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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.

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Most people try to eat healthy. I am one of them, despite being a foodie! Tell me a city you are visiting, and I can most likely tell you what you should eat there. Recommendations from the health profession seem to be a moving target; wine is good, wine is not good, coffee is great, then it's not so great, don't eat eggs, well maybe we were wrong, eat eggs! So, what is recommended from a coagulation point of view? This month an article came out about the association with of cardiovascular and thrombotic risk with the low calorie sweetener xylitol increasing these risks to between 57-80%.¹ Seems like this needs to be explored!

CAUSES:

Blood clots form for a number of reasons: a surgical procedure, obesity, a medical condition, or an injury. A number of conditions increase the risk of developing a life-threatening blood clot, such as higher ratios of LDL cholesterol than HDL cholesterol and high levels of triglycerides. High levels of LDL cause atherosclerosis resulting in plaque buildup in the blood vessels causing decreased blood flow resulting in a clot. When it breaks off and floats through the blood it can block an artery or cause a stroke, heart attack, or PE.²

There have been several theories about the connection between food and inflammation. One trigger is diseases that arise from unhealthy eating which can cause metabolic dysfunction leading to insulin resistance which are major pathways for active inflammation.³ Both the coagulation and inflammation systems are the two main host defense systems that interact. Inflammation activates coagulation and coagulation modulates the inflammatory process.⁴

Platelets are derived from megakaryocytes in the bone marrow and stores multiple metabolic enzymes which are released upon activation. This includes: lysosomes, dense granules, α-granules, exosomes and microvesicles. Platelets have a high turnover rate and the ability to change in shape and respond to their environmental conditions.⁵

Metabolic syndrome which includes a cluster of risk factors including obesity, hypertriglyceridemia, high low-density lipoprotein levels in blood, hypertension, and hyperglycemia with insulin resistance and has been associated with platelet hyperactivity in which inflammation is a contributing factor, however it is difficult to determine the main cause or factor. High glucose levels were found to enhance platelet reactivity and secretion via ADP, TRAP and fibrinogen binding.

The pro-inflammatory cellular effects of coagulation proteases as well as anti-inflammatory effects of activated protein C (APC) and its receptor EPCR are mediated by signaling via protease activated receptors PAR on mononuclear cells, endothelial cells, platelets, fibroblast, and smooth muscle cells. The beneficial effects of APC in sepsis are mainly dependent on the PAR-mediated cell-protective properties rather than the anticoagulant protease function on coagulation cofactors FV/Va and FVIII/VIIIa.⁴

FOODS:

Obesity puts extra pressure on your pelvis and legs and doubles your chances of a DVT. A healthy diet helps to control inflammation by providing nutrients including flavonoids and antioxidants. This includes fish, poultry, fruits, vegetables, whole grains, nuts, beans and healthy fats like olive and canola oil. Foods that contribute to inflammation can contribute to diseases that result in blood clots. The ones to avoid include refined and processed foods, fast food, soda and sugary drinks, candy, trans fats (margarine, shortening and lard), red and processed meats. Salt should also be limited to 2300 milligrams of sodium per day. Alcohol ingested in small amounts can thin your blood, however more than 2 servings can raise platelets.⁶

Phytochemicals are physiologically active compounds found in many plants. While not generally considered essential nutrients, they have shown benefits in reducing potential for heart disease and cancer. Foods containing flavonoids and phenols may prove beneficial in clot prevention. Flavonoids reduce plaque buildup in arteries, improve cholesterol levels, act as antioxidants, and decrease inflammation.²

Delphinidin-3-glucoside (Dp-3-g) is one of the predominant bioactive compounds of anthocyanins in many plant foods and is known to be protective in CVD. A study looked at the role of Dp-3-g in platelet activation and in both in vitro and in vivo thrombosis models. It was found that it significantly inhibited human and murine platelet aggregation in both platelet rich plasma and purified platelets. It also reduced thrombus growth in human and murine blood in perfusion chambers. Under microscopy, Dp-3-g decreased platelet deposition, destabilized thrombi, and prolonged the time required for vessel occlusion. Platelet activation markers were measured by flow cytometry and demonstrated that Dp-3-g significantly inhibited the expression of P-selectin, CD63, CD40L, which reflect platelet α- and δ-granule release, and cytosol protein secretion, respectively. It was demonstrated that Dp-3-g downregulated the expression of active integrin αIIbβ3 on platelets, and attenuated fibrinogen binding to platelets following agonist treatment, without interfering with the direct interaction between fibrinogen and integrin αIIbβ3. Based on these finds, Dp-3-g significantly inhibits platelet activation and thrombus growth which contributes to it being protective against thrombosis and CVD.⁷

