inflammatory proteins and cytokines, clotting factors, and other circulating proteins.³

Blood clotting is a hemostatic mechanism that prevents blood loss. When a blood vessel injury occurs, the blood vessel constricts and the clotting process, a complex series of overlapping steps, is rapidly set in motion^3,11:

• Initiation. Damage to endothelial cells that form the lining of the inner blood vessel exposes an underlying layer of collagen and cells that express an important pro-coagulation protein called tissue factor. The interaction between platelets and tissue factor helps stimulate clot formation by triggering conversion of prothrombin into thrombin, a reaction that requires vitamin K1. The enzyme thrombin activates platelets and stimulates conversion of circulating fibrinogen molecules into strands of fibrin.^1,2
• Amplification. Injured endothelial cells release inflammatory cytokines that transmit platelet-activating signals and a platelet-binding protein called von Willebrand factor. Von Willebrand factor also binds to collagen and acts as a bridge between platelets and collagen in the blood vessel wall at the site of injury. In addition, it plays a role in the clotting cascade—a sequence of reactions that convert clotting factors into enzymes and ultimately leads to the production of thrombin and fibrin. Vitamin K1 is a cofactor needed for several steps in the clotting cascade.^2,11  
  
  Activation signals cause platelets to change shape and release pro-coagulant proteins, including von Willebrand factor and tissue factor, facilitating their ability to bind to other platelets (aggregation). The accumulation of platelets forms a plug that seals the site of injury and performs the critical function of preventing blood loss. Activated platelets also release pro-inflammatory molecules and amplify the clotting cascade, accelerating the production of thrombin and fibrin.^1,2,11
• Propagation. Activated platelets generate large amounts of thrombin. They also bind to fibrinogen, which, when converted to fibrin through the action of thrombin, forms a structural matrix that strengthens and stabilizes the blood clot.
• Fibrinolysis. The blood clot, or thrombus, is broken down during tissue repair through an enzymatic process called fibrinolysis, during which a protein fragment known as D-dimer is released.^2,11

In healthy conditions and the absence of blood vessel injury, the tendency to form venous and arterial clots is kept in check by molecules that inhibit activation of the clotting cascade and promote fibrinolysis. These include tissue factor pathway inhibitor, antithrombin, heparin, and proteins C and S (which are also vitamin K-dependent).¹ In addition, anti-inflammatory pathways are favored and endothelial cells produce nitric oxide, which helps keep blood vessels dilated and inhibits platelet adhesion.¹²

Hemostasis is tightly controlled, but conditions that alter regulatory mechanisms can shift the balance in favor of coagulation and increase the risk of excessive blood clotting or abnormal formation of blood clots, known as thrombosis.^2,3 Thrombosis can occur as venous or arterial clots, and while venous and arterial thrombosis are distinct pathologies, both are related to inflammation, endothelial cell damage, and platelet activation, and share common risk factors.⁵

Venous Thrombosis

Blood clots that form in the veins are mainly composed of red blood cells with an outer layer of platelets held together by a protein matrix formed by fibrin.¹⁵ Deep vein thrombosis (DVT) is the most serious form of venous thrombosis. Venous stasis (lack of blood movement in a vein) is the most important promoter of DVT, but vascular injury and hypercoagulability (a high propensity to form clots) also contribute to risk.¹⁶ DVT usually occurs in the lower legs, but can occur in any deep vein, including the cerebral, abdominal, and retinal veins.¹⁷ In about 20% of cases, DVT causes blockage of blood flow away from the tissue, resulting in swelling, pain, and other symptoms depending on its location.^17,18

Approximately one-third of DVT patients, especially those with DVT in the legs, experience pulmonary embolism.¹⁶ This occurs when a blood clot breaks free and travels through the bloodstream to the lungs, where it can become lodged and obstruct blood flow. Venous thromboembolism (VTE) is a condition that includes DVT and pulmonary embolism and affects approximately 375,000–425,000 people in the United States annually.¹⁹ About 10‒30% of DVT and pulmonary embolism episodes cause death within 30 days (with the risk of death being higher in pulmonary embolism), and the 10-year mortality rate among those with venous thromboembolism is reported to be as high as 40%.^18,20-22 DVT patients also have a high risk of experiencing recurrences (roughly one-third of cases) and developing long-term complications such as post-thrombotic syndrome and chronic pulmonary hypertension.¹⁸ Post-thrombotic syndrome is caused by thickening and scarring of the vein due to DVT-induced vascular inflammation and is marked by venous hypertension. Symptoms include pain, heaviness, swelling, and sometimes ulceration in the limb affected by DVT.^19,20

Venous thrombosis can also occur in superficial veins, usually in the legs and frequently due to varicosities. In most cases, superficial vein thrombosis resolves without treatment, but some cases evolve into DVT with a risk of pulmonary embolism.⁹ In fact, reports suggest as many as 18.1% of superficial vein thrombosis cases involve deep veins and 6.9% result in pulmonary embolism.²³ In particular, superficial vein thrombosis that occurs near a critical venous junction in the upper leg carries the same risks as DVT and is treated similarly. A large thrombus (more than 1.5–2 inches in length) in a superficial vein can also lead to complications or post-thrombotic syndrome and may warrant medical management.⁹

Arterial Thrombosis

Blood clots that form in arteries, or arterial clots, are mainly made of platelets and fibrin, with small numbers of red and white blood cells trapped in the matrix.¹⁵ Arterial thrombosis causes reduced blood flow (ischemia), resulting in reduced oxygen and nutrient delivery and ischemic tissue damage. A blood flow-obstructing clot that develops in a coronary artery can lead to acute coronary syndrome (unstable angina or heart attack), and in a cerebral artery, it can cause a stroke.^3,12 An arterial blood clot can also break away from the vessel wall. The dislodged or fragmented blood clot may then travel as an embolus, become lodged in a distant artery, and block downstream blood flow, causing acute symptoms.^12,24 For example, blood clots that form in the coronary vessels often become embolic (thromboembolism) and travel to the cerebral vascular system, where they can cause transient ischemic attack (TIA) or ischemic stroke.^25,26 The aorta and carotid arteries are other frequent sites of thromboembolism.²⁷

One of the major contributors to arterial thrombosis is atherosclerosis. In addition to contributing to altered blood flow, atherosclerotic plaques are associated with vascular dysfunction and chronic inflammatory signaling, which leads to chronic platelet activation.^28-30 Furthermore, the inflammatory state induced by atherosclerosis increases plaque vulnerability to destabilization and rupture—an event that triggers pronounced pro-coagulation processes.^28,31,32 Another common trigger of arterial thrombosis is atrial fibrillation, a type of arrhythmia. Atrial fibrillation causes turbulence of blood flow through the heart chambers and is associated with a five-fold increase in embolic stroke risk.³³

Dietary and lifestyle interventions are crucial components of a program to reduce thrombosis risk. Habits that reduce oxidative stress, inflammatory signaling, LDL-cholesterol levels, and blood pressure, support metabolic health and weight maintenance, and promote gut microbial balance are key to preventing both venous and arterial clots and their consequences (eg, VTE or post-thrombotic syndrome).³⁴

Dietary patterns high in plant foods can supply ample amounts of antioxidant nutrients, mono- and polyunsaturated fatty acids, vitamins, minerals, fiber, and phytochemicals that are associated with anti-inflammatory, platelet activation-inhibiting, and antithrombotic effects.^35-37 A Mediterranean diet in particular is well studied for its positive impacts on cardiovascular and metabolic health and conditions associated with thrombosis risk.^35,36 Foods that characterize a Mediterranean diet, such as olive oil, fruits and vegetables, nuts and seeds, whole grains, legumes, and fish, have each been found to reduce venous and arterial thrombosis risk in observational and animal studies.³⁸ Dietary Approaches to Stop Hypertension (DASH) is another set of dietary guidelines that promotes a mainly plant-based diet and, like a Mediterranean diet, is linked to broad health benefits that could potentially reduce excessive blood clotting and the risk of thrombosis.³⁶

Blood Thinning Foods, Drinks & Nutrients

Some specific foods have been found to lower the risk of thrombosis, including:

• Dark chocolate. Cocoa contains flavanols that have demonstrated antithrombotic effects.^39,40 Consumption of dark chocolate has been linked to cardiovascular health and lower risk of conditions related to thrombosis like hypertension, coronary and peripheral vascular disease, and atrial fibrillation.⁴¹ One clinical trial reported 300 mL of a flavonol-rich chocolate beverage had a similar, though weaker, effect on platelets to 80 mg of aspirin in healthy adults.⁴²
• Onion. Laboratory and animal research showed onion extracts reduced platelet activation and thrombosis. This may be due to onions’ high content of the flavonoid quercetin.⁴³ An observational study noted individuals with higher consumption of onions and garlic had a lower incidence of cardiovascular events.⁴⁴ In a crossover trial, blood samples taken after eating a bowl of onion soup or a control soup suggested onions may have an immediate inhibiting effect on platelet aggregation.⁴⁵
• Garlic. Garlic and its active constituents have been shown to reduce inflammation, scavenge free radicals, and improve lipid metabolism.⁴⁶ Garlic and onion intake has been associated with reduced cardiovascular risk.⁴⁴ A clinical trial found eating one clove of fresh garlic per day for 16 weeks lowered levels of an enzyme that promotes constriction of blood vessels and stimulates platelet aggregation.⁴⁷
• Ginger. Preclinical evidence suggests ginger can inhibit platelet aggregation, lower blood pressure, reduce inflammatory cytokine levels, and improve lipid levels,^48,49 although findings from clinical trials have been mixed.⁵⁰ An observational study found increased ginger intake was correlated with lower risk of coronary artery disease in older adults.⁵¹
• Tomato. Tomatoes are rich in lycopene and other oxidative stress-reducing compounds that have demonstrated antithrombotic effects.⁵² Cooking tomatoes with oil enhances lycopene bioavailability.⁵³ A study that included almost 24,000 participants found higher tomato intake was correlated with better markers of cardiovascular health and lower risk of death due to coronary artery disease or stroke.⁵⁴ A meta-analysis of 25 observational studies found the highest consumption or serum levels of lycopene were associated with the lowest incidences of cardiovascular disease and stroke.⁵⁵
• Fruit. Citrus fruit and citrus juice have demonstrated platelet inhibition in laboratory studies.⁵⁶ In clinical studies, purple grape juice lowered platelet reactivity in healthy subjects.⁵⁷
• Fish. Fish provides anti-inflammatory omega-3 fatty acids, and regular intake has been found to reduce platelet aggregation in human studies.⁵⁸ In one observational study that included 2,033 men who recently experienced a heart attack, the addition of two fish servings per week was associated with 29% lower mortality risk over two years of monitoring.⁵⁹ Higher dietary intake of fish fatty acids was also associated with lower risk of recurrent VTE in a study in patients with a previous DVT and without cancer or another known trigger of the first event, and the relationship was stronger in those not using anticoagulant (blood thinner) drugs.⁶⁰ Some evidence suggests eating a diet with a lower omega-6:omega-3 fatty acid ratio may reduce thrombosis risk. Although the exact optimal ratio of omega-6:omega-3 fatty acid intake remains in question, it is increasingly clear that lower ratios, such as less than 4:1, are associated with lower risk of heart disease and other chronic conditions.^61,62
• Olive oil. Extra virgin olive oil (EVOO) is rich in monounsaturated fatty acids and antioxidant polyphenols, and high intake has consistently been associated with lower cardiovascular risk.⁶³ Evidence suggests olive oil may suppress the rise in coagulation enzyme activity typically induced by a high-fat meal.⁶⁴ Including 30 mL (one ounce) of olive oil in the daily diet for four months was found to improve vascular function and lower inflammation in individuals with early signs of atherosclerosis.⁶⁵
• Alcohol. Light-to-moderate alcohol consumption, especially red wine, has been correlated with cardiovascular benefits, including reduced risk of thromboembolic events and deaths.^66-68 Light-to-moderate drinking consists of a maximum of two drinks per day for men and one drink per day for women, with a drink being 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of spirits.⁶⁹ However, heavy consumption is linked to poor cardiovascular health, increased risk of atrial fibrillation, and higher rates of cardiovascular events.^68,70 The relationship between alcohol consumption and venous thrombosis is uncertain.^71-74

It is important to note that many foods, particularly those rich in vitamin K, can interact with warfarin. Among the foods that can interfere with warfarin’s action (increasing the likelihood of excessive blood clotting) are green leafy vegetables (eg, kale, spinach, collards, Swiss chard, broccoli, Brussels sprouts, cabbage, lettuce), green tea, soy foods, blueberries, and soybean and canola oils. On the other hand, grapefruit, cranberry juice, mango, and alcohol are examples of foods that may increase bleeding risk in patients taking warfarin by slowing its metabolism.^75,76 Evidence from observational and experimental research suggests dietary stability is more important than dietary restriction during warfarin therapy.⁷⁷ Warfarin-treated patients should consult with their healthcare provider before making dietary changes.

