In Vein

Thrombosis kills 1 in 4 of us (1). It is the underlying cause of most heart attacks, strokes, and venous thromboembolism (VTE), which includes deep vein thrombosis and pulmonary embolism. And it is, like so many other bad things, increasing (2, 3) …

Isn’t modern medicine wonderful?

Some of this increase reflects an ageing population (at least in some countries), and the figures were given an additional boost by Covid and the Covid mRNA vaccines (ie 3-8), both of which expose the victim to pro-inflammatory spike protein (9-11).

And some of it talks to us about the modern exposome. I looked at arterial health in June, so let us now consider veins.

A recent brace of cohort studies (circa 70,000 subjects were observed over nearly two decades) found cigarette smoking to be a risk factor for VTE, although only in women (12). This could be a statistical anomaly, as men are somewhat more prone than women to VTE’s and the impact of cigarettes on males might have been diluted out. Taking more exercise and eating a healthy diet, on the other hand, were both slightly protective.

The researchers were referring here to versions of DASH, aka the Dietary Approaches to Stop Hypertension diet. DASH is a step in the right direction (ie away from the deep fryer) but it is dated and, in my opinion, far from optimal. Nonetheless, these results indicated that nutritional factors were relevant and, if correctly identified, might form the basis for a more effective pharmaconutritional approach.

It’s a complicated story.

DASH lowers blood pressure, and as hypertension is a risk factor for VTE (13) the reduction of VTE’s may have been secondary to a fall in blood pressure. DASH is also a reduced GL diet, and so eating DASH and taking more exercise would result in improved metabolic control which may also be protective against VTE (14, 15 but see also 16). Unfortunately, the last paper did not include data on BP or glycemic control so I cannot tell if these were involved.

DASH promotes fish, but the ability of fish or fish oil to reduce the risk of VTE is unclear (17, 18). It also promotes polyphenols, and these at least exert plausibly anti-thrombotic effects (19). Furthermore, both fish oil and polyphenols are broadly anti-inflammatory, and an anti-inflammatory diet is associated with a reduced risk of VTE (20).

Inflammation and anti-inflammation, however, are insufficiently precise terms. As thrombosis forms in close association with the vascular endothelium, it is chronic vascular inflammation that we should focus on; as there is strong evidence that chronic inflammation affecting vascular endothelium (aka endothelial dysfunction) is the key player in driving VTE (21-23).

Both the omega-3 PUFA’s (24) and many of the polyphenols (25) have the ability to damp endothelial dysfunction, but neither of them on their own exerts a sufficiently strong protective effect. This is shown by their inability, when used alone, to lower blood pressure more than modestly (26, 27).

Taking omega-3 PUFAs and polyphenols together (as in oily fish) appears to provide a significantly stronger and dose-related anti-hypertensive effect (28). This matches my own observations when using combinations of fish oil and high polyphenol olive oil to manage and in many cases normalise essential hypertension.

The increased anti-hypertensive efficacy of the combination of PUFAs and polyphenols is logical, given their complementary modes of anti-inflammatory action (29). The slow and progressive onset of the effect also makes sense, given the slow incorporation of omega-3 loaded phosphatidyl phospholipids into cell membranes (30-33), and specifically, in this case, endothelial cell membranes.

As the gradual fall in blood pressure over time indicates a lessening in total peripheral resistance in conjunction with the restored endothelial function, this will not only reduce the risk of VTE’s but also the development of cardiovascular disease (34, 35).

As the same pharmaconutritional regime also reduces arterial stiffening (36), the level of overall cardiovascular protection will be further enhanced. And there’s more. Reduced arterial stiffening provides further benefits by lowering the risk of end-organ damage in highly perfused tissues such as the kidneys and brain (36).

Even this is not the end of the therapeutic story. Endotoxaemia is a risk factor for endothelial dysfunction (37, 38) and VTE’s (39-41). Logically, therefore, and for even better protection, prebiotics should be added to the program (42, 43).

This may be a low-tech anti-ageing strategy but it is cheap, safe, available to all and likely to be highly effective. It could also be built, possibly via the inoffensive omega-3 SDA, into the next generation of ultra-processed foods.