Antiplatelet effects were seen with olive oils, alperujo (by-product of oil from the olive), ginseng, curcuminoids and garlic. It was demonstrated that in vitro ADP- and TRAP-induced platelet activation was significantly decreased by alperujo extract. It has also been found that oral supplementation for one year with extra virgin olive oil reduced blood platelet aggregation with ADP. Ginseng antiplatelet effects could be attributed to the ability to attenuate internal calcium mobilization and granule secretions. Garlic extract inhibits platelet aggregation by increasing cyclic nucleotides, inhibiting fibrinogen binding, attenuating platelet shape changes and changing the functional properties of platelets to respond to collagen.⁵

A high fat meal can induce platelet aggregation; however it can be attenuated when the meal is enriched with antioxidants such as vegetables and vitamins. Which is the basis of the Mediterranean diet.⁵

SWEETENERS

Many of the low calorie sweeteners are sugar alcohols that can also be produced endogenously. However, they can be at levels over 1000 fold lower than when compared with a sugar substitute. Xylitol is a sugar alcohol found naturally in strawberries, spinach, cauliflower, but it is commercially made from corncobs, birch trees or genetically engineered bacteria. It is used in sugarless gum, breath mints and other processed foods with presumed health benefits. The pathways and metabolites that contribute to residual cardiovascular disease risks are unclear.¹

A study was conducted using metabolic studies on overnight fasting plasma samples (n=1157) using sequential stable subjects undergoing elective diagnostic cardiac evaluations. LC-MS/MS) analyses were performed on an independent, non-overlapping validation cohort (n = 2149). Complementary isolated human platelet, platelet-rich plasma, whole blood, and animal model studies examined the effect of xylitol on platelet responsiveness and thrombus formation in vivo. Finally, an intervention study was performed to assess the effects of xylitol consumption on platelet function in healthy volunteers (n = 10).M¹

The results showed that samples that had circulatory xylitol were associated with incident major adverse cardiovascular event (MACE) risk. Also demonstrated were multiple indices of platelet reactivity and in vivo thrombosis formation. In the 10 healthy individuals who consumed a typical dose of xylitol sweetened drink rapidly, every measure of platelet activation in every volunteer was impacted when compared to those drinking a sugar sweetened beverage. Additionally, augmented activation of glycoprotein IIb/IIIa and expression of p-selectin was observed using flow post addition of xylitol. This may warrant a closer look at sugar alcohol sweeteners as a possible cardiovascular hazard and the impact of chronic exposures.¹

The initial benefit of these sweeteners was the reduction of excessive sugar intake, reducing weight gain and cardiovascular risk and used in the group at risk for obesity and diabetes. It also extends to other sugar alcohols such as erythritol when healthy volunteers were challenged with an erythritol sweetened drink.¹

CAFFEINE

There are still many conflicting theories on the relationship with caffeine and blood clots. Different studies have shown that drinking one to four cups of coffee a day can raise your chances of DVT by 11%, and if you drink more than five cups a day, you can lower your odds by 25%.⁶

The role of coffee, energy drinks and their selected components such as caffeine may pose an effect on hemostasis, in particular platelets and their underlying mechanisms. This may occur due to the modification of platelet reactivity by changing signaling enzymes and by modifying cAMP. Some studies show that energy drinks have pro-aggregatory effects which may be associated with an elevated with a risk of thrombosis. Other studies show that coffee reduces platelet aggregation, which may be beneficial for prophylaxis of thrombosis. Neither coffee nor energy drinks are regulated as to display their level of caffeine. Some energy drinks may contain 50 mg–505 mg of caffeine, compared with the 80 mg found in standard cup of coffee, which can also vary depending on the type of bean or brew. Some reports indicate that energy drinks may elevate the risk of CVA and MI due to increasing platelet aggregation which is dependent on the bioactive components of the drink, however they are not always well documented.⁸

Blood platelet activation, and the consequent alteration of platelet function, plays a specific role in cardiovascular disorders; this is measured by various markers, including platelet aggregate formation and the secretion of ADP, proteins and other compounds from platelet granules. Various in vivo studies have examined the effect of coffee on blood platelet functions, especially platelet aggregation.⁸

