Antithrombotic Effect Of Aspirin Research Articles

Effect of Centhaquine on the Coagulation Cascade in Normal State and Uncontrolled Hemorrhage: A Multiphase Study Combining Ex Vivo and In Vivo Experiments in Different Species.

Centhaquine is a novel vasopressor acting on α2A- and α2B-adrenoreceptors, increasing venous return and improving tissue perfusion. We investigated the effects of centhaquine on blood coagulation in normal state and uncontrolled hemorrhage using ex vivo and in vivo experiments in different species. Thromboelastography (TEG) parameters included clotting time (R), clot kinetics [K and angle (α)], clot strength (MA), and percent lysis 30 min post-MA (LY30). In normal rat blood, centhaquine did not alter R, K, α, MA, or LY30 values of the normal vehicle group or the antithrombotic effects of aspirin and heparin. Subsequently, New Zealand white rabbits with uncontrolled hemorrhage were assigned to three resuscitation groups: Sal-MAP 45 group (normal saline to maintain a mean arterial pressure, MAP, of 45 mmHg), Centh-MAP 45 group (0.05 mg kg-1 centhaquine plus normal saline to maintain a MAP of 45 mmHg), and Sal-MAP 60 group (normal saline to maintain a MAP of 60 mmHg). The Sal-MAP 45 group was characterized by no change in R, reduced K and MA, and increased α. In the Centh-MAP 45 group, TEG showed no change in R, K, and α compared to saline; however, MA increased significantly (p = 0.018). In the Sal-MAP 60 group, TEG showed no change in R, an increase in α (p < 0.001), a decrease in K (p < 0.01), and a decrease in MA (p = 0.029) compared to the Centh-MAP 45 group. In conclusion, centhaquine does not impair coagulation and facilitates hemostatic resuscitation.

Abstract 17654: Sarpogrelate versus Clopidogrel for Arterial Interventions Systematic Review and Meta Analysis

Background: Sarpogrelate has been used to alleviate ischemic changes by preventing thrombosis, vasoconstriction, and vascular smoothmuscle proliferation. The worldwide use of Sarpogrelate is arguable due to the lack of reliable data regarding its efficacy and safety.Accordingly, our meta-analysis aims to compare the complications after receiving Sarpogrelate with Aspirin (S&amp;A) vs. Clopidogrel withAspirin (C&amp;A) as part of dual anti-platelet therapy in patients with endovascular intervention. Methods: Multiple electronic databases weresearched to identify relevant articles, including MEDLINE, Cochrane CENTRAL, Scopus, Google Scholar, Web of Science, and EMBASE. Allclinical studies that investigated the complication after performing Sarpogrelate versus clopidogrel with Aspirin for arterial interventionswere included in the meta-analysis. Reviews, case reports, conference abstracts, editorials, and animal studies were all excluded. Data wereanalyzed by using comprehensive meta-analysis studies. A complete quality assessment was performed using the Cochrane Risk of Bias toolversion 2 for randomized clinical trials (RCTs). Results: A total of 2588 studies were screened, with three studies included. Two multicenterRCTs and one retrospective cohort study including 527 patients (251 S&amp;A and 276 C&amp;A) were included. The overall quality was high in 2studies and fair in one. No statistically significant difference in restenosis, mortality, and bleeding risk as follows, respectively: (RR:0.81, 95%CI:0.52-1.2, P-value:0.36), (RR:0.37, 95% CI:0.06-2, P-value:0.25) and (RR:0.4, 95% CI:0.13-1.19, P-value:0.1). Conclusion: The antithromboticeffects of Aspirin with Sarpogrelate after vascular intervention are comparable to those of Aspirin plus Clopidogrel. Further large clinicalstudies are required to identify the actual difference in early and late complications after using Sarpogrelate versus clopidogrel.