Next week: Cary Grant, Doris Day and why zombies eat brains.

References

1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T, Aggarwal R, Ahn SY, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095–2128.
2. GBD 2019 Diseases and Injuries Collaborators. Global burden of 369 diseases and injuries in 204 countries and territories, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020 Oct 17;396(10258):1204-1222. 
3. Sidney S, Lee C, Liu J, Khan SS, Lloyd-Jones DM, Rana JS. Age-Adjusted Mortality Rates and Age and Risk-Associated Contributions to Change in Heart Disease and Stroke Mortality, 2011-2019 and 2019-2020. JAMA Netw Open. 2022 Mar 1;5(3):e223872.
4. Liu J, Wang J, Xu J, Xia H, Wang Y, Zhang C, Chen W, Zhang H, Liu Q, Zhu R, Shi Y, Shen Z, Xing Z, Gao W, Zhou L, Shao J, Shi J, Yang X, Deng Y, Wu L, Lin Q, Zheng C, Zhu W, Wang C, Sun YE, Liu Z. Comprehensive investigations revealed consistent pathophysiological alterations after vaccination with COVID-19 vaccines. Cell Discov. 2021 Oct 26;7(1):99.
5. Wu JF, Bajwa U, Hammad M. Vaccine-induced immune thrombotic thrombocytopenia in a male after Ad26.COV2.S vaccination presenting as cerebral venous sinus thrombosis. Platelets. 2022 Jul 4;33(5):797-800. 
6. Perico L, Morigi M, Pezzotta A, Locatelli M, Imberti B, Corna D, Cerullo D, Benigni A, Remuzzi G. SARS-CoV-2 spike protein induces lung endothelial cell dysfunction and thrombo-inflammation depending on the C3a/C3a receptor signalling. Sci Rep. 2023 Jul 14;13(1):11392. 
7. De Michele M, d’Amati G, Leopizzi M, Iacobucci M, Berto I, Lorenzano S, Mazzuti L, Turriziani O, Schiavo OG, Toni D. Evidence of SARS-CoV-2 spike protein on retrieved thrombi from COVID-19 patients. J Hematol Oncol. 2022 Aug 16;15(1):108.
8. Ryu JK, Sozmen EG, Dixit K, Montano M, Matsui Y, Liu Y, Helmy E, Deerinck TJ, Yan Z, Schuck R, Acevedo RM, Spencer CM, Thomas R, Pico AR, Zamvil SS, Lynch KL, Ellisman MH, Greene WC, Akassoglou K. SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy. bioRxiv [Preprint]. 2021 Oct 13:2021.10.12.464152.
9. Cai J, Ma W, Wang X, Chang H, Wei Z, Li J, Zeng M. The spike protein of SARS-CoV-2 induces inflammation and EMT of lung epithelial cells and fibroblasts through the upregulation of GADD45A. Open Med (Wars). 2023 Nov 15;18(1):20230779.
10. Montezano AC, Camargo LL, Mary S, Neves KB, Rios FJ, Stein R, Lopes RA, Beattie W, Thomson J, Herder V, Szemiel AM, McFarlane S, Palmarini M, Touyz RM. SARS-CoV-2 spike protein induces endothelial inflammation via ACE2 independently of viral replication. Sci Rep. 2023 Aug 28;13(1):14086. 
11. Khan S, Shafiei MS, Longoria C, Schoggins J, Savani RC, Zaki H. SARS-CoV-2 spike protein induces inflammation via TLR2-dependent activation of the NF-κB pathway. bioRxiv [Preprint]. 2021 Mar 17:2021.03.16.435700.
12. Yuan S, Bruzelius M, Håkansson N, Åkesson A, Larsson SC. Lifestyle factors and venous thromboembolism in two cohort studies. Thromb Res. 2021 Jun;202:119-124.
13. Nazarzadeh M, Bidel Z, Mohseni H, Canoy D, Pinho-Gomes AC, Hassaine A, Dehghan A, Tregouet DA, Smith NL, Rahimi K; INVENT Consortium. Blood pressure and risk of venous thromboembolism: a cohort analysis of 5.5 million UK adults and Mendelian randomization studies. Cardiovasc Res. 2023 May 2;119(3):835-842. 
