Thrombin Generation and Atherothrombosis: What Does the Evidence Indicate?

T hrombin is a key enzyme in hemostasis and thrombosis, regulating proand anticoagulant reactions by interacting with other coagulation proteins and cellular receptors. Thrombin also carries out a plethora of biologically relevant actions that link to other complex biological processes such as angiogenesis, inflammation, and cell proliferation. Thrombin is therefore likely to be involved in cancer, chronic inflammatory diseases, atherosclerosis, and other diseases. The capacity of blood to form thrombin is a critical determinant of hemostasis and according to Hemker’s first law, a low amount of thrombin produced in clotting blood results in a bleeding risk, whereas high thrombin production translates into a risk of venous thrombosis. In case of arterial thrombosis, we distinguish thrombosis related to atherosclerosis (atherothrombosis) from arterial thromboembolism such as in atrial fibrillation. The role of the coagulation system in the latter follows from the efficacy of oral anticoagulants in preventing ischemic stroke. Here we want to focus on a less obvious question: What is the relation between thrombin generation and clinical manifestations of atherothrombotic disease? The clinical manifestations of atherothrombosis evolve from ischemia and organ damage downstream of the thrombus, notably in the heart (myocardial infarction), the brain (ischemic stroke), and peripheral arteries (peripheral artery disease, PAD). That thrombin plays a role here is strongly suggested by the observation that oral anticoagulation as well as heparin have a preventive action on the reoccurrence of myocardial reinfarction, all the more as the effect superimposes on that of aspirin; nevertheless, the role of thrombin remains rather equivocal. While straightforward risk associations between thrombin generation and thrombosis have been published, also by us, several other studies show inverse relationships (to be discussed below). The problem therefore merits reconsideration. Before reviewing the available evidence, it is necessary to stress the fundamental difference between in vivo and in vitro thrombin generation. In vivo thrombin generation (ie, the appearance of active thrombin inside the body) is to a limited degree a normal phenomenon; markers of thrombin activity, such as prothrombin fragment 1.2, thrombin-antithrombin (TAT) complexes, and forms of degraded fibrin such as D-dimers, are always detectable in blood. In vitro thrombin generation (TG) is a test that probes the capacity of blood (plasma) to form thrombin. A completely normal person with a provoked thrombosis will show signs of in vivo increased thrombin generation while their capacity to form thrombin may be normal. A toddler with an antithrombin deficiency will have a high in vitro TG but no signs (yet) of excessive thrombin production in their body.