Macrophage activity regulation by high dilution of aspirin and its possible mechanism

Background: Under LPS-stimulus, platelets can activate macrophages by a cell-to-cell contact or through cytokine degranulation. Rebound effects of anti-thrombotic agents, such as prostanoids and COX inhibitors can lead to thrombosis, infarct, and stroke. Aspirin has been prescribed for decades due to its powerful antiplatelet action, but it is also related to paradoxical effects such as withdrawal syndrome peaks, resistance, and thrombogenesis. Ultra-diluted aspirin can also produce the same effect in one hour, regardless of Cox-2, by still unknown pathways. Antithrombotic effects of aspirin are also reversed by its high dilutions. Aims: This study aims to characterize the effects of aspirin 15cH on macrophages challenged with LPS, a Cox-2 activator. Methodology: RAW 264.7 macrophages were sown in 24 wells plates using R10 medium, boosted with 1μg/ml LPS, and treated with aspirin 15 cH and controls. The activity was evaluated after 24 hours. Supernatants were evaluated for cytokines, nitric oxide, and dielectric oscillations, through solvatochromic dyes (Cartwright’s method). Results and discussion: macrophage spreading was increased by aspirin 15 cH, an LPS-like effect. Paradoxically, a significant reduction of this effect was noted when both, LPS and aspirin 15 cH, were added. Succussed water reversed the effect of LPS, leading to TNF (p&lt;0.05) production close to baseline levels. Also, the single treatment with succussed water inhibited IL-10 production (p&lt;0.05), but aspirin 200 µg/mL (positive control) highly increased it (p&lt;0.0001), showing the validity of the model. Nitric oxide production was strengthened by LPS presence (p&lt;0.0001), as expected, but partially downregulated after treatment with aspirin 200 µg/mL, water and succussed water. A pilot study with solvatochromic dyes showed no significant difference among treatments. Conclusion: The main data suggest that aspirin 15 cH increases macrophage activity but presents a paradoxal effect when mixed with LPS. On the other hand, succussed water itself has modulatory effects on macrophages.

Thromboelastography With Platelet Mapping is Not an Effective Measure of Platelet Inhibition in Patients With Spontaneous Intracerebral Hemorrhage on Antiplatelet Therapy.

Thromboelastography with platelet mapping (TEG-PM) is a modality to measure platelet function, especially in patients taking antiplatelet medications. It consists of two components: arachidonic acid (AA), which is sensitive to aspirin, and adenosine diphosphate (ADP), which is sensitive to clopidogrel. In patients with spontaneous intracerebral hemorrhages (sICH), the clinical interpretation of platelet mapping is unclear. The objective of this study was to evaluate TEG-PM in patients with sICH on aspirin and/or clopidogrel who receive platelet transfusions. This study was an IRB-approved, retrospective case-control study over three years at an academic medical center. Adult patients with sICH were included if they had an admission computed tomography head (CTH) and platelet mapping followed by a repeat platelet mapping and CTH post platelet transfusion. A threshold of 50% inhibition was used as the benchmark for both ADP and AA inhibition. Around 248 subjects with sICH were identified, and 107 were excluded for incomplete documentation, leaving 141 for analysis. Of these, nine met our inclusion criteria. No statistical significance was found on the antithrombotic effects of aspirin or clopidogrel on TEG-PM (p=1.00 for both). Sensitivity and specificity of TEG-PM for clopidogrel was 100% and 42.9%, respectively, and 80% and 0%, respectively, for aspirin. Platelet transfusion did not significantly change AA or ADP inhibition (p=1.00). Hemorrhagic expansion on CTH was not associated with a decrease AA or ADP inhibition (p=1.00). TEG-PM is not an effective measure of platelet inhibition in sICH patients who were on antiplatelet medications and is not a reliable measurement following platelet transfusion.

