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肝素诱导的血小板减少症:血小板遗传多态性的作用。

Heparin-induced thrombocytopenia: the role of platelets genetic polymorphisms.

机构信息

Department of Medicine-DIMED, University of Padua Medical School, Padua, Italy.

出版信息

Platelets. 2013;24(5):362-8. doi: 10.3109/09537104.2012.701026. Epub 2012 Jul 13.

Abstract

Heparin-induced thrombocytopenia (HIT) is a severe complication of heparin therapy, characterized by thrombocytopenia and an increased risk for thrombotic complications secondary to the formation of IgG antibodies (Ab), recognizing a complex of heparin (H) and PF4. Using the 4T clinical score for HIT and the presence of heparin-associated Ab assayed by enzyme-linked immunosorbent assay and heparin-induced platelet aggregation, we define the phenotype of three groups of patients: 51 H/PF4/Ab patients with antibodies and without thrombocytopenia; 50 patients with thrombocytopenia (HIT) and 53 patients with thrombosis (HITT). In these patients we studied four polymorphisms: FcγRIIA-H131R, GpIIb/IIIa-HP-1, PECAM1-L125V (in linkage-disequilibrium with S563N and R670G), and FcγRIIIA-F158V, to understand if these variations may influence the different phenotypes of the patients. There were no difference in genotype or allele frequencies between controls and the three groups of patients. Afterward, we created a genotype score for multiple risk alleles for thrombosis considering as risk genotype FcγRIIA R/R131, HPA-1a/b, and PECAM1-V/V125. These polymorphisms were overrepresented in HITT patients, ascertained by a permutation test (10 000 replicates) p = 0.0198 for the two-single-nucleotide polymorphism (SNP) model and p = 0.0119 for the three-SNP model. The calculated odds ratio for thrombosis was 4.01[CI: 2.30-6.96] in the case of the presence of two at risk genotypes and 8.002 [CI: 4.59-13.93] if all the three at risk genotypes were present. In conclusion these polymorphisms could contribute to the risk of thrombotic complications in HIT.

摘要

肝素诱导的血小板减少症 (HIT) 是肝素治疗的严重并发症,其特征是血小板减少症和由于 IgG 抗体(Ab)形成而导致的血栓形成并发症风险增加,这些抗体识别肝素(H)和 PF4 的复合物。我们使用 HIT 的 4T 临床评分和通过酶联免疫吸附试验和肝素诱导的血小板聚集测定的肝素相关 Ab 的存在,定义了三组患者的表型:51 名 H/PF4/Ab 患者有抗体但无血小板减少症;50 名血小板减少症(HIT)患者和 53 名血栓形成(HITT)患者。在这些患者中,我们研究了四个多态性:FcγRIIA-H131R、GpIIb/IIIa-HP-1、PECAM1-L125V(与 S563N 和 R670G 连锁不平衡)和 FcγRIIIA-F158V,以了解这些变异是否会影响患者的不同表型。在基因型或等位基因频率方面,对照组与三组患者之间无差异。随后,我们考虑了 FcγRIIA R/R131、HPA-1a/b 和 PECAM1-V/V125 的血栓形成多风险等位基因,创建了一个用于血栓形成的基因型评分。通过置换检验,这些多态性在 HITT 患者中过表达(10000 次重复),两个单核苷酸多态性(SNP)模型的 p=0.0198,三个 SNP 模型的 p=0.0119。存在两个风险基因型时,血栓形成的优势比为 4.01[CI:2.30-6.96],如果存在所有三个风险基因型,则为 8.002[CI:4.59-13.93]。总之,这些多态性可能导致 HIT 中的血栓形成并发症风险增加。

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