Klinkhardt U, Dragutinovic I, Harder S
pharmazentrum frankfurt, Institute for Clinical Pharmacology, University Hospital Frankfurt, Frankfurt/Main, Germany.
Int J Clin Pharmacol Ther. 2005 Jun;43(6):255-63. doi: 10.5414/cpp43255.
Formation of platelet-leukocyte aggregates (PLA) via the CD62p-ligand PSGL-1 represents an important mechanism by which leukocytes contribute to thrombotic and inflammatory events. Deficient variants (namely the Thr715Pro-SNP for CD62p and a VNTR-polymorphism for PSGL-1) might affect PLA formation and probably the response to clopidogrel (which is known to reduce PLA-formation).
CD62p-expression, PLA-formation and the up-regulation of CD11b before (V1) and 24 hours after (V2) a loading dose of clopidogrel 225 mg were investigated in ten wild-type controls, ten heterozygote carriers of the Thr715Pro-allele and five carriers of the rare PSGL-1 B-allele (2 A/B and 3 B/B).
CD62p-expression before application of clopidogrel and under clopidogrel treatment in Pro715-haplotype samples did not differ from that in wild-type subjects. The response to clopidogrel was similar in all subjects. Pro715-carriers exhibited a significantly lower percentage of monocytes with platelets attached prior to clopidogrel treatment (ADP: median 22 (1st-3rd quartile 20-23), TRAP: 27 (25 - 38)) compared to the wild-type (ADP: 37 (31-44), TRAP: 55 (37-63)). These differences were not present under clopidogrel, and CD11b-expression was significantly reduced in both groups (controls: median 150 (quartile range 121 - 230) to 113 (121 - 230), Pro715-carriers: 147 (139 - 221) to 126 (109 - 170); all values refer to mean fluorescence intensity). Statistical analysis was not done in the case of PSGL-1 B-allele carriers, but PLA-formation before and under clopidogrel was always at the bottom end of the range seen in the control group and the Pro715-carriers or even below this range.
Minor phenotypic differences in the CD62p-PSGL-1 axis could be demonstrated in this study. Carriers of these polymorphisms showed a full response to clopidogrel comparable to that in control subjects.
通过CD62p配体PSGL-1形成血小板-白细胞聚集体（PLA）是白细胞促成血栓形成和炎症事件的一种重要机制。缺陷变体（即CD62p的Thr715Pro单核苷酸多态性和PSGL-1的可变数目串联重复序列多态性）可能会影响PLA的形成，也可能影响对氯吡格雷的反应（已知氯吡格雷可减少PLA的形成）。
在10名野生型对照者、10名Thr715Pro等位基因杂合携带者和5名罕见PSGL-1 B等位基因携带者（2名A/B和3名B/B）中，研究了225 mg氯吡格雷负荷剂量给药前（V1）和给药后24小时（V2）的CD62p表达、PLA形成以及CD11b的上调情况。
在Pro715单倍型样本中，应用氯吡格雷前及氯吡格雷治疗期间的CD62p表达与野生型受试者无差异。所有受试者对氯吡格雷的反应相似。与野生型相比（ADP：中位数22（第1-3四分位数20-23），TRAP：27（25-38）），Pro715携带者在氯吡格雷治疗前，单核细胞与血小板附着的百分比显著较低（ADP：37（31-44），TRAP：55（37-63））。在氯吡格雷作用下，这些差异不存在，且两组的CD11b表达均显著降低（对照组：中位数150（四分位数范围121-230）降至113（121-230），Pro715携带者：147（139-221）降至126（109-170）；所有数值均指平均荧光强度）。未对PSGL-1 B等位基因携带者进行统计分析，但在氯吡格雷治疗前及治疗期间，PLA的形成始终处于对照组和Pro715携带者所见范围的底端，甚至低于该范围。
本研究可证明CD62p-PSGL-1轴存在微小的表型差异。这些多态性的携带者对氯吡格雷的反应与对照受试者相当。
