Acetylsalicylic acid was first synthesized by Felix Hoffman at Bayer in Germany in 1897 and entered the clinic in 1899 as an anti-inflammatory, antipyretic, and analgesic drug under the trade name aspirin. aspirin was reported by Quick in 1967 to prolong bleeding time and was later reported to have an antiplatelet effect [1]. in 1966 Quick found that not all patients with VIII Smith and Willis subsequently reported that aspirin inhibited platelet production of prostaglandins, but not thrombin-induced platelet aggregation [2]. Antiplatelet therapy reduces the risk of cerebrovascular disease by 23% in patients with cardioembolic disease, but aspirin resistance is also present in a significant number of patients [3-5].
1. The concept of aspirin resistance
Aspirin resistance refers to the inability of aspirin to block thrombosis, prolong bleeding time, inhibit thromboxane biosynthesis, and exert antiplatelet effects in in vitro assays [6].Gum et al [7,8] studied 325 patients with stable cardiovascular disease taking 325 mg/d of aspirin alone for 7 d or more. He proposed laboratory criteria for aspirin resistance, i.e. 70% mean platelet aggregation at 10 mmol/L concentration of adenosine diphosphate and 20% platelet aggregation at 0, 5 mg/ml concentration of arachidonic acid, those who met the above 2 bars were called aspirin resistant and those who met one of them were called aspirin semisensitive (aspirin semiresponders). Aspirin-resistant or aspirin semiresponders are mostly women and less often smokers. There is a tendency for aspirin resistance and aspirin semisensitivity to increase with age. Aspirin sensitivity did not differ significantly between patients of different races, with or without diabetes, high or low platelet counts, and with or without liver or kidney disease [9].
Grundmann et al [4] reported that 53 patients took aspirin (100 mg/d) for secondary prevention, 18 of whom had no symptoms of cerebrovascular disease for at least 24 months in the asymptomatic and 35 of whom had ischemic cerebrovascular disease or TIA within 3 d in the symptomatic, for a mean duration of at least 60 months. It was found that clotting times were significantly shorter in symptomatic individuals and normal in 12 cases (34% null), whereas clotting times were prolonged in all asymptomatic individuals. Helgason et al [10] studied platelet function inhibition in 113 patients taking different doses of aspirin (325, 650, 975 and 1,300 mg/d) during stroke prophylaxis and in 33 patients taking different doses of aspirin (325, 650, 975 and 1,300 mg/d) before the onset of acute stroke. The results showed that platelet aggregation was completely inhibited in 85 patients at 325 mg/d and 6 at 650 mg/d, and partially inhibited in 22 patients at 325 mg/d in increments of 9, 650 mg/d in 5, and 975 mg/d in 1. Platelet aggregation was still only partially inhibited in 3 patients at 1 300 mg/d. Helgason et al [11] studied 306 patients with recurrent stroke in which the aspirin dose was increased from 325 mg/d to 1,300 mg/d over a 33-month follow-up period. The results found that the incidence of aspirin resistance was 8,2%. 29652 high-risk patients on long-term aspirin had a 12,9% incidence of vascular disease (acute myocardial infarction, stroke, vascular death) after 2 years compared with 16,0% in 29743 controls, with a significant difference (P<0,05) [8]. Friend et al [3] studied the effect of aspirin on Macchi et al [12] reported that the incidence of aspirin resistance was 29,6% in 98 patients who had been taking aspirin (160 mg/d) for at least 1 month, and that aspirin resistance was mostly Pl(A1/A1) genotype. Among them, 25 cases were reviewed after switching to aspirin 300 mg/d for at least 1 month, resulting in 11 cases with no prolongation of clotting time and all with Pl(A1/A1) genotype. Certain authors have found a 2, 9-fold increased risk of elevated CK-MB in aspirin-resistant compared to controls despite anticoagulation with clopidogrel and heparin [13].
