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Diet and Thrombosis Risk: Nutrients for Prevention of Thrombotic Disease
Abstract
An increased prothrombotic state is a major risk factor for the development of heart attacks, strokes, and venous thromboembolism. Platelet activation and aggregation play an important role in determining a prothrombotic state. Although pharmaceutical agents such as aspirin, heparin, and warfarin are able to reduce prothrombotic tendency, long-term drug treatment may produce a variety of side effects, including bleeding. Diet is generally recognized to be significantly involved in modifying the individual risk for the development of thrombotic diseases, although its influence during the treatment of these disorders is probably less important. Dietary intervention has proven effective in lowering serum lipid levels, which are otherwise essential elements in the pathogenesis of cardiovascular disease. Likewise, certain dietary components have also been proven effective in decreasing platelet activation through various mechanisms and therefore may contribute to attenuating the future risk of thrombosis. This article provides an up-to-date review of the role of nutrient and nonnutrient supplements on platelet aggregation and risk of thrombosis.
... The combination of 4 µmol lycopene/L with 140 µmol aspirin/L showed better results than a single dose of 140 µmol aspirin/L. Phang et al. (43) found an inverse association between plasma and tissue levels of lycopene and the incidence of acute coronary disorders, development of early atherosclerosis, and mortality from heart disease. In addition, Thies et al. (44) showed that subjects with higher lycopene concentrations had a lower risk of suffering a myocardial infarction (59%) and showed a significant improvement in HDL functionality enhancing HDLantiatherogenic properties. ...
Cardiovascular disease (CVD) includes a group of disorders of the heart and blood vessels that includes numerous problems, many of which are related to the process called atherosclerosis. The present work is aimed to analyze the most relevant studies examining the potentially beneficial effects of tomato products on both CVD prevention and antiplatelet aggregation as well as an European Food Safety Authority health claims evaluation on tomato and tomato products. To date, only one health claim has been approved for a concentrated extract of tomato soluble in water (WSTC) marketed under the patented name of Fruitflow® with two forms of presentation: WSTC I and II, with the following claim “helping to maintain normal platelet aggregation, which contributes to healthy blood flow.” Other studies also demonstrate similar beneficial effects for fresh tomatoes, tomato products and tomato pomace extracts.
... Consumption of French fries was linked to an increased risk of VTE, in particular pulmonary embolism, an association that warrants confirmation. Data on the associations of the other studied food groups with VTE risk are limited [20]. ...
Background and aims
Inflammation has been revealed to facilitate thrombogenesis and to increase the risk of venous thromboembolism (VTE). However, limited data are available on the association between the anti-inflammatory diet and incident VTE. We conducted a cohort analysis to examine this association and to further examine whether this association is modified by smoking status, a trigger of systemic inflammation.
Methods and results
We used data from two cohorts including 81 507 middle-aged and older Swedish adults without previous VTE at baseline. An empirically validated anti-inflammatory diet index (AIDI), based on 12 foods with anti-inflammatory potential and 5 foods with pro-inflammatory potential, was employed to estimate the anti-inflammatory potential of diet. Hazard ratios (HRs), with corresponding 95% confidence intervals (CIs), of VTE were estimated by Cox proportional hazards regression models. During a mean follow-up of 17.8-years, 5241 VTE cases were diagnosed. Compared with individuals in the lowest quartile of the AIDI (score ≤4), those in the highest quartile (score ≥8) had a 9% (95% CI, 0-17%) lower risk of VTE. The inverse association was observed in current and past smokers (HR between the two extreme quartiles, 0.80, 95% CI, 0.70-0.91) but not in never smokers (HR, 1.03, 95% CI, 0.91-1.17). French fries (HR per serving, 1.33, 95% CI, 1.06, 1.67) but no other foods included in AIDI was associated with VTE.
Conclusion
The study suggests that a consumption of foods with high anti-inflammatory potential may play a role in the prevention of VTE in smokers.
... As expected, astragalin suppressed thrombin-stimulated alveolar induction of PAR proteins and enhanced tPA induction along with concurrent reduction of PAI-1. Since oxidative stress promotes thrombosis [39], natural compounds that reduce the level of oxidative stress may be candidates for treating thrombotic complications [38,40]. This study found that astragalin inhibited thrombin-induced ROS production and ensuing MAPK signaling, which would be a safe and effective novel antithrombotic pharmacotherapy. ...
