- Email: [email protected]
Editorial: Platelet function — The role of essential fatty acids and eicosanoids
Prostaglandins Leukotrienes and Essential 0 Lonqnaman Group UK Ltd 1989
Editorial: Essential
Fatty
Acids:
Reviews
(1989) 35. 187- 188
Platelet Function - The Role of Fatty Acids and Eicosanoids
There is evidence that fatty acids (FAs) influence platelet function. ’ The best examples are probably gamma-linolenic (GLA), dihomogammalinolenic (DHLA), docasahexanoic (DHA) and eicosapentaenoic acids (EPA). Briefly, the actions of these FAs may involve competition for platelet cyclooxygenase, changes in the type of prostanoid released (e.g. PGEi from DHLA; TXA3 from EPA), altered membrane properties (e.g. fluidity) and diminished arachidonate incorporation into phospholipids.‘. 3 Less well known however, is the effect of oleic acid (from olive oil). We have recently shown4 that supplementing the diet of healthy volunteers with this FA results in diminished arachidonate content in platelet phospholipids, inhibited platelet aggregation and reduced thromboxane A2 (TXA2) release. Disease may also affect FA composition and delta 5 and 6 desaturases activity (e.g. in diabetes mellitus). ’ This aspect will be reviewed in a future issue of the journal. The effects of FAs may even account for the reduced incidence of ischaemic heart disease in certain populations (e.g. fish-eating Eskimos and the Mediterranean populations who consume large amounts of olive oil and probably fish). The principal platelet eicosanoid is TXA?. This prostanoid is a vasoconstrictor and an enhancer of platelet aggregation (see recent review) .5 Its release has been reported to be increased in several forms of vascular disease like acute myocardial infarction, peripheral vascular disease, diabetes mellitus with macrovascular complications (reviewed in this issue), migraine, Raynaud’s phenomenon. These findings have led to the development of drugs that inhibit TXA2 synthesis or that act as TXA2
receptor. antagonists. These drugs will be the subject of a forthcoming review. The methodology for measuring the release of this prostanoid from platelets usually involves assays for TXB2, the stable and spontaneous breakdown product of TXA?. Measurements have been carried out in serum (i.e. coagulated blood), in plasma (with cyclooxygenase inhibitors added to prevent in vitro release), in platelets that were aggregated by various agonists (or high concentrations of arachidonate) and in urine (to reflect overall vascular production). The validity of has been plasma and urine measurements considerably improved by assaying the (di-nor) metabolite of TXA2. In our opinion, using various doses of different agonists to induce TXB2 release remains a very useful technique for in vitro experiments.6 It is of interest, however, that the relationship between aggregation and TXA? release is not yet clearly defined. It would seem that for aggregation induced by certain agonists the two processes are inseparable while for other agonists they appear to be somewhat poorly related.’ An improved understanding of the role of TXAz in platelet function is clearly going to be of benefit. To that end. we have developed” a technique which measures traumainduced_ TXAz release in order to obviate the need for aggregation and the involvement of specific agonist receptors on the platelet membrane. Platelets also release very small amounts of PGE, and PGD?. PGEr has been recently reviewed;” PGD2 will be the subject of a forthcoming review. The role of platelet lipooxygenase products seems to be poorly documented and we therefore extend an open invitation to readers for a review on this subject.
187
188
PROSTAGLANDINS
A fact that is not widely appreciated is that proteins, like albumin and fibrinogen, influence platelet prostanoid production. The role of albumin is reviewed in the present issue; the role of fibrinogen has been discussed elsewhere. “’ Platelet aggregation, in platelet rich plasma (PRP) or in washed platelets, is the most commonly used technique for the investigation of platelet function. This approach however ignores the potential role of leucocytes (which release eicosanoids, leucotrienes, bioamines, platelet activating factor) and erythrocytes (which release ADP, a potent aggregating agent, if haemolysis occurs). Platelet behaviour in the presence of other blood cells should therefore be given careful consideration in the future. Obviously, platelet interactions with the endothelium and the coagulation system should also be considered. In this context, it is important that several products of the platelet release reaction stimulate vascular prostacyclin synthesis. “Jo Several drugs influence platelet eicosanoids. These include the non-steroidal anti-inflammatory drugs (NSAIDs) (see recent review)13, dipyridamole, iloprost (and other prostacyclin calcium channel blockers, betaanalogues), blockers, angiotensin converting enzyme {‘CE) inhibitors, penicillamine, cyclosporine A and ethanol. Heparin-associated thrombocytopenia and thrombosis (HABIT) is know well documented and a discussion of this syndrome will be included in a forthcoming review. Platelet eicosanoid metabolism may be altered in several disease states. These include various forms of vascular disease (see above), diabetes mellitus, hyperlipidaemias, cystic fibrosis and various forms of liver and renal disease. Platelets may also play a role in the pathogenesis of asthma and in the spread of metastases (recently reviewed). I5 We have also shown that severe emaciation, in patients with anorexia nervosa, is associated with hyperaggregability-increased TXAz release which is at least partially reversed on weight gain.16 Finally, we would like to take this opportunity to announce a new journal, PLATELETS, which will be devoted to platelet research. qublication of the first issue will be in late 1989. As part of an international team of editors, we are ready to consider publications on this subject and we hope that this editorial demonstrates the need for such a journal. D P Mikhailidis, J Y Jeremy REVIEW EDITORS.