MY APPROACH to the use of aspirin

Multiple randomized clinical trials have established that aspirin reduces the incidence of stroke andmyocardial infarction in patients with established cardiovascular disease. The antithrombotic effect of aspirin is due to inhibition of platelet aggregation by blocking the production of thromboxane A2. Long-term aspirin is recommended in all patients with known cardiovascular disease who do not have relative contraindications, such as a history of gastrointestinal (GI) bleeding or peptic ulcer. The recommended dose in the United States is 81mg/day. The indications for aspirin in primary prevention—that is in patients with risk factors for cardiovascular disease who do not have a history of coronary heart disease or stroke—are not as clear. The Physicians’ Health study in 1989 randomized 22,071 physicians without a history of coronary artery disease to 325 mg aspirin every other day or placebo. After 5 years of therapy, they reported a very significant (P o .00001) reduction in myocardial infarction in those in the aspirin arm. However, multiple primary prevention trials since have been negative. As a result, many have concluded that aspirin is not indicated for primary prevention because the potential benefit is exceeded by the risk for GI bleeding. All of the primary prevention trials have used doses of aspirin of 100 mg or less

Aspirin and aspirin resistance in coronary artery disease

Aspirin is still the mainstay of antiplatelet therapy in the secondary prevention of coronary artery disease. However certain patients do not benefit from the antithrombotic effects of aspirin. The phenomenon of so-called aspirin resistance can be considered from the clinical and laboratory perspective. A variety of methods have emerged for the laboratory diagnosis of aspirin resistance. None of them is considered ideal as they provide conflicting information with significant inter-individual variability and weak correlation between them. With the mechanisms of aspirin resistance not fully understood and the phenomenon commonly observed in individuals with poor compliance, the existence of aspirin resistance has been challenged. The aim of this review is to present recent data on the impact of aspirin resistance in primary and secondary prevention of coronary artery disease.

New analogues of 13-hydroxyocatdecadienoic acid and 12-hydroxyeicosatetraenoic acid block human blood platelet aggregation and cyclooxygenase-1 activity

BackgroundThromboxane A2 is derived from arachidonic acid through the action of cyclooxygenases and thromboxane synthase. It is mainly formed in blood platelets upon activation and plays an important role in aggregation. Aspirin is effective in reducing the incidence of complications following acute coronary syndrome and stroke. The anti-thrombotic effect of aspirin is obtained through the irreversible inhibition of cyclooxygenases. Analogues of 12-hydroxyeicosatetraenoic acid and 13-hydroxyocatdecadienoic acid were shown previously to modulate platelet activation and to block thromboxane receptors.Results and discussionWe synthesized 10 compounds based on the structures of analogues of 12-hydroxyeicosatetraenoic acid and 13-hydroxyocatdecadienoic acid and evaluated their effect on platelet aggregation triggered by arachidonic acid. The structure activity relationship was evaluated. Five compounds showed a significant inhibition of platelet aggregation and highlighted the importance of the lipidic hydrophobic hydrocarbon chain and the phenol group. Their IC50 ranged from 7.5 ± 0.8 to 14.2 ± 5.7 μM (Mean ± S.E.M.). All five compounds decreased platelet aggregation and thromboxane synthesis in response to collagen whereas no modification of platelet aggregation in response to thromboxane receptor agonist, U46619, was observed. Using COS-7 cells overexpressing human cyclooxygenase-1, we showed that these compounds are specific inhibitors of cyclooxygenase-1 with IC50 ranging from 1.3 to 12 μM. Docking observation of human recombinant cyclooxygenase-1 supported a role of the phenol group in the fitting of cyclooxygenase-1, most likely related to hydrogen bonding with the Tyr 355 of cyclooxygenase-1.ConclusionsIn conclusion, the compounds we synthesized at first based on the structures of analogues of 12 lipoxygenase metabolites showed a role of the phenol group in the anti-platelet and anti-cyclooxygenase-1 activities. These compounds mediate their effects via blockade of cyclooxygenase-1.

