Effects of Ultra-Low-Dose Aspirin in Thrombosis and Haemorrhage
20 August 2018
31 October 2018
20 April 2019 (online)
Background Aspirin is the oldest and possibly the most widely used pharmacologically active substance still used in allopathic medicine. Its effect on fever and inflammation has paved the way to its anti-thrombotic effect. Dilutions of aspirin have been tested for many years in the University of Bordeaux, in humans as well as in animal models.
Methods This article is a review of the totality of articles published by the Laboratory of Hematology of the Faculty of Pharmacy of the University of Bordeaux, reporting different doses and dilutions of aspirin, different kinds of inhibitors, transgenic mice and animal models of disease such as portal hypertension and cirrhosis.
Results Homeopathic dilutions of aspirin, notably 15 cH, have shown a pro-thrombotic effect in humans and in in-vivo animal studies. Longitudinal studies in rats have also shown an initial anti-thrombotic effect followed by a pro-thrombotic effect of aspirin several days after a single high-dose administration. This pro-thrombotic effect seems to act by inhibiting the cyclooxygenase (COX)-2 pathway in studies performed with COX selective inhibitors and in knock-out mice without COX-1 or COX-2. This effect may explain the thrombo-embolic complications described after aspirin withdrawal for the purposes of surgery or after non-compliance with anti-platelet therapy, and it may be beneficial in normalising primary haemostasis and decreasing haemorrhage in animal models of portal hypertension and cirrhosis.
Conclusions Aspirin 15 cH acts through the inhibition of the COX-2 pathway producing a clear pro-thrombotic effect. Further studies should clarify if the pro-thrombotic effect of aspirin withdrawal and the effect of aspirin 15 cH are related, as secondary effects of the same drug. Clarifying this last outcome may be of great significance to public health.
Keywordsaspirin 15 cH - thrombosis - portal hypertension - homeopathy - COX inhibition - aspirin withdrawal
• ASA 15 cH has a strong pro-thrombotic effect, opposite to that of low-dose aspirin used to prevent ischaemic accidents.
• Prior inhibition or the absence of COX-2 blunts the pro-thrombotic effect.
• The evidence examined in this article may contribute to clarifying the mechanism of effect of homeopathic dilutions.
• It may also help in understanding the complications observed after withdrawal of the larger doses of aspirin used to treat thrombo-embolic events.
- 1 Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res 2003; 110: 255-258
- 2 Doutremepuich C, de Seze O, Anne MC, Hariveau E, Quilichini R. Platelet aggregation on whole blood after administration of ultra low dosage acetylsalicylic acid in healthy volunteers. Thromb Res 1987; 47: 373-377
- 3 Doutremepuich C, Pailley D, Anne MC, de Sèze O, Paccalin J, Quilichini R. Template bleeding time after ingestion of ultra low dosages of acetyl salicylic acid in healthy subjects. Preliminary study. Thromb Res 1987; 48: 501-504
- 4 Doutremepuich C, Paillet D, De Seze O, Anne MC, Paccalin J, Quilichini R. Variation of bleeding time after administration of acetyl salicylic acid at different doses in the healthy volunteer [article in French]. Ann Pharm Fr 1988; 46: 35-39
- 5 Doutremepuich C, de Sèze O, Le Roy D, Lalanne MC, Anne MC. Aspirin at very ultra low dosage in healthy volunteers: effects on bleeding time, platelet aggregation and coagulation. Haemostasis 1990; 20: 99-105
- 6 Lalanne MC, Doutremepuich C, de Sèze O, Belon P. What is the effect of acetylsalicylic acid at ultra low dose on the interaction platelets/vessel wall?. Thromb Res 1990; 60: 231-236
- 7 Lalanne MC, de Seze O, Doutremepuich C, Belon P. Could proteolytic enzyme modulate the interaction platelets/vessel wall in presence of ASA at ultra low doses?. Thromb Res 1991; 63: 419-426
- 8 Doutremepuich C, Aguejouf O, Belon P. Effects of ultra-low-dose aspirin on embolisation in a model of laser-induced thrombus formation. Semin Thromb Hemost 1996; 22: 67-70
- 9 Aguejouf O, Belougne-Malfatti E, Doutremepuich F, Belon P, Doutremepuich C. Thromboembolic complications several days after a single-dose administration of aspirin. Thromb Res 1998; 89: 123-127
- 10 Belougne-Malfatti E, Aguejouf O, Doutremepuich F, Belon P, Doutremepuich C. Combination of two doses of acetyl salicylic acid: experimental study of arterial thrombosis. Thromb Res 1998; 90: 215-221
- 11 Aguejouf O, Malfatti E, Belon P, Doutremepuich C. Time related neutralization of two doses acetyl salicylic acid. Thromb Res 2000; 100: 317-323
- 12 Aguejouf O, Eizayaga F, Desplat V, Belon P, Doutremepuich C. Prothrombotic and hemorrhagic effects of aspirin. Clin Appl Thromb Hemost 2009; 15: 523-528
- 13 Doutremepuich CR, Aguejouf OM, Eizayaga FX, Desplat VL. Abstract 483: Reverse effect of aspirin: is the prothrombotic effect after aspirin discontinuation mediated by COX-2 blockade?. Circulation 2007; 114: 2-73