Epidemiological evidence shows that smoking causes a thrombophilic milieu that may play a role in the pathophysiology of chronic obstructive pulmonary disease (COPD) as well as pulmonary thromboembolism. The increased nicotine level induces a prothrombotic status and abnormal blood coagulation in smokers. Since several anticoagulants increase bleeding risk, alternative therapies need to be identified to protect against thrombosis without affecting hemostasis. Astragalin is a flavonoid present in persimmon leaves and green tea seeds and exhibits diverse activities of antioxidant and anti-inflammation. The current study investigated that astragalin attenuated smoking-induced pulmonary thrombosis and alveolar inflammation. In addition, it was explored that molecular links between thrombosis and inflammation entailed protease-activated receptor (PAR) activation and oxidative stress-responsive mitogen-activated protein kinase (MAPK)-signaling. BALB/c mice were orally administrated with 10–20 mg/kg astragalin and exposed to cigarette smoke for 8 weeks. For the in vitro study, 10 U/mL thrombin was added to alveolar epithelial A549 cells in the presence of 1–20 µM astragalin. The cigarette smoking-induced the expression of PAR-1 and PAR-2 in lung tissues, which was attenuated by the administration of ≥10 mg/kg astragalin. The oral supplementation of ≥10 mg/kg astragalin to cigarette smoke-challenged mice attenuated the protein induction of urokinase plasminogen activator, plasminogen activator inhibitor-1and tissue factor, and instead enhanced the induction of tissue plasminogen activator in lung tissues. The astragalin treatment alleviated cigarette smoke-induced lung emphysema and pulmonary thrombosis. Astragalin caused lymphocytosis and neutrophilia in bronchoalveolar lavage fluid due to cigarette smoke but curtailed infiltration of neutrophils and macrophages in airways. Furthermore, this compound retarded thrombin-induced activation of PAR proteins and expression of inflammatory mediators in alveolar cells. Treating astragalin interrupted PAR proteins-activated reactive oxygen species production and MAPK signaling leading to alveolar inflammation. Accordingly, astragalin may interrupt the smoking-induced oxidative stress–MAPK signaling–inflammation axis via disconnection between alveolar PAR activation and pulmonary thromboembolism.
... Oxidative stress promotes thrombotic complications. Therefore, various substances of natural origin reduce the level of oxidative stress and may be important in the treatment of thrombotic complications [260]. Inactivation of ROS and alleviation of oxidative stress can reduce the risk of platelet hyperactivation, which leads to cardiovascular diseases including thrombosis [261]. ...
Venous thromboembolism (VTE) refers to deep vein thrombosis (DVT), whose consequence may be a pulmonary embolism (PE). Thrombosis is associated with significant morbidity and mortality and is the third most common cardiovascular disease after myocardial infarction and stroke. DVT is associated with the formation of a blood clot in a deep vein in the body. Thrombosis promotes slowed blood flow, hypoxia, cell activation, and the associated release of many active substances involved in blood clot formation. All thrombi which adhere to endothelium consist of fibrin, platelets, and trapped red and white blood cells. In this review, we summarise the impact of various factors affecting haemostatic disorders leading to blood clot formation. The paper discusses the causes of thrombosis, the mechanism of blood clot formation, and factors such as hypoxia, the involvement of endothelial cells (ECs), and the activation of platelets and neutrophils along with the effects of bacteria and reactive oxygen species (ROS). Mechanisms related to the action of anticoagulants affecting coagulation factors including antiplatelet drugs have also been discussed. However, many aspects related to the pathogenesis of thrombosis still need to be clarified. A review of the drugs used to treat and prevent thrombosis and natural anticoagulants that occur in the plant world and are traditionally used in Far Eastern medicine has also been carried out.
... Some of these perturbed metabolic areas have been individually observed previously in patients with VTE, however the previous studies focused on a smaller number of metabolites. [20][21][22]25 Comparisons remain difficult with studies examining mechanistic aspects during or around the VTE, as they can be associated together with other diseases. At the time of sampling, our patients with VTE were supposed to be clinically recovered, but we still found numerous resilient metabolic changes at the function level ( Figure 3), but not necessarily at the single metabolite level. ...