Aspirin

> Among the many useful discoveries which this age has made, there are very few which better deserve the attention of the public that what I am going to lay before your Lordship. > > —Reverend Edward Stone –Chipping-Norton, Oxfordshire –April 25, 1763 These prophetic words, written by Reverend Edward Stone in a 1763 letter to George Parker, the second Earl of Macclesfield, describe the results of the first clinical trial recorded in medical history.1 Stone's report on the rediscovery of the medicinal value of willow bark among subjects suffering from malarial symptoms is considered a significant milestone in the development of aspirin. Although society now takes many of its beneficial effects for granted, aspirin did not suddenly appear for medicinal use after Reverend Stone's discovery. Instead, its tumultuous journey was fueled by individual scientific curiosity, accidental discoveries, and intense business rivalry.1 No other drug is used by a greater number of people worldwide than aspirin, the benefits of which span centuries, beginning with the very first uses of willow bark by Egyptian physicians (Figure 1). Aspirin single-handedly transformed a coal-dye company into a pharmaceutical giant and has emerged as a cornerstone in the present-day therapies available for treating cardiovascular disease (CVD), pain, and inflammation. This article discusses the sentinel historical aspects of the discovery and clinical cardiovascular developments of aspirin, as well as its contemporary use in today's medical arena. Figure 1. Timeline of historical events in the development of aspirin. ### Historical Developments of Salicylates On January 20, 1862, Edwin Smith made one of the most historically important purchases of his life. Well-regarded among his peers for his keen scholarship and intricate knowledge of Egyptology, Smith purchased, for £12, 2 worn papyrus scrolls in a local Luxor street market1 that later turned out to be a formative medical textbook unlocking ancient Egyptian's practice of medicine. Although authorless, the Ebers Papyrus is 110 pages …

Laboratory detection of 'aspirin resistance': what test should we use (if any)?

Aspirin is widely used to decrease the risk of occlusive arterial events in patients at risk. It irreversibly inhibits the cyclooxygenase-1 (COX-1)-dependent synthesis of thromboxane A2 (TxA2), which is essential for the full aggregation response of platelets. In the last years, the issue of ‘aspirin resistance’ has been emphasized in the medical literature.1–4 Despite several studies published on this subject, its definition, diagnosis, prevalence, causes, and clinical consequences are still uncertain.1 The term ‘resistance’ to a drug should be used when a drug is unable to hit its pharmacological target, due to inability to reach it (as a consequence of reduced bioavailability, in vivo inactivation, negative interaction with other substances) or to alterations of the target.1 Based on this definition, the term ‘resistance’ to aspirin should be limited to situations in which aspirin is unable to inhibit COX-1-dependent TxA2 production (and, consequently, TxA2-dependent platelet functions). ### ‘Aspirin resistance’ vs. ‘treatment failure’ If the anti-thrombotic effects of aspirin are dependent on inhibition of COX-1, one would expect that patients in whom aspirin does not inhibit COX-1 do not benefit from the protection that this drug provides and are exposed to high risk of atherothrombotic events. However, it is incorrect to consider ‘resistant’ to aspirin all those patients who experience atherothrombotic events while on treatment. This phenomenon has been named ‘clinical resistance’, but it should be more properly termed ‘treatment failure’.1,2 It can be observed with any kind of treatment and is expected to be particularly frequent for drugs, like aspirin and all other anti-thrombotic agents, that are used to prevent multi-factorial diseases, such as those associated with vascular occlusion, independently of their efficacy to hit their pharmacological targets. ### ‘Aspirin resistance’ vs. ‘high on-treatment residual platelet reactivity’ In consideration of the importance of TxA2 pathway in platelet activation, one would expect that … Corresponding author. Tel: +39 (0) 250323095; fax: +39 (0) 250323095. E-mail address : marco.cattaneo{at}unimi.it

The antithrombotic efficacy of lotrafiban (SB 214857) in canine models of acute coronary thrombosis.