LEUKOTRIENES
AND ESSENTIAL
FAT-I-Y ACIDS:
REVIEWS
References 1. Horrobin
D F. The roles of essential fatty acids in the development of diabetic neuropathy and other complications of diabetes mellitus. Prostagl Leukotr Essentl Fatty Acids-Reviews 1988; 31: 181-97. 2. Leaf A, Weber P C. Cardiovascular effects of n-3 fatty acids. N Engl J Med 1988; 318: 549-57. 3. von Schacky C. Prophylaxis of atherosclerosis with marine omega-3 fatty acids. Ann Intern Med 1987; 107: 890-99. 4. Barradas M A, Christofides J A, Jeremy J Y, Mikhailidis D P. Frv D E. Dandona P. Oleic acid suoolementation alteis ilatelet’ function and membrane’ ‘phospholipid arachidonic acid content. Biochem Sot Transact 1988; in press. 5. Oates J A. Fitzgerald G A, Branch R A, Jackson E A, Knapp H R. Roberts L J. Clinical implications of prostaglartdin and thromboxane Az formation. N Engl J Med 1988; 319: 689-98. 6. Mikhailidis D P, Jeremy J Y, Barradas M A, Green N. Dandona P. Effect of ethanol on vascular prostacyclin (prostaglandin I?) synthesis, platelet aggregation and platelet thromboxane release. Br Med J 1983; 287: 1495-98. 7. Best L C, Holland T K, Jones P B B, Russell R G G. The interrelationship between thromboxane biosynthesis, aggregation and 5-hydroxytryptamine secretion in human piitekts in vitro. Thromb %mostas 1980; 43: 38-40. 8. Jeremv J Y. Mikhailidis D P. ThomDson C S, Barradas M A, ‘Dandona P. Platelet thromboxine A1 synthesising capacity is enhanced by fasting but diminished by diabetes mellitus in the rat. Diabetes Res 1988; in press. 9. Kirtland S J. Prostaglandin E,: a review. Prostagl Leukotr Essntl Fatty Acids - Reviews 1988; 32: 165-74. 10. Mikhailidis D P, Barradas M A, Maris A, Jeremy J Y. Dandona P. Fibrinogen mediated activation of platelet aggregation and thromboxane AZ release: pathological implications in vascular disease. J Clin Pathol 1985; 38: 1166-71. 11. Boeynaems J-M. Drugs influencing the vascular production of prostacyclin. Prostagl Leukotr Essntl Fatty Acids Reviews 1988; 34: 197-204. 12. Jeremy J Y, Mikhailidis D P, Dandona P. Thromboxane A2 analogue (U-46619) stimulates vascular PC12 synthesis. Eur J Pharmacol 1985; 107: 259-52. 13. Peplow P V. Properties and actions of non-steroidal antiinflammatory drugs, including their effects on prostaglandin and macromolecular biosynthesis. Prostagl Leukotr Essntl Fatty Acids - Reviews 1988; 33: 239-52. 14. Grace A A. Cyclosporine A nephrotoxicity - the role of thromboxane AZ. Prostagl Leukotr Essntl Fatty Acids - Reviews 1988; 32: 157-64. 15. Fulton A M. The role of eicosanoids in tumour metastasis. Prostagl Leukotr Essntl Fatty Acids Reviews 1988; 34: 229-37. 16. Mikhailidis D P, Barradas M A, De Souza V, Jeremy J Y, Wakeling A, Dandona P. Adrenaline-induced hyperaggregability of platelets and enhanced thromboxane release in anorexia nervosa. Prostagl Leukotr Med 1986; 24: 27-34.
