Introduction

Plant‑based diets primarily contain foods of plant origin, which include not only vegetables and fruit, but also nuts and seeds, legumes and beans, oils, and whole grains. Plant‑based diets do not necessarily exclude all animal products and can range from total exclusion (eg, vegan) to meat consumption once to twice a week (eg, flexitarian). The unifying focus is on the consumption of more foods from plant sources proportional to animal‑based foods.¹

Consumption of plant‑based diets have been associated with a significant reduction in cardiovascular disease (CVD) risk,^2-4 CVD mortality,^5,6 and also all‑cause mortality.^7,8 The beneficial effect of plant‑based diets on cardiometabolic health has been attributed to, amongst others, the low caloric density, lower saturated fat, and higher mono- and polyunsaturated fat content, high fiber content as well as its antioxidant and anti‑inflammatory compounds.¹

Randomized control trials and observational studies have identified a number of pathways through which plant‑based diets can improve cardiometabolic health. These include a number of risk factors recognized by the European Society of Cardiology guidelines for CVD prevention⁹: reduction of obesity and its downstream sequelae, improved glycemic control and decreased insulin resistance, decreased blood pressure, and an improved lipid profile (reviewed by Kahleova et al¹⁰). In addition, plant‑based diets have been shown to improve other CVD‑related pathways such as cessation and reversal of atherosclerotic plaque deposition, decreased inflammation and thrombosis. There is a vast amount of literature investigating the relationship of diet with thrombosis, but most of these studies assessed the effect of individual nutrients or foods such as alcohol, dietary fat, n‑3 fatty acid supplementation, fiber, carbohydrates, and a variety of micronutrients (vitamins, minerals and phytochemicals) (reviewed by Pieters and De Maat¹¹). Much less is known regarding the influence of whole diets—in particular, plant‑based diets and dietary patterns—on thrombotic factors such as platelet aggregation, coagulation, and fibrinolysis, with the existing literature reporting inconsistent and inconclusive findings. This is likely the result of the differences in composition of the investigated plant‑based diets (ranging from strictly vegan, to diets containing some meat or even high intakes of fish), the specific outcomes measured, and differences in study designs such as randomized controlled trials or observational studies, duration, selection of control groups, and health status of the participants (eg, healthy vs patients with CVD). Here we aim to review the existing literature describing the effect of different plant‑based diets (but not the individual constituent nutrients or foods) on specific thrombotic risk factors in order to better clarify these relationships and to try to explain the apparent discrepant findings. The thrombotic factors the review will focus on include platelet function, coagulation proteins (fibrinogen and factor VII [FVII]), and fibrinolysis, as most of the available evidence focuses on these outcomes.

Plant‑based diets

We first describe the composition of different plant‑based diets and dietary patterns in order to better interpret their potential varying effects on the discussed thrombotic factors. The 2021 European Society of Cardiology guidelines on CVD prevention in clinical practice recommend the adoption of a more plant‑based and less animal‑based food pattern consisting of less than 10% of total energy from saturated fatty acids, less than 5 g of salt, 30 to 45 g of fiber, at least 200 g of fruit, and at least 200 g of vegetables per day. They also recommend red meat consumption of no more than 350 to 500 g per week, with strict minimization of processed meat, (fatty) fish consumption 1 to 2 times per week, 30 g of unsalted nuts per day, no more than 100 g of alcohol per week, and discourage consumption of sugar‑sweetened beverages.⁹ These guidelines, in essence, describe the underpinning of plant‑based diets.

Although plant‑based diets center around plant‑based foods, they do not necessarily exclude all animal products. Therefore, plant‑based eating is comprised of a range of intakes that vary according to the type and the proportion of animal products included in the diet (Figure 1).