In patients with acute coronary syndromes, inhibition of platelet aggregation with parenteral alpha(IIb)/beta(III) antagonists has proven effective at preventing nonfatal myocardial infarction and repeat percutaneous coronary interventions. Paradoxically, the efficacy observed for acute indications and parenteral agents has not extended to oral agents and chronic prevention of secondary thrombotic events, despite robust antithrombotic properties in preclinical thrombosis models. This report documents the preclinical data of Lotrafiban, an oral alpha(IIb)/beta(III) antagonist that recently failed in a phase III clinical trial (BRAVO) for the prevention of secondary thrombosis. Lotrafiban was characterized in a dog circumflex artery electrical injury model, and a cyclic flow reduction model ("Folts"). The data demonstrate that both oral (1.0-50.0 mg/kg) and intravenous (0.1-0.8ug/kg/min) administration of lotrafiban produced dose-related inhibition (45%-95%) of ex vivo platelet aggregation. In the electrical injury model, the dose-related inhibition correlated with a significant reduction in the frequency of coronary occlusion, size of the developing thrombus, and the extent of left ventricular ischemic damage. Effects on blood flow and bleeding time were also dose related. The combination of low dose lotrafiban (0.1ug/kg/min) and aspirin (5.0 mg/kg) generated additive antithrombotic effects, approximating the antithrombotic efficacy of a 2-4 fold higher dose of lotrafiban while only modestly prolonging the bleeding time. For purposes of comparison, the ADP receptor antagonist clopidogrel was also assessed in the electrical injury model. Clopidogrel (5.0-10.0 mg/kg, iv.) significantly reduced the resulting left ventricular infarct areas, but lacked the overall efficacy of lotrafiban. In the "Folts" model, lotrafiban inhibited cyclic blood flow reductions (CFR's) by 100% in animals insensitive to the antithrombotic effects of aspirin. Overall, the preclinical data demonstrated that alpha(IIb)/beta(III) antagonism with lotrafiban was a well tolerated and effective strategy for attenuating acute arterial thrombosis. The lack of a correlation between these preclinical data and the outcome of the clinical trial BRAVO are unexplained. However, the combined evidence suggests that these acute canine thrombosis studies may not completely capture the pathology reflected in chronic human atherothrombotic disease.

Why Are Some Individuals Resistant to the Cardioprotective Effects of Aspirin?

It has been slightly more than 100 years since the synthesis, development, and commercialization of acetylsalicylic acid, the most widely consumed drug in the world. It is estimated that 35 000 kg are consumed daily in the United States and 6000 kg in the UK.1 Who would have ever thought that this widely consumed drug would achieve significant uses other than as an analgesic, antipyretic, and anti-inflammatory. The first report of a possible antithrombotic effect of aspirin appeared in 1953 in the Mississippi Valley Medical Journal .2 Dr Craven noticed that the patients who took Aspergum had a tendency to bleed more easily. He concluded that aspirin must be thinning the blood and because thrombosis of the coronary arteries led to myocardial infarction, if his patients took aspirin, they might be less prone to experiencing a myocardial infarction. See p 1650 These prescient observations were succeeded by the discovery by numerous investigators that aspirin could significantly decrease platelet function. In 1971, the mechanism by which aspirin inhibited platelet function began to unfold when Smith and Willis3 demonstrated that aspirin inhibited platelet prostaglandin synthesis. It was subsequently shown that aspirin irreversibly acetylated serine-529 close to the active site of the fatty acid cyclooxygenase (COX).4 In the case of the anucleate platelet, the enzyme is rendered inactive for its lifetime. Samuelsson and co-workers5 demonstrated that thromboxane A2 along with prostaglandin H2 were the arachidonic acid metabolites responsible for activation of the platelet. Thromboxane A2 is also a very effective vasoconstrictor and mitogenic substance. After the discovery of thromboxane A2, numerous studies followed that investigated its potential role in thrombotic cardiovascular diseases. Platelet thromboxane A2 synthesis is increased in acute myocardial infarction, unstable angina, thrombolysis therapy, percutaneous transluminal coronary artery angioplasty, and …

Vascular biology of thrombosis: platelet-vessel wall interactions and aspirin effects.