Exercise

A sedentary lifestyle is a risk factor for arterial thrombosis and individuals who engage in regular exercise appear to be less susceptible to thrombosis.^78,79 Overall, moderate-intensity exercise can improve vascular function, reduce oxidative stress, lower levels of proteins involved in clotting, and reverse conditions that lead to pro-thrombotic signaling.⁷⁹ Regular exercise may even help regulate heart rhythm and lower the risk of atrial fibrillation.⁸⁰ In a randomized controlled trial, the addition of high-intensity interval training to a 12-week moderate-intensity exercise program reduced platelet reactivity and aggregation compared with moderate-intensity exercise alone.⁸¹ On the other hand, a bout of high intensity physical exertion can sometimes trigger a thromboembolic event, particularly in untrained individuals, possibly due to vascular injury and higher levels of stress hormones caused by acute exercise.^78,79

Although evidence suggests aerobic exercise may also decrease the likelihood of VTE, the protective effect does not appear to be as strong as for arterial clots.⁸² Nevertheless, controlled trials have found targeted exercises, such as ankle, lower limb, or hand exercises, can reduce the risk of venous thrombosis related to surgery or catheter placement.^83-85

Stress Management

Stress is a major driver of inflammation and coagulation and the conditions associated with thrombosis.^29,86 Acute stress, negative emotions, and psychological trauma can precipitate thromboembolic events by triggering atherosclerotic plaque rupture. Individuals with poor vascular health are especially vulnerable to heart attack and stroke within two hours after an intense psychological stressor.⁸⁷ In addition, chronic stress has been found to more than double the risk of heart attack.²⁹ Both acute and chronic stress signaling via hormones and neurotransmitters can increase thrombosis risk by increasing platelet numbers, reactivity, and aggregation, disrupting normal vascular function, up-regulating the clotting cascade, and altering fibrinolysis mechanisms. The strongest effects of stress are seen in those with pre-existing cardiovascular disease.⁸⁶

Meditation and stress management practices may lower the risk of thrombosis. In a study that included data from more than 61,000 participants, those who reported having any meditation practice were noted to have a lower incidence of heart attack and stroke.⁸⁸ In a randomized controlled trial in 47 patients referred to cardiac rehabilitation after a heart attack or coronary procedure, those who received eight weeks of mindfulness-based stress reduction training had greater improvement in cardiovascular health markers, as well as lower depression and anxiety scores and more improved health-related quality of life, than those who received standard care.⁸⁹

There are many nutritional options for potentially lowering the risk of blood clots or excessive blood clotting. If you are taking an antiplatelet or anticoagulant (blood thinner) medication, it is important to note there may be additive effects from these supplements, which could lead to increased bleeding risk. There is also a risk of drug‒supplement interactions that could reduce the effectiveness of anticoagulant medications, especially warfarin. If you are taking any anticoagulant or antiplatelet medications, a consultation with the prescribing health care provider is essential before adding any of these supplements to your program.

The following nutrient supplements have evidence supporting their possible ability to promote balanced hemostasis and reduce blood clot risk. A comprehensive approach to preventing blood clots includes maintaining optimal cardiovascular and metabolic health. You can find more guidance in the Atherosclerosis and Cardiovascular Disease protocol, as well as protocols for other associated conditions.

Fish Oil

Fish oil-derived omega-3 fatty acids, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are used by cells to make compounds that affect hemostasis and thrombosis by modulating platelet and endothelial function. EPA and DHA have been shown to reduce platelet reactivity and aggregation, increase production of nitric oxide, inhibit oxidized LDL generation, and decrease expression of adhesion molecules on endothelial cell surfaces. They may also promote fibrinolysis and inhibit the coagulation cascade by reducing tissue factor expression.⁶¹

A meta-analysis of data from eight randomized controlled trials found a combination of omega-3 fatty acids plus statin therapy was more effective than statin therapy alone for stabilizing and promoting regression of atherosclerotic plaques in the coronary arteries, possibly reducing the risk of arterial thromboembolism.⁹⁰ Another meta-analysis of 40 randomized controlled trials with a combined total of 135,267 participants found supplementing with EPA and DHA lowered the risk of heart attack and cardiovascular death. The analysis further calculated that the risk of cardiovascular events was reduced by 5.8% for every additional gram of EPA plus DHA taken daily.⁹¹

A study performed using observational evidence from three large cohort studies indicated higher blood levels of DHA were associated with lower risk of atherothrombotic stroke (caused by arterial clots formed in a cerebral artery) and higher blood levels of docosapentaenoic acid (DPA) were associated with lower risk of cardioembolic stroke (cause by an embolism from a coronary artery).⁹² DPA is another omega-3 fatty acid found in fish; it can be made in the body from EPA and further converted into DHA.

However, a meta-analysis of 14 trials in 125,763 subjects found, despite their association with lower risk of heart attack and other major cardiovascular events, taking 1 gram or more of omega-3 fatty acids was associated with increased risk of bleeding and of developing atrial fibrillation.⁹³

It is important to note that the results of multiple meta-analyses showing an increased risk of atrial fibrillation with omega-3 fatty acids are driven by studies that have methodological characteristics that limit their extrapolation to typical fish oil supplements. For example, some of the studies in these meta-analyses utilized high dosages of EPA-based pharmaceutical preparations (eg, icosapent ethyl [Vascepa, among others]). Also, in an attempt to improve the pharmacological effects of omega-3 fats, some of the studies used fatty acid forms (eg, carboxylic acid-based EPA and DHA preparations) other than the ethyl ester form that has been extensively studied.⁹⁴ A large ongoing cohort study of a multi-ethnic population suggests both EPA and DHA play important roles in cardiovascular health. Preliminary analysis of data from this study highlights an association between EPA levels and reduced bleeding risk as well as DHA levels and reduced atrial fibrillation risk. These observations draw attention to the role that DHA may play in reducing atrial fibrillation as well as the overall cardiovascular benefits that have been reported with fatty fish and omega-3 intake.⁹⁵ Preclinical research also points toward the importance of DHA in reducing atrial fibrillation risk.⁹⁶ However, since the totality of the literature is inconsistent and complex, caution is advised for individuals with a history or high risk of atrial fibrillation. More information on this topic can be found in Life Extension’s Arrhythmias protocol.

A randomized placebo-controlled trial in 452 elderly participants requiring leg surgery due to a fracture found 1 gram of omega-3 fatty acids, taken for 30 days following surgery, reduced the risks of DVT and pulmonary embolism without increasing bleeding events or other complications.⁹⁷ In 567 patients with chronic kidney disease, 4 grams of omega-3 fatty acids daily for three months reduced the risk of acute thrombosis in the arterio-venous fistulas used for dialysis.⁹⁸ An observational study with 21,970 participants found a weekly intake of more than 4.7 grams of fish omega-3 fatty acids from diet and supplements was correlated with a 22–26% lower risk of VTE and 39–60% lower risk of pulmonary embolism after a median follow-up period of 11.6 years. ⁹⁹ Higher omega-3 fatty acid intake has also been associated with lower rate of recurrence of DVT or other venous thromboembolic events, especially in those whose first event had no known trigger (eg, surgery, hospitalization, cancer, or acute illness).^60,100

Ginkgo

Ginkgo (Ginkgo biloba) has been used for centuries as an anti-aging medicine. Ginkgo extract has been found to stimulate peripheral and coronary circulation and may protect against neurological and cardiovascular disorders.^101-104

Studies show compounds from ginkgo reduce oxidative and inflammatory endothelial cell injury and improve vascular function, inhibiting atherosclerotic plaque development and possibly decreasing the risk of arterial clots.^105,106 In a clinical trial involving patients at high risk of venous thrombosis due to chronic venous insufficiency, treatment with ginkgo extract led to reduced levels of circulating endothelial cells. Circulating endothelial cells are considered a marker of ongoing vascular injury.¹⁰⁷ Evidence also suggests ginkgo may improve conditions associated with thrombosis, including high blood pressure, unhealthy lipid levels, and high blood glucose levels.¹⁰⁸

Ginkgo extract has been shown in preclinical studies to inhibit platelet activating factor (involved in platelet activation) and increase endothelial cell expression of thrombomodulin (activates thrombin) and production of tissue plasminogen activator (stimulates fibrinolysis).^109,110 Other research shows ginkgo flavonoids can directly inhibit thrombin activity.¹¹¹ However, ginkgo does not appear to affect bleeding time and its use has not been associated with an increased risk of bleeding.^112,113

Garlic

A growing body of research indicates garlic can slow progression of atherosclerosis and improve cardiometabolic health.⁴⁶ Garlic and garlic extracts may lower thrombosis risk by inhibiting platelet aggregation, reducing fibrinogen levels, and increasing fibrinolytic processes.^114,115 In animal research, garlic delayed platelet aggregation and clot formation in response to thrombotic triggers.^116,117 Some evidence suggests ajoene, an active compound from garlic, may contribute to its antithrombotic properties.^118,119

In a clinical trial, 36 healthy young men received 600 mg, 1,200 mg, or 2,400 mg of garlic extract or 75 mg of the blood thinner drug clopidogrel daily for three weeks. Blood samples from those who received 1,200 mg or 2,400 mg of garlic showed significantly reduced platelet aggregation in response to various triggers, and a stronger effect was seen with the higher dose. The 2,400 mg dose of garlic was more effective than clopidogrel for inhibiting platelet response to some but not all thrombotic triggers. In addition, bleeding time was prolonged (but stayed within the normal range) in all participants, with the longest bleeding time seen in those taking 2,400 mg of garlic extract.¹²⁰ A 12-week placebo-controlled trial examined the safety of combining aged garlic extract with warfarin therapy. The trial included 48 closely monitored participants and found taking aged garlic extract along with warfarin did not increase bleeding or other adverse side effects.¹²¹

Cocoa

Cocoa is rich in flavanols and other polyphenols with strong free radical-scavenging effects. Cocoa and dark chocolate have been found to reduce platelet activation, inhibit expression of proteins involved in platelet aggregation, and limit the effects of platelet activity on hemostasis.^39,40 In addition to its polyphenols, cocoa is a source of theobromine, a compound in the methylxanthine family, that also inhibits platelet aggregation.⁴⁰ Clinical trials have found polyphenols from cocoa increase nitric oxide production and support healthy endothelial function, decrease inflammatory marker levels, reduce oxidative damage to lipids, and promote growth of beneficial bacteria in the gut.^40,122,123

