1. Extrinsic: This pathway involves a protein, tissue factor (TF), that is not in the blood but becomes exposed when blood vessels get injured. TF (or, FIII) is a transmembrane glycoprotein abundant in vascular subendothelium. It is an extravascular accessory protein and not a protease. Any injury that exposes FIII to blood rapidly (within seconds) initiates the extrinsic (or, TF) pathway. Once exposed, TF binds a circulating Gla-containing protein, FVII, activating it through conformational change. [Note: FVII can also be activated proteolytically by thrombin (see 3. below).] Binding of FVII to TF requires the presence of Ca2+ and phospholipids. The TF–FVIIa complex then binds and activates FX by proteolysis (Fig. 35.8). Therefore, activation of FX by the extrinsic pathway occurs in association with the cell membrane. The extrinsic pathway is quickly inactivated by tissue factor pathway inhibitor (TFPI) that, in a FXa-dependent process, binds to the TF–FVIIa complex and prevents further production of FXa. [Note: TF and FVII are unique to the extrinsic pathway.] 2. Intrinsic: All of the protein factors involved in the intrinsic pathway are present in the blood and are, therefore, intravascular. The intrinsic pathway involves two phases: the contact phase and the FX-activation phase, each with known deficiencies.
a.
Contact phase: This phase results in the activation of FXII (Hageman factor) by conformational change through binding to a negative surface. Deficiencies in FXII (or in the other proteins of this phase, high molecular weight kininogen and prekallikrein) do not result in bleeding, calling into question the importance of this phase in coagulation. However, the contact phase does play a role in inflammation. [Note: FXII can be activated proteolytically by thrombin (see 3. below)].
b.
Factor X–activation phase: The sequence of events leading to the activation of FX to FXa by the intrinsic pathway is initiated by FXIIa (Fig. 35.9). FXIIa activates FXI, and FXIa activates FIX, a Glacontaining serine protease. FIXa combines with FVIIIa (a bloodborne accessory protein), and the complex activates FX, a Gla-containing serine protease. [Note: The complex containing FIXa, FVIIIa, and FX forms on exposed negatively charged membrane regions, and FX gets activated to FXa. This complex is sometimes referred to as Xase. Binding of the complex to membrane phospholipids requires Ca2+.] c.
Factor XII deficiency: A deficiency in FXII does not lead to a bleeding disorder. This is because FXI, the next protein in the cascade, can be activated proteolytically by thrombin (see 3. below).
d.
Hemophilia: Hemophilia is a coagulopathy, a defect in the ability to clot. Hemophilia A, which accounts for 80% of all hemophilia, results from deficiency of FVIII, whereas deficiency of FIX results in hemophilia B. Each deficiency is characterized by decreased and delayed ability to clot and/or formation of abnormally friable (easily disrupted) clots. This can be manifested, for example, by bleeding into the joints (Fig. 35.10). The extent of the factor deficiency determines the severity of the disease. Current treatment for hemophilia is factor replacement therapy using FVIII or FIX obtained from pooled human blood or from recombinant DNA technology. However, antibodies to the factors can develop. Gene therapy is a goal. Because the genes for both proteins are on the X chromosome, hemophilia is an X-linked disorder. [Note: Deficiency of FXI results in a bleeding disorder that sometimes is referred to as hemophilia C.] with hemophilia.