Editorial: Essential
Fatty
Acids:
Reviews
(1989) 35. 187- 188
Platelet Function - The Role of Fatty Acids and Eicosanoids
There is evidence that fatty acids (FAs) influence platelet function. ’ The best examples are probably gamma-linolenic (GLA), dihomogammalinolenic (DHLA), docasahexanoic (DHA) and eicosapentaenoic acids (EPA). Briefly, the actions of these FAs may involve competition for platelet cyclooxygenase, changes in the type of prostanoid released (e.g. PGEi from DHLA; TXA3 from EPA), altered membrane properties (e.g. fluidity) and diminished arachidonate incorporation into phospholipids.‘. 3 Less well known however, is the effect of oleic acid (from olive oil). We have recently shown4 that supplementing the diet of healthy volunteers with this FA results in diminished arachidonate content in platelet phospholipids, inhibited platelet aggregation and reduced thromboxane A2 (TXA2) release. Disease may also affect FA composition and delta 5 and 6 desaturases activity (e.g. in diabetes mellitus). ’ This aspect will be reviewed in a future issue of the journal. The effects of FAs may even account for the reduced incidence of ischaemic heart disease in certain populations (e.g. fish-eating Eskimos and the Mediterranean populations who consume large amounts of olive oil and probably fish). The principal platelet eicosanoid is TXA?. This prostanoid is a vasoconstrictor and an enhancer of platelet aggregation (see recent review) .5 Its release has been reported to be increased in several forms of vascular disease like acute myocardial infarction, peripheral vascular disease, diabetes mellitus with macrovascular complications (reviewed in this issue), migraine, Raynaud’s phenomenon. These findings have led to the development of drugs that inhibit TXA2 synthesis or that act as TXA2
receptor. antagonists. These drugs will be the subject of a forthcoming review. The methodology for measuring the release of this prostanoid from platelets usually involves assays for TXB2, the stable and spontaneous breakdown product of TXA?. Measurements have been carried out in serum (i.e. coagulated blood), in plasma (with cyclooxygenase inhibitors added to prevent in vitro release), in platelets that were aggregated by various agonists (or high concentrations of arachidonate) and in urine (to reflect overall vascular production). The validity of has been plasma and urine measurements considerably improved by assaying the (di-nor) metabolite of TXA2. In our opinion, using various doses of different agonists to induce TXB2 release remains a very useful technique for in vitro experiments.6 It is of interest, however, that the relationship between aggregation and TXA? release is not yet clearly defined. It would seem that for aggregation induced by certain agonists the two processes are inseparable while for other agonists they appear to be somewhat poorly related.’ An improved understanding of the role of TXAz in platelet function is clearly going to be of benefit. To that end. we have developed” a technique which measures traumainduced_ TXAz release in order to obviate the need for aggregation and the involvement of specific agonist receptors on the platelet membrane. Platelets also release very small amounts of PGE, and PGD?. PGEr has been recently reviewed;” PGD2 will be the subject of a forthcoming review. The role of platelet lipooxygenase products seems to be poorly documented and we therefore extend an open invitation to readers for a review on this subject.
187
188
PROSTAGLANDINS
A fact that is not widely appreciated is that proteins, like albumin and fibrinogen, influence platelet prostanoid production. The role of albumin is reviewed in the present issue; the role of fibrinogen has been discussed elsewhere. “’ Platelet aggregation, in platelet rich plasma (PRP) or in washed platelets, is the most commonly used technique for the investigation of platelet function. This approach however ignores the potential role of leucocytes (which release eicosanoids, leucotrienes, bioamines, platelet activating factor) and erythrocytes (which release ADP, a potent aggregating agent, if haemolysis occurs). Platelet behaviour in the presence of other blood cells should therefore be given careful consideration in the future. Obviously, platelet interactions with the endothelium and the coagulation system should also be considered. In this context, it is important that several products of the platelet release reaction stimulate vascular prostacyclin synthesis. “Jo Several drugs influence platelet eicosanoids. These include the non-steroidal anti-inflammatory drugs (NSAIDs) (see recent review)13, dipyridamole, iloprost (and other prostacyclin calcium channel blockers, betaanalogues), blockers, angiotensin converting enzyme {‘CE) inhibitors, penicillamine, cyclosporine A and ethanol. Heparin-associated thrombocytopenia and thrombosis (HABIT) is know well documented and a discussion of this syndrome will be included in a forthcoming review. Platelet eicosanoid metabolism may be altered in several disease states. These include various forms of vascular disease (see above), diabetes mellitus, hyperlipidaemias, cystic fibrosis and various forms of liver and renal disease. Platelets may also play a role in the pathogenesis of asthma and in the spread of metastases (recently reviewed). I5 We have also shown that severe emaciation, in patients with anorexia nervosa, is associated with hyperaggregability-increased TXAz release which is at least partially reversed on weight gain.16 Finally, we would like to take this opportunity to announce a new journal, PLATELETS, which will be devoted to platelet research. qublication of the first issue will be in late 1989. As part of an international team of editors, we are ready to consider publications on this subject and we hope that this editorial demonstrates the need for such a journal. D P Mikhailidis, J Y Jeremy REVIEW EDITORS.