The antithrombotic effect of aspirin has long been recognized, and administration of low doses (80-160 mg/day) for the prevention of ischemic events in patients with coronary artery disease (CAD) is now generally considered to be routine practice. The action of aspirin derives mostly from the selective inhibition of cyclo-oxygenases (Cox). These enzymes (Cox-1 and Cox-2) catalyze the synthesis of eicosanoids, which play an important part in platelet-vessel wall interactions. Cox-1 catalyzes the synthesis of thromboxane A2 (Tx-A2), which causes platelet activation, vasoconstriction, and smooth muscle proliferation. Tx-A2 levels are elevated in conditions associated with platelet activation, including unstable angina and cerebral ischemia. Conversely, Cox-2 controls the synthesis of prostacyclin (PGI2), a local platelet regulator with an effect opposite to that of Tx-A2. PGI2 is produced as a compensatory response to increases in Tx-A2 during ischemic events. Aspirin is a more potent inhibitor of Cox-1 than of Cox-2, unlike other non-steroidal anti-inflammatory drugs (NSAIDs), which have limited selectivity. Aspirin at low doses selectively inhibits the formation of Tx-A2 without inhibiting the basal biosynthesis of cardioprotective PGI2. Furthermore, aspirin causes complete enzyme inhibition, without the recovery of enzyme activity at trough drug levels associated with conventional NSAIDs. The effect of aspirin in the prevention of ischemic events has been well documented in many recent clinical trials involving more than 50,000 patients with CAD. It is clear from these studies that aspirin, alone or in combination with other antithrombotics, significantly reduces the incidence of cardiovascular death, stroke, and myocardial infarction.

Aspirin: new cardiovascular uses for an old drug

Inhibition of TXA2-dependent platelet function by aspirin may lead to prevention of thrombosis as well as to excess bleeding. The balance between the two depends critically on the absolute thrombotic versus hemorrhagic risk of the patient. As the risk of experiencing a major vascular event increases, so does the absolute benefit of antiplatelet prophylaxis with aspirin [Figure-see text]. The antithrombotic effect of aspirin does not appear to be dose related over a wide range of daily doses (30 to 1,300 mg), an observation consistent with saturability of platelet COX-1 inhibition by aspirin at very low doses. In contrast, GI toxicity of the drug does appear to be dose related, consistent with dose- and dosing interval-dependent inhibition of COX-1 activity in the nucleated lining cells of the GI mucosa. Thus, aspirin once daily is recommended in all clinical conditions where antiplatelet therapy is effective. Because of safety considerations, physicians are encouraged to use the lowest dose of aspirin shown effective in each clinical setting [Table-see text].

Antithrombotic effects of aspirin after renal transplantation

Antithrombotic effects of aspirin after renal transplantation

Activated Protein C Resistance: Effect of Platelet Activation, Platelet-Derived Microparticles, and Atherogenic Lipoproteins

AbstractPlasma and platelet factor Va represent different substrates for activated protein C (APC). In this study, we have measured platelet-dependent APC resistance and the effect of aspirin and a platelet glycoprotein IIbIIIa antagonist (GR144053F) on this phenomenon. In platelet rich plasma (PRP), progressive APC resistance was observed with increasing platelet activation. APC sensitivity ratios of 1.8, 1.7, and 1.4 were observed after platelet activation with thrombin receptor activating peptide (TRAP), collagen, and A23187, respectively. Ultracentrifugation at 77,000g for 1 hour abolished APC resistance indicating that the phenotype is associated exclusively with the platelet membrane. APC resistance was not observed in the presence of phosphatidylcholine-phosphatidylserine (PCPS) vesicles or purified human plasma lipoproteins. APC resistance was observed in the presence of platelet-derived microparticles, but to a lesser degree than that in the presence of activated platelets. The platelet-dependent APC resistance phenotype was also observed when endogenous APC was generated by Protac (American Diagnostica, Inc, Greenwich, CT). In vitro inhibition of platelet activation with aspirin had no effect, but the fibrinogen receptor antagonist, GR144053F, inhibited platelet-dependent APC resistance. These results indicate that platelet activation results in an APC-resistant phenotype comparable to that observed in the plasma of patients with factor V gene mutations affecting critical APC cleavage sites. This suggests that platelet activation at the site of endothelial damage downregulates a critical natural anticoagulant mechanism. The antithrombotic effect of aspirin may be due to an indirect effect on platelet-dependent APC resistance with reduced platelet retention within a developing thrombus. The more potent antithrombotic effect of glycoprotein IIbIIIa antagonists may in addition be the result of reduced platelet factor Va expression and modulation of the platelet-dependent APC resistance phenotype.

