Glycoprotein IIb/IIIa antagonist eptifibatide in acute coronary syndrome without elevation of ST segment

Clinical effects of glycoprotein (GP) IIb-IIIa antagonist eptifibatide (Integrilin) and its inhibitory effects on platelet aggregation were studied upon administration of eptifibatide for the treatment of acute coronary syndrome (ACS) without ST segment elevation. Eptifibatide was introduced to 25 patients with unstable angina and non-Q-wave myocardial infarction (MI) according to the following scheme: two boluses with 10 min interval at the dose of 180 mg/kg followed by supporting infusion of 2 mg/kg per min for the first 24 hours and of 1.3 mg/kg for the next 48 hours. Comparative group in which GP IIb-IIIa antagonists were not used upon therapeutic treatment also included 25 patients. All patients received standard basic therapy. 11 patients from the control group and 13 patients from the group with administration of eptifibatide underwent coronary angioplasty during in hospital period. Eptifibatide completely inhibited ADP-induced platelet aggregation within the whole infusion period but after that platelet aggregating activity was quickly recovered--for more than 50% within 6 hours, and completely within 12 hours after the end of infusion. Eptifibatide administration in none of patients was accompanied with the development of dangerous side effects. Thrombocytopenia (50,000 platelets per mm3) was registered in one, and minor bleeding events--in 3 patients. The rate of unfavourable outcomes (MI, refractory or recurrent angina) within first 30 days was almost the same in eptifibatide and control group--32% (8 out of 25) and 36% (9 out of 25) respectively. Thus, despite the complete inhibition of platelet aggregation for 72 hours, eptifibatide administration failed to decrease the amount of adverse events upon treatment of patients with ACS without ST segment elevation.     

Clinical pharmacology of higher dose eptifibatide in percutaneous coronary intervention (the PRIDE study).

This study describes the dose-exploration phase of the PRIDE trial, an investigation of the clinical pharmacology of higher dose eptifibatide in patients who underwent elective percutaneous coronary intervention (PCI). Outcomes of treatment with the platelet glycoprotein IIb/IIIa inhibitors were dependent upon proper dosing selection. In this multicenter, placebo-controlled clinical study, 127 patients were randomized 1:1:2:2 into 1 of the following treatment groups: placebo; eptifibatide as a 135 microg/kg bolus followed by a 0.75 microg/kg/min infusion; eptifibatide as a 180 microg/kg bolus with a 2.0 microg/kg/min infusion; or eptifibatide as a 250 microg/kg bolus with a 3.0 microg/kg/min infusion. Light transmission aggregometry was used to determine platelet aggregation in response to 20 microM adenosine diphosphate, and platelet receptor occupancy was also determined. Eptifibatide exhibited linear pharmacokinetics over the dose range studied. Inhibition of platelet aggregation was greater in samples collected in sodium citrate compared with those collected in D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone. The 180/2.0 dosing regimen achieved 90% inhibition of platelet aggregation immediately (5 minutes) and at steady state (8 to 24 hours). At 1 hour, mean inhibition of platelet aggregation was 80%. Eptifibatide exhibited dose-dependent pharmacodynamics that were dependent upon choice of anticoagulant. A 180 microg/kg bolus followed by a 2.0 microg/kg/min infusion at steady state achieved >80% inhibition of platelet aggregation. With the single-bolus regimen, however, there was an early loss of the inhibition of platelet aggregation before steady state was reached. Additional dose-exploration studies may further optimize eptifibatide dosing.     

