Is thrombin a key player in the 'coagulation-atherogenesis' maze?

Area of Science:

• Cardiovascular Biology
• Thrombosis and Hemostasis
• Atherosclerosis Pathophysiology

Background:

• Thrombin, a coagulation protease, has established roles in hemostasis.
• Emerging evidence implicates thrombin in diverse cellular processes crucial to atherosclerosis.
• These processes include vascular tone regulation, endothelial permeability, and smooth muscle cell migration.

Purpose of the Study:

• To review thrombin-induced mechanisms contributing to atherosclerosis.
• To highlight thrombin's role in plaque initiation, progression, and destabilization.
• To contextualize findings with the clinical development of direct thrombin inhibitors.

Main Methods:

• Review of recent studies and transgenic mouse models.
• Analysis of thrombin's effects on endothelial cells, VSMCs, monocytes, and platelets.
• Examination of data from studies using heparin cofactor II and direct thrombin inhibitors like melagatran.

Main Results:

• Thrombin modulates key processes in vascular pathophysiology, including VSMC proliferation and monocyte recruitment.
• Genetic deletion of heparin cofactor II accelerates atherogenesis in mice.
• Direct thrombin inhibition with melagatran attenuates plaque progression and enhances stability in apolipoprotein E-deficient mice.

Conclusions:

• Thrombin is a pivotal contributor to vascular pathophysiology and atherosclerosis progression.
• Targeting thrombin activity represents a potential therapeutic strategy for cardiovascular disease.
• Understanding thrombin's multifaceted roles is critical given the advancement of direct thrombin inhibitors.