Aspirin at Very Ultra Low Dosage in Healthy Volunteers: Effects on Bleeding Time, Platelet Aggregation and Coagulation

Doutremépuich, Christian; Sèze, O. De; Roy, Didier Le; Lalanne, Magalie; Anne, M.C.

doi:10.1159/000216114

Cited by 22 publications

(21 citation statements)

References 9 publications

(14 reference statements)

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“…Although NO plays an important role in modifying platelet adhesion in portal hypertension [2] , PGI2, a powerful vasodilator prostanoid with antithrombotic properties, was also found increased in mesenteric vascular bed [3] . Ultra low dose aspirin (ULDA) has shown prothrombotic activity when analysed in humans and in the interface platelet-endothelial cell [4,5] . Previous papers have shown the potentially beneficial effect of ULDA in portal hypertensive animals normalizing altered platelet activity and induced hemorrhagic time [6] .…”

Section: Introductionmentioning

confidence: 99%

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

Eizayaga

Aguejouf²,

Desplat³

et al. 2007

WJG

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INTRODUCTIONPortal hypertension is a major complication of chronic liver disease. In its pathophysiology, increased hepatic resistance is followed by a hyperdynamic circulatory state [1] . This hyperdynamic state, in which nitric oxide (NO) and prosatcyclin (PGI2) are important vasoactive substances, induces a decreased platelet activity, even in the absence of hepatic damage. Although NO plays an important role in modifying platelet adhesion in portal hypertension [2] , PGI2, a powerful vasodilator prostanoid with antithrombotic properties, was also found increased in mesenteric vascular bed [3] . Ultra low dose aspirin (ULDA) has shown prothrombotic activity when analysed in humans and in the interface platelet-endothelial cell [4,5] . Previous papers have shown the potentially beneficial effect of ULDA in portal hypertensive animals normalizing altered platelet activity and induced hemorrhagic time [6] . Further experiments were performed to clarify if this effect was mediated mostly by a cyclooxigenase (COX) pathway or by modifying NO synthesis, the two aspirin mechanisms of action [7] , although a previous study with a different model suggested that ULDA could decrease PGI2 synthesis [8] . The same in vivo Laser induced thrombus formation, was used in portal hypertensive rats to investigate the effects of Indomethacin, a non selective COX inhibitor, and L-Nitro Arginin Methyl Ester (NAME), a non selective inhibitor of NO production. The results suggested that the effects of ULDA were more influenced by COX pathway than by NO synthesis inhibition [9] . Addition of ULDA in portal hypertensive rats, when previously inhibiting COX with Indomethacin, increased number of emboli and duration Abstract AIM: To study the mechanism involved in the potentially beneficial effect of ultra low dose aspirin (ULDA) in prehepatic portal hypertension, rats were pretreated with selective COX 1 or 2 inhibitors (SC-560 or NS-398 respectively), and subsequently injected with ULDA or placebo. METHODS:Portal hypertension was induced by portal vein ligation. Platelet activity was investigated with an in-vivo model of laser induced thrombus production in mesenteric circulation and induced hemorrhagic time (IHT). Platelet aggregation induced by ADP and dosing of prostanoid products 6-keto-PGF1α, TXB2, PGE2 and LTB4 were also performed. RESULTS:The portal hypertensive group receiving a placebo showed a decreased in vivo platelet activity with prolonged IHT, an effect that was normalized by ULDA. SC-560 induced a mild antithrombotic effect in the normal rats, and an unmodified effect of ULDA. NS-398 had a mild prothrombotic action in portal hypertensive rats, similar to ULDA, but inhibited a further effect when ULDA was added. An increased 6-keto-PGF1α was observed in portal hypertensive group that was normalised after ULDA administration. TXA2 level after ULDA, remained unchanged. CONCLUSION:These results suggest that the effect of ULDA on platelet activity in portal hypertensive rats, could act through a COX 2

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Section: Introductionmentioning

confidence: 99%

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

Eizayaga

Aguejouf²,

Desplat³

et al. 2007

WJG

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show abstract

“…There are few reports that investigate platelet aggregation in vivo in portal hypertension, and none of them utilize a prehepatic portal hypertension model. Aspirin (ASA) in ultra-low doses (ULD) was reported as a potent enhancer of platelet aggregation in several reports [4][5][6][7] , in experimental and clinical research studies. The aim of this study was to evaluate in vivo the changes in platelet aggregation in a model of portal hypertension in the absence of liver damage and the modifi cations observed after administering ASA in ULD.…”

Section: Introductionmentioning

confidence: 99%

Platelet Aggregation in Portal Hypertension and Its Modification by Ultra-Low Doses of Aspirin

