Blood Clot Prevention
Dietary Approaches to Reduce Thrombosis Risk
The successful nutritional approach to reduce thrombosis risk does not depend solely on a set of "antithrombotic nutrients." Rather, Life Extension supports a multifactorial approach that includes nutrition and lifestyle interventions to reduce the risk of thrombosis. These include abnormal blood lipids, chronic inflammation, hypertension, elevated plasma homocysteine, and obesity.
Reducing platelet activation and aggregation
Platelet activation and aggregation occurs via a complex, multifactorial process. Several natural ingredients can target varying steps involved in clot formation, and a diversified regimen can provide multiple defenses against aberrant clotting.
Olive (Olea europaea) has a history of use against high blood pressure, atherosclerosis, and diabetes (Jänicke 2003). The leaves contain the active iridoid compounds oleuropein and oleacein (Somova 2003), which are thought to be responsible for its blood pressure-lowering and cholesterol-lowering properties demonstrated in recent human trials (Perrinjaquet-Moccetti 2008).
In laboratory tests, olive leaf extract also demonstrated antiplatelet activity in blood isolated from healthy male volunteers (Singh 2008). High-oleuropein extracts from olive tree wood also inhibit aggregation of human platelets in laboratory tests, especially those from type II diabetic patients (Zbidi 2009). Hydroxytyrosol and hydroxytyrol acetate, two metabolites of oleuropein that are found in olive fruit and oil, have well-established anti-inflammatory and antiplatelet activities in laboratory tests and in animal models (reviewed in Granados-Principal 2010).
Olive oil is a rich source of monounsaturated fats. Unsaturated fats, including monounsaturated fats, have been found to increase blood levels of cardioprotective apolipoprotein A-IV (apoA-IV) more than saturated fats (Kratz 2003). ApoA-IV has recently been discovered to inhibit platelet aggregation by blocking fibrinogen from binding to receptors known as glycoprotein IIB/IIIA (Xu 2018).Phenolic-rich olive oil preparations have demonstrated decreases in the production of proinflammatory and prothrombotic factors in human studies as well (Bogani 2007; Visioli 2005). In a study in healthy men, olive oil’s oleocanthal content was correlated with its ability to inhibit platelet aggregation (Agrawal 2017). Hydroxytyrosol acetate inhibits platelet aggregation with an efficacy similar to aspirin in vitro using whole blood samples from healthy volunteers (Correa 2009). Hydroxytyrosol-rich extracts (25mg/day) for 4 days reduced production of the prothrombotic factor thromboxane A2 in a pilot trial of 5 diabetic adults (Léger 2005). High-fat diets rich in olive oil lowered the plasma levels of several clotting factors in a larger study of 20 healthy young adults (Junker 2001).
Tea consumption has established protective effects on cardiovascular health; reductions in risk of coronary heart disease and stroke from tea consumption have been confirmed through the analyses of several population studies (Peters 2001). Purified green tea polyphenols, such as EGCG, increase clotting time in rats and reduce platelet aggregation in isolated human platelets (Kang 1999).
Human trials of tea consumption and thrombosis risk have had mixed results. While short-term consumption (2 weeks) of green tea showed no measurable effect of platelet activity (Hirano-Ohmori 2005), longer-term studies showed modest improvements in platelet function (Wolfram 2002). The most promising results have been observed in a randomized, blinded trial of tea consumption; 6 weeks of black tea consumption (4 cups/day) in 37 healthy volunteers significantly reduced platelet activation, as measured by the presence of platelet aggregates (Steptoe 2007). Tea catechins and the flavonoid quercetin have demonstrated synergistic reductions in platelet adhesion, activation, and aggregation in vitro (Pignatelli 2000).