The platelet CD40L/GP IIb-IIIa axis in atherothrombotic disease

Platelet aggregation, a process mediated by GP IIb-IIIa, is responsible for the occlusive events in thrombosis: indeed, GP IIb-IIIa antagonists are effective in blocking arterial thrombosis. Recent studies have suggested that activated platelets and platelet thrombi can contribute significantly to the initiation and progression of atherosclerosis, a chronic inflammatory disease. Platelets store inflammatory cytokines such as CD40L and RANTES, which are now known to be important in this pathologic process. CD40L appears to be particularly relevant because high levels of the circulating soluble form of CD40L, termed sCD40L, are released in response to platelet thrombosis and because elevated levels of sCD40L are a reliable predictor of cardiovascular events. sCD40L is also a ligand of GP IIb-IIIa and is involved in thrombus stabilization and platelet activation. In addition, GP IIb-IIIa antagonists unexpectedly block release of sCD40L. These observations suggest that long-term benefit of GP IIb-IIIa antagonists treatment could be due not only to the inhibition of the acute ischemic complications, but also to the inhibition of autocrine function of sCD40L, thereby interrupting the platelet CD40L/GP IIb-IIIa axis.     

GP IIb/IIIa inhibition with eptifibatide lowers levels of soluble CD40L and RANTES after percutaneous coronary intervention.

Platelets are the most abundant blood source of CD40L, a proinflammatory and prothrombotic costimulatory molecule implicated in atherosclerosis. Agonist stimulation results in the secretion of a soluble form of CD40L (sCD40L) and GP IIb/IIIa receptor inhibition blocks secretion of sCD40L in vitro. However, the effect of GP IIb/IIIa inhibition on sCD40L levels in humans is unknown. Plasma sCD40L and inflammatory markers were measured (t = 0, 0.5, 2, and 24 hr post-PCI) in a cohort of patients receiving abciximab (n = 15), eptifibatide (n = 15), or no GP IIb/IIIa inhibitor (n = 15). PCI in the absence of GP IIb/IIIa inhibitor was associated with a small but measurable rise in sCD40L and the platelet-derived chemokine RANTES. In contrast, eptifibatide significantly lowered baseline sCD40L (P = 0.018) and RANTES (P = 0.006) levels. This effect was not observed with abciximab. GP IIb/IIIa inhibition with eptifibatide lowers levels of sCD40L and RANTES post-stenting, possibly conferring anti-inflammatory as well as antithrombotic effects.     

Increased soluble and platelet-associated CD40 ligand in essential thrombocythemia and reactive thrombocytosis

CD40 ligand (CD40L) is expressed on activated CD4(+) T lymphocytes and at the activated platelet surface. A circulating soluble form of CD40L (sCD40L) is generated by the way of a proteolytic cleavage. We measured sCD40L in the plasma of either healthy subjects; patients with inflammatory disorders and low, normal, or high platelet count (reactive thrombocytosis); or patients with essential thrombocythemia (ET). A tight correlation was found between the platelet count and plasma sCD40L. ET patients had the highest levels of sCD40L. Platelet-associated CD40L was increased in ET and reactive thrombocytosis, conditions associated with increased platelet regeneration. Platelet-associated CD40L was released upon platelet activation. In conclusion, platelets appear as a reservoir of CD40L that may be a major contributor to circulating sCD40L. Platelet-associated CD40L may be a potential marker of platelet regeneration.     

急性冠脉综合征患者血浆sCD40L与血清基质金属蛋白酶水平的变化及其意义

目的：观察急性冠脉综合征（ACS）患者可溶性CD40配体（sCD40L）及血清基质金属蛋白酶-9（MMP-9）、血清组织金属蛋白酶抑制物-1（TIMP-1）水平变化及其相关性。方法：采用酶联免疫吸附法测定70例冠心病患者[ACS患者35例、稳定型心绞痛（SAP）患者35例]、35例非冠心病患者（正常对照组）sCD40L、MMP-9、TIMP-1的水平。结果：与正常对照组及SAP组比较,ACS组sCD40L[（2.73±0.92）μg/ml比（3.05±0.98）μg/ml比（4.72±1.15）μg/ml]、MMP-9[（152.38±54.22）ng/ml比（341.12±69.96）ng/ml比（574.2±139.20）ng/ml]水平明显升高（P均〈0.01）,而TIMP-1[（415.92±13.96）ng/ml比（249.32±36.80）ng/ml比（172.20±40.10）ng/ml]水平明显降低（P〈0.01）;且MMP-9与sCD40L呈正相关（r=0.42,P〈0.05）。结论：急性冠脉综合征患者可溶性CD40配体、血清基质金属蛋白酶-9水平升高,血清组织金属蛋白酶抑制物-1水平下降提示这两指标与粥样斑块不稳定相关,可作为判断粥样斑块不稳定的血清学指标。     