14. Deischinger C, Dervic E, Nopp S, Kaleta M, Klimek P, Kautzky-Willer A. Diabetes mellitus is associated with a higher relative risk for venous thromboembolism in females than in males. Diabetes Res Clin Pract. 2022 Dec;194:110190. 
15. R Charlier SH, Meier C, Jick SS, Meier CR, Becker C. Association between glycemic control and risk of venous thromboembolism in diabetic patients: a nested case-control study. Cardiovasc Diabetol. 2022 Jan 4;21(1):2. 
16. Hu S, Tan JS, Hu MJ, Guo TT, Chen L, Hua L, Cao J. The Causality between Diabetes and Venous Thromboembolism: A Bidirectional Two-Sample Mendelian Randomization Study. Thromb Haemost. 2023 Sep;123(9):913-919.
17. Zhang Y, Ding J, Guo H, Liang J, Li Y. Associations of Fish and Omega-3 Fatty Acids Consumption With the Risk of Venous Thromboembolism. A Meta-Analysis of Prospective Cohort Studies. Front Nutr. 2020 Dec 17;7:614784.
18. Mattiuzzi C, Cervellin G, Franchini M, Lippi G. Fish Intake and Venous Thromboembolism: A Systematic Literature Review. Clin Appl Thromb Hemost. 2016 May;22(4):309-13.
19. Grosso G, Godos J, Currenti W, Micek A, Falzone L, Libra M, Giampieri F, Forbes-Hernández TY, Quiles JL, Battino M, La Vignera S, Galvano F. The Effect of Dietary Polyphenols on Vascular Health and Hypertension: Current Evidence and Mechanisms of Action. Nutrients. 2022 Jan 27;14(3):545.
20. Yuan S, Bruzelius M, Damrauer SM, Håkansson N, Wolk A, Åkesson A, Larsson SC. Anti-inflammatory diet and venous thromboembolism: Two prospective cohort studies. Nutr Metab Cardiovasc Dis. 2021 Sep 22;31(10):2831-2838.
21. Verhamme P, Hoylaerts MF. The pivotal role of the endothelium in haemostasis and thrombosis. Acta Clin Belg. 2006 Sep-Oct;61(5):213-9.
22. Iba T, Levy JH. Inflammation and thrombosis: roles of neutrophils, platelets and endothelial cells and their interactions in thrombus formation during sepsis. J Thromb Haemost. 2018 Feb;16(2):231-241. 
23. Pilard M, Ollivier EL, Gourdou-Latyszenok V, Couturaud F, Lemarié CA. Endothelial Cell Phenotype, a Major Determinant of Venous Thrombo-Inflammation. Front Cardiovasc Med. 2022 Apr 21;9:864735. 
24. Zehr KR, Walker MK. Omega-3 polyunsaturated fatty acids improve endothelial function in humans at risk for atherosclerosis: A review. Prostaglandins Other Lipid Mediat. 2018 Jan;134:131-140.
25. Iqbal I, Wilairatana P, Saqib F, Nasir B, Wahid M, Latif MF, Iqbal A, Naz R, Mubarak MS. Plant Polyphenols and Their Potential Benefits on Cardiovascular Health: A Review. Molecules. 2023 Sep 1;28(17):6403.
26. Morris MC, Sacks F, Rosner B. Does fish oil lower blood pressure? A meta-analysis of controlled trials. Circulation. 1993 Aug;88(2):523-33.
27. de Brito Alves JL, de Sousa VP, Cavalcanti Neto MP, Magnani M, Braga VA, da Costa-Silva JH, Leandro CG, Vidal H, Pirola L. New Insights on the Use of Dietary Polyphenols or Probiotics for the Management of Arterial Hypertension. Front Physiol. 2016 Oct 6;7:448. 
28. Del Brutto OH, Mera RM, Gillman J, Castillo PR, Zambrano M, Ha JE. Dietary Oily Fish Intake and Blood Pressure Levels: A Population-Based Study. J Clin Hypertens (Greenwich). 2016 Apr;18(4):337-41.