Quercetin has demonstrated success inhibiting platelet aggregation. Single doses of quercetin glucosides, the naturally occurring form of quercetin (150 or 300 mg), from food sources and higher quality dietary supplements, were able to significantly inhibit collagen-induced platelet aggregation in one small human study (Hubbard 2004). However, long-term supplementation with 1 gram/day of quercetin aglycone (the form typically found in lower quality dietary supplements) for 28 days had no significant effect on platelet aggregation in healthy human volunteers (Conquer 1998). It should be noted that the plasma concentrations of quercetin in the former study (successful) were significantly higher than in the latter at the time of aggregation measurements, suggesting that quercetin glucosides are absorbed more efficiently than quercetin aglycone. Quercetin from food sources (onions) have shown positive trends on platelet aggregation (Hubbard 2006).
Salvia is a diverse genus of plants encompassing hundreds of species, many with ornamental, culinary, or medicinal importance. Salvia miltiorrhiza (red sage or danshen) is one of the most versatile Chinese herbal drugs, used for hundreds of years in the treatment of cardiovascular diseases (Cheng 2007) and still widely used as standard thrombolytic treatment in Chinese hospitals (Wu 2007). Salvianolic acids A and B, water soluble polyphenols from S. miltiorrhiza root, are responsible for its observed antiplatelet activity in animal models (Fan 2010) and in blood samples from healthy human volunteers (Huang 2010).
The seeds of Salvia hispanica (chia) are rich in protein and the omega-3 fatty acid α-linolenic acid. In a small study of 27 patients with type II diabetes, whole chia seed (15g / 1000 kcal of intake) for 12 weeks showed significant reductions in plasma fibrinogen and the platelet adhesion protein von Willebrand factor (vWF). Small reductions in additional cardiovascular risk factors (systolic blood pressure and high-sensitivity C-reactive protein) were also observed (Vuksan 2007).
Resveratrol has several effects on blood platelets as determined in vitro (using human platelets) and in animal models, including inhibition of platelet adhesion and aggregation, reduction in secretion of clotting factors from platelets, and inhibition of cyclooxygenase, the proinflammatory enzyme involved in platelet activation (Olas 2005; Yang 2011). Plasma resveratrol from consumption of red or white wine increases the release of nitric oxide from platelets in healthy volunteers, inhibiting their activation (Gresele 2008). In an experimental study, resveratrol was able to suppress the detrimental effects of homocysteine on platelet aggregation and free radical generation (Malinowska 2011).
Grape Seed Extract contains oligomeric procyanidins that support cardiovascular health through vasodilation and an increase in nitric oxide production (Clouatre 2010). They have significantly reduced blood pressure in human trials (Siva 2006). Grape seed extract also exhibits antithrombotic activity in animals (Sano 2005) and in platelets isolated from healthy human volunteers (Vitseva 2005). This may be related to an anti-inflammatory effect (Zhang 2011).
In a small, 8-week study of 17 post-menopausal women taking 400 mg of flavonoid-rich grape seed extract /day, a significant (23%) lengthening of clotting time compared to the control was observed on day 1 of the study. (Increased clotting time indicates reduced platelet activation and aggregation.) (Shenoy 2007). After 8 weeks, the difference in clotting time was not as significant, but trended higher in the test group (Shenoy 2007). Similar short-term reductions in platelet activity also were observed in a study of 23 male smokers (Polagruto 2007). When combined with grape skin polyphenols, grape seed extracts demonstrated better antiplatelet properties than either extract alone in animal models as well as human platelets (Shanmuganayagam 2002).
Tomatoes contain several nutrients with established protective effects on the cardiovascular system. Lycopene has demonstrated hypotensive activity in humans (Engelhard 2006), and several human trials indicate a cholesterol-lowering effect (Ried 2011). One mechanism by which lycopene may limit platelet aggregation is by activating cyclic-GMP, a signaling molecule involved in vessel dilation.
Tomatoes also exert potent antiplatelet activity in laboratory tests (Dutta-Roy 2001). The antithrombotic compounds of tomato are small molecules found within its water-soluble fractions, which are also high in soluble sugar content. Removal of these sugars increases the concentration of tomato actives and stimulates their inhibition of platelet aggregation by up to 50 times (O'Kennedy 2006a).