In clinical trials in healthy men, eating 50 grams (1.67 ounces) of chocolate with 90% cocoa led to reduced platelet reactivity and prolonged clotting time in blood samples taken four hours later.^124,125 Another clinical trial found dark chocolate consumption blunted the rise in D-dimer levels caused by an experimental psychological stressor in healthy men.¹²⁶ In an open-label controlled trial in healthy middle-aged adults, 900 mg of cocoa flavanols per day for 30 days improved endothelial function, an important factor in thrombotic risk, and in a follow-up controlled trial the same dose was also shown to improve blood pressure and lipid levels.¹²⁷ A randomized controlled trial found cocoa providing 750 mg of flavanols per day improved vascular function and markers of endothelial integrity more than low-flavanol cocoa after 30 days in subjects with coronary artery disease.¹²⁸ Furthermore, flavanol-rich cocoa has also been found to improve vascular function in young African Americans,¹²⁹ healthy young adults,¹³⁰ post-menopausal women,¹³¹ patients with end-stage kidney disease,¹³² men with high blood pressure,¹³³ and healthy elderly men.¹³⁴

Coenzyme Q10

Coenzyme Q10 (CoQ10), which may be in the reduced form as ubiquinol or non-reduced form as ubiquinone, is a nutrient involved in reduction-oxidation balance and energy production in the mitochondria. A low CoQ10 level increases inflammatory signaling and is linked to poor cardiovascular health and outcomes, and CoQ10 supplements have a potential role in preventing and as an adjuvant to treating cardiovascular disease and associated metabolic conditions.^135-138 CoQ10 has been found to improve vascular function by reducing oxidized LDL accumulation in arterial walls, decreasing vascular injury and stiffness, and increasing nitric oxide availability.¹³⁷ Laboratory research further suggests CoQ10 may inhibit platelet aggregation and signaling, reducing thrombus growth.¹³⁹ Because the use of a common class of cholesterol-lowering drugs called statins lowers CoQ10 production, patients taking statins in particular may benefit from supplementing with CoQ10.^136,138,140

In a randomized controlled trial in 213 elderly individuals with low selenium status, taking 200 mg CoQ10 plus 200 mcg selenium for four years led to reduced D-dimer levels. D-dimer levels are a reflection of thrombotic potential. In participants whose baseline D-dimer levels were higher than the median (mid-point), those given CoQ10 plus selenium had a lower incidence of cardiovascular death during 4.9 years of follow-up.¹⁴¹ The same combination of CoQ10 and selenium was also found to reduce levels of von Willebrand factor and tissue plasminogen activator inhibitor-1, molecules with critical roles in promoting thrombosis, in another four-year placebo-controlled trial in 308 elderly individuals with low selenium status.¹⁴² In a randomized controlled trial in 51 subjects with high LDL-cholesterol levels, supplementing with 100 or 200 mg of CoQ10 daily for eight weeks led to improved endothelial function, reduced LDL oxidation, and increased nitric oxide availability compared with placebo.¹⁴³ In a randomized placebo-controlled crossover trial in 36 patients with antiphospholipid syndrome, an immune disorder associated with an increased risk of thrombosis, 200 mg CoQ10 daily for one month improved vascular function; lowered markers of thrombotic risk, inflammation, and oxidative stress; and modified expression of 23 of 29 atherosclerosis-related genes.¹⁴⁴

French Maritime Pine Bark Extract (Pycnogenol)

Pycnogenol, an extract from French maritime pine bark, has been reported to prevent edema and venous thrombosis during long airplane flights and may help chronic venous insufficiency.^145,146 In one controlled trial, 198 airline passengers with moderate to high risk of venous thrombosis were given either pycnogenol, at 200 mg before and during a long flight (averaging 8 hours 15 minutes) plus 100 mg the next day, or placebo. There were five venous thrombotic events in the placebo group and none in the pycnogenol group.¹⁴⁷

In a randomized controlled trial in 156 subjects with a history of a single DVT episode, 150 mg pycnogenol was as effective as compression stockings at reducing edema after one year, but was associated with better compliance due to the discomfort of compression stockings.¹⁴⁸ In an observational study that followed 222 subjects with a history of DVT for six years, those taking 200 mg pycnogenol per day had lower risks of recurrent DVT and post-thrombotic syndrome compared with those treated with blood thinner medications such as aspirin, ticlopidine (Ticlid), sulodexide (Aterina, a formulation composed of 80% low-molecular weight heparin), or no medication.¹⁴⁹ Pycnogenol has also been found to improve arterial endothelial function by increasing nitric oxide production in healthy subjects and those with coronary artery disease.^150,151 One research team found a dose of 200 mg pycnogenol per day for two months suppressed the smoking-induced rise in platelet aggregation in chronic smokers but had no effect on platelet aggregation in non-smokers.¹⁵²

Observational evidence from a study in 307 subjects with a history of retinal vein thrombosis found taking 100 mg pycnogenol daily was associated with the lowest incidence of repeat retinal vein thrombosis compared with aspirin, ticlopidine, sulodexide, or no medication, and was the only treatment associated with reduction in edema.¹⁵³ A smaller study of similar design found pycnogenol, at 100 mg daily, was associated with better vision, lower risks of retinal edema and recurrent retinal vein thrombosis, and lower frequency of adverse side effects compared with aspirin after nine months.¹⁵⁴

Probiotics

The relationship between the gut microbiome and cardiovascular health is an area of intense research. A growing body of evidence suggests dysbiosis (an imbalance in microbiome composition) is an important underlying contributor to atherosclerosis and thrombosis.^155,156

A meta-analysis of 15 randomized controlled trials with a combined total of 976 participants found supplementing with Lactobacillus species, especially L. reuteri and L. plantarum, can lower total and LDL-cholesterol levels, potentially reducing cardiovascular risk.¹⁵⁷ The probiotic strain L. reuteri NCIMB 30242 has demonstrated several positive effects that might lower thrombosis risk. In a randomized placebo-controlled trial in 127 subjects with high cholesterol levels, taking a supplement providing at least 4 billion colony forming units (CFUs) of L. reuteri NCIMB 30242 per day for nine weeks reduced LDL-cholesterol levels, as well as hs-CRP, apolipoprotein B-100 (apoB-100) (a lipid fraction associated with atherosclerosis development), and fibrinogen levels, and increased vitamin D levels.^158,159 Similarly, a yogurt providing 1.4 billion CFUs of L. reuteri NCIMB 30242 taken twice daily for six weeks reduced LDL-cholesterol, apoB-100, and non-HDL-cholesterol levels compared with placebo yogurt in a trial that included 114 individuals with high cholesterol levels.¹⁶⁰

Other probiotic strains have been found to improve parameters related to thrombosis risk. In a placebo-controlled trial in 34 healthy individuals, consuming yogurt fortified with 10 billion CFUs of Bifidobacterium animalis subspecies lactis plus 600 mg of the amino acid arginine (a precursor to nitric oxide) daily for 12 weeks improved vascular function and was therefore suggested to reduce atherosclerosis risk.¹⁶¹ A placebo-controlled trial in 36 heavy smokers found a drink providing 20 billion CFUs of L. plantarum per day for six weeks decreased blood pressure and fibrinogen levels, as well as levels of an inflammatory cytokine and a marker of oxidative stress.¹⁶² Another trial in 32 patients with human immunodeficiency virus (HIV) compared the effect of a daily multi-strain probiotic supplement to placebo or no supplement; those who received the probiotic had greater reductions in D-dimer levels after eight weeks.¹⁶³ In mice, intake of a milk product fermented with a Bacillus subtilis strain that produces the thrombolytic enzyme nattokinase reduced the development of thrombosis.¹⁶⁴

Nattokinase

Nattokinase is a thrombolytic enzyme produced by certain bacteria and found in a fermented soybean product called natto. Through its enzymatic action and ability to activate plasmin, nattokinase breaks down the fibrin structure that holds blood clots together.¹⁶⁵ It has also been shown to decrease levels of fibrinogen, factor VII, and factor VIII in multiple subgroups of participants when taken at a dose of 2,000 fibrinolytic units daily for two months.¹⁶⁶ In a controlled trial in 204 individuals at high risk of venous thrombosis, a combination of French maritime pine bark (Pycnogenol) plus nattokinase or placebo was taken before and after a seven- to eight-hour airplane flight; no venous thrombi occurred in the pycnogenol/nattokinase group, while five DVT and two superficial venous thrombi occurred in the placebo group. In addition, pycnogenol plus nattokinase-treated subjects had a 15% reduction in edema at the end of the flight versus a 12% increase in edema in the placebo group.¹⁶⁷

Nattokinase has been found in animal studies to prevent arterial thrombosis and dissolve existing blood clots.¹⁶⁸ Evidence suggests nattokinase reduces the formation of intravascular blood clots by reducing oxidative stress and inflammatory signaling.^169-171 Nattokinase has also been found to reduce thickening of the femoral artery wall in response to arterial injury in research animals.^172,173 Unfortunately, in a randomized placebo-controlled trial in 265 healthy elderly subjects, no difference in carotid artery wall thickness (an indicator of atherosclerosis), measured using ultrasound imaging, were seen in those who received 2,000 fibrinolytic units of oral nattokinase per day versus placebo for three years.¹⁷⁴

B Vitamins

Niacin (vitamin B3) is one of the more effective agents for raising high-density lipoprotein (HDL)-cholesterol levels.¹⁷⁵ HDL has antithrombotic effects due to its ability to protect endothelial cells from oxidative and other injury and to remove excess cholesterol from the artery wall, preventing plaque formation that can lead to thrombosis.¹⁷⁶ Before the development of statin drugs, niacin was commonly used to treat abnormal lipid profiles. Because recent evidence shows little benefit on cardiovascular outcomes from adding extended-release niacin to statin therapy, or from raising HDL-cholesterol levels, niacin is no longer considered standard of care for reducing cardiovascular risk.^175-178 Nevertheless, niacin has demonstrated antithrombotic effects, including inhibiting a coagulation cascade enzyme called factor VII, reducing fibrinogen levels, decreasing expression of tissue factor, suppressing plasminogen activator inhibitor-1 (an enzyme that inhibits fibrinolysis), lowering blood viscosity, and decreasing platelet aggregation.¹⁷⁹

Vitamins B6, B12, and folate are needed for metabolism of homocysteine, high levels of which are associated with vascular damage and increased thrombosis risk. Low levels of these B vitamins, especially folate and B12, and high homocysteine levels are associated with increased risk of atherosclerosis, stroke, and venous thrombosis.^180-182 For example, in patients with atrial fibrillation, high homocysteine (often from B12 deficiency) increases the risk of stroke four-fold.¹⁸³ In addition, pernicious anemia, a condition that impairs intestinal B12 absorption, has a well-documented association with high homocysteine levels and elevated risk of venous thrombosis.^184,185

Lowering homocysteine levels through supplementation with folic acid and B12 has been shown to lower the risk of stroke.^183,186 In a randomized controlled trial, 10,789 Chinese adults with high blood pressure were treated daily either with enalapril (Vasotec) (a blood pressure-lowering drug) or enalapril along with 800 mcg folic acid and followed for 4.2 years. Subjects with low platelet numbers and high homocysteine levels had the highest stroke risk, and in this high-risk subgroup, the risk was 73% lower in those receiving folic acid.¹⁸⁷ In another controlled trial in stroke patients with a history of DVT, lowering high homocysteine levels using folic acid and B12 was shown to reduce the rate of DVT recurrence from 28.9% to 4.4%.¹⁸⁸