Observational studies have shown coffee to lower risk of CVD, stroke and heart failure; however, it is difficult to determine if these results are causal or due to residual confounding factors such as dietary intake, levels of physical activity and other biases. A Mendelian randomization looked at twelve independent genetic variants used to proxy coffee consumption. Up to 35,979 cases were reviewed and was found that a genetic predisposition to higher coffee consumption was not associated with any of the 15 studied cardiovascular outcomes. Results included 0,97 for ICH, 1.26 DVT, 0,86 subararchnoid hemorrhage. These results show limited evidence that coffee consumption affects the risk of CVD.⁹

Natella et al. (2008) examined ten healthy subjects who drank 200 ml coffee, containing 180 mg caffeine, or a capsule of caffeine with 200 ml of water. Platelets were collected at baseline, 30 and 60 minutes post coffee drinking. Platelet aggregation testing was performed using collagen, arachidonic acid (AA) and ADP. Results showed that coffee drinking inhibited collagen from baseline at 30 min and AA at 60 minutes induced platelet aggregation. Caffeine intake from the capsule did not affect platelet aggregation with any of the agonists. Coffee consumption induced a significant increase of platelet phenolic acids (likely present as glucuronate and sulphate derivatives), caffeic acid, the principal phenolic acid in coffee. Caffeine was not detectable in platelets. Results showed that coffee drinking decreases platelet aggregation and induces a significant increase in phenolic acid platelet concentration. However, the antiplatelet effect of coffee is independent of caffeine and could be due to the interaction of coffee phenolic acids with the intracellular signaling network leading to platelet aggregation.¹⁰

CONCLUSION:

It has been said that you are what you eat! More and more reasons to stay within moderation for your choices. There is overwhelming evidence that the most impacted parameter of coagulation is platelet activation. Balancing your choices and keeping triggers to a minimum will ensure that your platelet activation is kept in check.

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References:

1. Marco Witkowski, Ina Nemet, Xinmin S Li, Jennifer Wilcox, Marc Ferrell, Hassan Alamri, Nilaksh Gupta, Zeneng Wang, Wai Hong Wilson Tang, Stanley L Hazen, Xylitol is prothrombotic and associated with cardiovascular risk, European Heart Journal, June 2024.
2. Foods that Prevent Blood Clots, American Blood Clot Association, May 27,2022 https://bloodclot.org/foods-that-prevent-blood-clots/
3. Inflammation, Diet, Health, and Clots: What You Need to Know, July 2021, https://thrombosis.org/2020/11/inflammation-diet-health-need-know/
4. Jari Petäjä,, Inflammation and coagulation. An overview,Thrombosis Research, Volume 127, Supplement 2, 2011,Pages S34-S37,
5. Ilse A. C. Arnoldussen1,2,* and Renger F. Witkamp1Effects of Nutrients on Platelet Function: A Modifiable Link between Metabolic Syndrome and Neurodegeneration? Biomolecules. 2021 Oct; 11(10): 1455.
6. Bonvissulo, D and DerSarkissian,C., Foods to Help Prevent DVT, March 23, 2023, https://www.webmd.com/dvt/foods-help-prevent-dvt
7. Yan Yang 1, Zhenyin Shi, Adili Reheman, Joseph W Jin, Conglei Li, Yiming Wang, Marc C Andrews, Pingguo Chen, Guangheng Zhu, Wenhua Ling, Heyu Ni, Plant food delphinidin-3-glucoside significantly inhibits platelet activation and thrombosis: novel protective roles against cardiovascular diseases, PLoS One, 2012;7(5):e37323.
8. Beata Olas , Magdalena BryśI, Effects of coffee, energy drinks and their components on hemostasis: The hypothetical mechanisms of their action, Food Chem Toxicol, 2019 May:127:31-41.
9. Yuan S, Carter P, Mason AM, Burgess S, Larsson SC. Coffee Consumption and Cardiovascular Diseases: A Mendelian Randomization Study. Nutrients. 2021 Jun 28;13(7):2218.
10. Natella F, Nardini M, Belelli F, Pignatelli P, Di Santo S, Ghiselli A, Violi F, Scaccini C. Effect of coffee drinking on platelets: inhibition of aggregation and phenols incorporation. Br J Nutr. 2008 Dec;100(6):1276-82.

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