Two studies examined the effects of these standardized tomato extracts on platelet function in healthy human volunteers: High dose (18 g, equivalent to 6 whole tomatoes) and low dose (equivalent to 2 tomatoes) standardized tomato extracts both exhibited significant reductions in platelet aggregation up to 6 hours after ingestion (O'Kennedy 2006a ; O'Kennedy 2006b). Standardized bioactives from tomato suppress platelet adhesion and aggregation by reversibly inhibiting P-selectin and GPIIb/IIIa, two receptors necessary for clot formation (O'Kennedy 2006b; O'Kennedy 2006a).
Pomegranate contains several bioactive antioxidant polyphenols, including the unique tannins punicaligins. Pomegranate juice consumption has been associated with significant decreases in blood pressure in hypertensive subjects (Aviram 2001; Sumner 2005) and decreases in LDL cholesterol oxidation (Aviram 2004). Pomegranate juice polyphenols also function as vasodilators by supporting endothelial function, and as inhibitors of angiotensin-converting enzyme, an enzyme associated with high blood pressure. Two weeks of pomegranate juice consumption (50ml/day) reduced platelet aggregation by 11% in a small study of 13 healthy individuals (Aviram 2000). In a human clinical trial, pomegranate juice consumption was shown to prolong clotting time as little as 6 hours after consumption (Polagruto 2003).
Garlic's (Allium sativum) promotion of cardiovascular health has been substantiated by several human trials, particularly its blood pressure-lowering activity (Ried 2008) and its ability to induce favorable blood lipid profiles (Reinhart 2009). In cell models, garlic extracts inhibit platelet aggregation by reducing ion signaling involved in platelet activation, and by increasing synthesis of c-GMP, a vasodilator. Garlic bioactives also promote endothelial nitric oxide release and enhance fibrinolysis (Rahman 2006; Rahman 2007). Moreover, garlic inhibits the COX-1 and COX-2 enzymes, which suppresses TXA2 levels (Park 2011).
The antithrombotic activity of garlic has also been the subject of several human trials in both healthy subjects and patients with cardiovascular disease, using aged extracts (Steiner 1998), water extracts (Bordia 1998), or garlic oil (Wojcikowski 2007). Garlic demonstrated reductions in platelet aggregation in each of the studies.
Fish Oil is a source of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are essential for several metabolic processes. Studies of tens of thousands of moderate- and high-risk cardiovascular disease patients demonstrated the ability of fish oil to reduce plasma triglycerides, blood pressure, and the risk of cardiovascular mortality (Marik 2009). Several human studies observed the antithrombotic activities of fish oil (McEwen 2010), due in part to its ability to reduce the production of the platelet aggregator thromboxane A2, a metabolite of the inflammatory omega-6 fatty acid arachidonic acid.
Fish oil consumption decreases platelet activation (Nomura 2003) and aggregation (Mori 1997), and plasma fibrinogen levels (Vanschoonbeek 2004). In type 2 diabetic patients, the pooled data from three human trials of 159 participants demonstrated a reduction in plasma fibrinogen by 32 mg/dL, and platelet aggregation by more than 10% (Hartweg 2009).
Capsaicinoids, (capsaicin and dihydrocapsaicin), are the major pungent constituents of chili peppers from the genus Capsicum. Regular intake of chili peppers delays oxidation of serum lipids, and lowers and improves insulin and glucose profiles following a meal, both of which contribute to reducing the risk of cardiovascular disease (Ahuja 2006). In animal models, capsaicin reduces platelet aggregation (Wang 1984). An early study attributed the reduced plasma fibrinogen and increased fibrinolytic activity of native Thai individuals, compared to Americans living in Thailand, to the amounts of capsaicin in their diets (Visudhiphan 1982). In laboratory tests, both capsaicin and dihydrocapsaicin reduced platelet aggregation and reduced the activity of clotting proteins in blood samples from 6 healthy patients (Adams 2009).
