The importance of factor VIII in clotting can be understood by the fact that the disease hemophilia which causes excessive bleeding occurs due to the absence of this factor. In few cases, hemophilia has been reported due to an abrupt loss or absence of factor IX.

Now, let us understand the steps involved in the extrinsic pathway for initiating the clotting cascade.

• •  As explained in the introduction, this pathway involves an intrinsic membrane protein called the tissue factor. It is not a plasma protein and is located on the adventitious surface or the outer surface of the plasma membrane of various tissue cells, including fibroblasts and other cells in the walls of blood vessels below the endothelium.

•  The blood when exposed to the subendothelial cells during vessel damage (causing disruption in the endothelial lining) comes in contact with the tissue factor on these cells which bind to factor VII (a plasma protein). Factor VII is activated to factor VIIa.

•  The complex formation between the tissue factor and the factor VIIa takes place on the plasma membrane of the tissue cell. Once the complex is formed it begins the catalytic activation of the factor X.

•  Tissue factor and factor VIIa complex also performs the catalytic activation of factor IX, resulting in the catalytic activation of larger quantity of factor X by entering into the intrinsic pathway. As a result amplification in the production of Xa takes place.

In short, by the mechanism studied till now we can assume that clotting begins either by the activation of factor XII to XIIa or by the formation of the tissue factor and factor VIIa complex.