Pleiotropic Effects of PCSK9: Focus on Thrombosis and Haemostasis

Abstract

The proprotein convertase subtilisin/keying 9 (PCSK9) is a serine protease that has gained importance in recent years as a drug target, mainly due to its effect on cholesterol metabolism in promoting the degradation of the low-density lipoprotein receptor (LDLR). However, this protease may also play an important role in lipid-independent reactions, including the process of thrombogenesis. Considering this, we reviewed the effects and implications of PCSK9 on platelet function and blood coagulation. PCSK9 knockout mice exhibited reduced platelet activity and developed less agonist-induced arterial thrombi compared to the respective control animals. This is in line with known research that elevated blood levels of PCSK9 are associated with an increased platelet reactivity and total number of circulating platelets in humans. Moreover, PCSK9 also has an effect on crucial factors of the coagulation cascade, such as increasing factor VIII plasma levels, since the degradation of this blood clotting factor is promoted by the LDLR. The aforementioned pleiotropic effects of the PCSK9 are important to take into account when evaluating the clinical benefit of PCSK9 inhibitors.

The Anti-Thrombotic Effects of PCSK9 Inhibitors

“…In another study, D-dimer and fibrinogen concentration changes were not observed in patients with familial hypercholesterolemia. On the other hand, a reduction in plasma PAI-1 levels was documented [ 39 , 40 ]. Additionally, PCSK9 inhibitors raised HDL cholesterol concentrations [ 41 ], which may prevent platelet aggregation directly or indirectly by lowering platelet membrane cholesterol [ 42 ].…”

PCSK9 Inhibitor Wars: How Does Inclisiran Fit in with Current Monoclonal Antibody Inhibitor Therapy? Considerations for Patient Selection

“…The intriguing point remains whether inclisiran would provide an even stronger benefit on CV morbidity and mortality, compared to PCSK-9 inhibition by mAbs, due to the fact that in contrast to anti-PCSK9 mAbs, which are directed against circulating PCSK9, inclisiran inhibits PCSK9 synthesis intracellularly, thereby potentially having additional effects beyond modulation of LDL-R expression. Indeed, PCSK9 has a variety of pleiotropic effects, including involvement in inflammatory pathways or thrombogenesis [ 63 ]. On the other hand, theoretically, one could speculate that mAbs lead to a more complete inactivation of PCSK9, since they bind to all circulating PCSK9, including that generated by other organs like, e.g., intestine, endocrine pancreas, or the brain [ 64 •], whereas inclisiran only inhibits intracellular hepatic biosynthesis of PCSK9.…”

Drug–Drug Interaction between Antiplatelet Therapy and Lipid-Lowering Agents (Statins and PCSK9 Inhibitors)

“…4 ). 22 This action is amplified in the presence of LDL-C. 99 It might be responsible for platelet hyperreactivity in dyslipidemia 100 and further initiates activation of multiple CD36-downstream signaling pathways. These include Scr, ERK5, JNK, increased generation of ROS, and activation of p38/cPLA 2 /COX-1/TXA 2 -signaling pathways.…”

“…Genetic studies have identified the serin protease proprotein convertase subtilisin/kexin type 9 (PCSK9) as the most relevant regulator of LDL-C receptor availability. In addition to its effect on LDL-C plasma levels, PCSK9 has also pleiotropic action beyond this, [17][18][19][20][21][22] including direct stimulatory actions on platelets 23 with platelets as a source of PCSK9 in coronary artery disease (CAD). 24 The finding that the effects of PCSK9 on platelet activation are inhibited by aspirin in vitro 25 underlines the possible synergistic effects between PCSK9 antibodies and aspirin and clearly favors these compounds over statins with their therapeutic limitations as discussed above.…”