The control of prothrombin conversion. Kinetic control by mechanisms inherent in two activation pathways

It is known that the activation of prothrombin to thrombin can proceed via two pathways: one initiated by the prothrombin-converting complex (factor Xa, factor V, phospholipid, and CA2+ ions) and the other initiated by the product, thrombin. A kinetic study has shown that the pathways do not proceed with equal ease under all conditions. At high levels of the converting complex, both go to completion: some prothrombin is always cleaved by thrombin, but the resulting intermediate is then activated to give quantitative conversion to thrombin. At slower rates of activation, the product-initiated pathway occurs to a relatively greater extent. Moreover, the intermediate then is not cleaved further but accumulates, so that the generation of thrombin is curtailed. The reason the intermediate is productive only at higher levels of activator may be partly that it is a poorer substrate for the converting complex than prothrombin. More importantly, the activity of the complex is also modulated by thrombin, which rapidly destroys the activity of factor V and factor Xa in a feedback reaction. These concerted controls ensure that prothrombin activation damps itself. Thus thrombin production occurs as a burst, the size of which is regulated by the amounts of factor Xa and factor V initially available.