背景:Hutchinson-GilfordProgeriaSyndrome(HGPS)是一种由层粘连蛋白A基因的点突变引起的超罕见的早衰遗传性疾病,LMNA.患有HGPS的儿童寿命短,通常死于心肌梗塞或缺血性中风,这两种急性心血管事件都与动脉血栓形成密切相关。尽管如此,经典HGPSLMNA基因突变对动脉血栓形成的影响尚不清楚.
方法:杂合LmnaG609G敲入(LmnaG609G/+)小鼠,产生在HGPS患者中观察到的等效经典突变(c.1824C>T;人LMNA基因中的pG608G突变)和相应的野生型(WT)对照同窝进行光化学激光诱导的颈动脉损伤以引发血栓形成.测量凝血和纤溶因子。此外,研究了血小板活化和反应性。
结果:LmnaG609G/+小鼠表现出加速的动脉血栓形成,与WT同窝动物相比,缩短了闭塞时间。参与凝血和纤溶系统的因素水平在组间具有可比性,而LmnaG609G/+动物显示血浆凝血酶-抗凝血酶复合物水平较高,抗凝血酶水平较低。骨髓分析显示孕鼠中较大的巨核细胞。最后,二磷酸腺苷增强血小板活化,胶原相关肽,与WT组相比,在LmnaG609G/+动物中观察到凝血酶刺激,表明孕激素动物的血小板反应性较高。
结论:HGPS小鼠的LMNA突变加速动脉血栓形成,这是中介的,至少在某种程度上,通过增强血小板反应性,从而增加凝血酶的产生。鉴于临床上广泛的抗血小板药物,需要进一步研究,以考虑最适合HGPS患儿的抗血小板治疗方案,以降低疾病死亡率和发病率.
BACKGROUND: Hutchinson-Gilford
Progeria Syndrome (HGPS) is an ultra-rare premature aging genetic disorder caused by a point mutation in the lamin A gene, LMNA. Children with HGPS display short lifespans and typically die due to myocardial infarction or ischemic stroke, both acute cardiovascular events that are tightly linked to arterial thrombosis. Despite this fact, the effect of the classic HGPS LMNA gene mutation on arterial thrombosis remains unknown.
METHODS: Heterozygous LmnaG609G knock-in (LmnaG609G/+) mice, yielding an equivalent classic mutation observed in HGPS patients (c.1824C>T; pG608G mutation in the human LMNA gene) and corresponding wild-type (WT) control littermates underwent photochemically laser-induced carotid injury to trigger thrombosis. Coagulation and fibrinolytic factors were measured. Furthermore, platelet activation and reactivity were investigated.
RESULTS: LmnaG609G/+ mice displayed accelerated arterial thrombus formation, as underlined by shortened time to occlusion compared to WT littermates. Levels of factors involved in the coagulation and fibrinolytic system were comparable between groups, while LmnaG609G/+ animals showed higher plasma levels of thrombin-antithrombin complex and lower levels of antithrombin. Bone marrow analysis showed larger megakaryocytes in progeric mice. Lastly, enhanced platelet activation upon adenosine diphosphate, collagen-related peptide, and thrombin stimulation was observed in LmnaG609G/+ animals compared to the WT group, indicating a higher platelet reactivity in progeric animals.
CONCLUSIONS: LMNA mutation in HGPS mice accelerates arterial thrombus formation, which is mediated, at least in part, by enhanced platelet reactivity, which consequently augments thrombin generation. Given the wide spectrum of antiplatelet agents available clinically, further investigation is warranted to consider the most suitable antiplatelet regimen for children with HGPS to mitigate disease mortality and morbidity.