Persistent production of platelet thromboxane A2 in patients chronically treated with aspirin

BACKGROUND: Patients treated with aspirin may have a reduced sensitivity to its antiplatelet effect. The mechanism accounting for such a reduced sensitivity might involve an impaired interaction of aspirin with cyclooxygenase-1 (COX)-1. OBJECTIVE: We sought to investigate whether platelets from patients under chronic treatment with aspirin still produce TxA2 and whether there is any relationship between the eventual persistent TxA2 formation and platelet aggregation. Finally, whether platelet-derived TxA2 can be inhibited by in vitro addition of aspirin. METHODS: Collagen-induced platelet aggregation and thromboxane-A2 (TxA2) were measured in 196 patients treated with aspirin (100-330 mg day(-1)) because of previous vascular events or presence of risk factors of atherosclerosis. RESULTS: Collagen-induced TxA2 production of the entire cohort was 128.7 +/- 21.6 pg 10(-8) cells, and was significantly correlated with platelet aggregation (Spearman's correlation coefficient = 0.44; P < 0.0001). Patients in the highest quartile of TxA2 showed higher platelet response to collagen (P < 0.0001) when compared with those in the lowest quartile. In a subgroup of 96 patients, platelets were treated in vitro with a TxA2 receptor antagonist (13-azaprostanoic acid) or aspirin before stimulation with collagen. 13-APA acid significantly inhibited platelet aggregation. Aspirin reduced (-72.9%) TxA2 production in patients with TxA2 values above the median but it was ineffective in those with TxA2 values below the median. CONCLUSION: In some patients chronically treated with aspirin platelet production of TxA2 may persist and account for enhanced platelet aggregation. Incomplete inhibition of COX-1 seems to be implicated in persistent TxA2 production.     

Improved metabolic control decreases platelet activation markers in patients with type-2 diabetes

BACKGROUND: Cardiovascular disease is associated with platelet dysfunction in patients with diabetes. Hyperglycaemia is known as an independent risk factor for micro- and macrovascular complications, and improvement of metabolic control has shown beneficial effects on diabetic late complications. Our study attempts to clarify the effect of improved metabolic control on platelet activation markers in patients with type-2 diabetes. MATERIALS AND METHODS: Thirty patients were studied at baseline and 3 months after improvement of metabolic control and compared with an age-matched nondiabetic control group. Platelet activation markers (CD31, CD36, CD49b, CD62P and CD63) were assessed by flow cytometry analysis. RESULTS:Significantly more activated platelets were detected in patients with diabetes compared with controls. After 3 months' improvement of metabolic control, a significant decline of all platelet activation markers except CD36 was noted. Furthermore a significant correlation between CD62P, CD63 and HbA(1c) levels was observed. CONCLUSIONS: We conclude therefore that improvement of metabolic control has a beneficial effect on platelet activation. This may have an implication in the pathogenesis of vascular disease in patients with type-2 diabetes.     

The influence of aspirin dose and glycemic control on platelet inhibition in patients with type 2 diabetes mellitus

Summary. Background: Low‐dose aspirin seems to offer no benefit in the primary prevention of cardiovascular disease in type 2 diabetes mellitus (DM2). The anti‐platelet effect may be diminished by poor glycemic control or inadequate dosing of aspirin. Objectives: To study the effects of both glycemic control and increasing aspirin dose on platelet response to aspirin in DM2 patients and matched controls. Patients/methods: Platelet effects of increasing doses of aspirin (30, 100 and 300 mg daily) were prospectively assessed in 94 DM2 patients and 25 matched controls by measuring thromboxane levels in urine (11‐dhTxB2) and platelet aggregation using VerifyNow^® and light transmission aggregometry (LTA). DM2 patients were stratified for glycemic control (hemoglobin‐A1c [HbA1c] ≤ 53, 53–69, ≥ 69 mmol mol^?1). Results: At baseline, median 11‐dhTxB2 excretion was higher in the poorly controlled patients (77 ng mmol^?1), and the moderately controlled (84 ng mmol^?1) compared with the well‐controlled patients (64 ng mmol^?1) and controls (53 ng mmol^?1), P < 0.01. Next, 30 mg of aspirin reduced 11‐dhTxB2 excretion to 31, 29 and 24 ng mmol^?1 in the poorly, moderately and well‐controlled patients, respectively, and to 19 ng mmol^?1 in controls, P < 0.001. VerifyNow^® and LTA were also incompletely suppressed in DM2 patients using 30 mg of aspirin, but 100 mg resulted in similar platelet suppression in all groups, with no additional effect of 300 mg. Conclusions: DM2 patients with inadequate glycemic control (HbA1c > 53 mmol mol^?1) have higher baseline platelet activity and incomplete suppression of platelet activity with 30 mg of aspirin. However, 100 mg of aspirin leads to optimal inhibition irrespective of glycemic control, and 300 mg does not further improve platelet suppression.     