Ginger has been shown to inhibit platelet aggregation and to decrease platelet thromboxane production in laboratory tests (Srivas 1984). Both raw and powdered preparations reduced platelet aggregation in small human trials (Chrubasik 2005). Five grams /day of fresh ginger for 7 days inhibited thromboxane production in 7 healthy volunteers (Srivastava 1989), while two additional studies (a single dose of 2.5 g dried powder in 10 healthy volunteers and 10 grams dried powder /day for 3 months in 30 patients with coronary artery disease) demonstrated inhibition of platelet aggregation (Verma 1993; Bordia 1997). Doses lower than 2.5 grams had no effect in human trials (Lumb 1994).
Curcumin has a variety of protective roles in cardiovascular health, reducing oxidative stress, inflammation, and the proliferation of vascular smooth muscle cells and monocytes (immune cells that contribute to atherosclerosis in the presence of oxidized LDL cholesterol). Human trials revealed the effects of curcumin on reducing lipid peroxidation (Ramirez Boscá 1995; Ramirez Boscá 1997) and plasma fibrinogen (Ramirez Boscá 2000), both factors in the progression of atherosclerosis (Wongcharoen 2009). Another mechanism by which curcumin inhibits platelet aggregation is through dampening expression of P-selectin, an adhesion molecule expressed on both activated endothelial cells and platelets that mediates aggregation between these two cell types (Vachharajani 2010). P-selectin also recruits leukocytes to the forming thrombus.
In 8 subjects with abnormally high plasma fibrinogen, 20 mg of curcumin for 15 days reduced fibrinogen levels by nearly 50% (Ramirez Boscá 2000). Experiments using human platelets or whole blood have demonstrated curcumin's ability to inhibit platelet aggregation (Jantan 2008).
French maritime pine bark extract (commercially known as Pycnogenol), which has strong anti-inflammatory and free radical-scavenging effects, has been found to stabilize vascular collagen and prevent blood clots (Gulati 2014). In in vitro research, an extract from New Zealand pine bark reduced cytokine-related expression of adhesion molecules by endothelial cells, thereby reducing the likelihood of blood cell aggregation, in response to inflammatory signaling (Kim 2010).
Pine bark extract may help travelers avoid blood clots during and after long flights. One study compared the effect of pine bark extract to placebo in 198 long-haul air travelers with a high risk of blood clots. Travelers received 200 mg pine bark extract or placebo two to three hours before flight time and six hours later, and 100 mg the next day. Flights averaged 8.25 hours. No thrombotic events occurred in those given pine bark extract, but five occurred in the placebo group (Belcaro 2004). In another trial, 186 travelers on seven to eight hour flights received two tablets containing 150 mg of a proprietary blend of pine bark extract plus nattokinase or placebo two hours before travel and six hours later, and completed pre- and post-flight monitoring of edema and blood clots. No thrombotic events occurred in the treated group, but seven flight-related thrombotic events occurred in the placebo group. In addition, edema scores based on measurements taken before treatment and after air travel decreased by 15% in the pine bark-nattokinase combination group and increased 12% in those receiving placebo, with a significant difference between the two (Cesarone 2003).
One trial examined the effect of pine bark extract in 156 participants who experienced a single episode of deep vein thrombosis (DVT). Participants were assigned to one of three treatments: pine bark extract, compression stockings, or both. After one year, two new episodes of DVT occurred in participants using compression stockings versus none in either of the groups receiving pine bark extract. In addition, pine bark extract was more effective than compression stockings in reducing edema and as effective in improving microcirculation, while the combination of both was the most effective. This may be especially significant because compression stockings are historically associated with low compliance due to discomfort (Errichi 2011).