Green Tea

Green tea contains bioactive polyphenols known as catechins, the most studied of which is epigallocatechin gallate (EGCG). Clinical trials and observational studies have found green tea is associated with reduced cardiovascular risk due to increased nitric oxide availability, reduced inflammation and oxidative stress levels, and improved endothelial function.^189,190 Research using blood samples from subjects given the blood thinner medications aspirin, clopidogrel, or ticagrelor (Brilinta) suggests EGCG may improve their antiplatelet effects without increasing the risk of bleeding.¹⁹¹ EGCG has been shown to inhibit inflammatory enzyme activity in platelets¹⁹² and suppress inflammatory signaling, inhibit expression of adhesion molecules, and promote expression of nuclear factor erythroid 2-related factor 2 (Nrf2, a protein that upregulates antioxidant pathways) in endothelial cells.^189,193 EGCG also inhibited expression of tissue factor, a protein that triggers coagulation, on arterial and venous endothelial cells.¹⁹⁴ In laboratory animals, EGCG inhibited platelet aggregation, prevented thrombus formation in injured vessels, and prolonged bleeding time.^194,195

Lycopene

Lycopene is a carotenoid found in high concentrations in tomato skins. Laboratory and animal research suggests lycopene may suppress tissue factor activity and inhibit platelet aggregation.^196-198 Lycopene has been suggested to potentially prevent thrombosis through mechanisms such as reducing endothelial injury, inhibiting oxidation of LDL, reducing inflammatory immune activity, and decreasing cholesterol synthesis.¹⁹⁹ A meta-analysis of 28 observational studies found higher intake or blood levels of lycopene were correlated with a lower risk of stroke and cardiovascular disease.⁵⁵

Tomato pomace is a byproduct of tomato product manufacturing and contains mainly tomato seeds and skins. Tomato pomace contains lycopene and a number of tomato flavonoids that may work together to inhibit platelet aggregation and reduce thrombosis risk.^200,201 In a placebo-controlled trial in 99 healthy young men, taking 1 gram of tomato pomace extract daily for five days reduced platelet aggregation.²⁰²

Olive Oil and Olive Leaf

Extra virgin olive oil (EVOO) is high in monounsaturated fatty acids and antioxidant polyphenols, and high intake has consistently been associated with lower cardiovascular risk.⁶³ Olive oil has been shown to lower oxidative stress and inflammatory marker levels, improve endothelial function and lipid and carbohydrate metabolism, and inhibit thrombosis.^63,203 Preclinical research shows olive oil can reduce platelet activity and aggregation, reduce endothelial cell expression of adhesion molecules, and decrease the coagulation enzyme factor VII and plasminogen activator inhibitor-1, both of which are implicated in coronary artery disease.²⁰⁴ Some evidence suggests olive oil may mitigate the rise in coagulation enzyme activity typically induced by a high-fat meal.⁶⁴ In one clinical trial in 82 patients with early atherosclerosis, 30 mL (one ounce) of olive oil per day for four months improved vascular function and inflammatory marker levels.⁶⁵

Oleuropein and its derivative hydroxytyrosol are polyphenols found in olives, EVOO, and olive leaf. These compounds have demonstrated inflammation- and oxidative stress-lowering properties, and have been found to improve vascular function as well as glucose and lipid metabolism.²⁰⁵ Findings from multiple preclinical studies suggest oleuropein, hydroxytyrosol, and other phenolics extracted from EVOO and olive leaf can inhibit platelet activation and aggregation.^206-209

Pomegranate

Pomegranate is rich in flavonoids, tannins, and other polyphenols that have strong free radical-scavenging and anti-inflammatory properties.²¹⁰

In laboratory studies, pomegranate extracts have been found to reduce platelet activation and aggregation in response to thrombotic triggers.^211,212 A meta-analysis of eight randomized controlled trials found drinking up to 8 ounces of pomegranate juice per day reduced high systolic blood pressure and more than eight ounces per day reduced both systolic and diastolic blood pressure.²¹³ In an open trial in 13 healthy subjects, drinking 50 mL (almost two ounces) of pomegranate juice per day for two weeks reduced platelet aggregation by 11%.²¹⁴ Another clinical trial found subjects who drank pomegranate juice exhibited prolonged clotting times six hours later.²¹⁵

Pomegranate has also been found to reduce oxidative stress and high blood pressure, and improve vascular function and glucose and lipid metabolism.^210,216,217 A randomized placebo-controlled trial in 100 heart disease patients found 450 mg of pomegranate extract plus 180 mg vitamin E (as synthetic dl-alpha tocopherol) daily for eight weeks reduced expression of two vascular adhesion proteins and lowered levels of inflammatory markers.²¹⁸ In another placebo-controlled trial in 48 subjects who were overweight or obese, 1,000 mg pomegranate extract for 30 days reduced inflammatory marker levels and improved blood glucose, insulin, and LDL-cholesterol levels.²¹⁹

Yerba Mate

Yerba mate (Ilex paraguariensis) is high in chlorogenic acids that have anti-inflammatory and free radical-scavenging properties.²²⁰ In a randomized placebo-controlled trial in 142 participants with high blood viscosity, a condition related to increased thrombosis risk, 5 grams of yerba mate tea per day for six weeks led to reduced blood viscosity and improved circulation in small vessels.²²¹ Another controlled clinical trial found 580 mg of chlorogenic acids from yerba mate per day improved markers of cardiometabolic health in 34 middle-aged men at high risk of metabolic syndrome.²²² In preclinical research, a constituent from yerba mate reduced thrombin activation and venous thrombosis.²²³

Some evidence suggests yerba mate tea, when consumed in large amounts and especially when consumed very hot, may raise the risk of esophageal and head and neck cancers. It is thought this possible carcinogenic effect may be related to the presence of polycyclic aromatic hydrocarbons produced through a drying procedure involving smoke. Although a carcinogenic effect for yerba mate tea has not been confirmed, it is prudent to drink yerba mate tea at a slightly lower temperature and limit intake to less than one liter per day.^220,224

Quercetin

Quercetin is a flavonoid found in most fruits and vegetables, with high amounts found in onions, apples, tea, and wine. Higher intake of flavonoids, including quercetin, is associated with lower cardiovascular risk.²²⁵ Quercetin supplementation, at doses of 150 mg and 300 mg, has been found to inhibit platelet activation, signaling, and aggregation within 30 minutes in healthy adults.²²⁶ Supplementation with 150 mg quercetin for six weeks has also been shown to significantly reduce systolic blood pressure and oxidized LDL levels.²²⁷ Preclinical research has shown quercetin reduces expression of adhesion molecules on endothelial cells and platelets, lowers oxidative stress, inhibits LDL oxidation, supports nitric oxide production and healthy blood vessel function, improves glucose metabolism, and reduces inflammatory marker levels.^225,228 Quercetin, along with other flavonoids, is thought to be responsible for antithrombotic and cardioprotective properties of the bee products propolis and honey.^229,230

Saffron

Saffron’s distinctive red-orange color is due to its carotenoids, including crocin and crocetin. Saffron extracts have been found to suppress platelet aggregation, scavenge free radicals, lower oxidative stress, reduce LDL oxidation, inhibit expression of endothelial adhesion molecules, and improve endothelial function.^231,232 Crocetin alone has also demonstrated antithrombotic effects in laboratory and animal studies.^233-235 In a randomized controlled trial in 84 subjects with coronary artery disease, 30 mg per day of crocin for eight weeks lowered levels of oxidized LDL and an inflammatory marker (monocyte chemoattractant protein-1, or MCP-1), and inhibited expression of genes related to atherosclerosis compared with placebo.²³⁶

Ginger

Ginger is a culinary spice and a medicinal herb that has clinically demonstrated cardioprotective effects such as improving lipid levels, reducing levels of inflammatory cytokines, lowering blood pressure, and inhibiting platelet aggregation.^48,49 An observational study that examined health records and dietary surveys from 4,628 participants found, among those 60 years and older, those who reported higher ginger use had a lower incidence of coronary artery disease.⁵¹ Ginger may also be beneficial in metabolic disorders such as obesity and type 2 diabetes.²³⁷ In a study in mice, zingerone (an active compound from ginger) inhibited not only platelet aggregation but also the activity of factor Xa, an enzyme in the clotting cascade.²³⁸ Laboratory research also found a polysaccharide extracted from ginger inhibited coagulation pathways.²³⁹ A systematic review of eight clinical trials was unable to draw a firm conclusion about the effect of ginger on platelet aggregation in humans due to the small sample sizes and variable methodologies used.⁵⁰ In one of the trials, taking 4 grams of ginger for three months did not change platelet aggregation, fibrinogen level, or fibrinolytic activity in subjects with coronary artery disease, but a single dose of 10 grams reduced platelet aggregation.²⁴⁰

Vitamin C

Vitamin C is a water-soluble antioxidant and has demonstrated an ability to reduce platelet aggregation and promote fibrinolysis, without impacting coagulation pathways, in high-oxidative stress pro-thrombotic conditions in the laboratory.^241-243 In particular, vitamin C appears to reduce expression of adhesion proteins by endothelial cells and platelets.^242,244 A large population study of more than 20,000 adults ranging from 40‒79 years of age followed the individuals for an average of 9.5 years and found that those in the top quartile of baseline plasma vitamin C concentration had a 42% lower risk of stroke than those in the bottom quartile.²⁴⁵ A meta-analysis of 17 randomized controlled trials found vitamin C supplementation at doses of 500 to 2,000 mg per day improved measures of vascular function.^246,247 Some evidence suggests vitamin C supplementation may improve atherosclerosis and other conditions associated with increased risk of venous and arterial clots, but the effect is likely to be mild and of greater importance in those with lower vitamin C levels and higher cardiovascular risk.^246,247 Indeed, positive effects on blood vessel dilation were seen in patients with chronic heart failure after taking 1 gram of vitamin C twice daily for four weeks.²⁴⁸ In smokers, whom have been proven in multiple studies to have low blood levels of vitamin C, oral supplementation with 2 grams vitamin C per day has been shown to significantly decrease urinary isoprostanes,²⁴⁹ markers of oxidative stress, and monocyte adhesion to the endothelial lining of blood vessels, one of the early stages in the development of dangerous atherosclerotic plaque.²⁵⁰

Grape Seed Extract

Grape seeds are high in polyphenols with health benefits based on their anti-inflammatory, oxidative stress-reducing, and cardiovascular protectant effects. Preclinical research has shown grape seed extract has anticoagulant and antiplatelet properties.²⁵¹ In mice, grape seed extract reduced platelet aggregation without increasing bleeding.²⁵² Grape seed extract also reduced thrombus formation and spread in a rat model of DVT.²⁵³ A meta-analysis of 16 clinical trials found grape seed extract supplementation significantly decreased systolic blood pressure in younger (<50 years) or obese subjects and individuals with metabolic syndrome.²⁵⁴

Capsaicin

Capsaicin is an active compound found in red chili pepper and responsible for their characteristic spicy taste. Capsaicin is used to treat inflammatory, metabolic, and infectious disorders.²⁵⁵ Preclinical and clinical evidence suggests capsaicin can improve lipid and glucose metabolism, support weight loss, and lower the risk of both type 2 diabetes and cardiovascular disease.^255-257 Laboratory evidence shows capsaicin has the potential to reduce platelet aggregation, without affecting coagulation, in response to an array of pro-thrombotic triggers, possibly by inhibiting inflammatory pathways.^257-261 However, in healthy male volunteers, neither 400 mcg nor 800 mcg capsaicin affected platelet aggregation.²⁶²

