Regulation of fibrin clotting by flow via the factor VII activation by factor Xa. The diagram illustrates the mechanisms controlling initiation of coagulation in the presence of flow. Factor VIIa initially present in plasma binds to TF and activates factor X; it is also inhibits by TFPI. Factor Xa can activate TF-bound factor VII in a positive feedback manner. In the absence of flow, both inhibition by TFPI and activation by factor Xa are not significant, because high concentrations of TF present on fibroblast rapidly bind factor VIIa; they do not need additional factor VII activation and are not particularly sensitive to factor VIIa-TF complex inhibition. When blood flow is present, factor Xa is rapidly removed, and the rate of factor X production becomes insufficient to create fibrin clot (factor VIIa-TF complex being inhibited by TFPI). This is when factor Xa-dependent feedback becomes important: factor Xa activates factor VII and increases its own production, counteracting the effects of flow. At higher shear rates, this feedback is insufficient, and factor Xa production is strongly inhibited. Thus, inhibition of factor VIIa-TF complex by TFPI and factor VII activation by factor Xa combine to create a threshold-like response of the system in flow: rapid clotting at low shear rates and almost no thrombus formation at higher shear rates.