Inverse correlation between soluble CD40 ligand and soluble CD40 is absent in patients with unstable angina

The CD40/CD40 ligand (CD40L) system mediates inflammatory processes important in atherogenesis and plaque instability. The expression of CD40L on activated T cells was suppressed by soluble CD40 (sCD40) in vitro. However, the relationship between soluble CD40L (sCD40L) and sCD40 in unstable angina (UA) is still unknown. Thirty-seven consecutive patients with recent chest pain or discomfort were recruited. Patients with both Braunwald's class IB–IIIB and with coronary stenosis (or stenoses) of >75% were assigned to the UA group (n = 19, aged 67.2 ± 8.2 years), and the rest to the control group (n = 18, aged 63.4 ± 8.7 years). The serum levels of sCD40L and sCD40, and the plasma levels of matrix metalloproteinase (MMP)-9, were measured by enzyme-linked immunosorbent assays. A significantly inverse correlation between sCD40L and sCD40 was shown in the controls (r = −0.72, P = 0.0007), but was absent in the UA group (r = −0.16, P not significant), although there was no statistical significance between these groups in terms of serum levels of sCD40L or sCD40. The difference of the regression slopes of these regression lines was statistically significant (P < 0.01). Additionally, there was a significant correlation between sCD40 and plasma levels of MMP-9 in the patients with and without UA (r = 0.58, P = 0.0096), but no significant correlation between sCD40L and MMP-9 levels (r = 0.00, P not significant). The balance between CD40 and CD40L may be lost in patients with UA. Soluble CD40 expression may also be related to MMP-9 expression in atherosclerotic tissues.     

Relationship between plasma inflammatory markers and platelet aggregation in patients with clopidogrel resistance after angioplasty

We evaluated the relationship between plasma inflammation markers and clopidogrel resistance in patients after stent implantation. The plasma levels of C-reactive protein (CRP), P-selectin, platelet soluble CD40 ligand (sCD40L), interleukin 6 (IL-6) and platelet aggregation were measured in 352 patients undergoing percutaneous coronary intervention (PCI) at baseline and after 6 months. The plasma levels of CRP, P-selectin, sCD40L, IL-6 was higher in 65 (18.5%) patients with clopidogrel resistance than in those with normal responsiveness at 6 months after PCI. There was a significant positive correlation between soluble CD40L levels and platelet aggregation (r = .28, P < .05). Diabetes (DM) and sCD40L level were independent predictors for unresponsiveness after stent implantation according to stepwise multivariate analyses. The hazard ratio (HR) for sCD40L level was 3.02 (95% CI = 1.28 to 3.25; P = .036) and for DM 2.53 (95% CI = 1.28 to 6.55, P = .03). We conclude that sCD40L and DM may influence clopidogrel resistance.     

Release of soluble CD40L from platelets is regulated by glycoprotein IIb/IIIa and actin polymerization