Objective:
Deep vein thrombosis and pulmonary embolism referred as venous thromboembolism (VTE) are a common cause of morbidity and mortality. Plasma from healthy controls or individuals who have experienced a VTE were analyzed using metabolomics to characterize biomarkers and metabolic systems of patients with VTE. Approach and Results: Polar metabolite and lipidomic profiles from plasma collected 3 months after an incident VTE were obtained using liquid chromatography mass spectrometry. Fasting-state plasma samples from 42 patients with VTE and 42 healthy controls were measured. Plasma metabolomic profiling identified 512 metabolites forming 62 biological clusters. Multivariate analysis revealed a panel of 21 metabolites altogether capable of predicting VTE status with an area under the curve of 0.92 (P=0.00174, selectivity=0.857, sensitivity=0.971). Multiblock systems analysis revealed 25 of the 62 functional biological groups as significantly affected in the VTE group (P<0.05 to control). Complementary correlation network analysis of the dysregulated functions highlighting a subset of the lipidome composed mainly of n-3 long-chain polyunsaturated fatty acids within the predominant triglycerides as a potential regulator of the post-VTE event biological response, possibly controlling oxidative and inflammatory defence systems, and metabolic disorder associated dysregulations. Of interest was microbiota metabolites including trimethylamine N-oxide that remained associated to post incident VTE patients, highlighting a possible involvement of gut microbiota on VTE risk and relapse.
Conclusions:
These findings show promise for the elucidation of underlying mechanisms and the design of a diagnostic test to assess the likely efficacy of clinical care in patients with VTE.
... Docosahexaenoic acid (DHA) (C22:6) has unique stereochemical structure, features the highest unsaturatedness, ensures effective signal conductance in neurons thereby preventing spasms of the heart and blood vessels [108], and can have antithrombotic, antiatherogenic, antiarrhythmic, and vasoprotective actions. ...
This review presents existing evidence of the influence of saturated and unsaturated fatty acids on cardiovascular diseases (CVD). Data are discussed regarding the roles of the most relevant fatty acids, such as myristic (C14:0), palmitic (C16:0), stearic (C18:0), palmitoleic (C16:1), oleic (C18:1), linoleic (C18:2), α-linolenic (C18:3, ω-3), γ-linolenic (C18:3, ω-6), arachidonic (C20:4), eicosapentaenoic (C20:5), docosahexaenoic (C22:6), and docosapentaenoic (C22:5) acid. The accumulated knowledge has expanded the understanding of the involvement of fatty acids in metabolic processes, thereby enabling the transition from basic exploratory studies to practical issues of application of these biomolecules to CVD treatment. In the future, these findings are expected to facilitate the interpretation and prognosis of changes in metabolic lipid aberrations in CVD.
... Platelets or other prothrombotic proteins that play pivotal roles in regulating hemostasis have been shown as one of the key targets of oxidative stress. Therefore, measures to prevent elevated levels of oxidative stress via different chemical or naturally occurring compounds could serve as a major therapeutic strategy for the treatment of thrombotic complications (Phang et al. 2011). ...
The failure of mechanisms of natural anti-coagulation either due to genetic impairment or due to severe external injuries may result in a condition called thrombosis. This is believed to be the primary cause for a variety of life-threatening conditions such as: heart attack, stroke, pulmonary embolism, thrombophlebitis, and deep venous thrombosis (DVT). The growing number of these incidents requires an alternative anti-coagulant or anti-thrombotic agent that has minimal side effects and improved efficiency. For decades, plant polyphenols, especially flavonoids, were known for their vital role in preventing various diseases such as cancer. Mitigating excessive oxidative stress caused by reactive oxygen species (ROS) with anti-oxidant-rich flavonoids may reduce the risk of hyper-activation of platelets, cardiovascular diseases (CVD), pain, and thrombosis. Furthermore, flavonoids may mitigate endothelial dysfunction (ED), which generally correlates to the development of coronary artery and vascular diseases. Flavonoids also reduce the risk of atherosclerosis and atherothrombotic disease by inhibiting excessive tissue factor (TF) availability in the endothelium. Although the role of flavonoids in CVD is widely discussed, to the best of our knowledge, their role as anti-thrombotic lead has not been discussed. This review aims to focus on the biological uses of dietary flavonoids and their role in the treatment of various coagulation disorders, and may provide some potential lead to the drug discovery process in this area.