2, Mechanisms of aspirin resistance
2, 1 Bioavailability
Inadequate dosing, poor compliance, salicylic acid accumulation interfering with aspirin’s proximity to the cyclooxygenase (COX)-1 binding site, concomitant administration of short-acting nonsteroidal anti-inflammatory drugs (NSAIDs) that block the long-acting effects of aspirin or proton pump inhibitors can deprive aspirin of efficacy [2].Catella-Lawson et al. found that NSAIDs (e.g., ibuprofen) can interfere with aspirin’s effect on irreversible inhibition of COX-1, associated with competitive inhibition of the docking site within the COX ion channel [6].
2,2 Abnormal platelet function
Altered platelet conversion rate with generation of new non-aspirinized platelets; varying degrees of COX-2 expression in newly synthesized platelets; increased sensitivity of platelets to adenosine diphosphate and collagen.
COX is the rate-limiting enzyme of prostaglandin biosynthesis and is available in two forms, COX-1 and COX-2. COX-1 is expressed in most cells and tissues, regulates platelet functional activity, and regulates hemostasis. Normally, COX-2 mRNA and protein are undetectable in most tissues. COX-2 is seen in vascular endothelial cells, smooth muscle cells and platelets and has a short half-life. COX-2 induction provides an alternative pathway for prostaglandin H2 production and even platelet production of thromboxane A2 (TXA2) in aspirin-treated platelets, stimulating platelet aggregation. The degree of COX-2 expression varies from patient to patient. Certain pro-inflammatory or mitogenic stimuli, such as cytokines, growth factors, and endothelin, can induce COX-2 expression and mediate inflammatory and immune responses. TXA2 promotes platelet aggregation and vasoconstriction, while PGI2 inhibits platelet aggregation and induces vasodilation, so aspirin has both antithrombotic and Therefore, aspirin has both anti-thrombotic and pro-thrombotic effects. Aspirin inhibits COX-1 but not high concentrations of COX-2 [1, 8, 14].Weber et al [14] identified three COX-2 protein-specific antibodies. Compared to COX-1, aspirin inhibited COX-2 170-fold weaker. If aspirin inhibits more than 90% of TXA2, a very small amount of COX-2 can affect the clinical outcome.
2,3 Platelet polymorphisms
PI collagen receptor polymorphism; COX-1, COX-2, TXA2 synthase or other arachidonic acid metabolizing enzyme polymorphisms; PI fibronectin GPIIbIIIa polymorphism; FVal34Leu polymorphism, resulting in inhibition of factor XIII activation by small doses of aspirin.
2,3,1 COX-1 gene polymorphism
PGG/H synthase or COX-1 is the 1st enzyme produced by arachidonate and converts arachidonic acid (AA) to PGG and PGH. COX has two enzymatic activities: COX activity catalyzes PGG formation and hydroperoxidase activity (HOX) reduces PG to PGH. PGH is further catabolized to PG and TX by COX enzyme action. aspirin irreversibly inhibits COX -1, which blocks TXA2 formation, and COX-1 gene polymorphisms may be the structural basis of aspirin resistance. Years ago, researchers studying sheep PG/H synthase (COX-1) isolated DNA containing the entire coding region of COX-1 and found that COX-1 has three possible glycosylation sites, two of which are located at the amino molecular terminus. Aspirin acetylates the COX-1 amino site at the serine 530 site near the carboxyl terminus. In sheep experiments, researchers replaced Ser-530 with alanine to form mutant Ala-530 and found that both natural and mutant COX complementary DNA (cDNA) had similar COX-1 and HOX (COX-2) activity, but only the natural type COX Ser-530 was irreversibly blocked by aspirin. Aspirin causes COX-1 acetylation at the 530 site to form a protruding side chain that interferes with amino acid binding, but not in the mutant form. Other researchers later expressed human PI and human erythroleukemia cell cDNAs at site 529 in simian cells and found that serine 529 site polymorphism resulted in a significant decrease in COX activity that was barely detectable [15].