- 14 Doutremepuich C, Aguejouf O, Eizayaga FX, Desplat V. Reverse effect of aspirin: is the prothrombotic effect after aspirin discontinuation mediated by cyclooxygenase 2 inhibition?. Pathophysiol Haemost Thromb 2007; 36: 40-44
- 15 Doutremepuich C, Aguejouf O, Desplat V, Eizayaga FX. Paradoxical thrombotic effects of aspirin: experimental study on 1000 animals. Cardiovasc Hematol Disord Drug Targets 2010; 10: 103-110
- 16 Doutremepuich C, Aguejouf O, Desplat V, Eizayaga F. Prothrombotic Effect After Aspirin Discontinuation is COX 2-dependent. Circulation 2009; 120: S1032-S1033
- 17 Doutremepuich C, Aguejouf O, Desplat V, Eizayaga FX. Aspirin therapy: an attempt to explain the events of prothrombotic complications after treatment discontinuation. Thromb Haemost 2010; 103: 171-180
- 18 Eizayaga FX, Aguejouf O, Belon P, Doutremepuich C. Platelet aggregation in portal hypertension and its modification by ultra-low doses of aspirin. Pathophysiol Haemost Thromb 2005; 34: 29-34
- 19 Eizayaga FX, Aguejouf O, Desplat V, Belon P, Doutremepuich C. Modifications produced by indomethacin and L-NAME in the effect of ultralow-dose aspirin on platelet activity in portal hypertension. Pathophysiol Haemost Thromb 2006; 35: 357-363
- 20 Eizayaga FX, Aguejouf O, Desplat V, Belon P, Doutremepuich C. Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension. World J Gastroenterol 2007; 13: 5065-5070
- 21 Eizayaga FX, Aguejouf O, Desplat V, Doutremepuich C. Beneficial effect of ultra-low-dose aspirin in platelet activity alterations and haemorrhage observed in experimental portal hypertension. Thrombosis 2012; 2012: 430460
- 22 Doutremepuich C, Aguejouf O, Desplat V, Eizayaga FX. Aspirin discontinuation syndromes: clinical implications of basic research studies. Am J Cardiovasc Drugs 2013; 13: 377-384
- 23 Sibon I, Orgogozo JM. Antiplatelet drug discontinuation is a risk factor for ischemic stroke. Neurology 2004; 62: 1187-1189
- 24 Maulaz AB, Bezerra DC, Michel P, Bogousslavsky J. Effect of discontinuing aspirin therapy on the risk of brain ischemic stroke. Arch Neurol 2005; 62: 1217-1220
- 25 Armstrong MJ, Schneck MJ, Biller J. Discontinuation of perioperative antiplatelet and anticoagulant therapy in stroke patients. Neurol Clin 2006; 24: 607-630
- 26 Fischer LM, Schlienger RG, Matter CM, Jick H, Meier CR. Discontinuation of nonsteroidal anti-inflammatory drug therapy and risk of acute myocardial infarction. Arch Intern Med 2004; 164: 2472-2476
- 27 Ferrari E, Benhamou M, Cerboni P, Marcel B. Coronary syndromes following aspirin withdrawal: a special risk for late stent thrombosis. J Am Coll Cardiol 2005; 45: 456-459
- 28 Burger W, Chemnitius JM, Kneissl GD, Rücker G. Low-dose aspirin for secondary cardiovascular prevention—cardiovascular risks after its perioperative withdrawal versus bleeding risks with its continuation—review and meta-analysis. J Intern Med 2005; 257: 399-414
- 29 Collet JP, Montalescot G, Blanchet B. , et al. Impact of prior use or recent withdrawal of oral antiplatelet agents on acute coronary syndromes. Circulation 2004; 110: 2361-2367
- 30 Ho PM, Spertus JA, Masoudi FA. , et al. Impact of medication therapy discontinuation on mortality after myocardial infarction. Arch Intern Med 2006; 166: 1842-1847
- 31 Biondi-Zoccai GG, Lotrionte M, Agostoni P. , et al. A systematic review and meta-analysis on the hazards of discontinuing or not adhering to aspirin among 50,279 patients at risk for coronary artery disease. Eur Heart J 2006; 27: 2667-2674
- 32 Collet JP, Himbet F, Steg PG. Myocardial infarction after aspirin cessation in stable coronary artery disease patients. Int J Cardiol 2000; 76: 257-258
- 33 Albaladejo P, Geeraerts T, Francis F, Castier Y, Lesèche G, Marty J. Aspirin withdrawal and acute lower limb ischemia. Anesth Analg 2004; 99: 440-443
- 34 Eisenberg MJ, Richard PR, Libersan D, Filion KB. Safety of short-term discontinuation of antiplatelet therapy in patients with drug-eluting stents. Circulation 2009; 119: 1634-1642
- 35 Reidenberg MM. Drug discontinuation effects are part of the pharmacology of a drug. J Pharmacol Exp Ther 2011; 339: 324-328
- 36 Teixeira MZ. Evidence of the principle of similitude in modern fatal iatrogenic events. Homeopathy 2006; 95: 229-236
- 37 Teixeira MZ. NSAIDs, myocardial infarction, rebound effect and similitude. Homeopathy 2007; 96: 67-68
- 38 Teixeira MZ. Rebound effect of modern drugs: serious adverse event unknown by health professionals. Rev Assoc Med Bras 2013; 59: 629-638
- 39 Sainte-Laudy J, Belon P. Inhibition of basophil activation by histamine: a sensitive and reproducible model for the study of the biological activity of high dilutions. Homeopathy 2009; 98: 186-197
- 40 Calabrese EJ. Hormesis: why it is important to toxicology and toxicologists. Environ Toxicol Chem 2008; 27: 1451-1474
- 41 Sundström J, Hedberg J, Thuresson M, Aarskog P, Johannesen KM, Oldgren J. Low-dose aspirin discontinuation and risk of cardiovascular events: a Swedish nationwide, population-based cohort study. Circulation 2017; 136: 1183-1192