Resveratrol

Resveratrol is a flavonoid found in purple grapes, red wine, peanuts, soybeans, and berries. It has well-established anti-inflammatory and free radical-scavenging effects and may slow the effects of aging on blood vessels.^263-265 Preclinical research indicates resveratrol suppresses the effect of triggers such as collagen, thrombin, and oxidized LDL on platelet activation and aggregation.^266-268 One study found resveratrol inhibited platelet aggregation and fibrinogen adhesion induced by the stress hormone epinephrine.²⁶⁹ Some clinical evidence shows a potential role for resveratrol in protecting cardiovascular and metabolic health and improving conditions associated with thrombosis risk.²⁶⁴

Ginseng

Extracts from Chinese ginseng (Panax notoginseng) are used intravenously in China to treat acute thrombosis, and some evidence suggests oral extracts from ginseng species may also have antithrombotic benefits. Biologically active saponins, known as ginsenosides, are present in Chinese ginseng as well as red ginseng (Panax ginseng) and American ginseng (Panax quinquefolium).^270-272 An oral formulation of ginsenosides was found in a 28-day clinical trial to reduce platelet aggregation.²⁷³ Preclinical research suggests ginsenosides can inhibit platelet expression of adhesion molecules, platelet aggregation, and platelet reactivity to thrombotic triggers, which may confer protection against excessive blood clotting.^274,275 In addition, ginsenosides have been shown in laboratory and animal studies to reduce vascular inflammation and stiffness, stabilize atherosclerotic plaques, and slow atherosclerosis progression, which may help prevent thromboembolism.²⁷⁶ Ginsenosides may also improve vascular function by reducing free radical production, increasing nitric oxide, and regulating lipid levels.²⁷⁰ Ginseng and ginsenosides have anti-inflammatory and broad health-promoting effects that may benefit individuals with conditions associated with thrombosis risk.^270,277 Other compounds from ginseng may further contribute to its antiplatelet activity.²⁷⁸

Curcumin

Curcumin, a carotenoid found in the culinary spice turmeric, possesses oxidative stress-reducing and anti-inflammatory properties. Its potential antithrombotic effects have been demonstrated in laboratory and animal studies.^279,280 Both antiplatelet and anticoagulant actions have been reported.²⁷⁹ Findings from a preclinical study indicate curcumin may be helpful in promoting endothelial repair and the resolution of venous thrombosis.²⁸¹ In mice, treatment with curcumin prevented the rise in inflammatory factors, blood pressure, and D-dimer seen with exposure to air pollution (diesel exhaust), a common environmental factor known to increase inflammation and blood clot risk.²⁸²

Guavirova

The South American plant guavirova (Campomanesia xanthocarpa) has been used traditionally to treat high cholesterol levels, obesity, and various inflammatory conditions.²⁸³ In preclinical research, guavirova extract reduced platelet aggregation, prolonged coagulation time, stimulated fibrinolysis, and decreased inflammatory signaling in endothelial cells.^283,284 In a small controlled trial, 23 healthy adults were given either 1,000 mg of guavirova, 100 mg of aspirin, or 500 mg of guavirova plus 50 mg of aspirin daily for five days. Guavirova inhibited platelet aggregation more strongly than the blood thinner drug aspirin and had a synergistic effect when combined with aspirin.²⁸⁵ In two clinical trials, guavirova was found to reduce total and LDL-cholesterol levels, lower oxidative stress, and increase endothelial nitric oxide production in individuals with high cholesterol levels.^286,287

There are three overarching mechanisms, known collectively as Virchow’s triad, associated with thrombosis risk: 1) disturbed blood flow, including stasis (stoppage or slowing of circulation) and turbulence; 2) endothelial (inner blood vessel) inflammation/injury; and 3) a high propensity to form clots, also known as excessive blood clotting or hypercoagulability, due to widespread platelet and clotting protein activation.^3,11 All of the conditions associated with thrombosis involve one or more of these mechanisms.

Although venous and arterial thrombosis are distinct conditions, the factors and conditions that increase their likelihood overlap. Furthermore, thromboembolic conditions of the arteries and veins frequently co-occur.^5,288,289 The role of platelets, through their inflammation- and coagulation-promoting effects, is increasingly understood to be central to both pathologies.²⁹⁰

Aging

Older age is accompanied by an increasing level of oxidative stress, which is linked to endothelial inflammation and platelet activation. In addition, levels of fibrinogen (used to make fibrin, a component of blood clots) rise with age. Fibrinogen is known to promote thrombosis. Aging is also frequently associated with blood clot symptoms and conditions that promote venous stasis, such as decreased physical activity and greater immobility.⁵

Chronic Venous Disease

Chronic venous insufficiency and varicose veins are characterized by weakness in the venous walls and can result in venous stasis. Stasis is a major cause of DVT, pulmonary embolism, and post-thrombotic syndrome.²⁹¹ Interestingly, patients with chronic venous insufficiency may be more likely to have arterial disease, such as atherosclerosis. In one study, 17% of those with chronic venous insufficiency also had peripheral (non-coronary) artery disease, which is mainly due to atherosclerosis, and the incidence was higher in those with more severe venous disease.²⁹²

Atherosclerosis

Atherosclerosis is a primary underlying condition in arterial thrombosis and embolism.^31,293 In the coronary arteries, it is also a risk factor for atrial fibrillation, a common type of arrhythmia linked to increased thromboembolism and a 5-fold increase in risk of stroke.^33,294,295 In the peripheral arteries, atherosclerosis increases inflammatory signaling and changes in blood flow that contribute to thrombosis.²⁹⁶ Peripheral artery disease is associated with increased incidence of chronic venous insufficiency. In one study, 21% of those with peripheral artery disease showed signs of venous insufficiency on vascular imaging, and the presence of venous insufficiency was correlated with increased severity of arterial disease.²⁹⁷

Smoking

Smoking is an independent risk factor for arterial thrombosis, through its damaging effects on arterial health, and is a factor in hypercoagulability (excessive blood clotting). Smoking has also been associated with increased risk of venous thrombosis, pulmonary embolism, and post-thrombotic syndrome.^5,288,289

Oxidative Stress

Free radicals, especially oxidized low-density lipoprotein (LDL), promote vascular inflammation, increase the expression of tissue factor on cellular surfaces, damage proteins that regulate coagulation, heighten reactivity of platelets, and disrupt antithrombotic hemostatic mechanisms, raising the risk of thrombosis.^293,298,299

Abnormal Lipid Levels

Dysregulation of cholesterol, triglycerides, and dietary fatty acids results in high levels of oxidized lipids. This stimulates an increase in the number of platelets, as well as increased production of larger, prothrombotic platelets, in the blood and sensitizes platelets so that they are more easily activated. The risk of both venous and arterial thrombosis are higher in this state.⁴ In addition, high concentrations of LDL increase blood viscosity, which slows blood flow and inhibits anticoagulation and fibrinolytic mechanisms.³⁰⁰

Diabetes

Insulin resistance and high blood glucose levels increase oxidative stress, trigger vascular inflammation and endothelial dysfunction, activate platelets and pro-coagulation proteins, and inhibit fibrinolysis. Through these mechanisms, diabetes is a major risk factor for atherosclerosis and its thromboembolic complications, including heart attack and stroke.³⁰¹ In addition, diabetes has been associated with increased risk of VTE in multiple observational studies.²⁸⁹

Obesity

Obesity is consistently and closely linked to higher risk of atherosclerosis and its thromboembolic complications.³¹ People with obesity also have more than twice the risk of VTE as those without obesity. This may be related to stasis resulting from increased venous pressure or pro-inflammatory and pro-thrombotic conditions resulting from metabolic disturbance.²⁸⁹

High Blood Pressure

High blood pressure causes vascular injury that triggers inflammatory signaling and activates platelets.^12,31 Hypertension is a known risk factor for cardiovascular events related to arterial thrombosis and has been associated with a higher likelihood of VTE.²⁸⁹

High Homocysteine Levels

Elevated concentrations of homocysteine appear to raise platelet activity and lipid oxidation, and have been linked to venous thrombosis as well as arterial thrombosis.^181,302 High homocysteine levels are associated with increased risk of cardiovascular events related to arterial thrombosis, particularly stroke.^186,302 Homocysteine has also been implicated as a contributor to atrial fibrillation, a type of arrhythmia that disrupts normal blood flow and increases the risk of clot formation.^186,303

Sleep Apnea

Sleep apnea is marked by intermittent bouts of hypoxia (low oxygenation), heightened activation of the sympathetic (fight-or-flight) nervous system, and disruption of the body’s circadian control system. These conditions trigger systemic inflammation, vascular injury, and increased production of proteins involved in the clotting process, including von Willebrand factor, tissue factor, and fibrinogen.^304,305 Hypoxia also interferes with the breakdown of blood clots through fibrinolysis.^304,305 The procoagulatory state induced by sleep apnea may be a contributing factor in its association with an increased risk of heart attack and stroke.³⁰⁴

Cancer

Venous and arterial thromboembolism are major complications of cancer, especially solid tumors.³⁰⁶ In fact, tumor-induced thromboembolism is the second most frequent cause of death in cancer patients.³⁰⁷ Microparticles secreted by cancer cells have been noted to express high amounts of tissue factor, a protein that helps initiate a procoagulatory state and facilitates cancer progression and metastasis.^1,307 In addition, the tumor microenvironment is rich in platelets and clotting proteins that enhance coagulation.³⁰⁷

Hospitalization and Surgery

Hospitalization and surgery are often associated with physical trauma, critical illness, and prolonged immobility, and greatly increase the risk of venous stasis, DVT, pulmonary embolism, and post-thrombotic syndrome.^16,19 Venous thrombosis can also be related to use of venous catheters, intravenous medications, and venous blood draws.⁹ Pulmonary embolism is the most common cause of preventable death in hospitalized patients.¹⁸ In addition, stasis, as well as increased propensity to form clots due to trauma or infection, result in greater risk of arterial thrombosis and stroke. As many as 17% of all strokes affect patients hospitalized for other diagnoses or procedures.³⁰⁸ Intravenous administration of clot busters may be used in severe cases of thrombosis in hospitalized patients.

Prolonged Inactivity

Long periods without physical activity, such as long car rides or air travel, increase susceptibility to venous thrombosis and pulmonary embolism in people with other risk factors.^309,310 Over time, sedentary behavior also contributes to metabolic disturbances that increase risk of arterial thrombosis.²⁹³

Prolonged computer use in particular has been recognized as a new major cause of inactivity and a risk factor for thrombosis, giving rise to a condition termed “e-thrombosis,” or computer-related thrombosis.³¹¹ While most risk factors for thrombosis affect mainly the elderly, computer-related thrombosis tends to occur in younger individuals. Cases have even been reported in adolescents who play video games for extended periods of time.³¹² Avoiding long, uninterrupted, seated immobility while using a computer as well as wearing non-restrictive clothing and using comfortable sitting positions and ergonomically-designed work stations may help mitigate computer-related thrombosis risk.³¹¹

Thyroid Disease

High levels of thyroid hormone, which occur in hyperthyroidism, activate pro-coagulation pathways and reduce fibrinolytic activity. Hyperthyroidism increases risk of DVT, post-thrombotic syndrome, and pulmonary embolism, as well as the likelihood of arterial thromboembolism, in part by triggering atrial fibrillation and flutter.^313,314 Hypothyroidism has the opposite effect on hemostasis and raises risk of bleeding and hemorrhage; however, it can also be a risk factor for thromboembolism.^314-316

Infection, Transplant, and Transfusion Reactions

In some cases, acute immune reactions can escape control mechanisms leading to a hyperinflammatory syndrome and overactivation of coagulation pathways that may cause excessive blood clotting. This hypercoagulable state is sometimes called thrombophilia and is associated with severe illness and poor outcomes. Acute viral infections such as influenza increase the risk of thromboembolic coronary events, such as heart attack, six-fold.²⁸ Thrombophilia can also be triggered by transplant or transfusion reactions.^3,11

Other Causes of Thrombophilia

Thrombophilia can also be due to inherited and non-inherited conditions that affect hemostasis. Among the inherited conditions are rare genetic deficiencies in anticoagulant proteins.³ Autoimmune diseases like inflammatory bowel disease and anti-phospholipid syndrome, as well as liver disease, kidney disease, pregnancy, and the use of oral estrogens (eg, hormone replacement therapy or high-dose oral birth control pills) are among the many potential causes of non-inherited thrombophilia.³ However, low-dose estrogens (<50 mcg/day), such as those typically used in transdermal postmenopausal hormone replacement therapy or low-dose oral birth control pills, do not appear to increase risk of thrombosis. The transdermal route of administration in general appears to be a safer option with regard to thrombosis risk.^317,318 Heparin-induced thrombocytopenia is an unusual condition that occurs in some people being treated with the anticoagulant heparin. In heparin-induced thrombocytopenia, an immune reaction to heparin causes breakdown of platelets, releasing their contents and triggering widespread platelet activation, initiation of coagulation pathways, and a dramatic increase in risk of thrombosis.³¹⁹

Blood clot symptoms associated with thromboembolism are related to blood flow obstruction and depend on the location of the blood clot.