Veganism is considered the purest form of plant‑based eating, characterized by the omission of all animal products from the diet as well as foods that are high in fat, salt, and sugar while only whole food of plant origin is consumed. If not carefully planned and well‑balanced, vegan diets can lead to deficiencies in, amongst others, long‑chain n‑3 polyunsaturated fatty acids and vitamin B₁₂ because of strict exclusion of animal products.¹² Lacto‑vegetarian diets, while excluding meat and fish, include dairy products, whereas lacto‑ovo‑vegetarian diets include both dairy and eggs while excluding meat and fish.¹³ Pescatarian diets, also referred to as pesca‑vegetarian diets, include seafood along with eggs and dairy products while other animal products (poultry and red meat) are not consumed.¹⁴ Flexitarian diets, also known as semivegetarian diets, are mainly plant‑based but occasionally include meat, dairy and eggs and focus on variety while attempting to minimize animal product consumption.¹⁵

Within the context of the above‑mentioned plant‑based diets, a number of specific plant‑based dietary patterns that fall within the pescatarian and flexitarian diets (depending on whether only fish or both fish and red meat are consumed) have been investigated, and demonstrated to have cardiometabolic health benefits. These include the Mediterranean, Nordic, Portfolio, and DASH diets.¹³

Plant‑based diets and fibrinogen

Fifteen studies investigated the association between plant‑based diets and fibrinogen (Table 1), 10 of which were cross‑sectional investigations and 5 were interventions. Of the 10 cross‑sectional studies, 5 reported lower fibrinogen concentration in plant‑based diet consumers (ranging from vegan to flexitarian)^41-45 and 5 reported no difference^46-50 compared with omnivores. Two studies reported an inverse association between fibrinogen concentration and plant protein and fiber intake^44,48 and one an inverse association with the adherence to the Mediterranean dietary pattern.⁴¹ One study also reported a positive association between fibrinogen concentration and food patterns containing high intakes of red meat, low‑fiber bread, and dairy products.⁴⁵ The potential beneficial effect of habitual consumption of plant‑based diets on fibrinogen concentration has been attributed to lower intakes of saturated fats and higher intakes of non‑nutritive components, fish oil (in flexitarian and pescatarian diets) as well as the tendency for vegetarians to have a more‑healthy body mass index—all which have been linked to fibrinogen concentration.^51,52 None of the intervention studies ranging from 2 weeks to 6 months, however, demonstrated a beneficial effect of plant‑based diets on reducing fibrinogen concentration.^53-57 One study reported an increase in fibrinogen concentration, but this was related to a significant decrease in body mass index.⁵⁴ Increased fibrinogen during rapid weight loss has been ascribed to a parallel increase in fatty acids which stimulate hepatic fibrinogen production.⁵⁸ Furthermore, James et al⁴⁴ previously reported that both under- and overnutrition were associated with higher fibrinogen and that dietary guidelines should therefore focus on preventing overnutrition and its consequences such as noncommunicable diseases, but also they should not be too limiting which could result in undernutrition. In a previous review,⁵⁹ we concluded that the direct effects of the diet on fibrinogen concentration is likely modest, which is in agreement with the lack of effect observed in the intervention studies, but if the diet results in longer‑term health consequences, such as obesity, insulin resistance or diabetes, the effects become more pronounced.

Plant‑based diets and platelets

The effect of plant‑based diets on platelet function is varied, as summarized in Table 2. Two of the 6 cross‑sectional studies investigating the association between different plant‑based diets and platelets found increased platelet aggregation / function in vegetarians compared with omnivores.^43,49 Three studies found no difference^47,60,61 and a single report inhibited platelet activity measured as lower concentrations of platelet‑derived microparticles in individuals consuming a Nordic diet.²⁸ There were also no consistent effects in the 4 intervention studies with durations ranging from 2 weeks to 6 months. Two of the studies (vegetarian and Mediterranean diet [with and without wine]) found increased platelet aggregation with at least one platelet agonist, while no difference in platelet function was reported with other agonists used.^62,63 Two studies comparing the DASH diet to a control diet reported decreased platelet activation.^64,65 In contrast to plant‑based diets, Mann et al⁶³ found red and white meat not to affect platelet function while fish consumption resulted in a decreased collagen‑stimulated platelet thromboxane production but did not affect platelet aggregation.