Activated Protein C Resistance: Effect of Platelet Activation, Platelet-Derived Microparticles, and Atherogenic Lipoproteins

Plasma and platelet factor Va represent different substrates for activated protein C (APC). In this study, we have measured platelet-dependent APC resistance and the effect of aspirin and a platelet glycoprotein IIbIIIa antagonist (GR144053F) on this phenomenon. In platelet rich plasma (PRP), progressive APC resistance was observed with increasing platelet activation. APC sensitivity ratios of 1.8, 1.7, and 1.4 were observed after platelet activation with thrombin receptor activating peptide (TRAP), collagen, and A23187, respectively. Ultracentrifugation at 77,000g for 1 hour abolished APC resistance indicating that the phenotype is associated exclusively with the platelet membrane. APC resistance was not observed in the presence of phosphatidylcholine-phosphatidylserine (PCPS) vesicles or purified human plasma lipoproteins. APC resistance was observed in the presence of platelet-derived microparticles, but to a lesser degree than that in the presence of activated platelets. The platelet-dependent APC resistance phenotype was also observed when endogenous APC was generated by Protac (American Diagnostica, Inc, Greenwich, CT). In vitro inhibition of platelet activation with aspirin had no effect, but the fibrinogen receptor antagonist, GR144053F, inhibited platelet-dependent APC resistance. These results indicate that platelet activation results in an APC-resistant phenotype comparable to that observed in the plasma of patients with factor V gene mutations affecting critical APC cleavage sites. This suggests that platelet activation at the site of endothelial damage downregulates a critical natural anticoagulant mechanism. The antithrombotic effect of aspirin may be due to an indirect effect on platelet-dependent APC resistance with reduced platelet retention within a developing thrombus. The more potent antithrombotic effect of glycoprotein IIbIIIa antagonists may in addition be the result of reduced platelet factor Va expression and modulation of the platelet-dependent APC resistance phenotype.

The differential effects of aspirin on platelets, leucocytes and vascular endothelium in an in vivo model of thrombus formation.

Unanswered questions remain with regard to the therapeutic use of aspirin and the selective inhibition of thromboxane A2 and prostacyclin in platelets and endothelial cells. In the present study, the effects of aspirin on platelets and endothelial cells in vivo were examined using a helium-neon (He-Ne) laser-induced thrombosis model. Single intravenous injections of aspirin at concentrations of more than 0.5 mg/kg body weight mediated a dose dependent inhibition of thrombus formation in arterioles but not in venules. This antithrombotic effect was optimum after 15 min and declined after 90 min. Potent antithrombotic activity in arterioles was manifest at doses of 2.5 mg/kg to 50 mg/kg, and initial inhibition of thrombogenesis in vivo was most pronounced at high doses. Oral aspirin also inhibited thrombus formation in arterioles but not in venules, although the antithrombotic effects were delayed and prolonged. Maximum inhibition of ex vivo, collagen induced platelet aggregation by aspirin was observed approximately 180 min after intravenous injection. The results demonstrated that, although aspirin might have differential effects on platelets and endothelial cells, potent antithrombotic activity was manifest in arterioles at all concentrations. The findings suggest that the concept of the aspirin dilemma might be ignored for therapeutic purposes in many clinical circumstances. The antithrombotic effects of aspirin were unchanged in granulocyte-depleted animals, indicating that leucocyte-related mechanisms including neutrophil superoxide anion production did not modulate the potency of aspirin in this model.