血小板及CD62P在Ⅱ型糖尿病患者中的变化

目的 探讨血小板、平均血小板容积、血小板体积分布宽度、大血小板比率及血小板a颗粒膜糖蛋白(CD62P)在Ⅱ型糖尿病患者中的变化.方法 使用血细胞分析仪对40例Ⅱ型糖尿病患者及40例健康体检者进行血小板及其参数的测量,用流式细胞仪法观察血小板CD62P的变化.结果 与对照组相比,Ⅱ型糖尿病患者中血小板、平均血小板容积、血小板体积分布宽度及大血小板比率均有显著性变化(MPV分别为12.13±1.18 fl和10.98±1.07fl,PLT分别为188±65 × 109/L和223±55×109/L,P-LCR分别为41.04±10.04%和32.11±8.17%,PDW分别为17.01±3.47 fl和14.10±2.53 fl,P均<0.01),血小板CD62P阳性程度显著高于对照组(18.8±9.4%和3.1±5.3%,P<0.01),血小板CD62P表达与MPV为正相关关系(r=0.57,P<0.01).结论 血小板的各项参数在Ⅱ型糖尿病患者中有显著性改变,提示糖尿病患者存在着血小板活化及凝血活性增高的现象,血小板活性改变在糖尿病患者的病情发展及血栓性并发症的发生中起着一定的作用.     

Postprandial hyperglycemia is a determinant of platelet activation in early type 2 diabetes mellitus

Summary. Background: Chronic hyperglycemia is a major contributor to in vivo platelet activation in diabetes mellitus. Objectives: To evaluate the effects of acarbose, an α‐glucosidase inhibitor, on platelet activation and its determinants in newly diagnosed type 2 diabetic patients. Methods: Forty‐eight subjects (26 males, aged 61 ± 8 years) with early type 2 diabetes (baseline hemoglobin A_1c ≤ 7% and no previous hypoglycemic treatment) were randomly assigned to acarbose up to 100 mg three times a day or placebo, and evaluated every 4 weeks for 20 weeks. The main outcome measures were urinary 11‐dehydro‐thromboxane (TX)B₂ (marker of in vivo platelet activation) and 8‐iso‐prostaglandin (PG)F_2α (marker of in vivo lipid peroxidation) excretion rate, 2‐h postprandial plasma glucose (PPG) after a test meal, and assessment of glucose fluctuations by mean amplitude of glycemic excursions (MAGE). Results: Baseline measurements revealed biochemical evidence of enhanced lipid peroxidation and platelet activation. As compared with the placebo group, patients treated with acarbose had statistically significant reductions in urinary 11‐dehydro‐TXB₂ and 8‐iso‐PGF_2α excretion rate as early as after 8 weeks and at each subsequent time point (between‐group P < 0.0001 at 12, 16 and 20 weeks), following earlier decreases in PPG and MAGE. Multiple regression analyses in the acarbose group revealed that PPG was the only significant predictor of 11‐dehydro‐TXB₂ urinary excretion rate (β = 0.39, P = 0.002) and MAGE the only predictor of 8‐iso‐PGF_2α urinary excretion rate (β = 0.42, P = 0.001). Conclusions: Postprandial hyperglycemia is associated with enhanced lipid peroxidation and platelet activation in early type 2 diabetes. A moderate decrease in PPG achieved with acarbose causes time‐dependent downregulation of these phenomena, suggesting a causal link between early metabolic abnormalities and platelet activation in this setting.     

