Introduction
This topic covers the coagulation factors and cascade that produce a stable fibrin clot, the mechanisms that keep coagulation confined to the site of injury (the physiological anticoagulants), and the fibrinolytic system that later removes the clot. Together they form a balanced hemostatic system; when the balance is disturbed the result is bleeding or thrombosis.
Coagulation factors and the cascade
The coagulation cascade is classically divided into three pathways. The tissue factor (extrinsic) and contact activation (intrinsic) pathways both activate the common pathway of factor X, thrombin (II) and fibrin (I).
Most factors are plasma proteins synthesised in the liver and circulate as inactive precursors (zymogens of serine proteases or cofactors); activation is marked by the suffix "a". Factors II, VII, IX and X are vitamin K-dependent: vitamin K is needed for gamma-carboxylation of glutamate residues, which lets them bind Ca2+ and phospholipid surfaces. There is no factor VI.
Other participants are prekallikrein, high-molecular-weight kininogen (HMWK) and platelet phospholipid (formerly platelet factor 3).
Coagulation is an amplifying enzyme cascade; the classical scheme has two pathways converging on factor X:
- Extrinsic pathway: tissue factor binds factor VIIa; the TF-VIIa complex (with Ca2+) activates factor X and also factor IX. It is fast (seconds) and is the main physiological trigger in vivo.
- Intrinsic pathway: contact of factor XII with negatively charged surfaces (e.g. glass, collagen) activates XII with prekallikrein and HMWK; XIIa activates XI, XIa activates IX. IXa + VIIIa on phospholipid with Ca2+ form the intrinsic tenase, which activates X. Slower (minutes) but generates large amounts of Xa.
- Common pathway: Xa + Va on phospholipid with Ca2+ form prothrombinase, which converts prothrombin to thrombin. Thrombin cleaves fibrinopeptides A and B from fibrinogen, producing fibrin monomers that polymerise spontaneously into a soft gel. Factor XIIIa (activated by thrombin) forms covalent cross-links, giving a stable, insoluble clot that traps blood cells.
The modern cell-based model describes coagulation on cell surfaces in three phases: initiation (TF-VIIa on TF-bearing cells generates small amounts of thrombin), amplification (this thrombin activates platelets and factors V, VIII and XI), and propagation (tenase and prothrombinase on activated platelets produce a burst of thrombin). It explains why deficiency of VIII or IX causes severe bleeding although the extrinsic pathway is intact, while XII deficiency does not.
Thrombin is the central enzyme: it converts fibrinogen to fibrin, activates factors V, VIII, XI and XIII, and activates platelets via protease-activated receptors (PARs).