The coagulation cascade consists of the intrinsic and extrinsic pathways. The extrinsic pathway includes tissue factor, and factors VII, X, V, and II, and fibrin. The intrinsic pathway consists of factors, all of which are contained in the blood, specifically, high molecular weight kininogen, pre-kallikrein, and factors XII, XI, IX, VIII, X, and V, as well as prothrombin (factor II) and fibrinogen. The extrinsic pathway is viewed as the primary pathway of coagulation and is triggered by vascular damage and exposure of tissue factor to blood. Thrombin, created by the extrinsic pathway, activates factor XI of the intrinsic pathway in a positive feedback manner, assuring that clot will be formed independently of tissue factor.

Controls within this system exist to prevent excess thrombin formation and undesired thrombosis. Specifically, plasma proteins and endothelial receptors act to counterbalance the coagulation cascade. Antithrombin III acts as an inhibitor of thrombin and other coagulation factors to a lesser degree. The activity of antithrombin III is enhanced by heparin and heparinlike molecules (polysaccharides) exposed on the endothelium of blood vessels. Also exposed on the endothelial cell is the receptor thrombomodulin. Thrombin binds to thrombomodulin and loses its procoagulant potential. It then participates, with thrombomodulin, in the activation of the protein C system. Protein C is a proenzyme of a serine protease, which inactivates the clotting factors Va and VIIIa. Protein S is a cofactor to protein C and greatly accelerates its activity, thereby further preventing clot formation. As factor V is a central coagulation factor common to both the intrinsic and extrinsic pathways, its inactivation by protein C is especially important in controlling hypercoagulability and excess clot formation.

Of all patients with a hypercoagulable condition, a genetic or familial cause can be identified nearly 40% of the time. Discovery of antithrombin III deficiency and characterization of the protein C and protein S systems identified an important but very small percentage of individuals and families affected by familial thrombosis. Protein C and S and antithrombin III deficiencies are autosomal dominant forms of inherited hypercoagulability and were among the first of this category to be described; however, they are responsible for only 5% to 10% of cases of familial thrombosis (Table 3.1).

In 1994, a point mutation in factor V of the coagulation pathway was identified by Bertina et al. in Leiden (the Netherlands). This genetic mutation was found to cause activated protein C resistance and an associated hypercoagulable condition. This mutation at position 506 of the factor V polypeptide is called factor V Leiden and leads to an activated protein C resistance (APC resistance). Factor V Leiden is absent in certain ethnic groups but is present in up to 15% of some Caucasian populations. In contrast to the relative rarity of the protein deficiencies, APC resistance has been described in up to 60% of patients with familial thrombosis. Importantly, some individuals may be affected by more than one genetic disorder and usually present early in life with one or more thrombotic events.