As thrombin generation proceeds, the body has natural anticoagulant systems opposing further thrombus formation. Natural anticoagulants include:

b. Antithrombin III 

c. Activated protein C

d. Heparin cofactor II

Just as thrombin generation is the key to coagulation, antithrombin III is the most central anticoagulant proteins. This glycoprotein binds to thrombin, preventing its removal of fibrinoprotein A and B from fibrinogen, prevents the activation of factor V and VIII and the activation and aggregation of platelets. The second line of defense is the activated protein C, which inactivates factors Va and VIIIa. This inactivation reduces the ability of the prothrombinase complex to accelerate the rate of thrombin formation. A third natural anticoagulant is heparin cofactor II. Its concentration in plasma is estimated to be some four-fold lower than antithrombin III, and its action is primarily implicated in the regulation of thrombin formation in extravascular tissues. Tissue plasminogen activator (TPA) is a natural catalyst for the activation of plasminogen to plasmin, the main fibrinolytic enzyme in the body. Therefore, TPA is part of the fibrinolytic system rather than a natural anticoagulant.