OBJECTIVES: The purpose of this study was to examine the effects of glycoprotein (GP) IIb/IIIa antagonists (abciximab, eptifibatide, and tirofiban) and other inhibitors on translocation of CD40L from intraplatelet stores to the platelet surface and on the release of soluble CD40L (sCD40L) from platelets. BACKGROUND: CD40L is a proinflammatory and prothrombotic ligand in the tumor necrosis factor family. METHODS: Platelet surface CD40L was measured by flow cytometry, and sCD40L was measured by enzyme-linked immunosorbent assay. RESULTS: Translocation of CD40L from intraplatelet stores to the platelet surface was not inhibited by GP IIb/IIIa antagonists. However, release of sCD40L from the surface of activated platelets was inhibited by GP IIb/IIIa antagonists in a dose-dependent manner, in concert with inhibition of PAC1 binding to platelets (a surrogate marker for fibrinogen binding). Release of sCD40L from activated platelets was also markedly reduced in Glanzmann platelets (deficient in GP IIb/IIIa). Ethylenediaminetetraacetic acid was an effective inhibitor of sCD40L release, but only when added before platelet activation. Both cytochalasin D (an inhibitor of actin polymerization) and GM6001 (an inhibitor of matrix metalloproteinases [MMPs]) inhibited the release of sCD40L from platelets when added before, as well as 3 min after, platelet activation. However, neither cytochalasin D nor GM6001 affected translocation of CD40L to the platelet surface. CONCLUSIONS: The GP IIb/IIIa antagonists inhibit release of sCD40L from activated platelets. Release of sCD40L from platelets is regulated, at least in part, by GP IIb/IIIa, actin polymerization, and an MMP inhibitor-sensitive pathway. In addition to their well-characterized inhibition of platelet aggregation, GP IIb/IIIa antagonists may obviate the proinflammatory and prothrombotic effects of sCD40L.     

Comparative Pharmacodynamic Evaluation of Eptifibatide and Abciximab in Patients with Non-ST-Segment Elevation Acute Coronary Syndromes: The TAM2 Study

Background: The importance of the relationship between clinical outcome and degree of platelet aggregation inhibition (PAI) achieved with the dosing regimens of GPIIb-IIIa inhibitors used in large trials in patients with non-ST segment elevation (NSTE) acute coronary syndromes (ACS) is increasingly appreciated. In the PURSUIT trial, eptifibatide treatment that consistently provided >80% PAI was associated with clinical benefit at 30 days and 6 months. The GUSTO IV ACS trial, however, did not show any effect of abciximab on 30-day outcomes. This difference might be due to variability of antiplatelet effects of these drugs. As previous studies found, a 12 hr abciximab infusion had <80% PAI, particularly at 6 and 12 hr. These studies did not evaluate PAI with a longer, 24-hour infusion as used in GUSTO IV ACS.Methods: We conducted a prospective study in 40 patients with NSTE ACS prior to catheterization or coronary intervention at 3 centers using the PURSUIT dose of eptifibatide (180/0.2) and the GUSTO IV dose of abciximab (0.25, 0.125). Blood samples were collected at baseline, and during the infusion at 10 min, 1 hr, 6 hr, 8 hr, 12 hr, 18 hr, and 24 hr. Measurements of ex vivo light transmission aggregometry (LTA) were performed using PPACK anticoagulant and 20 M ADP agonist. Receptor Occupancy (RO) was also determined in a subset of patients.Results: Eptifibatide achieves higher PAI during the entire infusion period than abciximab (p < 0.01). At 10 min, average PAI with eptifibatide and abciximab was 88% and 80%, respectively, 95% and 79% at 6 hr, and 97% and 79% at 24 hr. There was also more variability in individual patient response to abciximab. Although average RO for eptifibatide was similar to that of abciximab at 10 min, 67% versus 69%, respectively, average RO was higher in the eptifibatide cohort at all subsequent timepoints. By 24 hr, average RO for eptifibatide was 86%, whereas abciximab averaged 67%.Conclusion: These data support the hypothesis that differences in clinical outcomes of large GPIIb-IIIa trials in patients with NSTE ACS may be related to the consistency and potency of antiplatelet effects of the dosing regimens used.Abbreviated abstract. We compared platelet aggregation inhibition (PAI) with the glycoprotein IIb-IIIa inhibitors eptifibatide and abciximab in patients with non–ST-segment elevation (NSTE) acute coronary syndromes (ACS), using light transmission aggregometry assays with D-phenylalanyl-L-propyl-L-arginine chloromethylketone (PPACK) as the anticoagulant and 20 mol adenosine diphosphate (ADP) as the platelet agonist. Mean PAI with eptifibatide during the entire 24-hour infusion period was >80%, and it was significantly higher than the mean PAI achieved with abciximab (p < 0.0001). Mean PAI with abciximab was <80% at 6, 8, 12, 18, and 24 hr. Most patients in the eptifibatide arm had >80% PAI at all time points, whereas many patients treated with abciximab had <80% PAI throughout the infusion period, particularly at later times (6 hr and beyond). Mean GPIIb-IIIa receptor occupancy with eptifibatide was also higher than with abciximab. These pharmacodynamic differences may have contributed to differing clinical effects of eptifibatide and abciximab in large clinical trials in patients with NSTE ACS.     