Superficial venous blood clots typically cause redness and tenderness along a cord of skin over the affected vein segment.⁹ At least 50% of patients with DVT have no blood clot symptoms, but those who do frequently experience swelling, cramping pain, warmth, and redness near the blockage, usually in a calf or thigh.^3,327 They may also describe difficulty moving the limb and pain that radiates away from the site of the blood clot.³

A pulmonary embolism is generally marked by symptoms such as sharp chest pain with breathing, shortness of breath, fatigue, back pain, and fainting. Rapid breathing, rapid heart rate, fever, and low oxygen saturation may be noted on physical exam. In severe cases, pulmonary embolism can quickly evolve into a life-threatening emergency.^3,6

Arterial thrombosis becomes symptomatic when a coronary, cerebral, or another critical artery becomes occluded. The classic blood clot symptoms of angina or heart attack caused by acute thrombosis of a coronary artery include crushing left-sided chest heaviness or pain, radiating to the left arm or jaw. Pain described as stabbing or burning in the epigastric region or back also frequently occur, especially in women.^3,328 Acute thromboembolism affecting a cerebral artery is a cause of transient ischemic attack or stroke, which are associated with a range of symptoms such as confusion, headache, vision changes, weakness, difficulty walking or moving the extremities, difficulty swallowing, and unusual nerve sensations.³ Thrombosis and embolism can affect other arteries, including lower limb, mesenteric, renal, and retinal arteries, resulting in site-specific symptoms.^27,329

Venous Thrombosis

Screening. The first step in diagnosing DVT is to assess its likelihood using history and physical exam findings. A scoring system called the Wells score is an accepted tool for assessing DVT probability. The Wells score is determined by major risk factors (recent history of surgery or bed rest, immobilization, or presence of cancer), physical exam findings (edema, engorgement, enlargement, tenderness, and superficial vein dilation in the affected limb), and history (previous DVT and absence of another likely explanation for signs and symptoms).³³⁰ If the Wells score indicates DVT is likely, further assessment may be warranted.

Another screening test used in assessing thrombosis is D-dimer. D-dimer is a byproduct of fibrinolysis, and levels are elevated in patients with thrombosis due to the simultaneous activation of thrombotic and fibrinolytic pathways.³³⁰ A normal D-dimer level indicates a diagnosis other than thrombosis; however, an elevated D-dimer level is not necessarily diagnostic, since higher levels are seen in patients with infection or cancer, those who have recently undergone surgery or experienced a physical trauma, during pregnancy, and with aging.^3,330 A high D-dimer level, along with a high Wells score, supports further diagnostic work-up. A high level of C-reactive protein, a marker of systemic inflammation, increases the likelihood of a thrombosis diagnosis.³³¹

Imaging. Compression ultrasound (CUS), which is used as first-line imaging in most patients with suspected DVT,³³⁰ is performed by applying moderate probe pressure during ultrasound along a vein to assess compressibility. A lack of compressibility indicates the presence of a blood clot.⁶ CUS is highly accurate for diagnosing the more dangerous DVTs affecting proximal veins, but is less accurate in identifying distal DVTs. In some cases, a repeat CUS five to seven days after a negative result is recommended to detect distal DVTs that may have become proximal, and therefore pose an increased risk for pulmonary embolism.³³⁰ Computed tomography venography (CTV) and magnetic resonance venography (MRV) appear to have similar accuracy to CUS for diagnosing DVT, but are not widely used because of their invasive nature (ie, since they involve intravenous injections of contrast solutions).^6,330 CTV and MRV are generally reserved for cases when CUS is less reliable or not possible, such as those with severe obesity or in a cast, or individuals with suspected thrombosis in a pelvic or abdominal vein.³³⁰

Pulmonary Embolism

A set of clinical criteria is used to assess the likelihood of pulmonary embolism. D-dimer level may be checked in clinically uncertain cases. If pulmonary embolism is suspected, the diagnosis can be confirmed using computed tomography pulmonary angiography (CTPA).⁶

Arterial Thrombosis

Screening. Standard tests for cardiovascular risk can be considered indicators of arterial thrombosis risk. These include total, HDL-, and LDL-cholesterol, triglyceride, glucose, and homocysteine levels, as well as hemoglobin A1c, blood pressure, and waist circumference.¹² An elevated level of high-sensitivity C-reactive protein also suggests an increased risk of thromboembolic events like heart attack and stroke, and may be used to monitor progression of atherosclerosis.^332,333 In addition, fibrinogen level is a more specific indicator of thrombosis risk, since excess fibrinogen in circulation increases the likelihood of clot formation.³³⁴

Although D-dimer levels are not routinely measured to diagnose arterial thrombosis, some evidence suggests they may be useful as an indicator of arterial thromboembolic risk. A study that followed 7,863 subjects with a history of heart attack or unstable angina for six years found higher D-dimer levels were associated with a higher risk of major coronary artery and cardiovascular events, as well as VTE. Ten years later, elevated D-dimer levels were found to be linked to increased cardiovascular, cancer, and all-cause mortality, independently of other risk factors.³³⁵ D-dimer levels are increasingly being used to help with treatment decisions and assess risk of recurrence in stroke patients.³³⁶

Imaging. Multidetector computed tomography (MDCT) angiography is a first-line non-invasive procedure used to assess risk of thrombosis by visualizing arterial plaque and its calcium content. This technology allows for rapid and high-resolution imaging of the walls of the carotid and coronary arteries, showing narrowing of the inner diameter (lumen) and providing an estimated plaque volume. Furthermore, plaque characteristics that suggest vulnerability to thrombosis, such as evidence of vascular remodeling, spotty calcification, and lower plaque density, can be detected with MDCT angiography.⁷

Carotid ultrasonography is a first-line method that uses sound waves to detect narrowing and distortion of the carotid artery due to plaque, as well as qualities of plaque, such as greater thickness, low plaque density, spotty calcification, and ulceration, that indicate greater vulnerability following a stroke or TIA. Doppler ultrasound can be used to observe blood flow, such as in the cerebral vessels, where it can detect particles traveling in the cerebral bloodstream that may cause ischemia.^7,338 Ultrasound evaluation of atherosclerotic plaques can be further enhanced by the use of injected contrast agents.³³⁸

Magnetic resonance imaging (MRI) is sometimes used to visualize the carotid arteries. The advantage of MRI lies in its ability to detect features of the fibrous cap of a plaque that indicate its risk of rupture. An MRI can also show bleeding at the site of a ruptured plaque.^7,339

Positron emission tomography (PET) is an invasive nuclear imaging test that involves the use of an injected tracer to evaluate arteries affected by atherosclerosis. PET for this purpose is still in its investigational stage.^7,339

Intravascular ultrasound (IVUS) is performed by inserting an ultrasonic device into the arterial system using a catheter. Sound waves emitted by the device can show some characteristics of the inside of the blood vessel walls, including thickness, indicative of plaque.^7,338,339

Optical coherence tomography uses reflected near-infrared light to produce high-resolution images of the inner walls of arteries. It can detect the presence of plaque, features linked to risk of plaque rupture, and evidence of rupture and thrombosis. Near-infrared spectroscopy (NIRS) measures the absorption of near-infrared light to locate the exact position and density of lipids in the vessel wall. It has been suggested these modalities may provide the most useful information when used together or with other imaging technologies.^7,339

Clotting Disorders

Tests for underlying causes of thrombophilia may be performed in individuals who experience a blood clotting event without relevant risk factors. Thrombin time (TT) is a non-specific test of clotting capacity that measures how long it takes for a blood clot to form in a plasma sample to which thrombin has been added. If thrombin time is low, tests for autoimmune diseases, liver disease, cancer, and other conditions associated with increased clotting risk may be indicated. Protein C, protein S, and antithrombin levels can be measured to screen for clotting disorders caused by inherited deficiencies of these coagulation inhibitors.²

In a thromboembolic emergency, thrombolytic agents that promote fibrinolysis are often used, sometimes in conjunction with a medical ultrasound technique called sonothrombolysis. Surgical removal of the blood clot, known as thrombectomy, is sometimes performed to remove thrombi from accessible large arteries or veins, but is not possible for other locations.⁸ Because of the devastating nature of thromboembolic events, prevention using long-term medical therapy with antiplatelet or anticoagulant drugs (blood thinners) is the standard approach in those at highest risk. It is important to note that none of these medications address the underlying conditions that cause thrombosis and all alter hemostatic control of blood clotting, increasing the risk of bleeding with potentially dangerous outcomes.³ In addition to drugs, compression stockings are sometimes recommended to those who have experienced DVT.³⁴⁰

Thrombolytic Therapy

Thrombolytics, also known as plasminogen activators or “clot busters,” are used in the acute stage of a thromboembolic event to quickly dissolve dangerous intravascular clots and restore blood flow. These drugs are administered intravenously within several hours of the onset of acute heart attack, stroke, DVT, pulmonary embolism, peripheral artery occlusion, occlusion of an implanted catheter, or a blood clot in the heart.³⁴¹ Thrombolytics promote the production of the fibrinolytic protein, plasmin, from plasminogen in the fibrin matrix of a clot. FDA-approved clot busters include alteplase (Activase), urokinase (Kinlytic), and streptokinase (Streptase). A number of other plasminogen activators are currently under investigation.^8,341

In addition to the substantial risk of unintended bleeding, these drugs sometimes cause low blood pressure, allergic reactions, and arrhythmias. The risk of bleeding is especially high in those who are elderly, had a recent stroke or surgery, have uncontrolled hypertension, or have a bleeding tendency, and is compounded in those who regularly use anticoagulant medications.³⁴¹

Sonothrombolysis

Sonothrombolysis uses ultrasound to generate clot-breaking sound waves. It is mainly used in conjunction with thrombolytic drugs and has been found to make thrombolytic treatment faster and more effective in some circumstances.³⁴² Sonothrombolysis is thought to work by creating acoustic forces that can displace and loosen clots, facilitating thrombolytic drug diffusion into clots. This may potentially allow for lower thrombolytic drug exposure and reduced risk of hemorrhage.³⁴³

Antiplatelet Therapy

Antiplatelet drugs, a class of blood thinner medications that inhibit platelet activation and aggregation, are typically used in long-term prevention of arterial thrombosis.

