Summary
Thrombosis refers to blood clot (thrombus) formation which can block blood flow in vasculature, with negative health effects as a consequence. This thrombus can also break off and travel through the bloodstream (referred to as thromboembolism), potentially blocking vital organs such as the brain, heart or lungs. This obstruction of blood flow and the tissue oxygen deprivation that results from this can have dire life-threatening or disabling consequences, depending on which part of the body is affected. Omega-3 fatty acids EPA and DHA have a protective role against thrombosis, whilst not affecting normal wound healing ability.
 
Introduction
The formation of blood clots is a vital function: it prevents excessive blood loss during events such as the rupture of a blood vessel, allowing the body to form a scab and repair the vasculature. Blood platelets are a small cell type that permanently circulate in our blood vessels. When a bleeding event occurs, blood platelets become activated at the site of injury: they release thrombin and attract circulating immune system components. As a result of this, more platelets are activated and recruited to the site of injury where they start to generate a protein called fibrin. The production of fibrin enhances coagulation of platelets, leading to the formation of a blood clot which stops the bleeding. Crucially, the formation of blood clots can also occur in the absence of need for them or become excessive in relation to a minor injury; this pathological condition called thrombosis. This condition is characterized by the pathological presence of a blood clot (thrombus) in the vascular system that causes a partial or full blockade of the blood flow.
 
Thrombosis is a leading cause of death, in the previous decade thrombosis contributed to up to 1 in 4 deaths worldwide. Two main forms of thrombosis exist: venous and arterial thrombosis. In venous thrombosis, a thrombus blocks blood flow in veins, which carry oxygen-poor blood back to the heart and lungs. In arterial thrombosis, a thrombus obstructs blood flow in arteries, which carry oxygen-rich blood to tissues. The presence of a thrombus itself can have dire consequences depending on where blood flow is obstructed. Crucially, a (part of the) thrombus can also break off and travel through the blood stream until it becomes stuck in a different part of the vascular system. This condition is called thromboembolism; when these traveling clots end up in the blood vessels supplying the heart muscles or brain with oxygen, the life-threatening conditions of heart attack and stroke are created. If a travelling thrombus ends up blocking blood vessels in the lungs (pulmonary embolism), a life-threatening situation can ensue as well. Risk factors for thrombosis are high blood pressure, smoking, high cholesterol levels, diabetes, ageing. Omega-3 fatty acids such as EPA and DHA are known for their (cardio)vascular health benefits, which are relevant in the face of thrombosis. The studies described below discuss these benefits, which point towards a positive role for EPA and DHA in risk reduction of thrombosis.
 
Research findings
Using blood and blood plasma from healthy human subjects, Larson and collaborators studied the effects of EPA and DHA on platelet activation and thrombin generation (Larson et al. 2013). Each subject served as their own control: their samples were split into two fractions of which one was treated with EPA and DHA, and the other was untreated. First, the authors assessed if EPA and DHA are incorporated into platelets by incubating donor blood plasma with EPA and DHA or a control substance for 4 hours. They found that platelets incubated with EPA and DHA incorporated these omega-3 fatty acids in a concentration-dependent manner. Next, they incubated EPA- and DHA-treated platelets with factors that induce thrombin generation. Activated platelets generate thrombin in the process of blood clot formation. They found that treatment with EPA and DHA caused a decrease in the generation of thrombin. This indicates that blood clot formation ability is reduced, but not eliminated by EPA and DHA. Building on this, an experimental setup was used where human blood was added to a tube that replicates a blood flow in a (damaged) blood vessel. With this setup, the authors further investigated the effects of EPA and DHA on time to occlusion (blockage). This refers to the time it takes for the replicated blood vessel becomes blocked, and is used to make assessments about blood clot formation. They found treatment of blood with EPA and DHA increased the time to occlusion, though all treated blood samples occluded within one hour. Furthermore, they reported a reduced accumulation of fibrin in the replicated damaged blood vessel model, indicative of reduced, but not inhibited blood clot formation. With these results in mind, the authors concluded that omega-3 fatty acids minimally affect parameters of wound healing ability, whereas they do counter vessel-blocking levels of thrombin formation.
 
In a large study with data from 21970 participants, Isaksen and colleagues researched the relation between dietary intake of omega-3 fatty acids and venous thromboembolism (Isaksen et al. 2019). Self-reported dietary habits and supplement consumption were used to analyse the intake levels of omega-3 fatty acids, which were then coupled with incidence of venous thromboembolism. Participants were divided into 4 quartiles depending on the determined levels of omega-3 fatty acid intake, where quartile 1 had the lowest intake and quartile 4 had the highest intake. Compared to participants in the quartile 1, participants in quartile 2-4 (consuming over 4.7g omega-3 fatty acids per week) had a 22%-26% lower risk of venous thromboembolism. A further analysis by the authors looked into provoked versus unprovoked venous thromboembolism in relation to omega-3 fatty acid intake. Provoking factors for venous thromboembolism such as surgery, physical trauma, cancer, heart attacks, stroke or long-term immobilisation were included. Unprovoked venous thromboembolism was defined as the cases where these factors were absent. The results of this analysis showed that the protective effect of omega-3 fatty acid consumption was the strongest for provoked thromboembolism. This was especially significant for provoked pulmonary embolism, where participants in quartile 2-4 had a 39%-60% risk decrease.
 