2, 3, 2 PI and vascular endothelial cell COX-2 mRNA overexpression
COX-2 is the second COX activity gene discovered in 1991.COX-2 reduces PG to PGH, plays an important role in inflammation and cell growth, and is structurally similar to COX-1.COX-2 is mainly seen in brain and spinal cord, but can also be expressed during pregnancy and delivery. RT-PCR and western blot were used to study the expression of COX-2 mRNA and protein in 20 normal subjects, and positive expression of COX-2 was seen in all PIs. Another study examined the PG levels of COX-1 and COX-2 in human vascular endothelial cells and found that interleukin 1β (IL-1β) upregulated COX-2 activity compared with TAX2 (2-fold increase) and increased PGI2 and PGE2 production (54- and 84-fold increase, respectively), while the expression level of COX-1 did not change significantly. The above material suggests that COX-2 causes increased TXA2 production in vascular endothelial cells during inflammation and atherosclerosis [15].
2, 3, 3 PI receptor polymorphisms
PI membrane glycoproteins (GP) IIb/IIIa receptors play an important role in PI aggregation. Aspirin affects the regulation of GP IIb/IIIa by interfering with COX non-dependent intracellular signaling, including transmembrane protein receptors, phospholipase, calcium release, adenylate cyclase, guanylate cyclase, and protein kinase C. GP IIb/IIIa activation due to certain weak agonists, such as ADP, epinephrine, and collagen, can be partially blocked by aspirin. blocked, and in case of PLA2 genotype, the above replacement pathway can further weaken the anti-PI effect.The PI agonist, TXA2, activates GPIIb/IIIa receptors via intracellular signaling.GPIIb/IIIa receptors, once they become ligand-competitive, bind to fibrinogen and fibrinogen receptors and promote PI aggregation [15].PI genes Pl(A1/A2), C807T, C -5TKozak encode GP IIIa, GP Ⅰa/Ⅰia, and GP Ⅰb, respectively.
Integrin α2β 3 is a fibrinogen receptor, also known as von Willebrand factor. It is expressed in small amounts on the surface of normal PI and can mediate PI aggregation with individual differences. Integrin has several genetic dimorphisms (dimorphisms) of which the two most common alleles, allele 2, encode Leu-33 (PIA1 or HPA-1a) and Pro-33 (PIA2 or HPA-1b), with Caucasian allele frequencies of 0, 85, 0, and 15, respectively. 2 GP polymorphisms correlate with PI surface receptor density and involve GP Ia/IIa (C807T polymorphism) and GP Ib-IX-V (C-5TKozak polymorphism) receptor adhesion. A large body of evidence suggests that GP receptor polymorphisms are genetic risk factors for atherothrombosis and that multiple allelic variants of the GP receptor can lead to diversity in expression, function, and immunogenetics of adherent receptor components. Collagen is an important activator of PI and increased Gp Ia/IIa receptor density reflects possible coagulation risk factors. homoncik et al. studied 10 normal subjects taking 100 mg/d for 11 d and found the shortest clotting time in those with the highest GP Ia/IIa levels, suggesting that genetically determined collagen receptor density can affect basal clotting time and aspirin-induced clotting time. Macchi et al [12] found that aspirin resistance was not associated with the C807T and C-5T Kozak polymorphisms but with the pure type A1 allele.Cooke et al. found that PIA1/A2PIA1/A1PI aggregates identically in epinephrine and ADP and that isolated aspirin intervention strongly inhibited the PIA1/A2 genotype.Michelson et al. found that compared to PIA2(+) had a smaller threshold for ADP activation in the absence of aspirin intervention compared to other genotypes.Lutomski et al. found that epinephrine-induced PIA1/A2 was most sensitive at pharmacologically relevant concentrations of 2, 5 5 μmol/L of aspirin [8, 12, 15].Moshfegh et al. studied 177 infarcts and 89 controls and found that GpⅠa/Ⅱa gene 807T (873A) pure type was 16,4% and 5,6% in controls, and found a 3-fold increased risk in allele carriers. 807T pure type carriers have an increased risk of AMI if they also smoke, and smoking can cause enhanced PI aggregation [15].
