The inactivation of the extrinsic pathway by TFPI results in dependence on the intrinsic pathway for continued production of FXa. This explains why individuals with hemophilia bleed even though they have an intact extrinsic pathway.
3. Common: FXa produced by both the intrinsic and the extrinsic paths initiates the common pathway, a sequence of reactions that results in the generation of fibrin (FIa), as shown in Figure 35.11. FXa associates with FVa (a bloodborne accessory protein) and, in the presence of Ca2+ and phospholipids, forms a membrane-bound complex referred to as prothrombinase. The complex cleaves prothrombin (FII) to thrombin (FIIa). [Note: FVa potentiates the proteolytic activity of FXa.] The binding of Ca2+ to the Gla residues in FII facilitates the binding of FII to the membrane and to the prothrombinase complex, with subsequent cleavage to FIIa. Cleavage excises the Gla-containing region, releasing FIIa from the membrane and, thereby, freeing it to activate fibrinogen (FI) in the blood. [Note: This is the only example of cleavage of a Gla protein that results in the release of a Gla-containing peptide. The peptide travels to the liver where it is thought to act as a signal for increased production of clotting proteins.] Oral, direct inhibitors of FXa have been approved for clinical use as anticoagulants. In contrast to warfarin, they have a more rapid onset and shorter half-life and do not require routine monitoring.
A common point mutation (G20210A) in which an adenine (A) replaces a guanine (G) at nucleotide 20210 in the 3′ untranslated region of the gene for FII leads to increased levels of FII in the blood. This results in thrombophilia, a condition characterized by an increased tendency for blood to clot.
a. Fibrinogen cleavage to fibrin: FI is a soluble glycoprotein made by the liver. It consists of dimers of three different polypeptide chains [(αβγ)2] held together at the N termini by disulfide bonds. The N termini of the α and β chains form “tufts” on the central of three globular domains (Fig. 35.12). The tufts are negatively charged and result in repulsion between FI molecules. Thrombin (FIIa) cleaves the charged tufts (releasing fibrinopeptides A and B), and FI becomes FIa. As a result of the loss of charge, the FIa monomers are able to noncovalently associate in a staggered array, and a soft (soluble) fibrin clot is formed.
b.
Fibrin cross-linking: The associated FIa molecules get covalently cross-linked. This converts the soft clot to a hard (insoluble) clot. FXIIIa, a transglutaminase, covalently links the γ-carboxamide of a glutamine residue in one FIa molecule to the ε-amino of a lysine residue in another through formation of an isopeptide bond and release of ammonia (Fig. 35.13). [Note: FXIII is also activated by thrombin.] c.