This lack of consistency in findings is not entirely surprising given the variation in platelet function outcomes measured (ex vivo platelet aggregation, thromboxane secretion, plasma microvesicle concentration), type and concentration of agonists used (adenosine diphosphate, collagen, epinephrine, arachidonic acid), and platelet concentration in the analyzed sample (whole blood, platelet‑rich plasma, platelet‑adjusted plasma). In addition, the dietary interventions considered to be plant‑based ranged from strictly vegan to diets containing occasional consumption of white meat and fish (DASH) and diets with high intakes of fatty fish such as the Nordic diet and, in the case of the Mediterranean diet, also containing moderate amounts of alcohol, particularly red wine. Different components of plant‑based diets have been reported to have varying effects on platelet function and inclusion / exclusion of these dietary components in the study diets will therefore differentially influence the outcome of the platelet function tests. A detailed discussion of the effects of these nutrients and foods on platelet function has been published in a number of reviews.^11,12,66-74 While discussing the evidence for the individual nutrients and foods is outside the scope of this review, we aim to provide a broad overview of different components of plant‑based diets that may influence platelet function, highlighting the complexity of drawing conclusions regarding the effect of plant‑based diets on platelet function.

Foods and nutrients typically included in plant‑based diets such as dark chocolate, foods with a low glycemic index, garlic, ginger, onion, grapes (and juice), berries, tomato, vitamins, minerals, and phytochemicals (flavonoids and antioxidants) have all been shown to reduce platelet aggregation (reviewed by McEwen,⁶⁷ Pieters and De Maat,¹¹ Dutta‑Roy,⁶⁹ Tubek et al,⁷¹ and Phang et al⁶⁸). However, whether these changes are sufficient to alter thrombotic status is difficult to determine, as many of the micronutrients have limited bioavailability. The impact of alcohol (as the key component of the Mediterranean diet), on the other hand, is more complex and not yet fully elucidated, with a number of studies demonstrating inhibition of platelet activation, while evidence for enhanced platelet activation has also been reported (reviewed by Pieters and De Maat¹¹).

Another important component of plant‑based diets is the type of fat consumed with typically proportionally higher intakes of monounsaturated fatty acids (olive oil) and varying ratios of n‑3 to n‑6 polyunsaturated fatty acids. Vegans have low intakes of long‑chain n‑3 polyunsaturated fatty acids while flexitarian / pescatarian diets, such as the Nordic diet, containing fatty fish, have a high content. The influence of monounsaturated fatty acids on platelet function remains unclear with several studies reporting inhibited platelet aggregation, others reporting no effect, and others even found increased aggregability (reviewed by Rajaram⁶⁶ and Pieters and De Maat¹¹). The effect of polyunsaturated fatty acids on platelet function is largely dependent on being either n‑3 or n‑6, with n‑3 inhibiting and n‑6 promoting platelet aggregation by competing for cyclooxygenase and lipoxygenase and in doing so, producing different eicosanoids (reviewed by Dutta‑Roy⁶⁹). Compared with omnivores, vegetarians, especially vegans, have lower n‑3 polyunsaturated fatty acid levels in the platelet membrane phospholipids, which are associated with increased collagen and adenosine diphosphate–stimulated ex vivo blood platelet aggregation (reviewed by Li¹²). Fish consumers, on the other hand, have high n‑3 polyunsaturated fatty acid levels. Although the ability of fish oil to modulate platelet function by attenuating thromboxane A₂ production is well known, supplementation studies did not consistently find inhibited platelet aggregation. A meta‑analysis of randomized controlled trials concluded that the supplementation of n‑3 polyunsaturated fatty acids was associated with a reduced platelet aggregation in individuals in poor health, but not in healthy individuals.⁷⁰ This is in agreement with a recent review by Siniarski and Gajos⁷⁵ that a degree of uncertainty still remains regarding the use of polyunsaturated fatty acids in the prevention of CVD since the initial promising findings from intervention studies were not supported by recent meta‑analyses and differences in the approach of seminal clinical trials resulted in divergent results. Furthermore, plant‑based n‑3 fatty acids were found to be less effective inhibitors of platelet aggregation than fish oils.⁷⁶

Lastly, plant‑based diets are a source of dietary salicylic acid. It has previously been reported that vegetarians can have serum salicylic acid levels as high as patients taking 75 mg of aspirin a day.⁷⁷ In fact, Janossy et al⁷⁸ reported that a variety of plant foods can exert effects on platelet function comparable to those of prescription medicine and as such, dietary intake may need to be considered when prescribing antithrombotic (aspirin) treatment. This is in agreement with the recommendation by Aimo and De Caterina⁷⁹ that aspirin treatment for primary prevention of CVD should be based on a tailored approach that considers the combined assessment of thromboembolic and bleeding risk, the patient’s general health, general preventive measures (that can include a plant‑based diet), and the patient’s 10‑year CVD risk.