急性冠状动脉综合征患者sCD40L的变化及他汀类药物的影响

目的探讨急性冠状动脉综合征(ACS)患者血清可溶性CD40L(sCD40L)水平的变化及他汀类药物对其的影响。方法102例ACS患者随机分为2组:安慰剂组,辛伐他汀和普伐他汀组(他汀组)。用间接免疫荧光流式细胞术和酶联免疫吸附法(ELISA)及常规酶法分别测定2组患者用药前和用药2、4、6周后血清sCD40L水平及总胆固醇(TC)水平。结果(1)他汀组患者服药2,4及6周后血清sCD40L水平明显低于安慰剂组(均P<0.05)。(2)他汀组患者服药2、4、6周后血清sCD40L水平呈逐渐下降趋势,同用药前相比差异均有统计学意义(均P<0.05)。(3)他汀组患者服药2、4、6周后血浆TC水平与用药前相比差异均有统计学意义(均P<0.05)。(4)他汀组患者血清sCD40L水平的降低与血浆TC水平的降低无明显相关性(r=0.014,P>0.05)。结论他汀类药物能明显降低ACS患者体内sCD40L水平,对减轻炎症反应、稳定斑块有一定作用。     

芪参益气滴丸对冠状动脉介入术后炎症因子及心脏不良事件的影响

目的 观察芪参益气滴丸对急性冠脉综合征（ACS）患者经皮冠状动脉介入术（PCI）后炎症因子及主要不良心脏事件（MACE,包括复发心绞痛、急性心肌梗死、严重心律失常、心力衰竭、冠心病死亡）影响.方法纳入60例行PCI的ACS患者,随机分为常规治疗组（n=30）和芪参益气滴丸联合常规治疗组（芪参组,n=30）,采用酶联反应吸附法（ELISA法）比较两组术后24h和术后6个月血清高敏C反应蛋白（hs-CRP）、可溶性CD40配体（sCD40L）及基质金属蛋白酶-9（MMP-9）水平变化,并比较两组6个月MACE事件发生率.结果术后24h两组血清hs-CRP、sCD40L和MMP-9水平均无统计学差异（P＞0.05）;6个月后,两组hs-CRP、sCD40L和MMP-9水平分别是3.18±0.71mg/l、5.86±2.01 ng/dl和240.56±60.6 ng/dl.与对照组相比,芪参组血清hs-CRP、sCD40L及MMP-9均明显降低,差异有统计学意义（P＜0.05）,随访6个月,芪参组MACE发生率较对照组更低（13.33% vs.26.67%,P＜0.05）,且差异有统计学意义.结论 芪参益气滴丸可降低介入术后炎症因子hs-CRP、SCD40L和MMP-9的水平,同时降低MACE近期发生率.     

