Hutchinson-Gilford progeria syndrome mice display accelerated arterial thrombus formation and increased platelet reactivity.

Introduction: 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 Lmna ^G609G knock-in (Lmna ^G609G/+ ) 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: Lmna ^G609G/+ 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 Lmna ^G609G/+ 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 Lmna ^G609G/+ 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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Yustina M Puspitasari reports financial support was provided by Swiss Life Group. Giovanni G Camici reports financial support was provided by Swiss National Science Foundation. Luca Liberale reports a relationship with Daiichi Sankyo Inc. that includes: speaking and lecture fees. Giovanni G Camici reports a relationship with Sovida Solutions that includes: consulting or advisory. Thomas F Luescher reports a relationship with AstraZeneca Pharmaceuticals LP that includes: funding grants. Thomas F Luescher reports a relationship with Abbott that includes: funding grants. Thomas F Luescher reports a relationship with Amgen Inc. that includes: funding grants. Thomas F Luescher reports a relationship with Bayer HealthCare Pharmaceuticals Inc. that includes: funding grants. Thomas F Luescher reports a relationship with Boehringer Ingelheim GmbH that includes: funding grants. Thomas F Luescher reports a relationship with Daiichi Sankyo Inc. that includes: funding grants. Thomas F Luescher reports a relationship with Eli Lilly and Company that includes: funding grants. Thomas F Luescher reports a relationship with Novartis Pharmaceuticals Corporation that includes: funding grants. Thomas F Luescher reports a relationship with Novo Nordisk Inc. that includes: funding grants. Thomas F Luescher reports a relationship with Roche that includes: funding grants. Thomas F Luescher reports a relationship with Sanofi that includes: funding grants. Thomas F Luescher reports a relationship with Vifor Pharma Switzerland SA that includes: funding grants. Giovanni G Camici has patent #WO/2020/226993 pending to University of Zurich. Luca Liberale has patent #WO/2020/226993 pending to University of Zurich. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Disclosures LL and GGC are coinventors on the International Patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischemia-reperfusion injury to the central nervous system. GGC is a consultant to Sovida Solutions Limited. TFL has no conflicts related to this manuscript. Outside the work, he received unrestricted research and education grants from Abbott, Amgen, AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, Daichi-Sankyo, Eli Lilly, Novartis, Novo Nordisk, Roche Diagnostics, Sanofi and Vifor. LL reports speaker fees outside of this work from Daichi-Sankyo. The other authors report no conflict of interest.
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