Aspirin is a common anti-inflammatory antiplatelet medication that works by inhibiting cyclooxygenase, an enzyme that participates in inflammatory and pro-coagulation pathways. Low-dose aspirin (75‒100 mg per day) is widely recommended as a long-term preventive strategy in patients with a history of stroke or heart attack, in whom it has been found to lower risk of a second event by approximately 18–19%.^344,345 It is frequently used in combination with other antiplatelet agents that inhibit other platelet activation pathways and work additively or synergistically with aspirin.⁴ However, long-term use of aspirin, even at low doses, is associated with an increased risk of bleeding, most notably in the digestive tract and the brain. Since large clinical trials have found daily low-dose aspirin provides little to no cardiovascular benefit in those without a prior history of a coronary event or stroke, guidelines do not recommend its use for such individuals, except in those with exceptionally high cardiovascular risk and no other factors that increase bleeding risk.^344,346

Clopidogrel (Plavix) works by inhibiting receptors on platelet membranes called purinergic P2Y₁₂ receptors. When these receptors interact with a circulating platelet-activating molecule called adenosine diphosphate (ADP), they upregulate expression of a protein complex involved in platelet aggregation.³⁴⁷ Clopidogrel has been found to reduce the risk of recurrent stroke in patients who have experienced a non-disabling stroke that is not due to an embolism from a coronary artery.^344,347 It is frequently used in combination with aspirin in the first 90 days after a stroke to lower the risk of recurrent events, but has not been found to add to aspirin’s protective effect in long-term prevention of recurrent stroke and adds to the risk of bleeding. Clopidogrel is considered an acceptable alternative to aspirin in patients with a history of stroke, providing a similar degree of protection against recurrent stroke.³⁴⁷ Side effects of clopidogrel include increased bleeding, reduced number of neutrophils (a type of immune cell), and a rare dangerous condition called thrombotic thrombocytopenic purpura in which blood clots form in small blood vessels throughout the body.⁴

Two other drugs in the P2Y₁₂ receptor inhibitor class, ticagrelor (Brilinta) and prasugrel (Effient), are under investigation for their possible benefits during coronary artery stent implantation after a heart attack.^4,344

Dipyrimidole (Persantine) works in part by inhibiting platelet phosphodiesterase, an enzyme that increases platelet reactivity. The combination of dipyrimidole plus aspirin may be more effective than either drug alone for preventing stroke in patients with a recent non-embolic TIA or stroke.^344,347 In addition to increasing the risk of bleeding, this combination causes headaches in an estimated 40% of users.³⁴⁷

Cilostazol (Pletal) inhibits phosphodiesterase but has effects in both platelets and endothelial cells that line the blood vessel walls. Cilostazol inhibits platelet aggregation and promotes dilation of arteries, and is mainly used to treat peripheral artery disease.^4,344

Anticoagulant Therapy

Anticoagulant drugs, also referred to as blood thinners, inhibit various parts of the clotting cascade and are used long term to prevent thrombosis in high-risk patients.

Heparin is a naturally occurring anticoagulant produced by certain types of immune cells that interacts with antithrombin, increasing its inhibiting effect on several clotting factors and thrombin.³⁴⁸ Heparin is available in various forms, including unfractionated heparin, low-molecular weight heparin, and synthetic analogs, all of which require intravenous or subcutaneous injection. Because of its rapid ability to block the clotting cascade, heparin is usually used for 5–10 days in the acute stage of venous thrombosis to reduce expansion of the thrombus and prevent pulmonary embolism.^349,350 It may also be prescribed for long-term use in cancer-related thrombosis.³⁴⁹ However, heparin is often unable to completely resolve blood clots. Low platelet numbers can occur with heparin use, increasing the risk of bleeding.³⁵⁰

Warfarin (Coumadin) is a vitamin K antagonist and until recently was the only oral anticoagulant in use. It works by inhibiting vitamin K recycling, thereby reducing activation of vitamin K-dependent coagulation factors.³⁵⁰ Warfarin has a long half-life in the body, but in circumstances requiring rapid reversal of the anticoagulant effect, such as hemorrhage, overdose, or the need for emergency surgery, warfarin’s effects can be overridden by one of three antidotes: vitamin K, prothrombinase complex concentrate, or fresh frozen plasma.³⁵¹

Effective anticoagulant therapy using warfarin is especially challenging, in part because the therapeutic window—the dose range at which the likelihood of benefit from blood clot reduction outweighs the likelihood of harm from bleeding—is narrow. Responsiveness to warfarin therapy varies due to genetic differences that impact its metabolism. Because the effective dose depends partly on the blood concentration of vitamin K, dietary changes also affect responsiveness. Furthermore, warfarin is prone to interactions with foods unrelated to their vitamin K content, herbs, and other drugs. For these reasons, long-term warfarin use requires frequent monitoring, often leading to dose adjustments, to maintain both effectiveness and safety.³⁵⁰

Direct oral anticoagulants (DOACs) are members of a newer class of drugs that bind directly to specific clotting factors to interrupt the clotting cascade. Compared with warfarin, DOACs have a wider therapeutic window. Their use does not require constant monitoring, since their action is relatively predictable and less susceptible to interactions with drugs, herbs, vitamin K, and foods than warfarin.³⁵⁹ Observational evidence suggests DOACs in general are more effective and safer than warfarin³⁶⁰; nevertheless, bleeding is still an important potential side effect.^350,359

The potential of DOACs to cause bleeding may be compounded by the use of aspirin: One study found, in patients treated with a DOAC, regular aspirin use increased the risk of bleeding and did not add to the protective effect of DOAC therapy.³⁶¹ Furthermore, some evidence suggests the addition of aspirin to DOAC therapy may increase the risk of major adverse cardiac events compared with DOAC therapy alone.³⁶² More research is needed to clarify whether aspirin has beneficial effects in patients being treated with DOACs.

Individuals being treated with DOACs require an antidote to prevent hemorrhage in the event of overdose or if emergency surgery is needed.³⁵⁰ These antidotes exist but have limited availability and are expensive. Finally, the safety of DOACs in underweight and overweight patients, those with kidney or liver disease, and those older than 75 years is still uncertain.^350,359 Periodic testing of liver and kidney function are recommended in those receiving long-term DOAC therapy.³⁵⁹

Dabigatran (Pradaxa) is a DOAC that inhibits thrombin, reducing the conversion of fibrinogen to fibrin. Clinical trials have found dabigatran may prevent stroke, embolism, and recurrent venous thromboembolism with similar effectiveness to warfarin and fewer bleeding side effects. Dabigatran has been associated with digestive side effects such as gastroesophageal reflux and dyspepsia.³⁵⁰

Rivaroxaban (Xarelto), apixaban (Eliquis), edoxaban (Lixiana), and betrixaban (Bevyxxa) are DOACs that work by directly inhibiting activation of Factor Xa, a clotting factor that catalyzes thrombin production. In general, these drugs are prescribed for treatment and prevention of DVT and pulmonary embolism, as well as to prevent stroke and thromboembolic events in individuals with non-valvular atrial fibrillation.^350,359 In addition, rivaroxaban and apixaban may be used as an alternative to heparin in the first 7–21 days of acute VTE, and rivaroxaban is sometimes used in combination with aspirin to prevent stroke and heart attack in patients with coronary artery or peripheral artery disease.^349,359 In one randomized controlled trial in 18,278 patients with chronic coronary artery or peripheral artery disease, combined treatment with rivaroxaban plus aspirin reduced deaths due to cardiovascular causes more than aspirin alone during a median of 23 months of monitoring, and the benefits were greater in those with higher baseline cardiovascular risk.³⁶³

Comparing Anticoagulants

A systematic review of phase III randomized controlled trials reported dabigatran and apixaban demonstrated superiority to warfarin while rivaroxaban and edoxaban had similar effectiveness to warfarin for preventing thromboembolic events in atrial fibrillation patients. All four DOACs were less likely than warfarin to cause intracranial or other life-threatening bleeding, but only apixaban was found to reduce all-cause mortality compared with warfarin.³⁶⁴ In 807 patients with chronic DVT participating in an open comparison trial, those treated with DOACs (dabigatran, rivaroxaban, apixaban, or edoxaban) had similar improvement in thrombus status, as well as similar risk of bleeding, as those treated with warfarin after three to six months.³⁶⁵

Although randomized controlled clinical trials directly comparing the benefits and risks of the different DOACs have yet to be published, several analyses of the current data have been performed:

• An analysis of findings from 28 randomized controlled trials with more than 139,000 participants using anticoagulant therapy for any indication showed the risk of major gastrointestinal bleeding was as common in those treated with standard doses of DOACs as with warfarin; when considered separately, apixaban was found to be associated with a lower risk of major gastrointestinal bleeding than dabigatran and rivaroxaban.³⁶⁶
• An analysis of data from 11 observational studies in atrial fibrillation patients found apixaban was associated with a lower risk of major bleeding events than dabigatran, rivaroxaban, and warfarin; dabigatran was associated with a lower risk of major bleeding than rivaroxaban and warfarin; and rivaroxaban and warfarin had a similar propensity to cause major bleeding.³⁶⁷
• An observational study that compared outcomes in 21,265 patients who received prescriptions for dabigatran, rivaroxaban, apixaban, or warfarin found DOACs were generally more effective for stroke prevention than warfarin. When history of previous stroke or TIA was considered, the three DOACs performed similarly well in those who had not experienced a prior stroke or TIA, but in those who had experienced a stroke or TIA dabigatran and rivaroxaban lowered stroke risk more than apixaban.³⁶⁸
• An observational study analyzed data from more than 600,000 elderly atrial fibrillation patients to compare the effects of each of three DOACs (dabigatran, rivaroxaban, and apixaban) to warfarin on combined risk of major bleeding, stroke, or death. The study found dabigatran and rivaroxaban were associated with lower adverse event risk in non-frail individuals, but not in frail individuals, while apixaban was associated with lower adverse event risk across all levels of frailty.³⁶⁹
• A study that examined data from 320 atrial fibrillation patients over 90 years old found DOACs were associated with fewer thromboembolic events but more major bleeding events compared with warfarin during three years of monitoring.³⁷⁰
• An observational study included data from 117,912 atrial fibrillation patients prescribed warfarin, dabigatran, rivaroxaban, or apixaban. The risk of venous thromboembolism was lower in those receiving dabigatran or apixaban than in those receiving warfarin or rivaroxaban. Reduced risk of venous thromboembolism may be an additional benefit of anticoagulant therapy with apixaban or dabigatran.³⁷¹
• Using a variation of meta-analysis that included indirect findings, researchers examining results from 23 randomized controlled trials with a combined total of 94,656 participants found the evidence indicates apixaban may have the highest net benefit compared with other DOACs and warfarin.³⁷²

Compression Stockings

Graduated compression stockings, which apply the greatest amount of pressure at the ankle and the least at the knee, are sometimes used to prevent post-thrombotic syndrome in DVT patients and relieve symptoms in patients with chronic venous disease.³⁷³ One systematic review of data from eight trials found the use of compression stockings during air travel reduced edema and VTE, which may lead to post-thrombotic syndrome, in high-risk individuals.³⁷⁴ However, clinical trials assessing their general efficacy have so far yielded mixed results, and many patients stop using compression stockings due to discomfort.^340,375

Several tests are available for assessing the risk of recurrent thrombosis and monitoring long-term anticoagulant therapy.