Cardiopulmonary bypass induces release of soluble CD40 ligand

BACKGROUND: Cardiopulmonary bypass (CPB) is known to induce platelet activation, thrombosis, thrombocytopenia, and a systemic inflammatory response. It is known that CD40 ligand (CD40L) exists in platelets, that a soluble form of this protein (sCD40L) is released on platelet activation, that platelets are the primary source of sCD40L in blood, and that sCD40L is involved in thrombosis and inflammation. The present study was designed to determine whether sCD40L is released during CPB. Methods and Results- Blood was obtained from patients undergoing CPB-requiring surgery and analyzed for sCD40L, interleukin-6, and platelet factor 4 and beta-thromboglobulin (markers of platelet activation). Platelets were also isolated and analyzed for their levels of CD40L. Plasma levels of sCD40L increased >1.7-fold (from 0.29 to 0.51 ng/mL, P=0.001) within 1 hour on CPB and increased further to 3.7-fold (to 1.08 ng/mL, P=0.03) 2 hours after the procedure. Half of the released sCD40L was cleared in 2 hours, which allowed the sCD40L to return to approximately baseline levels 8 hours after the procedure. The platelet content of CD40L was decreased by 40% (2.675 to 1.64 ng/10(8) platelets, P=0.001) 1 hour after initiation of CPB and was similar to that observed for platelet factor 4 and beta-thromboglobulin. Interleukin-6, a marker of inflammation, also increased during CPB. CONCLUSIONS: The present study demonstrates that CPB causes an increase in the concentration of plasma sCD40L. The corresponding decrease in platelet CD40L suggests that this prothrombotic and proinflammatory protein was derived primarily from platelets and may contribute to the thrombotic and inflammatory complications associated with CPB.     

中国人群CD40L G基因单核苷酸多态性对急性冠状动脉综合征影响的相关性研究

目的新近的研究提示CD40/CD40L信号途径对急性冠状动脉综合征的发病及预后均具有一定影响。本研究旨在探讨CD40L G基因单核苷酸多态性与急性冠状动脉综合征患者冠状动脉病变程度间的关系。方法搜集2008年8月至2010年8月间在北京安贞医院抢救中心确诊为急性冠状动脉综合征的患者共482例,总结分析其临床特征、相关危险因素及血清单核细胞和血小板表达CD40水平以及CD40L G基因单核苷酸多态性对冠状动脉病变程度的影响。结果 (1)6.8%(n=33)的急性冠状动脉综合征患者未检测到血清sCD40L(<95 ng/L),449例患者平均血清sCD40L为296±25 ng/L,sCD40L平均水平男性为309 ng/L,女性为195 ng/L,男性高于女性(P<0.001),sCD40L水平随着冠状动脉病变程度加重而升高(P<0.001)。(2)不同基因型间血清sCD40L水平与冠状动脉评分存在显著性差异(P<0.001),趋势具有统计学意义。其中以GG基因型的sCD40L水平最高,为409ng/L,冠状动脉病变程度最严重(P<0.001)。(3)多因素分析显示,在矫正年龄、性别及高血脂、高血压、糖尿病等危险因素后,CD40L G基因多态性与冠状动脉病变程度密切相关,它们的OR值分别为1.00、1.32、3.41(P≤0.001)。结论急性冠状动脉综合征患者血清sCD40L水平及CD40L G基因多态性与冠状动脉病变程度密切相关,在急性冠状动脉综合征临床危险分层中,血清sCD40L水平及CD40L G基因多态性是一个不容忽视的方面。     

Eptifibatide does not suppress the increase of inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome

Background Platelets are involved in inflammatory reactions which play an important role in the development of atherosclerosis and its acute complications. The objective of this study was to test the ability of glycoprotein (GP) IIb-IIIa antagonist eptifibatide to suppress the increase of inflammatory markers in non-ST-segment elevation acute coronary syndrome (ACS). Methods Twenty-five patients with unstable angina and non-ST-segment elevation myocardial infarction received eptifibatide on admission (two 180 μg/kg boluses followed by infusion at 2.0 and 1.3 μg/kg/min for 24 and 48 h, respectively) and 25 were treated without GP IIb-IIIa antagonists. Plasma von Willebrand factor (vWF) and soluble P-selectin were determined at baseline, 48 h and 2 weeks after onset of ACS, and were also measured in a group of healthy volunteers. Serum C-reactive protein (CRP), tumor necrosis factor alpha (TNFα), and interleukin 6 (IL6) were measured at baseline, 48 h, 2 weeks and 6 months. Results P-selectin was increased at baseline and vWF at baseline, 48 h and 2 weeks in comparison with healthy donors. CRP, TNFα, but not IL6 were increased at baseline, 48 h and 2 weeks in comparison with their levels at 6 months. Maximal values of CRP, TNFα and vWF were detected at 48 h. At any time point eptifibatide failed to decrease the levels of all tested markers. Conclusion Eptifibatide does not suppress elevated levels of inflammatory markers in patients with non-ST-segment elevation ACS.     