Bioactive components underlying the antiplatelet activity of CH ingestion have not been clarified. This study aimed to identify antiplatelet peptides from CH after simulated gastrointestinal digestion and intestinal absorption. Four antiplatelet peptides containing Hyp-Gly (OG) sequence including OG, Hyp-Gly-Glu (OGE), Pro-Gly-Glu-Hyp-Gly (PGEOG) and Val-Gly-Pro-Hyp-Gly-Pro-Ala (VGPOGPA) were successfully identified. All four peptides exhibited antiplatelet activity, but OGE and PGEOG exerted stronger activity than OG and VGPOGPA. IC50 value of OGE and PGEOG was 1.076 mM and 1.167 mM, respectively. These four antiplatelet peptides could survive simulated gastrointestinal digestion and be absorbed intact by Caco-2 cells. Further, plasma stability experiments showed that OG and OGE had a good stability in human plasma, but PGEOG and VGPOGPA had a relatively poor stability. In vivo studies indicated that OG and OGE were present in blood after oral administration of CH. Meanwhile, OGE exerted a significant in vivo anti-thrombotic activity after ingestion. The present study clarifies the antiplatelet components underlying CH and highlights the potential application of CH or these four peptides as functional foods to combat thrombosis by inhibiting platelet aggregation.
The pharmaceutical effects of n-3 polyunsaturated fatty acids (n-3 PUFAs) as dietary nutrients on human health and diseases have gained much attention and are investigated for decades. Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and docosapentaenoic acid (DPA) are the three major n-3 PUFAs enriched in marine organisms, such as fish, shrimp, algae, and so on. It has been well known that n-3 PUFAs, especially DHA and EPA, are beneficial in reducing the risk of cardiovascular and cerebrovascular diseases. Accumulating evidence suggests that n-3 PUFAs might cure inflammatory diseases through several mechanisms, such as plasma membrane remodeling of lymphocytes, down-regulating pro-inflammatory cytokines, and alternating adhesion molecule expressions. Several molecular targets of n-3 PUFAs on immune-regulation have also been identified, such as GPR120 (FFA4), protein kinase C (PKC), and PPAR-γ. However, it remains inconclusive if dietary n-3 PUFAs function the same both in vitro and in vivo based on cohort studies. This review will focus on the molecular targets and mechanisms of anti-inflammatory and immunomodulatory effects of n-3 PUFAs on human health and diseases, such as obesity, tumor, diabetes, and autoimmune diseases.
The prevention of arterial thrombotic diseases has a high priority in developed countries. An inappropriate diet may be an important risk factor for thrombotic events. The daily intake of an anti-thrombotic diet may offer a convenient and effective way of prevention. The aim of the present study was to test tomato extracts for anti-thrombotic effects and to identify those varieties that have such an effect. A shear-induced platelet-function test (haemostatometry) was used to test anti-thrombotic potential in vitro. Extracts from those tomato varieties that showed a significant anti-thrombotic activity in vitro were further assessed in vivo, using a laser-induced thrombosis test in mice. One tomato variety (KG99-4) showed significant anti-thrombotic activity both in vitro and in vivo. KG99-4 inhibited not only platelet-rich thrombus formation but also had a thrombolytic effect. It is concluded that haemostatometry can detect and classify the anti-thrombotic potential of fruits and vegetables and offers a simple way of screening for such effects.
The cardiovascular health benefits of longchain n-3 polyunsaturated fatty acids (PUFAs) have been reported to exert at several different cellular control mechanisms. These include, effects on lipoprotein metabolism, haemostatic function, platelet/vessel wall interactions, anti-arrhythmic actions and also inhibition of proliferation of smooth muscle cells and therefore growth of the atherosclerotic plaque. Fish oil feeding has also been found to result in moderate reductions in blood pressure and to modify vascular neuroeffector mechanisms. The majority of such cardiovascular benefits of n-3 PUFAs are likely to be mediated in the vascular wall and at the vascular endothelium level, since this monolayer of cells plays a central role in the regulation and maintenance of cardiovascular homeostasis and function. While these processes include endothelium-derived vasorelaxant and vasoconstrictor compounds, the vascular endothelium also plays host to many receptors, binding proteins, transporters and signalling mechanisms. Accordingly, endothelial dysfunction, which underlies many cardiovascular disease conditions, can trigger acute vascular events including vasospasm, thrombosis or restenosis leading to ischaemia. The longchain n-3 PUFAs have been reported to possess several properties that may positively influence vascular function. These include favourable mediator profiles (nitric oxide, eicosanoids) that influence vascular reactivity, change in vascular tone via actions on selective ion channels, and maintenance of vascular integrity. In addition to direct effects on contractility, n-3 PUFAs may affect vascular function, and the process of atherogenesis, via inhibition of vascular smooth muscle cell proliferation at the gene expression level, and by modifying expression of inflammatory cytokinesis and adhesion molecules. Collectively, these properties are consistent with pleiotropic actions of longchain n-3 PUFAs, and may explain the beneficial cardiovascular protection of this family of fatty acids that have been clearly evident through epidemiological data as well from more recent large-scale clinical trials.