Plant‑based diets and factor VII

Although there is some evidence for the effect of plant‑based diets on FVII, less information is available than for fibrinogen and platelets. We found 5 cross‑sectional studies of which 3 report decreased FVII (measured as FVII coagulant activity [FVIIc], FVII activity, and percentage) in vegans and lacto‑ovo‑vegetarians compared with omnivores^43,49,50 and 2 report no differences (FVIIc)^46,48 (Table 3). Two intervention studies,^56,57 each with a duration of 2 weeks, investigating the Nordic diet, found lower FVIIc compared with the respective control diets while in one, no effect was observed for FVII antigen (FVIIag) or the FVIIc to FVIIag ratio.⁵⁷ Diet‑related factors that have been associated with higher FVII include obesity (reviewed by Pieters and De Maat¹¹) and consumption of saturated fatty acids, particularly C12–C16^80,81 which tend to be lower in plant‑based consumers. The mechanism whereby dietary fat leads to FVII activation remains uncertain. Possible explanations include association with triglyceride‑rich lipoproteins, chylomicron size, serum phospholipid concentration, and the presence of procoagulant aminophospholipids as minor components of lipoproteins.^82,83 Another novel proposal is that FVII activation follows the shift of pro‑coagulant phospholipids such as phosphatidylserine from the inner to the outer leaflet of cell‑surface membranes.⁸⁴ Alcohol⁸⁵ and fiber consumption,^57,86 on the other hand, have been demonstrated to decrease FVII. According to a review by Lee and Lip,⁸⁷ there is no consistent effect of n‑3 supplementation on FVII, with the majority of the studies finding no effect. Taken together, these data could suggest that the lower FVIIc observed in the studies employing the Nordic diet may not be the result of active lowering of FVII by the diet, but by higher levels in the control diets which were both high in fat. In agreement with this, none of vegetarian participants in any of the cross‑sectional studies listed above that reported lower FVII levels consumed fish, while 3 of the 5 studies reported the control groups to consume higher amounts of saturated fats,^43,46,49 with one study⁵⁰ not reporting fat intake. Lastly, the study by Mia and Vorster⁴⁸ that found no difference in FVII between vegetarians and omnivores explicitly stated that there was no difference in total fat or fiber intake between the 2 groups.

Plant‑based diets and fibrinolysis

There were 11 studies that investigated the association between plant‑based diets and fibrinolysis, measured either as concentration or activity of individual proteins in the lytic pathway (activators and inhibitors) or making use of global assays (Table 4). Four of the 7 cross‑sectional studies found no difference in fibrinolytic markers between vegetarians (vegans and lacto‑ovo‑vegetarians) and omnivores.^43,46,49,88 One reported higher fibrinolytic activity,⁴² one decreased fibrinolytic activity,⁵⁰ and another lower plasminogen levels.⁴³ One study reported a positive association between plasminogen activator inhibitor‑1 (PAI‑1) and a dietary pattern containing red meat, low‑fiber bread, and dairy.⁴⁵ Regarding intervention studies, a study comparing a 4‑week DASH diet to a control diet higher in total and saturated fats and lower in fruit, vegetables, and low‑fat dairy, found the DASH diet to have no effect on any of the fibrinolytic markers analyzed.⁸⁹ A 2‑week Nordic diet, compared with a high‑fat Danish diet, resulted in increased fibrinolytic activity (euglobulin lysis test) and increased tissue plasminogen activator activity but had no effect on PAI‑1.⁵⁷ Two studies comparing an 8‑week American Heart Association diet⁹⁰ and a 4‑week diet high in whole grains, nuts, legumes, and dairy⁹¹ with diets high in meat, both found PAI‑1 antigen to be higher in meat‑consumers. Kim et al⁹¹ additionally reported an inverse association between PAI‑1 and whole grain intake.