2, 3, 4 PITXA2 (TP) receptor
Cayatte et al. studied ApoE knockout mice and found that TP receptor antagonist administration significantly reduced aortic root damage and intercellular adhesion molecule 1 (ICAM-1) expression, whereas aspirin did not. Isolated experiments giving TP receptor antagonists blocked TP agonist-induced ICAM-1 expression in endothelial cells [16].
2, 4 Interaction of PI with other blood cells and derivatives
Other factors include insufficient erythrocyte-induced blockade of PI activation; aspirinized PI, transcytotic arachidonic acid metabolism by vascular cells; monocyte-local phage-derived TXA2; COX-1/COX-2-catalyzed release of vascular PGI2 as a TXA2 modulator or vascular fibrinogen activator (r-PA).
PI, erythrocyte interactions can affect PI responsiveness through PI release reactions, arachidonate biosynthesis, and PI recruitment. Erythrocytes induce increased thromboxane B2 (TXB2) synthesis and release of 5-hydroxytryptamine, β-platelet globulin (β-TG), and additional ADP, indicating that erythrocytes can regulate PI arachidonate formation. Studied the interaction of PI, erythrocytes in 5 healthy volunteers taking small doses of aspirin (50 mg/d for 15 d) and found that aspirin down-regulated the potentiation of erythrocyte response to PI, with maximum inhibition seen at the first dose of 500 mg, and after 2 3 weeks, erythrocytes escaped inhibition and PI responsiveness was enhanced. Studying 82 cases (62 heart disease cases on aspirin 200 mg/d and 20 stroke cases on aspirin 300 mg/d-1 for more than 3 months), it was found that 2/3 patients on 200-300 mg/d-1 aspirin could not block PI aggregation. It can be divided into 3 groups: group 1 (32 cases, 39%) had PI recruitment blocked by aspirin regardless of the presence or absence of erythrocytes; group 2 (37 cases, 45%) had PI recruitment blocked when PI was assessed alone; however, if erythrocytes were present, there was PI recruitment; group 3 (13 cases, 16%) had PI recruitment when PI was stimulated, which was enhanced by erythrocytes [5].
2,5 Other factors
Elevated adrenaline levels (excessive physical exercise, mental stress); smoking; oxidative stress and F2 isoprostane (PGF2α) biosynthesis, the latter being a non-enzymatic peroxidation of arachidonic acid bioproducts; aspirin and acetylcholine-mediated interaction of nitric oxide anti-PI and vasodilatation. Erythrocytes can promote thrombosis and enhance PI reactivity [2, 6, 8].
Aspirin promotes improved endothelial function with dose-dependent smooth muscle vasodilation and mediates nitric oxide and hyperpolarizing factor release, which can be attenuated by atherosclerosis, atherosclerotic risk factors such as hypertension, hyperlipidemia, diabetes, and smoking, and is associated with a lack of endothelium-derived release factors. A late study of 19 patients with coronary arteriosclerosis or atherosclerotic risk factors (confirmed by angiography) found that the vasodilatory effect was significantly enhanced after administration of 1 g of aspirin lysine saline sedation, but not in patients without atherosclerosis [1].
The non-enzymatic process of lipid peroxidation by oxygen radical decomposition produces a variety of PGF-like biomasses, 8-iso-PGF2α being one of the vasoconstrictors (also known as 8-epi-PGF2α) that enhances the response of PI to other PI agonists.PGF2α originates from the COX action of arachidonic acid, is released upon cellular activation, circulates in the plasma and is excreted in the urine.PGF2α Elevated levels are seen in unstable angina, diabetes, hyperlipidemia, and smokers, indicating an increased risk of oxidative damage, increased free radical generation, and reduced antioxidant action in the above patients, leading to aspirin-insensitive thromboxane biosynthesis. The possible explanation for COX-2 induction in monocytes and macrophages is the result of local inflammatory response. High levels of PGF2 cause dose-dependent, irreversible PI aggregation under collagen, ADP, arachidonic acid, and PGH2/TXA2 conditions [5].