• Activated partial thromboplastin time (APTT) assesses the function of a group of clotting proteins and fibrinogen. It can be used to monitor the effects of anticoagulation therapy, mainly in those receiving unfractionated heparin.^2,348 A low APTT value in the absence of anticoagulant therapy indicates an increased propensity for clotting. Some anticoagulant medications, including unfractionated heparin, increase APTT, reflecting prolongation of the time needed for clot formation.²
• Prothrombin time (PT) evaluates the function of the clotting cascade and international normalized ratio (INR) expresses it in standardized terms. PT measures the time to form a clot under certain laboratory conditions, while INR is a calculation based on the individual’s PT value and average PT values in order to standardize for differences in laboratory methods.² In those being treated with warfarin, PT and INR testing is performed regularly to make dosage adjustment decisions.³⁴⁸
• Diluted thrombin time and ecarin clotting time are used to directly assess the anticoagulation effects of dabigatran. Routine monitoring is not needed, but these tests may be helpful in circumstances such as before emergency surgery, when drug-drug interactions are in question, or in the event of a hemorrhage.³⁷⁶
• Anti-Xa assay measures inhibition of the clotting cascade protein Factor Xa and is used to assess the treatment effects of Factor Xa inhibitors like apixaban, rivaroxaban, and edoxaban. However, the clinical usefulness of anti-Xa assays in patients using these drugs has not been established.^359,376 It may provide helpful information in those receiving heparin.³⁴⁸

There is no generally accepted method for routine monitoring of antiplatelet therapy. However, a variety of platelet function tests may be useful under certain circumstances, such as optimizing timing of urgent surgery after oral antiplatelet drugs are stopped or individualizing care for an actively bleeding patient. Some examples of these tests include^377-379:

• Lab-based tests include light transmission aggregometry (LTA), which can assess the effects of aspirin or clopidogrel, and vasodilator-stimulated phosphoprotein assay, which is used to assess effects of clopidogrel.
• VerifyNow P2Y12 assay and Multiplate analyzer are in-office tests used specifically for assessing clopidogrel responsiveness.
• Platelet function analyzer-100 (PFA-100) and Plateletworks assay are additional tests that can be used to assess aspirin or clopidogrel effectiveness.

Sonothrombolysis Innovations

New technologies are being investigated for their potential to increase the effectiveness of sonothrombolysis. The use of microbubbles and nanodroplets that amplify and focus the ultrasonic mechanical action have demonstrated promising effects in laboratory and clinical studies. An ultrasonic device mounted on a catheter can deliver ultrasound from within the blood vessel and may be helpful in treating large blood clots.^343,380 High-intensity focused ultrasound and histotripsy are modified therapeutic ultrasound techniques that fractionate clots and may potentially eliminate the need for thrombolytic drugs.³⁴³

Canakinumab

Inflammasomes are large protein complexes in cells that initiate the inflammatory response by increasing the production of cytokines. In atherosclerotic blood vessels, cholesterol crystals stimulate an immune cell inflammasome called NLRP3 that then triggers a cascade of inflammatory and thrombotic signaling.³⁸¹

Canakinumab (Ilaris) is a monoclonal antibody that inhibits interleukin-1β, an inflammatory cytokine produced in response to NLRP3 inflammasome activation and closely linked to cardiovascular disease.^381,382 A large, randomized, placebo-controlled trial found canakinumab had beneficial effects in high-risk patients. The trial included 10,061 subjects who had experienced a heart attack 30 days or more prior to enrollment and had hs-CRP levels of 2.0 mg/L or higher, indicating ongoing inflammation despite standard medical therapy for their high cardiovascular risk. They received 50, 150, or 300 mg canakinumab, or placebo as subcutaneous injections every three months for a median of 3.7 years. Those receiving 150 mg canakinumab had a 15% lower risk of heart attack, stroke, or death from cardiovascular causes compared with placebo.³⁸³ A secondary analysis of the results showed, among subjects receiving canakinumab, those who achieved an hs-CRP level of less than 2.0 mg/L had 31% lower rates of cardiovascular and all-cause deaths, while those whose hs-CRP levels remained 2.0 mg/L or higher had no reduction in these outcomes.³⁸⁴ However, canakinumab was also associated with a small increase in fatal infections such as sepsis (an infection in the blood), cellulitis, and pneumonia.³⁸⁵

Abelacimab

Abelacimab (previously MAA868) is a novel monoclonal antibody that binds to clotting factor XI and thereby interrupts activation of other clotting factors and production of thrombin and fibrin. In a single randomized open-label controlled trial supported by the manufacturer, 412 subjects undergoing total knee replacement surgery received a single intravenous injection of one of three abelacimab doses immediately following surgery, or subcutaneous injections of the anticoagulant enoxaparin (Lovenox) once daily after surgery. Compared with those who received enoxaparin, the risk of venous thromboembolism was lower in those who received the middle and high doses of abelacimab and no different in those who received the low dose.³⁸⁶ A trial comparing safety and tolerability of abelacimab to rivaroxaban in atrial fibrillation patients is currently underway.³⁸⁷

Repurposing Statins

Statins are a family of medications used to lower high cholesterol levels. Examples of statins are atorvastatin (Lipitor), lovastatin (Mevacor), simvastatin (Zocor), and rosuvastatin (Crestor). Multiple randomized controlled trials have shown their use lowers the risk of arterial thromboembolic events, including heart attack and stroke, and observational studies have reported correlations between statin use and lower DVT/pulmonary embolism risk.^388-391 A meta-analysis that included data from 12 observational studies found venous thromboembolism (VTE) patients being treated with a statin drug for high cholesterol levels were 24% less likely to experience a recurrence of either DVT or pulmonary embolism.³⁹² In one study that followed 980 elderly participants with a previous DVT or pulmonary embolism for a median of 2.5 years, statin use was associated with a 50% reduction in risk of a recurrence, but only during periods when anticoagulant drugs were not being used.³⁹³ Some evidence suggests statin users are less likely to develop post-thrombotic syndrome, a complication of DVT.³⁹⁴

Several mechanisms may contribute to statin drugs’ antithrombotic effects. A meta-analysis of randomized controlled trials found statins reduced levels of plasminogen activator inhibitor-1, resulting in increased production of plasmin, a fibrinolytic enzyme.³⁹⁵ Other research has shown statins can reduce the expression of an adhesion molecule involved in platelet aggregation, inhibit steps in the clotting cascade, and increase production of nitric oxide synthase, an enzyme involved in regulating vascular function.^394,396 Statins may also decrease inflammatory marker levels, oxidative stress, platelet reactivity, and endothelial injury.^396,397 The most common adverse side effects of statin therapy include muscle pain and increased blood levels of liver enzymes, and some drugs in the statin family are linked to increased risk of type 2 diabetes; uncommonly, statins can cause serious muscle tissue injury.³⁹⁸ Because statin use lowers CoQ10 production, patients taking statins may benefit from supplementing with CoQ10.^136,138,140

Repurposing Colchicine

Colchicine (Mitigare, Colcrys) is an anti-inflammatory drug used to treat gout. In observational studies, gout patients treated with colchicine were noted to have fewer heart attacks, strokes, and TIAs, and had lower mortality than gout patients who were not treated with colchicine.³⁹⁹

In a randomized placebo-controlled trial, 5,522 patients with atherosclerosis receiving standard cardiovascular risk-lowering therapies were given 0.5 mg of colchicine or placebo daily. After an average of 28.6 months, the incidence of major cardiovascular events was 31% lower in those given colchicine.⁴⁰⁰ Another randomized placebo-controlled trial in 4,745 patients with a recent history of heart attack found 0.5 mg colchicine daily lowered the risk of major cardiovascular events by 23% during a median follow-up of 22.6 months; however, pneumonia occurred more frequently in those receiving colchicine.⁴⁰¹ A meta-analysis of five randomized controlled trials with a total of more than 11,000 participants found colchicine reduced the risk of major thromboembolic cardiovascular events in patients with coronary artery disease.⁴⁰² Another meta-analysis of nine trials with a total of 6,630 participants found colchicine lowered the risk of stroke, but not other major cardiovascular events.⁴⁰³

Colchicine inhibits the pro-inflammatory activity of the NLRP3 inflammasome protein complex, and has been found to reduce expression of tissue factor, a protein with a pivotal role in initiating thrombosis, in response to oxidized LDL-cholesterol.^404-406 The most common adverse side effects caused by colchicine are nausea, vomiting, and diarrhea. In rare cases, it can cause liver injury, severe muscle injury, allergy, and blood disorders.⁴⁰⁵

Repurposing Metformin

Metformin is a blood glucose-lowering medication used to treat type 2 diabetes. It has been shown to reduce cardiovascular risk in diabetic individuals, independently of its effect on blood glucose levels. Observational evidence from a study that monitored nearly 15,000 participants with type 2 diabetes for over three years noted metformin was correlated with reduced risk of deep vein thrombosis.⁴⁰⁷ Another study comparing outcomes in more than 32,000 diabetic subjects who had undergone knee replacement surgery found those who were taking metformin had better outcomes and lower risk of complications, including DVT.⁴⁰⁸ Preclinical and clinical research has shown metformin use is associated with improved endothelial function, lower levels of tissue factor, reduced levels of oxygen free radicals, and decreased platelet activation and aggregation.^409,410

Repurposing Pentoxifylline

Pentoxifylline (Pentopak, Pentoxil, or Trental) is a drug that reduces blood viscosity and improves blood flow. It is approved for use in treating claudication, a peripheral vascular disorder affecting the legs that is marked by ischemic pain, and is sometimes used to treat venous ulcers in the legs. Pentoxifylline stimulates fibrinolysis, inhibits platelet aggregation and adhesion, and reduces inflammatory cytokine and free radical production.⁴¹¹ Early observations suggested pentoxifylline may be helpful in treating stroke patients.⁴¹² In one trial that included 97 participants, pentoxifylline was found to be more effective than a combination of aspirin plus dipyridamole (Persantine) for preventing re-closure of blood vessels in the legs during six months following vascular surgery (for treatment of occlusion in the aortoiliac or femoropopliteal regions or both).⁴¹³ A placebo-controlled trial in 51 hemodialysis patients found pentoxifylline prevented blood clots from forming in arteriovenous shunts implanted to facilitate dialysis.⁴¹⁴ Pentoxifylline was also found to lower the risk of a dangerous blood clotting disorder in premature newborns,⁴¹⁵ and appeared to be helpful in treating a similar clotting emergency in adult patients with severe blood infections.⁴¹⁶ In a clinical trial comparing the effects of various antiplatelet agents, pentoxifylline was among the drugs shown to enhance the effectiveness of anticoagulant therapy in severe or recurrent DVT patients.⁴¹⁷

Side effects of pentoxifylline include digestive upset, dizziness, headache, and flushing; less commonly, it causes chest pain, arrhythmia, or low blood pressure. Pentoxifylline can enhance the effects of blood pressure- and blood glucose-lowering medications and increase the risk of bleeding in patients taking antiplatelet or anticoagulant drugs. Because pentoxifylline increases blood flow to the heart, it is not indicated for patients with severe coronary artery disease or after acute heart attack.⁴¹¹

Intravenous Ginseng

Chinese ginseng (Panax notoginseng) contains saponins known as ginsenosides that are used extensively in China to treat stroke due to their ability to inhibit platelet aggregation and protect neurons from injury.²⁷⁵ A meta-analysis of data from 23 randomized controlled trials with a combined total of 2,196 participants found adding ginseng saponins (formulated for intravenous injection) to standard medical therapy improved outcomes in acute stroke patients.⁴¹⁸ An intravenous preparation of Chinese ginseng saponins has also been widely studied for its ability to prevent and treat venous thrombosis, similar to Western “clot busters.” A meta-analysis of 20 randomized controlled trials with a total of 2,336 participants who had undergone orthopedic surgery due to fracture found those given injections containing ginseng saponins had fewer DVTs, lower D-dimer levels, and longer prothrombin and thrombin times.⁴¹⁹ Another meta-analysis of 12 randomized controlled trials that included a total of 1,018 DVT patients found the use of ginseng saponin injections as an add-on therapy resulted in better treatment outcomes.⁴²⁰