LEUKOTRIENES
AND ESSENTIAL
FAT-I-Y ACIDS:
REVIEWS
References 1. Horrobin
D F. The roles of essential fatty acids in the development of diabetic neuropathy and other complications of diabetes mellitus. Prostagl Leukotr Essentl Fatty Acids-Reviews 1988; 31: 181-97. 2. Leaf A, Weber P C. Cardiovascular effects of n-3 fatty acids. N Engl J Med 1988; 318: 549-57. 3. von Schacky C. Prophylaxis of atherosclerosis with marine omega-3 fatty acids. Ann Intern Med 1987; 107: 890-99. 4. Barradas M A, Christofides J A, Jeremy J Y, Mikhailidis D P. Frv D E. Dandona P. Oleic acid suoolementation alteis ilatelet’ function and membrane’ ‘phospholipid arachidonic acid content. Biochem Sot Transact 1988; in press. 5. Oates J A. Fitzgerald G A, Branch R A, Jackson E A, Knapp H R. Roberts L J. Clinical implications of prostaglartdin and thromboxane Az formation. N Engl J Med 1988; 319: 689-98. 6. Mikhailidis D P, Jeremy J Y, Barradas M A, Green N. Dandona P. Effect of ethanol on vascular prostacyclin (prostaglandin I?) synthesis, platelet aggregation and platelet thromboxane release. Br Med J 1983; 287: 1495-98. 7. Best L C, Holland T K, Jones P B B, Russell R G G. The interrelationship between thromboxane biosynthesis, aggregation and 5-hydroxytryptamine secretion in human piitekts in vitro. Thromb %mostas 1980; 43: 38-40. 8. Jeremv J Y. Mikhailidis D P. ThomDson C S, Barradas M A, ‘Dandona P. Platelet thromboxine A1 synthesising capacity is enhanced by fasting but diminished by diabetes mellitus in the rat. Diabetes Res 1988; in press. 9. Kirtland S J. Prostaglandin E,: a review. Prostagl Leukotr Essntl Fatty Acids - Reviews 1988; 32: 165-74. 10. Mikhailidis D P, Barradas M A, Maris A, Jeremy J Y. Dandona P. Fibrinogen mediated activation of platelet aggregation and thromboxane AZ release: pathological implications in vascular disease. J Clin Pathol 1985; 38: 1166-71. 11. Boeynaems J-M. Drugs influencing the vascular production of prostacyclin. Prostagl Leukotr Essntl Fatty Acids Reviews 1988; 34: 197-204. 12. Jeremy J Y, Mikhailidis D P, Dandona P. Thromboxane A2 analogue (U-46619) stimulates vascular PC12 synthesis. Eur J Pharmacol 1985; 107: 259-52. 13. Peplow P V. Properties and actions of non-steroidal antiinflammatory drugs, including their effects on prostaglandin and macromolecular biosynthesis. Prostagl Leukotr Essntl Fatty Acids - Reviews 1988; 33: 239-52. 14. Grace A A. Cyclosporine A nephrotoxicity - the role of thromboxane AZ. Prostagl Leukotr Essntl Fatty Acids - Reviews 1988; 32: 157-64. 15. Fulton A M. The role of eicosanoids in tumour metastasis. Prostagl Leukotr Essntl Fatty Acids Reviews 1988; 34: 229-37. 16. Mikhailidis D P, Barradas M A, De Souza V, Jeremy J Y, Wakeling A, Dandona P. Adrenaline-induced hyperaggregability of platelets and enhanced thromboxane release in anorexia nervosa. Prostagl Leukotr Med 1986; 24: 27-34.