29. https://drpaulclayton.eu/blog/children-of-the-corn/
30. Marangoni F, Colombo C, Galli C. A method for the direct evaluation of the fatty acid status in a drop of blood from a fingertip in humans. World Rev Nutr Diet. 2005;94:139-143. 
31. LANDS WE. LIPID METABOLISM. Annu Rev Biochem. 1965;34:313-46. 
32. Wendel AA, Lewin TM, Coleman RA. Glycerol-3-phosphate acyltransferases: rate limiting enzymes of triacylglycerol biosynthesis. Biochim Biophys Acta. 2009 Jun;1791(6):501-6.
33. Hishikawa D, Hashidate T, Shimizu T, Shindou H. Diversity and function of membrane glycerophospholipids generated by the remodeling pathway in mammalian cells. J Lipid Res. 2014 May;55(5):799-807.
34. Gallo G, Volpe M, Savoia C. Endothelial Dysfunction in Hypertension: Current Concepts and Clinical Implications. Front Med (Lausanne). 2022 Jan 20;8:798958.
35. Xu S, Ilyas I, Little PJ, Li H, Kamato D, Zheng X, Luo S, Li Z, Liu P, Han J, Harding IC, Ebong EE, Cameron SJ, Stewart AG, Weng J. Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies. Pharmacol Rev. 2021 Jul;73(3):924-967. 
36. https://drpaulclayton.eu/blog/all-about-eva/
37. Leskelä J, Toppila I, Härma MA, Palviainen T, Salminen A, Sandholm N, Pietiäinen M, Kopra E, Pais de Barros JP; FinnGen; Lassenius MI, Kumar A, Harjutsalo V, Roslund K, Forsblom C, Loukola A, Havulinna AS, Lagrost L, Salomaa V, Groop PH, Perola M, Kaprio J, Lehto M, Pussinen PJ. Genetic Profile of Endotoxemia Reveals an Association With Thromboembolism and Stroke. J Am Heart Assoc. 2021 Nov 2;10(21):e022482.
38. Violi F, Cammisotto V, Bartimoccia S, Pignatelli P, Carnevale R, Nocella C. Gut-derived low-grade endotoxaemia, atherothrombosis and cardiovascular disease. Nat Rev Cardiol. 2023 Jan;20(1):24-37. 
39. Obi AT, Andraska E, Kanthi Y, Kessinger CW, Elfline M, Luke C, Siahaan TJ, Jaffer FA, Wakefield TW, Henke PK. Endotoxaemia-augmented murine venous thrombosis is dependent on TLR-4 and ICAM-1, and potentiated by neutropenia. Thromb Haemost. 2017 Jan 26;117(2):339-348. S
40. Ząbczyk M, Kruk A, Natorska J, Undas A. Low-grade endotoxemia in acute pulmonary embolism: Links with prothrombotic plasma fibrin clot phenotype. Thromb Res. 2023 Dec;232:70-76. 
41. Bucci T, Ames PRJ, Cammisotto V, Cardamone C, Ciampa A, Mangoni B, Triggiani M, Carnevale R, Lip GYH, Pastori D, Pignatelli P; ATHERO-APS study group. Low-grade endotoxemia and risk of recurrent thrombosis in primary antiphospholipid syndrome. The multicenter ATHERO-APS study. Thromb Res. 2023 Nov;231:76-83.
42. Moludi J, Maleki V, Jafari-Vayghyan H, Vaghef-Mehrabany E, Alizadeh M. Metabolic endotoxemia and cardiovascular disease: A systematic review about potential roles of prebiotics and probiotics. Clin Exp Pharmacol Physiol. 2020 Jun;47(6):927-939.
43. Moludi J, Kafil HS, Qaisar SA, Gholizadeh P, Alizadeh M, Vayghyan HJ. Effect of probiotic supplementation along with calorie restriction on metabolic endotoxemia, and inflammation markers in coronary artery disease patients: a double blind placebo controlled randomized clinical trial. Nutr J. 2021 Jun 1;20(1):47.