Abstract Number: PB0346
Meeting: ISTH 2020 Congress
Background: Anti-PCSK9 reduce cholesterolemia enhancing the expression of LDL- receptors (LDLR) which mediate LDL-cholesterol clearance. Hepatic LRP1, a member of the LDLR family, is the most important receptor responsible for the hepatic clearance of FVIII. Previous in vitro and animal studies showed that statins increase LRP1 expression and recently statin intake was found to significantly reduce elevated plasma FVIII levels in patients with venous thromboembolism (VTE). No data instead are available on the influence of anti-PCSK9 on FVIII levels.
Aims: We aimed to evaluate the effect of lipid-lowering treatments on circulating FVIII levels and LRP1 expression in mice after an infusion-induced acute increase of circulating FVIII levels.
Methods: Male C57BL6 mice were randomized to treatment with atorvastatin 20 mg/kg o.i.d. by gavage, alirocumab 10 mg/kg o.i.d. by s.c. injection, alirocumab+atorvastatin o.i.d., or their veichles for five days, and on the last day i.v. injected with rhFVIII (50 IU/kg).
Plasma FVIII levels, liver and monocyte LRP1 expression were measured 90 min after infusion.
Results: Lipid lowering treatments reduced FVIII levels, significantly with the combination alirocumab + atorvastatin (88.3 ± 5.7 vs 50.9 ± 7.3% p< 0.05)(figure 1A). LRP1 expression by monocytes and hepatocytes was increased by lipid-lowering treatments compared with controls (figure 1B, 1C), especially by alirocumab (74 ±7.2 vs 49 ± 11.7% of positive cells).
Conclusions: Our data show that anti-PCSK9 reduce circulating FVIII levels by enhancing LRP1 expression. Given the role of elevated FVIII levels as cardiovascular risk factor, PCSK9 inhibitors, may exert an additional protective effect against cardiovascular events besides cholesterol lowering, by reducing FVIII. The effect of anti-PCSK9 on VTE incidence deserves to be assessed.
To cite this abstract in AMA style:Paciullo F, Falcinelli E, Petito E, Gresele P, Momi S. Pleiotropic Effects of PCSK9-inhibition on Hemostasis: Anti-PCSK9 Reduce FVIII Levels by Enhancing LRP1 Expression [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/pleiotropic-effects-of-pcsk9-inhibition-on-hemostasis-anti-pcsk9-reduce-fviii-levels-by-enhancing-lrp1-expression/. Accessed October 2, 2023.
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