Regulation of platelet function and thrombosis by omega-3 and omega-6 polyunsaturated fatty acids

Abstract

Thrombosis is the most common underlying pathology responsible for morbidity and mortality in cardiovascular disease (CVD). Platelet adhesion, activation, and aggregation play central roles in hemostasis; however, the same process may also cause thrombosis and vessel occlusion at the site of ruptured atherosclerotic lesions leading to heart attack and stroke. ω-3 and ω-6 polyunsaturated fatty acids (PUFAs) are an essential component of the platelet phospholipid membrane and play a major role in many aspects of platelet function. Dietary supplementation of ω-3 and ω-6 PUFAs has long been used to slow the progression of CVD and to prevent acute cardiovascular events. Despite this, the role of ω-3 and ω-6 PUFAs and their oxylipin metabolites in platelet function remains controversial due to the lack in our understanding of the mechanistic regulation controlling platelet reactivity in vitro and substantial evidence for PUFA regulation of thrombotic events in vivo. In this review, we will outline the role of platelet physiology in hemostasis and the effect of ω-3 and ω-6 PUFAs on platelet function, with special emphasis on in vivo effects on hemostasis and thrombosis due to the role of PUFAs and their bioactive lipids in circulation. Further, recent mechanistic insights and evidence for cardio-protective effects of PUFAs and their bioactive lipids will be discussed.

Platelet lipidome: Dismantling the “Trojan horse” in the bloodstream

“…Membrane lipid composition and consequently, thrombotic functions, can also be influenced by diet. Dietary intake of γ‐linolenic acid (18:3n‐6)‐containing borage oil, ω‐3‐FA in fish/fish oil/DHA, or similar marine and olive oil supplements enrich antithrombotic lipid precursor ω‐3‐FA (linoleic acid), dihomo‐γ‐linolenic acid‐(DGLA, 20:3n‐6) conjugated but not thrombogenic arachidonic acid (20:4n‐6) containing phospholipids (PLs), alters mean platelet volume, and decreases thromboxane and β‐thromboglobulin production …”

“…Ideally, with the advent of high‐throughput methods, platelet lipidomics might be introduced as routine analysis in the future. Such lipidomic profiles may also reveal the endogenous balance of prothrombotic AA‐derived oxylipins versus antithrombotic DGLA derivatives (Figure ), which can be corrected by dietary supplementation of PUFAs recommended for their cardio‐protective benefits, possibly attributed to their antithrombotic effects …”

“…However, the DGLA‐12‐HETrE antithrombotic axis operates independently of COX‐1, is not influenced by aspirin, and does not compromise primary hemostasis, making it a promising antiplatelet strategy . Limited amounts of DGLA in platelet membrane might be enhanced by dietary supplementation without altering levels of thrombogenic 12‐LOX (12‐HETE) or COX‐1 (TXA2) derivatives . It would be interesting to validate how antiplatelet therapies might influence the endogenous levels of antiplatelet lipids in CVD patients.…”

“…Platelets express SPM receptors Chem23 (resolvin E1), GRP18 (resolvin D1), GRP32 (resolvin D2), and ALX (resolvin D2 and lipoxin A4). But, the effects of specific SPMs vary with platelet stimulus (eg, ADP, thrombin, or collagen), and functional response (eg, aggregation, spreading, pro‐/anti‐inflammatory release) . The overall objective of SPMs is to resolve inflammation at a later stage without interfering with hemostatic “plug” formation essential during initial phases of healing …”

“…CYP450 derived metabolites have been shown in platelets; those from other cellular sources like endothelial cells mostly show antiplatelet properties 12-LOX (12-HETE) or COX-1 (TXA2) derivatives. 59,81,82 It would be interesting to validate how antiplatelet therapies might influence the endogenous levels of antiplatelet lipids in CVD patients.…”