Warlo Ellen M K, Pettersen Alf-Åge R, Arnesen Harald, Seljeflot Ingebjørg
Center for Clinical Heart Research, Department of Cardiology, Oslo University Hospital, Ullevaal, Pb 4956 Nydalen, 0424 Oslo, Norway.
Faculty of Medicine, University of Oslo, Oslo, Norway.
Thromb J. 2017 Nov 22;15:28. doi: 10.1186/s12959-017-0151-3. eCollection 2017.
The mechanisms behind residual platelet reactivity (RPR) despite aspirin treatment are not established. It has been shown that coronary artery disease (CAD) patients with high on-aspirin RPR have elevated levels of von Willebrand factor (vWF). ADAMTS13 is a metalloprotease cleaving ultra large vWF multimers into less active fragments.Our aim was to investigate whether ADAMTS13 and vWF/ADAMTS13 ratio were associated with high RPR, and further with clinical endpoints after 2 years.
Stable aspirin-treated CAD patients ( = 999) from the ASCET trial. RPR was assessed by PFA-100. ADAMTS13 antigen and activity were analysed using chromogenic assays. Endpoints were a composite of acute myocardial infarction, stroke and death.
The number of patients with high RPR was 258 (25.8%). Their serum thromboxane B (TxB) levels were low, indicating inhibition of COX-1. They had significantly lower levels of ADAMTS13 antigen compared to patients with low RPR (517 vs 544 ng/mL, = 0.001) and significantly lower ADAMTS13 activity (0.99 vs 1.04 IU/mL, = 0.020). The differences were more pronounced when relating RPR to ratios of vWF/ADAMTS13 antigen and vWF/ADAMTS13 activity ( < 0.001, both). We found an inverse correlation between vWF and ADAMTS13 antigen ( = -0.14, p < 0.001) and ADAMTS13 activity ( = -0.11, p < 0.001). No correlations between TxB and ADAMTS13 antigen or activity, were observed, implying that ADAMTS13 is not involved in TxB2 production. Patients who experienced endpoints ( = 73) had higher vWF level (113 vs 105%, = 0.032) and vWF/ADAMTS13 antigen ratio (0.23 vs 0.20, = 0.012) compared to patients without. When dichotomizing vWF/ADAMTS13 antigen at median level we observed that patients above median had higher risk for suffering endpoints, with an adjusted OR of 1.86 (95% CI 1.45, 2.82).
These results indicate that ADAMTS13 is of importance for RPR, and that it in combination with vWF also is associated with clinical endpoints in stable CAD patients on aspirin.
Clinicaltrials.gov NCT00222261. Registered 13.09.2005. Retrospectively registered.
尽管使用了阿司匹林治疗，但残余血小板反应性（RPR）背后的机制尚未明确。研究表明，阿司匹林治疗后RPR高的冠状动脉疾病（CAD）患者血管性血友病因子（vWF）水平升高。ADAMTS13是一种金属蛋白酶，可将超大vWF多聚体切割成活性较低的片段。我们的目的是研究ADAMTS13和vWF/ADAMTS13比值是否与高RPR相关，并进一步研究其与2年后临床终点的关系。
来自ASCET试验的稳定的接受阿司匹林治疗的CAD患者（n = 999）。通过PFA-100评估RPR。使用显色测定法分析ADAMTS13抗原和活性。终点为急性心肌梗死、中风和死亡的复合终点。
高RPR患者有258例（25.8%）。他们的血清血栓素B（TxB）水平较低，表明COX-1受到抑制。与低RPR患者相比，他们的ADAMTS13抗原水平显著较低（517 vs 544 ng/mL，P = 0.001），ADAMTS13活性也显著较低（0.99 vs 1.04 IU/mL，P = 0.020）。当将RPR与vWF/ADAMTS13抗原和vWF/ADAMTS13活性的比值相关联时，差异更为明显（两者P均<0.001）。我们发现vWF与ADAMTS13抗原（r = -0.14，P<0.001）和ADAMTS13活性（r = -0.11，P<0.001）呈负相关。未观察到TxB与ADAMTS13抗原或活性之间的相关性，这意味着ADAMTS13不参与TxB2的产生。发生终点事件的患者（n = 73）与未发生终点事件的患者相比，vWF水平更高（113 vs 105%，P = 0.032），vWF/ADAMTS13抗原比值更高（0.23 vs 0.20，P = 0.012）。当将vWF/ADAMTS13抗原按中位数水平进行二分法时，我们观察到高于中位数的患者发生终点事件的风险更高，调整后的OR为1.86（95%CI 1.45，2.82）。
这些结果表明，ADAMTS13对RPR很重要，并且它与vWF相结合也与接受阿司匹林治疗的稳定CAD患者的临床终点相关。
Clinicaltrials.gov NCT00222261。2005年9月13日注册。回顾性注册。