Smoking promotes PI aggregation. increased PI aggregation can be confirmed by a decrease in PI aggregation ratio (PAR). pi factor 4 is one of the components of lysosomes, called a particles. PI factor 4 is released upon PI aggregation, which neutralizes the antithrombotic effect. Aspirin administration before smoking in non-smokers and habitual smokers blocks the reduction of PAR [5].
Exercise increases factor VIII levels and PI activation, which affects coagulation. Certain agonists such as thrombin, epinephrine, and norepinephrine may promote PI activation. Increased PI aggregation after exercise may be associated with elevated norepinephrine levels, indicating the presence of PI activation by non-COX pathways. A study of 11 normal controls taking aspirin for 14 d and administering norepinephrine 0, 15, 0, and 75 nmol, kg-1 found that aspirin did not block PI aggregation after norepinephrine administration and that norepinephrine enhanced PI aggregation and secretion in normal subjects. Sympathetic activation under exercise or stress conditions was not effective with anti-PI treatment [5].
The duration of aspirin therapy also affects aspirin resistance. A study of ADP and collagen-induced platelet aggregation before and after 2, 6, and 12 months of oral aspirin (100 or 300 mg/d) in 150 normal subjects found that platelet aggregation was completely inhibited at 2 months of administration, but long-term administration resulted in a progressive decrease in its effectiveness [13].
3. Clinical interventions for aspirin resistance
There is no specific treatment for aspirin resistance, and the recommended interventions are: first, 5 to 40% of vascular disease is not due to atherosclerosis and requires other treatments. Second, poor compliance or inadequate dosing (long-term dose of 75 mg/d), and 5% of patients who cannot tolerate aspirin or are allergic to it, can be treated with the adenosine diphosphate receptor antagonist clopidogrel. Third, the use of other anti-PI drugs can block the pathway where aspirin is ineffective. The combination of clopidogrel and aspirin is superior to aspirin alone. The combination of pansentine and aspirin, or warfarin and aspirin can improve the outcome [8, 11]. Ticlopidine and clopidogrel are ticlopidine analogues that selectively inhibit ADP-induced PI aggregation and do not affect arachidonic acid metabolism. The combination of ticlopidine and aspirin can significantly reduce the incidence of stroke, and side effects such as leukopenia and PI-reducing purpura limit their application. Clopidogrel is relatively safe, with more complete PI inhibition than ticlopidine and lower incidence of gastrointestinal bleeding, skin and blood side effects. 20,000 people in phase 3 clinical trial studies have not experienced PI-reducing purpura, and only 11 cases of PI-reducing purpura have been reported recently. dehydrothromboxane
B2) concentration to monitor the risk of developing AMI or cardiovascular death and to intervene in a timely manner.
Other cyclooxygenase inhibitors, such as sulfinpyrazone, indobufen, and triflusal, do not have anti-PI effects. Using the combination of aspirin and pentoxifylline for stroke prevention, the 2nd Stroke Randomized Double-blind Controlled Prevention Trial (ESPS-2) studied 6602 cases of ischemic stroke (76%) or TIA attack within 3 months (24%) with a 24-month history of aspirin 25 mg/d, pentoxifylline 200 mg/d, the combination of both, and placebo, and found that those with the combination of drugs compared with placebo reduced The risk of fatal stroke was not significantly different from that of aspirin, but the risk of fatal stroke was not significantly different. Aggrenox (aspirin 25 mg + pansentine 200 mg) is approved by the US FDA for secondary prevention of ischemic stroke or TIA twice daily, and the monthly cost of the drug is 6 times that of aspirin, similar to clopidogrel (Plavix, 75 mg/d). Thromboxane receptor antagonists such as GR 32 191, BMS-180 291 (ifetroban), BM13, 177 (sulotroban) are not in clinical use. Glycoprotein receptor antagonists such as sibrafiban and xemilofiban have not entered clinical use.