Elevated thrombopoietin in plasma of burned patients without and with sepsis enhances platelet activation

Summary.  Background:  Thrombopoietin (TPO) is a humoral growth factor that does not induce platelet aggregation per se , but enhances platelet activation in response to several agonists. Circulating levels of TPO are increased in patients with sepsis and are mainly related to sepsis severity. Objectives:  To investigate the potential contribution of elevated TPO levels in platelet activation during burn injury complicated or not by sepsis. Methods:  We studied 22 burned patients, 10 without and 12 with sepsis, and 10 healthy subjects. We measured plasma levels of TPO, as well as leukocyte-platelet binding and P-selectin expression. The priming activity of plasma from burned patients or healthy subjects on platelet aggregation and leukocyte-platelet binding, and the role of TPO in these effects were also studied in vitro . Results:  Burned patients without and with sepsis showed higher circulating TPO levels and increased monocyte-platelet binding compared with healthy subjects. Moreover, TPO levels, monocyte-platelet binding and P-selectin expression were significantly higher in burned patients with sepsis than in burned patients without sepsis. In vitro , plasma from burned patients without and with sepsis, but not from healthy subjects, primed platelet aggregation, monocyte-platelet binding and platelet P-selectin expression. The effect of plasma from burned patients with sepsis was significantly higher than that of plasma from burned patients without sepsis. An inhibitor of TPO prevented the priming effect of plasma from burned patients. Conclusions:  Increased TPO levels may enhance platelet activation during burn injury and sepsis, potentially participating in the pathogenesis of multi-organ failure in these diseases.     

2型糖尿病合并脑梗死患者血清同型半胱氨酸和血小板聚集率检测的临床价值

目的探讨血清同型半胱氨酸(Hcy)和血小板聚集率(PagT)对诊断2型糖尿病合并脑梗死患者的临床价值。方法选取该院2型糖尿病合并脑梗死患者65例(合并脑梗死组),2型糖尿病患者55例(单纯糖尿病组),50例健康体检者作为健康对照组。分别检测3组研究对象的Hcy、PagT、血压、体质量、身高等各项指标并进行比较;再通过多因素Logistic回归分析确定2型糖尿病合并脑梗死的危险影响因子。结果合并脑梗死组Hcy、PagT水平明显高于单纯糖尿病组及健康对照组,差异有统计学意义(P0.05)。Hcy和PagT均为2型糖尿病合并脑梗死的危险影响因素;Person相关性分析显示,Hcy、PagT对糖尿病合并脑梗死疾病的严重程度呈正相关关系。结论 Hcy、PagT水平在2型糖尿病合并脑梗死患者中显著升高,可通过检测糖尿病患者Hcy、PagT水平预测脑血管疾病的发展进程。     

The recovery of platelet cyclooxygenase activity explains interindividual variability in responsiveness to low‐dose aspirin in patients with and without diabetes

