According to current theories of blood coagulation, the clotting mechanism is activated in two ways. The first activation pathway begins either when the endothelial lining of a blood vessel is damaged or when blood comes into contact with certain types of foreign surfaces. This activating sequence is begun by substances normally present within blood and is therefore called the intrinsic system pathway. The second trigger is a substance, tissue thromboplastin, which is not present in blood but which can be released from endothelial cells or other body tissues, usually when the tissue cells are injured. Tissue thromboplastin, sometimes called factor III, initiates the extrinsic system pathway. Activation of the clotting sequence by extrinsic system thromboplastin bypasses the first half of the intrinsic system pathway, although both systems share several final pathway coagulation factor reaction sequences.

Extrinsic system

The extrinsic system tissue thromboplastin forms a complex with calcium ionsand a proenzyme known as factor VII. Factor VII is normally inactive but now becomes activated by tissue thromboplastin. The thromboplastin complex with activated factor VII converts another inactive enzyme (proenzyme), factor X, to an active form. Activated factor X with two cofactors (phospholipid from tissue thromboplastin and activated factor V) in the presence of calcium ions converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin monomer. Fibrin monomer polymerizes; the polymer then becomes “stabilized” (resistant to dissociation) by adding cross-linkagesbetween molecules with the assistance of activated factor XIII. The stabilized fibrin also becomes insoluble in certain substances such as urea.

Intrinsic system

The intrinsic system is triggered by contact between blood and a suitable foreign surface. Within vessels, this usually occurs at a break in the vascular endothelial lining where collagen is exposed. Platelets adhere to the exposed collagen and release a phospholipid called platelet factor 3, or PF-3. In addition, a proenzyme in serum called factor XII becomes activated by exposure to the collagen. Activated factor XII initiates a side reaction involving high molecular weight kininogen (HMWK) as a cofactor, which converts a proenzyme called prekallikrein, to kallikrein which, in turn, helps convert more factor XII to its active form. The major consequence of activated factor XII is conversion of inactive factor XI to its active form, which, in turn, converts factor IX to its active form. Activated factor IX convertsfactor X to activated factor X with the assistance of activated factor VIII andPF-3 in the presence of calcium ions. (Thus, activated factors VIII and IX plusPF-3 produce the same effect as the tissue thromboplastin complex and activatedfactor VII. Tissue thromboplastin supplies phospholipid to the extrinsic systemand PF-3 does so for the intrinsic system.) Activated factor X plus activated factor V and PF-3 convert factor II (prothrombin) to thrombin, leading to conversion of fibrin to fibrinogen. The steps subsequent to formation of active factor X are the same in both the extrinsic and the intrinsic pathway (“final common pathway”), except that in the intrinsic system PF-3 supplies phospholipid cofactor for conversion of prothrombin to thrombin, whereas the phospholipid component of tissue thromboplastin performs this function for the extrinsic system.

Nine of the 13 coagulation factors are proenzymes that must be activated. Exceptions are factor I (fibrinogen), which is not an enzyme; factor III (tissue thromboplastin), which is a complex rather than a single protein; factor IV (calcium); and factor VI, which currently is a number that is not in use.