Citric Acid Enhances the Antithrombotic Effect of Aspirin in Many Aspirin-Resistant Subjects

This study had three objectives: (1) to determine the frequency of high platelet aggregators in a consecutive series of 268 apparently healthy volunteers who presented to our Center; (2) to assess the inhibitory effect of aspirin (ASA) on these high aggregators; (3) to determine, in a double-blind trial, whether or not the addition of citric acid (CTA) to ASA would increase its inhibitory effect in subjects who had a suboptimal response to aspirin alone. A platelet aggregation-scoring methodology developed for turbidimetric platelet aggregometry was used to quantify baseline aggregation and medicinal effects. We define a high aggregator as one whose unmedicated PA score is ≥30. We define the response of a high aggregator to ASA as poor if the medicated PA score stays at ≥30. We found that 58 of 268 apparently healthy unmedicated volunteers (22%) had PA scores ≥30. and that 27 of these (47%) had a poor response to 325 mg ASA, with an average drop in their PA scores from 49.5 ± 13.1 to 41.1 ± 8.6 (16%). Twenty-five of these 27 people were enrolled in the double-Mind study comparing the effect of ASA and ASA + CTA on platelet aggregability. Of these high aggregators who had a poor response to ASA, 12 of 25 (50%) had a good response to 162.5 mg of ASA plus 162.5 mg of CTA, with an average drop of their PA scores from 46.7 ± 13.2 to 22.0 ± 5.2 (53%). CTA alone had no effect on the PA score, which was similar to the control placebo. Our data suggest that a 1:1 combination of ASA and CTA may offer significantly greater protection agairtst arterial thrombotic events than ASA alone in subjects who respond poorly to ASA. Key Words: Platelet aggregation—Antithrombotic medication—Thrombosis.

Antithrombotic effects of aspirin and LMWH in a laser-induced model of arterials and venous thrombosis

Antiplatelet drug aspirin and anticoagulant low molecular weight heparin (LMWH) were compared as arterial and venous antithrombotic preparations in the rat experimental model of the laser induced thrombus formation. A method to induce microthrombi in small mesenteric vessel (15–25 μm) has been developed to investigate antithrombotic drugs and to study platelet reactions. Mesenteric injuries are induced in the vascular system of Wistar rats with an argon laser. The laser beam induced formation of the vessel wall injury with damage of endothelial cells. Thrombus was formed within seconds after laser injury and grew rapidly. The aggregate can be swept away by the flow and a new thrombus was formed again. This embolization began within the minute following the laser flash. Thrombus formation and embolization were repetitive phenoma. Aspirin (100 mg/kg) and LMWH (1 mg/kg) are approximately the same as to decrease the number of emboli detached from the thrombus and the duration of embolization; both in venules and in arterioles. This results suggest reflexion about the role of platelets in venous thrombosis induced by laser beam.

Thrombin Generation in Myocardial Infarction and Hypercholesterolemia: Effects of Aspirin

Over the last few years methods have been developed to assess appearance of thrombin during blood clotting in a clinical setting. This can be achieved either by measurement of the specific thrombin markers or by analysis of the thrombin generation kinetics. Thrombin markers rise following coronary occlusion and, surprisingly, their plasma levels become further increased during and after thrombolytic treatment with streptokinase or tissue-plasminogen activator. In myocardial infarction enhanced thrombin generation extends over the weeks, well beyond the acute phase of the disease. It indicates increased risk to a patient and might call for more anticoagulation or angioplasty. The benefit of aspirin as conjunctive treatment for thrombolysis has been clearly demonstrated. The well-founded concept is that aspirin exerts its anti-thrombotic action through inhibition of platelet cyclooxygenase. Recent evidence indicates that antithrombotic effects of aspirin might be explained, partly at least, by its inhibition of thrombin formation. Indeed, in both healthy subjects and survivors of myocardial infarction, aspirin, either at a single dose of 500 mg or at a dose of 300 mg per day administered over two weeks, effectively inhibits thrombinogenesis. Such response to aspirin is blunted in hypercholesterolemia. Subjects with high serum cholesterol levels might profit less than others from the anti-thrombotic action of aspirin.