See also Lordkipanidze M, Harrison P. Aspirin twice a day keeps new COX‐1 at bay. This issue, pp 1217–9. Summary Background. Interindividual variability in response to aspirin has been popularized as ‘resistance’. We hypothesized that faster recovery of platelet cyclooxygenase‐1 activity may explain incomplete thromboxane (TX) inhibition during the 24‐h dosing interval. Objective. To characterize the kinetics and determinants of platelet cyclooxygenase‐1 recovery in aspirin‐treated diabetic and non‐diabetic patients. Patients/Methods. One hundred type 2 diabetic and 73 non‐diabetic patients on chronic aspirin 100 mg daily were studied. Serum TXB₂ was measured every 3 h, between 12 and 24 h after a witnessed aspirin intake, to characterize the kinetics of platelet cyclooxygenase‐1 recovery. Patients with the fastest TXB₂ recovery were randomized to aspirin 100 mg once daily, 200 mg once daily or 100 mg twice daily, for 28 days and TXB₂ recovery was reassessed. Results and Conclusions. Platelet TXB₂ production was profoundly suppressed at 12 h in both groups. Serum TXB₂ recovered linearly, with a large interindividual variability in slope. Diabetic patients in the third tertile of recovery slopes (≥ 0.10 ng mL^?1 h^?1) showed significantly higher mean platelet volume and body mass index, and younger age. Higher body weight was the only independent predictor of a faster recovery in non‐diabetics. Aspirin 100 mg twice daily completely reversed the abnormal TXB₂ recovery in both groups. Interindividual variability in the recovery of platelet cyclooxygenase activity during the dosing interval may limit the duration of the antiplatelet effect of low‐dose aspirin in patients with and without diabetes. Inadequate thromboxane inhibition can be easily measured and corrected by a twice daily regimen.     

Lipid and protein oxidation contribute to a prothrombotic state in patients with type 2 diabetes mellitus

Summary.  Diabetes mellitus (DM) is associated with enhanced lipid oxidation and persistent platelet activation. We investigated whether oxidant stress (OS) also affects circulating proteins and is associated with an abnormal coagulative pattern. In 72 type 2 DM (T2DM) patients, urinary 8-iso-prostaglandin (PG) F _2α and 11-dehydro-thromboxane B₂ (TXM) were measured as markers of lipid peroxidation and platelet activation, respectively. The carbonyl content of plasma proteins (PCARB) was measured as global index of protein oxidation. 8-Iso-PGF_2α and PCARB levels were higher in DM patients than in controls ( P  < 0.05). Likewise, both TXM and prothrombin F ₁₊₂ levels were higher in diabetics ( P  < 0.05). By contrast, anticoagulant markers, such as activated protein C, protein C activation peptide, and soluble thrombomodulin (TM) were depressed in T2DM ( P  < 0.05). In conclusion, OS in T2DM involves circulating proteins and is associated with an unbalanced promotion of procoagulant reactions. These effects in concert with platelet activation may contribute to atherothrombotic complications in T2DM.     

急性脑梗死伴2型糖尿病患者血小板miR-223表达水平与阿司匹林抵抗的相关性研究

目的 研究急性脑梗死伴2型糖尿病患者血小板miR-223表达水平与阿司匹林抵抗的相关性.方法 回顾性选取2018年12月至2019年12月河北北方学院附属第一医院急性脑梗死患者120例,根据是否合并2型糖尿病分为合并组、未合并组两组,各60例.统计分析两组患者的血小板指标、血小板最大聚集率(MAR)、阿司匹林抵抗发生情...     

辛伐他汀对阿司匹林低反应者内皮功能及血小板聚集率的影响

目的探讨辛伐他汀对高血压病合并高脂血症及阿司匹林低生化反应患者内皮功能及血小板聚集率的影响。方法采用前瞻性随机对照研究,口服肠溶阿司匹林片1周后,高血压病合并高脂血症及阿司匹林低生化反应患者109例入选,检测用花生四烯酸(AA)和二磷酸腺苷(ADP)作诱导剂的血小板聚集率(PAG)和一氧化氮、内皮素指标;然后采用信封法随机分为辛伐他汀组和对照组,均继续口服阿司匹林,辛伐他汀组加用辛伐他汀。治疗2月后复查上述指标,观察辛伐他汀对上述指标的影响。结果对照组两次检测内皮素、一氧化氮浓度及以AA和ADP诱导的PAG,差异均无统计学意义(t分别=1.66、0.56、1.13、0.13,P均>0.05)。治疗2月后,辛伐他汀组内皮素及以AA和ADP诱导的PAG检测值明显降低,一氧化氮浓度增高,差异均有统计学意义(t分别=14.51、6.09、5.64、15.07,P均<0.05);同时与对照组治疗后比较,辛伐他汀组内皮素及以AA和ADP诱导的PAG明显降低,一氧化氮浓度明显升高,差异均有统计学意义(t分别=17.48、3.39、2.05、11.41,P均<0.05)。结论辛伐他汀可改善高血压病合并高脂血症及阿司匹林低生化反应患者血管内皮功能,可能同时改善阿司匹林抗血小板聚集功能。     