On the basis of the information discussed in this review, we can conclude that the effects of a high intake of monounsaturated fatty acids (MUFA) from olive oil include a wide range of healthy benefits beyond improvement in cholesterol levels, suggesting that this type of diet has great potential in preventing cardiovascular disease. MUFA-enriched diets reduce insulin requirements and decrease plasma concentrations of glucose and insulin in type 2 diabetic patients, unlike high-saturated fatty acid and low-fat, high-carbohydrate diets. Moreover, some data show that this dietary model could have a hypotensive effect. There is also substantial evidence that oleic-enriched low-density lipoprotein (LDL) is more resistant to oxidative modifications and that dietary MUFA may influence various components and functions related to the endothelium. These include endothelium-dependent vasodilatation and a reduced capacity of oleicenriched LDL to promote the adhesion and chemotaxis of monocytes. On the other hand, a MUFA diet decreases the prothrombotic environment, modifying platelet adhesion, coagulation, and fibrinolysis. Its reducing effect on PAI-1 plasma levels is of particular relevance. This wide range of anti-atherogenic effects could explain the low rate of cardiovascular mortality found in Mediterranean countries, where there is a moderate to high supply of dietary MUFA. Future studies need to focus on uncovering the mechanisms by which the Mediterranean diet exerts its beneficial effects
Fish oil diets, rich in n-3 polyunsaturated fatty acids, are considered to have an antithrombotic effect. Both platelets and endothelial cells play a crucial role in the regulation of thrombosis and haemostasis. There is substantial evidence that, in these cells, fish oil-derived polyunsaturated fatty acids can replace the n-6 polyunsaturated fatty acid, arachidonic acid, in the membrane phospholipids and can modify those cellular reactions in which the latter fatty acid participates. However, it now appears that dietary n-3 polyunsaturated fatty acids are less potent than, for example, aspirin in modifying the activation properties of these cell systems. This suggests the possible involvement of additional cells or factors in mediating the antithrombotic potential of fish oil fatty acids.
OBJECTIVE: We tested the hypothesis that hyperhomocysteinemia and hypercholesterolemia promote arterial thrombosis in mice. METHODS AND RESULTS: Male apolipoprotein E (Apoe)-deficient mice were fed one of four diets: control, hyperhomocysteinemic (HH), high fat (HF), or high fat/hyperhomocysteinemic (HF/HH). Total cholesterol was elevated 2-fold with the HF or HF/HH diets compared with the control or HH diets (P<0.001). Plasma total homocysteine (tHcy) was elevated (12 to 15 micromol/L) with the HH or HF/HH diets compared with the control or HF diets (4 to 6 micromol/L; P<0.001). Aortic sinus lesion area correlated strongly with total cholesterol (P<0.001) but was independent of tHcy. At 12 weeks of age, the time to thrombotic occlusion of the carotid artery after photochemical injury was >50% shorter in mice fed the HF diets, with or without hyperhomocysteinemia, compared with the control diet (P<0.05). At 24 weeks of age, carotid artery thrombosis was also accelerated in mice fed the HH diet (P<0.05). Endothelium-dependent nitric oxide-mediated relaxation of carotid artery rings was impaired in mice fed the HF, HH, or HF/HH diets compared with the control diet (P<0.05). CONCLUSIONS: Hyperhomocysteinemia and hypercholesterolemia, alone or in combination, produce endothelial dysfunction and increased susceptibility to thrombosis in Apoe-deficient mice.
