Thrombin Activation

Thrombin is activated in two ways (Figure 5):

• Extrinsic pathway
• Intrinsic pathway

Figure 5.  Flow chart of thrombin activation

Extrinsic Pathway

The extrinsic pathway converts small amounts of prothrombin to thrombin through the following:

• Tissue factor complexes with factor VIIa
• Tissue factor-factor VIIa complex activates factor X to X_a (Stuart factor)
• Factor X activates catalyzes the conversion of prothrombin to thrombin

Stuart factor in and of itself is not an efficient activator.  It requires:

• activated proaccelerin (V_a)
• Ca²⁺
• phospholipids

When these elements are present, Stuart factor activity increases by 2 X 10⁴.

Proaccelerin is an accessory factor that is activated by proteolytic cleavage via thrombin.

Ca²⁺ is needed to anchor prothrombin and Stuart factor (X_a) to the membrane via Ca²⁺ bridges.  Prothrombin and factor X_a produced by organisms deficient in vitamin K demonstrate decreased membrane binding affinities.  This is because Gla side chains are stronger chelators than Glu side chains.

Negatively charged phosphatidylserine phospholipids must be presented on the membrane surface.  These phospholipids bind prothrombin and X_a.

Intrinsic Pathway

Thrombin is capable of inducing a positive feedback stimulation of the clotting cascade.  The intrinsic pathway is initiated by thrombin produced by the extrinsic pathway:

• Thrombin activates factor XI to factor XI_a
• Factor XI_a activates factor X to X_a
• Factor X_a converts prothrombin to thrombin