阿司匹林与氯吡格林联合干预糖尿病并急性脑梗死的效果评价

目的探讨阿司匹林联合氯吡格林治疗糖尿病并急性脑梗死的有效性和安全性。方法随机选取我院2010-2013年间收治的2型糖尿病并急性脑梗死的患者102例,随机分为联合用药组（阿司匹林＋氯吡格林）和对照组（单纯阿司匹林）,通过NINSS评分评价患者入组时的病情,观察治疗第7天和第30天后的临床效果以及副作用等情况,讨论治疗效果与安全性情况。结果治疗后第7天联合用药组的有效率是90.0%,对照组为73.1%,差异显著（P〈0.05）。治疗30天后有效率在联合用药组优于对照组。两组患者均未出现严重副作用;且与对照组相比,联合用药组治疗后血清CRP水平显著下降（P〈0.05）。结论阿司匹林联合氯吡格林用药治疗糖尿病患者并急性脑梗死的效果优于单纯阿司匹林治疗,可以改善预后,未增加不良反应。     

糖尿病患者血小板4项参数与血管病变探讨

目的探讨糖尿病患者血小板参数变化及其临床意义。方法使用XE-2100型全自动血细胞分析仪分别测定健康对照、糖尿病和冠心病患者血小板计数（PLT）、血小板平均体积（MPV）、血小板分布宽度（PDW）及血小板比容（PCT）。结果与对照组比较,2型糖尿病有血管病变组和冠心病组的PLT、MPV、PDW差异有统计学意义（P〈0．01）,PCT差异无统计学意义（P〉0．05）;2型糖尿病无血管病变组血小板4项参数差异无统计学意义（P〉0．05）。结论血小板参数的变化在糖尿病血管病变发生、发展中有重要作用,对临床研究糖尿病并发症有较大参考价值。     

脑梗死患者阿司匹林抵抗的临床研究

目的 评价脑梗死患者阿司匹林抵抗（AR）发生的情况，分析其临床有关因素，探讨可能机制。方法 255例急性脑梗死患者，每日服用阿司匹林100mg，连服10d，服用最后1d后，24h内抽取空腹静脉血，分别用二磷酸腺苷（ADP）、花生四烯酸（AA）诱导做血小板聚集试验（PAgT），检测最大血小板聚集率（MAR）。结果 患者中AR发生率8．24％，阿司匹林半敏感（ASR）者占30．59％，年长者及女性AR或ASR患者中女性敏感者居多；如有吸烟者较AR或ASR者居多（11．53％ vs 5．05％）。结论 AR在脑梗死患者中确实存在。ASA用于抗血小板治疗及预防动脉硬化事件的脑血管病患者，若有AR存在，应及时换用其它安全有效的抗血小板制剂，因阿司匹林需要长期应用，今后预测AR及抗血小板治疗个体化，将是未来抗血小板治疗的研究方向。     

中国北方地区汉族人群血小板膜糖蛋白Ⅰbα VNTR多态性的分布与脑梗死患者CC基因型与阿司匹林敏感相关性分析

目的研究中国北方地区汉族人群血小板膜糖蛋白(GP)Ⅰbα数目可变串联重复(VNTR)多态性与阿司匹林抵抗(AR)的关系。方法用聚合酶链反应限制性片段长度多态性(PCR-RFLP)检测300例健康人及110脑梗死患者基因型。脑梗死患者服用阿司匹林(100mg/d)至少7d以上,用二磷酸腺苷(ADP)和花生四烯酸(AA)作诱导剂测定血小板聚集功能。结果中国北方地区汉族人群中只检测出GPⅠbα三种等位基因B、C、D,没有发现A基因型。阿司匹林敏感(AS)患者CC基因型比阿司匹林半抵抗(ASR)患者更多见。结论中国东北地区仅检测出B、C、D三种基因型。GPⅠb VNTR多态性CC基因型的出现对于低剂量阿司匹林抗血小板作用更为敏感。     

Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease

Summary. Background: Previous studies have demonstrated considerable variation in the antiplatelet effect of aspirin. Objectives: To investigate the impact of platelet turnover on the antiplatelet effect of aspirin in patients with stable coronary artery disease (CAD) and to identify determinants of platelet turnover. Methods: Platelet turnover was evaluated by measurements of immature platelets and thrombopoietin in 177 stable CAD patients on aspirin monotherapy, including 85 type 2 diabetics and 92 non‐diabetics. Whole blood platelet aggregation was determined using the VerifyNow^® Aspirin test and multiple electrode aggregometry (MEA, Multiplate^®) induced by arachidonic acid (AA) (1.0 mm ), adenosine diphosphate (ADP) (10 μm ) and collagen (1.0 μg mL^?1). Results: Immature platelet levels significantly correlated with MEA (r = 0.31–0.36, P‐values < 0.0001) and the platelet activation marker sP‐selectin (r = 0.19, P = 0.014). Contrary to the VerifyNow^® test, MEA significantly correlated with variations in platelet count (r = 0.45–0.68, P‐values < 0.0001). Among patients with residual platelet reactivity according to AA, there were significantly more diabetics (61% vs. 41%, P = 0.027) and higher levels of sP‐selectin (77.7 ± 29 vs. 70.2 ± 25 ng mL^?1, P = 0.070) and serum thromboxane B₂ (0.81 [0.46; 1.70] vs. 0.56 [0.31; 1.12] ng mL^?1, P = 0.034). In a multivariate regression analysis, immature platelet levels were determined by thrombopoietin levels (P < 0.001), smoking (P = 0.020) and type 2 diabetes (P = 0.042). Conclusions: The antiplatelet effect of aspirin was reduced in CAD patients with an increased platelet turnover. Once‐daily dosing of aspirin might not suffice to adequately inhibit platelet aggregation in patients with an increased platelet turnover.     

Ⅱ型糖尿病患者血小板活化与微血管病变的关系

目的探讨Ⅱ型糖尿病患者血小板活化与微血管病变的关系.方法应用流式细胞术测定51例Ⅱ型糖尿病患者(其中微血管病变者27例,无微血管病变者24例)及29名正常对照组的血小板糖蛋白,包括α颗粒膜糖蛋白(CD62p)、溶酶体颗粒膜糖蛋白(CD63)、血小板膜表面糖蛋白(CD41、CD61、CD42b)、凝血酶敏感蛋白(TSP),同时用放免法检测血浆内皮素和胰岛素.结果糖尿病组血小板CD62P、CD63、TSP阳性的百分率[(1.35±0.70)%、(5.04±2.73)%、(76.5±9.1)%]和CD41、CD61的平均荧光道数(MnX)[(14.22±6.03)%、(6.54±1.73)%]显著高于正常对照组[(0.54±0.34)%、(2.84±1.12)%、(66.3±8.4)%、(10.43±1.70)%、(4.36±0.62)%](P<0.005),有微血管病变组高于无微血管病变组(P<0.05).糖尿病组的血小板CD42b的阳性百分率显著低于正常对照组(P<0.005).但有无微血管病变组间差异无显著意义.血小板CD62P,CD63,CD61,TSP与血浆内皮素呈显著正相关(r分别为0.45,0.47,0.34和0.30,P均<0.05).结论活化血小板测定对于糖尿病微血管病变的早期诊断具有重要的临床应用和研究价值.     

2型糖尿病患者常见心理障碍患病情况的调查

2型糖尿病被认为是一种心身疾病[1],严重影响着人们的身心健康。目前,我国的2型糖尿病患者正以每年1‰的速度增加。近年来,世界卫生组织已把糖尿病(DM)归为与生活方式有关的非传染性慢性疾病,并强调心理应激在其发病中的重要作用。研究表明,各种应激、心理创伤等可促使DM的发生