Association between enhanced soluble CD40 ligand and prothrombotic state in inflammatory bowel disease

BACKGROUND: Inflammatory bowel disease is associated with an increased incidence of thromboembolic complications. The aim of this study was to investigate the role of the soluble CD40 ligand (sCD40L), which displays prothrombotic properties, in patients with ulcerative colitis (UC) and Crohn's disease (CD) in comparison with inflammatory and healthy controls. METHODS: Plasma levels of sCD40L, prothrombin fragment 1+2 (F1+2), thrombin-antithrombin (TAT) complex and soluble P-selectin were measured in 104 inflammatory bowel disease patients (54 ulcerative colitis and 50 Crohn's disease), in 18 cases with other causes of intestinal inflammation and in 80 healthy controls using commercially available enzyme-linked immunosorbent assays. Plasma levels of sCD40L were correlated with disease activity, type, localization and treatment as well as with the measured thrombophilic parameters. RESULTS: CD patients had significantly higher sCD40L levels than both groups of controls (CD vs HC P < 0.001; CD vs non-IBD P < 0.05). UC patients had higher but not significantly different sCD40L levels compared with the controls. Both UC and CD patients with active disease had significantly higher sCD40L levels in comparison with patients with inactive disease. Plasma levels of sCD40L were correlated with platelet count (r = 0.27, P = 0.001). They also showed a correlation with prothrombin F1+2 (r = 0.16, r = 0.03) and TAT (r = 0.15, r = 0.04) as well as with P-selectin (r = 0.19, P = 0.01). CONCLUSIONS: The increased sCD40L plasma levels may represent, at least in some degree, a molecular link between inflammatory bowel disease and the procoagualant state.     

Plasma, serum, and platelet expression of CD40 ligand in adults with cardiovascular disease

The application of soluble CD40 ligand (sCD40L) as a biomarker has garnered great scientific and clinical interest. However, there are many uncertainties with regard to the biology of sCD40L. Although presumed to be a marker of platelet activation, relative levels in plasma, serum, and platelet expression are unknown, as is the optimal method for its measurement. We measured CD40L from serum, platelet-poor plasma, and platelet surface in adults who had stable cardiovascular disease (CVD) and those who had unstable CVD (n = 40). Plasma sCD40L did not differ significantly between groups. Serum sCD40L was significantly lower (1.4 +/- 1.3 vs 5.2 +/- 3.7 ng/ml, p <0.001) and platelet membrane CD40L expression was higher (1.4 +/- 0.7% vs 0.9 +/- 0.6%, p = 0.03) in unstable compared with stable CVD. When the 2 groups were considered together, there was a significant correlation between plasma and serum sCD40L levels (rho = 0.4, p = 0.02) and negative correlations between plasma (rho = -0.3, p = 0.04) and serum (rho = -0.4, p = 0.01) sCD40L levels with platelet membrane CD40L expression. In unstable CVD, the correlation between sCD40L measurements was poor. Consistent with enhanced platelet activation, there was a positive correlation between platelet aggregation and surface CD40L expression (rho = 0.5, p = 0.02) and between platelet expression of CD40L and P-selectin (rho = 0.4, p = 0.05) in unstable CVD. There was no correlation between CD40L and platelet count or C-reactive protein. Only surface expression of CD40L compared with platelet-derived (plasma) or total (serum) CD40L level proved a reliable marker of platelet function in patients who had stable CVD and those who had unstable CVD. In conclusion, our data demonstrate the complex nature of CD40L and highlight the distinct processes of expression, shedding, and clearance of this ligand in patient populations.     