Findings from a clinical trial suggest pine bark extract may help prevent thrombosis and other side effects in cancer patients undergoing chemotherapy and radiation therapy. The study included 46 cancer patients who began supplementing with three 50 mg pine bark extract or placebo after meals (total of 150 mg daily) after completing their first course of chemotherapy or radiation. After two months, the patients receiving pine bark extract had decreased frequencies of all investigated side effects, including thrombotic events, compared with those receiving placebo (Belcaro 2008).
Suppressing fibrinogen levels
Niacin/Nicotinic acid (vitamin B3) is an essential nutrient with important effects throughout human metabolism. At dosages substantially above the Recommended Dietary Intake (RDI), niacin reduces risk factors for cardiovascular disease, and reduces cardiovascular events and mortality (Duggal 2010). Some of this risk reduction is due to niacin's ability to significantly raise HDL cholesterol by up to 35% (Morgan 2003), and reduce the amount of small, dense low-density lipoprotein (LDL) particles, a risk factor for atherosclerosis (Florentin 2010).
Niacin also lowers plasma fibrinogen levels, a risk factor for cardiovascular disease. In the multi-center Arterial Disease Multiple Intervention Trial (ADMIT), patients with peripheral arterial disease (PAD) who were randomized to niacin (initially 100 mg a day, raised to 3,000 mg/day over the 12 month study) saw an average reduction of fibrinogen by 48 mg/dL (~13.5%), as well as a reduction in prothrombin time, a measure of blood clotting (Philipp 1998). Similar reductions in plasma fibrinogen (-54 mg/dL, ~15%) were observed in a 6-week study of men with elevated triglycerides (Johansson 1997).
Vitamin C may possibly suppress fibrinogen levels, as suggested by some association studies. A study involving more than 3,200 men in the UK found those with the higher plasma levels of vitamin C also had lower levels of fibrinogen and superior endothelial function (Wannamethee 2006). Likewise, a study of 96 aging men and women found that an increase of dietary vitamin C of 60 mg daily, or the equivalent of about one orange, was associated with a reduction in fibrinogen that was estimated to cause a 10% reduction in risk of ischeamic heart disease (Khaw 1995).
In an animal model, vitamin C was shown to reduce levels of von Willebrand factor and fibrinogen, suggesting inhibition of platelet adhesion and aggregation. Moreover, vitamin C was able to reduce blood pressure in this study (Haidara 2004).
An experimental study found that incubation of fibrinogen molecules with vitamin C in vitro caused functional changes to fibrinogen, which may be associated with an impaired capacity for binding the surface of platelets (Sharma 1987).
Promoting fibrinolysis (clot breakdown)
Nattokinase is a fibrinolytic enzyme (an enzyme that breaks down fibrin clots) found in natto, a soy fermented by the bacteria Bacillus subtillis. The bacteria produce the enzyme—nattokinase is not a metabolite of soy. In laboratory tests it reduces platelet aggregation and blood viscosity (Pais 2006), and enhances the fibrinolytic activity of plasma in animal models (Fujita 1995).
At a dose of 4,000 fibrinolysis units (FUs)/day, nattokinase has been shown to reduce circulating fibrinogen and clotting factors (which are independent risk factors for cardiovascular disease) in patients undergoing dialysis or with cardiovascular disease, and in healthy volunteers (Hsia 2009). It was also able to reduce the frequency of deep vein thrombosis in 94 high-risk individuals on extended airline flights when combined with pine bark extract, or pycnogenol (Cesarone 2003). Nattokinase also has been shown to reduce blood pressure in hypertensive individuals, which may be attributed to its ability to lower blood viscosity (Kim 2008).
Ethanol (drinking alcohol), in low doses, reduces thrombotic risk by modifying platelet function and reducing platelet aggregation. As little as a half glass of red wine daily provides enough ethanol to reduce thrombotic risk. However, higher doses of ethanol increase the risk for clotting substantially (Salem 2005). All types of ethanol consumed in moderation (two drinks or less daily for men and one drink or less daily for women) should reduce thrombotic risk, but red wine also provides beneficial polyphenols such as quercetin.
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