Atherosclerosis and resulting clinical cardiovascular disease (CVD) are complex pathophysiologic processes involving a large number of genes and gene products in complicated interactions with a variety of environmental influences. An enormous body of research over the last 20 years has helped us understand that many of the biochemical processes involved in CVD are the same as those involved in ongoing defense against a hostile world, including blood coagulation, inflammation, and immune response. From this same body of research, we are beginning to understand that these processes are intricately linked and, in fact, are interdependent. While in its infancy, this understanding (which can be termed integrative molecular physiology) has already yielded major health advances, such as the use of activated protein C (APC), an anticoagulant, in the clinical setting of sepsis, an hyperinflammatory infectious condition. Table 1 lists some of the ways in which population studies, clinical trials, and more basic investigations have supported the interplay between coagulation, fibrinolysis, and inflammation. more
Within this framework, the generation of thrombin is a key event, with many ramifications. This article will attempt to review the possible roles for thrombin in CVD; discuss whether a preexisting hypercoagulable state predisposes a patient to CVD; highlight some of the known and hypothesized relationships of coagulation and fibrinolysis, and coagulation and inflammation; and review the known associations of coagulation and inflammation factors with CVD.
Connections of Thrombin to Clinical CVD
CVD is the major cause of death for Americans, and incidence rates around the world are reaching epidemic proportions.
Table 1—Findings Supporting the Interplay Between Coagulation, Fibrinolysis, and Inflammation
|Area of Science||Findings|
|Population studies||CRP levels correlate strongly with d-dimer, plasmin-antiplasmin complex levels CRP levels correlate weakly, but significantly, with many coagulation and fibrinolysis factors, such as factor VIII, factor X, PAI-13 4|
|Clinical trials||APC is used successfully in sepsisAspirin prevents thrombosis-dependent incident MI in a CRP-dependent manner Statins prevent incident and secondary MI in a CRP-dependent manner|
|Biochemistry and cell biology||IL-6 stimulates monocyte tissue factor expression CRP stimulates monocyte tissue factor expression FDPs stimulates monocyte IL-6 expression Thrombin stimulates monocyte IL-6 expression Thrombin inhibits IL-6-induced Stat3 signaling Statins cause decrease in tissue factor expression|