Effect of statins on measures of coagulation: potential role of low-density lipoprotein receptors

This commentary refers to ‘Rosuvastatin use improves measures of coagulation in patients with venous thrombosis’ by J.S. Biedermann et al., 2018;39:1740–1747. In their article on the effect of statins on coagulative parameters, Biedermann et al. 1 showed that a short-term therapy with high-dose rosuvastatin significantly lowers factor VIII (FVIII) levels in patients with venous thrombosis (VT). The mechanisms behind the effect of statins on circulating FVIII however remain unexplained. A recent meta-analysis showed that statins produce a significant reduction in plasma von Willebrand factor (VWF), the carrier of FVIII in the circulation.2 These observations corroborate the hypothesis of a beneficial effect of HMG-CoA inhibitors on VT possibly consequent to their beneficial effect on endothelial function,3 and may suggest that the effect of rosuvastatin depends on VWF decrease. However, no correlation was noted by Biedermann et al. between the changes of plasma levels of FVIII and VWF induced by rosuvastatin; moreover, among coagulation factors, FVIII was the most consistently reduced, suggesting a direct effect on this specific factor. Circulating FVIII is cleared by low-density lipoprotein receptor-related protein 1 (LRP1), a member of the family of LDL receptors, with the contribution of LDLR, both expressed by the liver.4 Statins, besides their inhibitory activity on HMG-CoA reductase, the rate-limiting cholesterol biosynthetic step, increase LDLR and LRP1 expression both in in vitro and in vivo. 5 The lowering effect of statins on factor VIII levels could therefore be explained by the up-regulation of these two receptors and consequently by an enhanced clearance of FVIII. Furthermore, given that also PCSK9 inhibitors enhance LDLR and LRP1 receptor expression, it may be expected that they also reduce FVIII levels. Finally, the authors underline that statins do not increase bleeding in the general population, because the reduction of FVIII is too small to impair haemostatic function. This might not be the case for subjects with congenitally reduced FVIII levels, such as haemophilia or von Willebrand disease, who, with the therapeutic improvements and the prolongation of life expectancy, now require frequently cardiovascular preventive therapies. Conflict of interest: none declared.