Effects of PCSK9 on thrombosis and haemostasis in a variety of metabolic states: Lipids and beyond (Review)

Abstract

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are widely recognised as being able to induce a potent reduction in low‑density lipoprotein‑cholesterol. An increasing number of studies have suggested that PCSK9 also influences the haemostatic system by altering platelet function and the coagulation cascade. These findings have significant implications for anti‑PCSK9 therapy in patients with specific coagulation conditions, including expanded indications, dose adjustments and drug interactions. The present review summarises the changes in PCSK9 levels in individuals with liver diseases, chronic kidney diseases, diabetes mellitus, cancer and other disease states, and discusses their impact on thrombosis and haemostasis. Furthermore, the structure, effects and regulatory mechanisms of PCSK9 on platelets, coagulation factors, inflammatory cells and endothelial cells during coagulation and haemostasis are described.

Keywords: haemostasis; metabolic states; proprotein convertase subtilisin kexin type 9; thrombosis.

Figure 1

Structure of PCSK9 and the mechanisms of LDLR downregulation. PCSK9, proprotein convertase subtilisin kexin type 9; LDLR, low-density lipoprotein receptor; SREBP, sterol regulatory element-binding protein; HNF1, hepatocyte nuclear factor 1; LDL-C, low-density lipoprotein-cholesterol; Pro, prodomain; Cata., catalytic domain; CHRD, C-terminal Cys/His-rich domain; EGF-A, epidermal growth factor-A.

Figure 2

Possible mechanisms of PCSK9 in thrombosis and haemostasis. PCSK9, proprotein convertase subtilisin kexin type 9; LDL, low-density lipoprotein; oxLDL, oxidized low-density lipoprotein; Apo, apolipoprotein; LOX-1, lectin-like oxLDL receptor 1; Lp(a), lipoprotein A; ROS, reactive oxygen species; NOX-2, NAD phosphate oxidase-2; cPLA2, cytosolic phospholipase A2; AA, arachidonic acid; TXA2, thromboxane A2; TXB2, thromboxane B2; PAI-1, plasminogen activator inhibitor type 1; tPA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator; LDLR, low-density lipoprotein receptor; SRA, scavenger receptor class A; TLR4, toll-like receptor 4; COX-2, cyclooxygenase 2; LRP, LDLR-related protein; TF, tissue factor; PF4, platelet factor 4.

Figure 3

PCSK9 is associated with a variety of disease states with special metabolic characteristics. PCSK9, proprotein convertase subtilisin kexin type 9; LRP1, LDLR-related protein; tPA, tissue-type plasminogen activator; RAAS, renin-angiotensin-aldosterone system; PAI-1, plasminogen activator inhibitor type 1; SMC, smooth muscle cell; GDM, gestational diabetes mellitus; LDLR, low-density lipoprotein receptor; TF, tissue factor; HCV, hepatitis C virus; TLR, Toll-like receptor; TAT, thrombin-antithrombin complex; GVD, graft vascular disease.