Eizayaga

Aguejouf²,

Belon³

et al. 2005

Pathophysiol Haemos Thromb

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Aspirin (ASA) is widely accepted as antithrombotic drug, but several reports point out that its use in ultra-low doses (ULD) has prothrombotic properties. In this study, we evaluate the effect of portal hypertension in rats on platelet aggregation in an in vivo arterial thrombosis model induced by a laser beam. Portal hypertension was produced by calibrated stenosis of the portal vein. ASA in ULD was injected to both control and portal hypertensive groups. Platelet aggregation induced by ADP, prothrombin time, activated partial thromboplastin time, fibrinogen and induced hemorrhagic time test were also performed. Portal hypertensive rats showed a diminished number of emboli and duration of embolization in the laser procedure and an increase in induced hemorrhagic time. These changes were reverted by one injection of ASA at ULD. This observation could be of importance for primary prevention or the treatment of recurrence in upper digestive tract hemorrhage in portal hypertensive patients.

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“…This may reflect the fact that aspirin is a relatively weak antiplatelet agent. However it has been suggested that some patients are resistant to the antiplatelet effects of aspirin [25]. The term aspirin nonresponder has been used to describe those patients who show a reduced response to aspirin as measured by platelet function assays.…”

Section: Aspirinmentioning

confidence: 99%

Pharmacogenetics of Antiplatelet Drugs

Curtin

Fitzgerald

2002

The Scientific World JOURNAL

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Pharmacogenetics refers to the genetic factors that influence the response to a drug, often involving genetic variations in drug metabolizing enzymes. The pharmacogenetics of antiplatelet agents is in its infancy and largely reflects variations in drug targets or related genes. One particular gene variant, the Pl A2 polymorphism of the glycoprotein (GP) IIb/IIIa receptor, is now emerging as a probable determinant of the response to antiplatelet agents including GPIIb/IIIa antagonists. This variant may in part explain the heterogeneity in the response to GPIIb/IIIa antagonists. The Pl A2 genotype appears to be associated with an adverse outcome in patients treated with an oral GPIIb/IIIa antagonist and may be a factor in the observed failure of these agents in unselected populations. However, there are preliminary indications that other antiplatelet agents may have an enhanced effect in Pl A2 subjects. Further clinical trials in particular are required to definitively characterize the pharmacogenetic effect of Pl A2. Other polymorphisms are also likely to contribute to the pharmacogenetics of antiplatelet agents, but these await investigation. KEY WORDS: pharmacogenetics, Pl A2, GPIIb/IIIa receptor, aspirin, dipyridamole, clopidogrel, GPIIb/IIIa antagonists DOMAINS: thrombosis, pharmacogenomics INTRODUCTIONAge, concurrent medications, and renal and liver dysfunction are well-characterized factors that can affect the efficacy or toxicity of drug treatment. Inherited factors are also emerging as determinants of the pharmacokinetics and pharmacodynamics of many medications. Pharmacogenetics is that field of science concerned with this hereditary component of drug response. Variations in genes that encode proteins involved in drug metabolism can be important determinants of a patient's response to therapy. Genetic variations in many drug metabolizing enzymes and their phenotypes have been characterized [1]. However, genetic variation in drug transporters and drug targets, as well as genetic heterogeneity underlying the disease being treated, can also modulate response to medications. Curtin and Fitzgerald: Pharmacogenetics of Antiplatelet Drugs TheScientificWorldJOURNAL (2002) 2, 791-800 792Initially, identification of inherited differences in drug metabolism was based on observations in patients who suffered adverse effects despite being treated with standard doses of a drug [2]. However the focus of research in pharmacogenetics, triggered in part by the human genome project, has shifted to identification of single nucleotide polymorphisms (SNPs) in target genes. Drug trials or disease cohorts provide an opportunity to determine whether such SNPs modify drug response. For example, a variant of the β 2 adrenergic receptor enhances the response to β-agonist therapy in asthmatics, as the receptor fails to desensitize [3]. Variants in genes that may not be targets for drugs but are involved in the disease may also influence drug response. For example, recent evidence suggests that the angiotensin converting enzyme...

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Aspirin at Very Ultra Low Dosage in Healthy Volunteers: Effects on Bleeding Time, Platelet Aggregation and Coagulation

Cited by 22 publications

References 9 publications

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

Modifications produced by selective inhibitors of cyclooxygenase and ultra low dose aspirin on platelet activity in portal hypertension

Platelet Aggregation in Portal Hypertension and Its Modification by Ultra-Low Doses of Aspirin

Pharmacogenetics of Antiplatelet Drugs

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