The evidence for dietary factors that can improve fibrinolysis is limited and inconclusive. Nutrients and foods that have, thus far, received the most attention include alcohol, fats (monounsaturated fatty acids, n‑3 fatty acid supplementation), and a number of micronutrients such as vitamin C, D, and E, retinol, and zinc (reviewed by Lee and Lip⁸⁷ and Pieters and De Maat¹¹). For most of these, the number of investigations is limited, and the available evidence produced contradictory findings. Also, most of the studies investigated individual activators or inhibitors in the fibrinolytic pathway such as plasminogen, or tissue plasminogen activator or PAI‑1 activity or antigen as surrogate markers of fibrinolytic activity, without directly measuring fibrinolytic potential.

The evidence for dietary habits that can inhibit fibrinolysis is much stronger. Again, for individual nutrients and foods, the evidence is limited, but there is a strong relationship between consequences of overnutrition such as obesity and metabolic syndrome and decreased fibrinolytic potential and in particular increased PAI‑1. A major source of PAI‑1 is adipose tissue, with visceral fat producing more PAI‑1 than subcutaneous fat, since it produces more proinflammatory cytokines, which stimulates PAI‑1 secretion (being an acute‑phase protein) and it contains more stromal cells, which is the cellular component of adipose tissue that produces PAI‑1.^92-94 The metabolic syndrome is characterized by abdominal obesity, as well as dyslipidemia, hypertension, and glucose intolerance (insulin resistance), all of which have been linked to increased PAI‑1.^95,96 In fact, the relationship of PAI‑1 with metabolic syndrome is so strong, that it is considered by some to be a true component of the metabolic syndrome.⁹⁷ In agreement with PAI‑1, global fibrinolytic assays have also demonstrated decreased lysis in both obesity and metabolic syndrome, confirming their hypofibrinolytic effects.^98,99

Thus, while the evidence for the effect of individual components of plant‑based diets on fibrinolysis is still to be confirmed, the lower prevalence of obesity⁷ and metabolic syndrome in plant‑based consumers (reviewed by Babio et al¹⁰⁰)supports a beneficial relationship between plant‑based diets and fibrinolytic potential.

Plant‑based diets and other hemostatic factors

The relationship between plant‑based diets and a number of other hemostatic variables have also been investigated and is summarized in Table 5, although the number of studies is small with varying results. Five cross‑sectional studies^{43,46,47,49,50} found no difference in some, but not all of the hemostatic variables measured between vegetarians (vegans and lacto‑ovo‑vegetarians) and omnivores, and 3^43,46,50 reported both lower levels of some and higher levels of other hemostatic variables in vegetarians. There was one intervention study of 90 days that reported longer bleeding times following a Mediterranean diet but no difference in von Willebrand factor levels compared with a high‑fat diet.⁶² The addition of wine did not significantly affect either outcome. Mezzano et al⁴³ concluded that these findings may be related to the origin of the hemostatic factors since plasma levels of coagulation or fibrinolytic factors and inhibitors synthesized in the liver were lower in vegetarians than in omnivorous controls while those of predominantly extrahepatic origin were not. Much more research, in particular large intervention trials, is required to corroborate findings regarding the effect of plant‑based diets on these hemostatic variables, before firm conclusions can be drawn or recommendations to the public can be made.

Conclusion

Healthy plant‑based diets have established benefits for cardiometabolic health, and they may do so, in part, through effects on thrombotic factors. However, this relationship is complex and depends on the energy, nutrient, and food composition of the diet. Strictly vegan diets, if not carefully planned and balanced may result in deficiencies (eg, n‑3 fatty acids and vitamin B₁₂) that may have a negative impact on thrombosis. While some components of plant‑based diets (eg, fiber, phytochemicals, long‑chain n‑3 polyunsaturated fatty acids, moderate alcohol consumption) may actively decrease thrombotic factors, the limiting of prothrombotic components (eg, saturated fat and animal protein), present in typical omnivorous diets, may provide indirect benefit. In addition, healthy plant‑based diets, being comparatively hypo‑caloric (regardless of the composition), generally protect against overnutrition and its metabolic consequences such as obesity and metabolic syndrome, which are also considered prothrombotic. A one‑size‑fits‑all conclusion can therefore not be drawn as the potential antithrombotic effect of different plant‑based diets depends on the nutrient composition (based on the degree of exclusion of animal products), the content of active antithrombotic dietary components, the relative absence of prothrombotic dietary factors as well as the degree of total caloric restriction.