急性心肌梗死早期普伐他汀治疗对血浆CD40L、金属蛋白酶-9及C反应蛋白的影响

目的　观察较大剂量普伐他汀治疗急性心肌梗死患者 3d后金属蛋白酶 9(MMP 9)、可溶性白细胞分化抗原 40配体 (sCD40L)及C 反应蛋白 (CRP)的变化 ,以了解短期普伐他汀治疗对斑块稳定和免疫炎症抑制的影响。方法　 35例急性心肌梗死患者随机分为常规治疗组 (无服用任何调脂药物 ,17例 )和普伐他汀组 ( 40mg/d ,18例 )治疗 ,测定治疗前后sCD40L、MMP 9、CRP和血脂水平的变化。结果　二组治疗前后血脂各组成分的变化差异均无显著性 ,而普伐他汀治疗组治疗后sCD40L、MMP 9及CRP水平分别降低 38%、48%、33%,与治疗前比较有统计学差异 (P <0 0 5 )。在普伐他汀治疗组 ,sCD40L、MMP 9的降低与TC(r =0 0 9,P =0 5 7;r =0 15 ,P =0 38)、LDL C(r =0 0 8,P =0 87;r= 0 0 3 ,P =0 83)的下降百分数之间无相关关系。结论　在急性心肌梗死的早期予以 3d的普伐他汀治疗 ,可明显减低血浆炎症因子的水平、可能有利于动脉粥样硬化斑块的稳定。     

氯吡格雷抑制急性冠状动脉综合征患者血小板释放可溶性CD40配体

目的探讨在非ST段抬高急性冠状动脉综合征（non—ST-segment elevation acute coronary syndromes，NSTEACS）患者短期应用氯吡格雷是否有抑制ADP诱导血小板释放可溶性CD40配体（sCD40L）的作用。方法NSTEACS42例，患者服用氯吡格雷6—8d，治疗前后采静脉血。提取富含血小板血浆（platelet rich plasma，PRP）并用二磷腺苷诱导血小板聚集和释放sCD40L，在不同时间点终止反应，用酶联免疫法测量sCD40L浓度，进行自身前后对照。结果治疗前后血浆sCD40L分别为（0．20±0．16）μg／L和（0．19±0．18）μg/L（P〉0．05）；治疗前后PRP受ADP诱导后20min释放的sCD40L浓度分别为（4．3±2．5）μg／L和（2.8±1．9）μg／L（P〈0．001），诱导后40min释放的sCD40L浓度分别为（5．3±3．1）μg／L和（2．9±1．6）μg／L（P〈0．001）。结论短期应用氯吡格雷可能对非sT段抬高急性冠状动脉综合征患者血小板炎症因子sCD40L释放具有抑制作用，提示氯吡格雷很可能具有抗炎效应．     

炎性因子CD40配体在急性冠脉综合征患者中的作用

目的探讨急性冠脉综合征（ACS）患者血清可溶性CD40配体（sCD40L）和超敏C反应蛋白（hs-CRP）的水平及临床意义。方法按照诊断标准入选研究对象137例,分为两组：冠状动脉造影无异常者为对照组,21例,ACS组116例,男86例,30例,年龄35～77（56.9±12.6）岁,包括不稳定型心绞痛88例,急性心肌梗死28例。采集患者空腹肘静脉血,采用酶联免疫吸附（ELISA）方法测定血清sCD40L浓度和hs-CRP浓度。所有患者入院第2～4天行冠状动脉造影检查,用直径法测定冠状动脉狭窄的程度,用Gensini评分系统进行评分,累计积分。结果 ACS组sCD40L与hs-CRP水平均高于对照组（P＜0.05）。sCD40L水平与Gensini积分呈正相关关系（r＝0.328,P＝0.000）,hs-CRP水平与Gensini积分呈正相关关系（r＝0.748,P＝0.000）,sCD40L与hs-CRP之间呈正相关关系（r＝0.192,P＝0.039）。结论 ACS患者外周血清sCD40L和hs-CRP水平明显升高,提示CD40/CD40L系统与ACS的发生有关。