Importantly, the formation of blood clots (coagulation) is an important protective function in the face of bleeding events. By forming a blood clot at the site of a damaged or ruptured blood vessel, excessive loss of blood is countered. To investigate if omega-3 fatty acid intake is associated with increased risk of bleeding, Jeansen and colleagues investigated blood clotting and bleeding events in clinical studies with omega-3 fatty acid supplementation (Jeansen et al. 2018). A total of 1561 patients from eight clinical studies investigating various conditions were included. Of these 1561 patients, 780 received daily supplementation with 1.5 g EPA + DHA or more; each study varied in concentrations and duration. Bleeding-related (serious) adverse events, as well as coagulation parameters were analysed. The authors found that EPA + DHA supplementation did not induce any difference with regard to coagulation parameters. Furthermore, no change in (serious) adverse bleeding events was measured, even in study participants that took platelet aggregation inhibitors. Therefore, Jeansen and colleagues concluded that daily supplementation with 1.5 g EPA + DHA or more did not increase risk of bleeding-related (serious) adverse events in these studies.
 
Conclusion
Thrombosis and thromboembolism are health conditions that can have severe disabling consequences, even death in certain cases. Crucially, research has put forward the beneficial effects of omega-3 fatty acids in regard to these conditions. In blood and blood plasma from healthy adults, EPA + DHA treatment causes a reduction in thrombin generation and fibrin accumulation. With regard to venous thromboembolism, Isaksen and colleagues showed that the protective effects of omega-3 fatty acid consumption is most pronounced against provoked venous thromboembolism. Crucially, Jeansen and collaborates found that reduced platelet aggregation as induced by EPA + DHA did not result in a change in (serious) adverse bleeding events across multiple studies with many participants. This was true even for study participants taking platelet aggregation inhibitors, who may have enhanced risk of bleeding events. Overall, the studies discussed above highlight the protective effects of omega-3 fatty acids EPA and DHA against thrombosis.
 
References
Adili, Reheman, Ellen M. Voigt, Jordan L. Bormann, Kaitlynn N. Foss, Luke J. Hurley, Evan S. Meyer, Amber J. Veldman, et al. 2019. ‘In Vivo Modeling of Docosahexaenoic Acid and Eicosapentaenoic Acid-Mediated Inhibition of Both Platelet Function and Accumulation in Arterial Thrombi’. Platelets 30 (2): 271–79. https://doi.org/10.1080/09537104.2017.1420154.
 
Isaksen, Trond, Line H. Evensen, Stein Harald Johnsen, Bjarne K. Jacobsen, Kristian Hindberg, Sigrid K. Brækkan, and John‐Bjarne Hansen. 2019. ‘Dietary Intake of Marine N‐3 Polyunsaturated Fatty Acids and Future Risk of Venous Thromboembolism’. Research and Practice in Thrombosis and Haemostasis 3 (1): 59–69. https://doi.org/10.1002/rth2.12168.
 
Jeansen, Stephanie, Renger F. Witkamp, Jossie A. Garthoff, Ardy van Helvoort, and Philip C. Calder. 2018. ‘Fish Oil LC-PUFAs Do Not Affect Blood Coagulation Parameters and Bleeding Manifestations: Analysis of 8 Clinical Studies with Selected Patient Groups on Omega-3-Enriched Medical Nutrition’. Clinical Nutrition 37 (3): 948–57. https://doi.org/10.1016/j.clnu.2017.03.027.
 
Larson, Mark K., Garth W. Tormoen, Lucinda J. Weaver, Kristen J. Luepke, Ishan A. Patel, Carl E. Hjelmen, Nicole M. Ensz, Leah S. McComas, and Owen J. T. McCarty. 2013. ‘Exogenous Modification of Platelet Membranes with the Omega-3 Fatty Acids EPA and DHA Reduces Platelet Procoagulant Activity and Thrombus Formation’. American Journal of Physiology-Cell Physiology 304 (3): C273–79. https://doi.org/10.1152/ajpcell.00174.2012.
 
Phang, Melinda, Fiona E. Scorgie, Michael Seldon, Manohar L. Garg, and Lisa F. Lincz. 2014. ‘Reduction of Prothrombin and Factor V Levels Following Supplementation with Omega-3 Fatty Acids Is Sex Dependent: A Randomised Controlled Study’. The Journal of Nutritional Biochemistry 25 (10): 997–1002. https://doi.org/10.1016/j.jnutbio.2014.05.001.