(+)-Catechin inhibited the copper-catalysed oxidation of human low density lipoprotein (LDL) in a dose-dependent manner with complete inhibition at 20 μg/mL. The flavonoid at a concentration of 50 μg/mL also inhibited oxidation of LDL induced by the mouse transformed macrophage J774, human monocyte-derived macrophages and vascular endothelial cells isolated from human umbilical cords. LDL modified by copper-catalysed or cell-induced oxidation was endocytosed and degraded by human macrophages at a much greater rate than native LDL. LDL reisolated from copper or cell incubations in the presence of (+)-catechin was endocytosed and degraded at rates similar to native LDL. (+)-Catechin appeared to inhibit the uptake and degradation by macrophages of cell-modified LDL. The actions of (+)-catechin on cell-induced oxidation of LDL are consistent with the ability of flavonoids of similar structure to inhibit lipoxygenases and with a role for lipoxygenases in cell-induced modification of LDL in vivo.
The effect of several vitamin K (Vit K) analogues on the aggregation of human platelets was examined. The analogues were potent inhibitors of aggregation induced by ADP, thrombin, collagen and arachidonate but were less active against aggregation induced by the calcium ionophore A23187. Vit K3 also prevented platelet membrane phosphatide breakdown induced by collagen. These effects were not due to a direct inhibition of enzymes involved in the liberation of arachidonate or its subsequent transformation. The analogues exerted no effects on enzymes regulating intraplatelet cAMP. However, these effects could be overcome by increasing extracellular Ca++ levels, indicating a possible interaction with Ca++ regulation in platelets.
Coronary artery disease is responsible for much mortality and morbidity around the world. Platelets are involved in atherosclerotic disease development and the reduction of platelet activity by medications reduces the incidence and severity of disease. Red wine and grapes contain polyphenolic compounds, including flavonoids, which can reduce platelet aggregation and have been associated with lower rates of cardiovascular disease. Citrus fruits contain different classes of polyphenolics that may not share the same properties. This study evaluated whether commercial grape, orange and grapefruit juices, taken daily, reduce ex vivo platelet activity. In a randomized cross-over design, ten healthy human subjects (ages 26-58 y, five of each gender) drank 5-7.5 mL/(kg. d) of purple grape juice, orange juice or grapefruit juice for 7-10 d each. Platelet aggregation (whole blood impedance aggregometry, Chronolog Model #590) at baseline was compared to results after consumption of each juice. Drinking purple grape juice for one week reduced the whole blood platelet aggregation response to 1 mg/L of collagen by 77% (from 17.9 +/- 2.3 to 4.0 +/- 6.8 ohms, P = 0.0002). Orange juice and grapefruit juice had no effect on platelet aggregation. The purple grape juice had approximately three times the total polyphenolic concentration of the citrus juices and was a potent platelet inhibitor in healthy subjects while the citrus juices showed no effect. The platelet inhibitory effect of the flavonoids in grape juice may decrease the risk of coronary thrombosis and myocardial infarction.
Welsh onion has been consumed for prevention of cardiovascular disorders. To study if it has antithrombotic effects, 9-wk-old male Sprague-Dawley rats were studied. Some rats were fed raw or boiled Welsh onion juice (2 g. kg(-1). d(-1)) for 4 wk, and the remaining acted as the control. Before and after feeding, their systolic blood pressure was measured by a tail-cuff method. Two days after the treatment period, tail bleeding time, platelet function (including platelet aggregation and adhesion), plasma levels of prostaglandins, and platelet cyclic nucleotide levels were determined. In comparison to the control, raw Welsh onion juice consumption significantly (1) lowered resting systolic blood pressure; (2) prolonged the bleeding time; (3) diminished platelet adhesion on a fibrinogen-coated surface, ADP-evoked platelet aggregation and ADP-stimulated thromboxane release; (4) elevated the concentration of cyclic AMP, but not cyclic GMP, in platelets; (5) increased the plasma level of 6-keto-prostaglandin F(1alpha), the stable prostacyclin metabolite, but not the plasma nitrite level. On the contrary, boiled Welsh onion juice consumption was totally ineffective. In conclusion, consuming raw Welsh onion juice, but not boiled juice, has blood pressure lowering and antithrombotic effects in rats. These effects may be mediated by PGI(2)-cAMP pathway.