Accelerated arterial thrombus formation in Hutchinson Gilford Progeria Syndrome

Abstract

Abstract Introduction Arterial thrombosis is an age-associated cause of myocardial infarction and stroke, which are the leading causes of mortality and morbidity worldwide. Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic disorder that is caused by a point mutation in the lamin A gene. It is characterized by progressive premature aging, in which caused a decreased life expectancy. Two most frequent causes of death of children with HGPS are myocardial infarction and ischemic stroke – cardiovascular events that are tightly linked to arterial thrombosis. Despite this fact, the effect of the specific lamin A gene mutation on arterial thrombus formation remains unknown. Methods Transgenic heterozygous LmnaG609G knock-in (HGPS) mice and the corresponding wild-type (WT) littermate controls underwent photochemically-induced carotid artery endothelial injury to trigger thrombosis. Coagulation and fibrinolytic factors were measured in these animals. Ex-vivo platelet activation assay was also performed. Results HGPS mice displayed accelerated thrombus formation as underlined by shortened time to occlusion compared to WT littermates (Figure 1A-B). The level of tissue factor and von Willebrand factors are comparable between groups. No significant differences were found on factors involved in the fibrinolytic system, which was confirmed by the comparable level of D-dimers in both groups. A higher level of thrombin-antithrombin complex was observed, accompanied by lower level of antithrombin. Interestingly, HGPS animals displayed enhanced platelet activation markers expression upon ADP, collagen, and thrombin stimulation compared to WT group, demonstrating a higher platelet reactivity in progeria animals (Figure 1C). Conclusions Our study demonstrated an increased arterial thrombotic response in HGPS mice as compared to WT littermates which is, at least in part, mediated by higher platelet reactivity. This novel observation may provide a mechanistic explanation for the increased incidence of acute cardiovascular events observed in children with HGPS and warrant further clinical investigations also in consideration of available antiplatelet therapies.