Thrombin plays a crucial role in blood clotting. It is initially activated by the extrinsic pathway, which leads to the activation of FXa. Thrombin then activates various factors in the common, intrinsic, and extrinsic pathways. Additionally, it activates FXII in the contact phase. While the extrinsic pathway initiates clotting by generating FXa, the intrinsic pathway amplifies and sustains clotting after TFPI inhibits the extrinsic pathway. Hirudin, a peptide produced by medicinal leeches, is a potent direct thrombin inhibitor (DTI). Recombinant hirudin can be injected and used clinically, while dabigatran is an oral DTI. The FVIIa-TF complex activates the intrinsic pathway, and FXIIa activates the extrinsic pathway, enabling cross-talk between the clotting pathways. The complete process of blood clotting and the formation of a hard fibrin clot can be seen in Figure 35.15, while Figure 35.16 organizes the clotting cascade factors based on their function. The activated form of a factor is denoted by adding "a" after the numeral. Calcium is denoted as IV, and there is no factor VI. Fibrin (factor I) is not a protease or an accessory protein, while factor XIII is a transglutaminase. Clinical laboratory tests assess clotting through the extrinsic to common pathways using prothrombin time (PT) and international normalized ratio (INR). The intrinsic to common pathways are evaluated using activated partial thromboplastin time (aPTT). Thromboplastin is a combination of phospholipids and FIII. Partial thromboplastin only contains the phospholipid component as FIII is not required for activating the intrinsic pathway. Limiting clotting and removing clots are vital aspects of hemostasis. Inactivating proteins synthesized by the liver and blood vessels help balance clot formation at the site of injury and prevent excessive clotting.
Importance of thrombin: The activation of FX by the extrinsic pathway provides the “spark” of FXa that results in the initial activation of thrombin. FIIa then activates factors of the common (FV, FI, FXIII), intrinsic (FXI, FVIII), and extrinsic (FVII) pathways (Fig. 35.14). It also activates FXII of the contact phase. The extrinsic pathway, then, initiates clotting by the generation of FXa, and the intrinsic pathway amplifies and sustains clotting after the extrinsic pathway has been inhibited by TFPI. [Note: Hirudin, a peptide secreted from the salivary gland of medicinal leeches, is a potent direct thrombin inhibitor (DTI).
Injectable recombinant hirudin has been approved for clinical use. Dabigatran is an oral DTI.] Additional crosstalk between the pathways of clotting is achieved by the FVIIa–TF-mediated activation of the intrinsic pathway and the FXIIa-mediated activation of the extrinsic pathway. The complete picture of physiologic blood clotting via the formation of a hard fibrin clot is shown in Figure 35.15. The factors of the clotting cascade are shown organized by function in Figure 35.16.
activated form would be denoted by an “a” after the numeral. [Note: Calcium is
IV. There is no VI. I (fibrin) is neither a protease nor an accessory protein. XIII is a transglutaminase.] Gla = γ-carboxyglutamate.
Clinical laboratory tests are available to evaluate the extrinsic through common pathways (prothrombin time [PT] using thromboplastin and expressed as the international normalized ratio [INR]) and the intrinsic through common pathways (activated partial thromboplastin time [aPTT]). Thromboplastin is a combination of phospholipids + FIII. A derivative, partial thromboplastin contains just the phospholipid portion because FIII is not needed to activate the intrinsic pathway.
III. LIMITING CLOTTING
The ability to limit clotting to areas of damage (anticoagulation) and to remove clots once repair processes are underway (fibrinolysis) are exceedingly important aspects of hemostasis. These actions are performed by proteins that inactivate clotting factors either by binding to them and removing them from the blood or by degrading them and also by proteins that degrade the fibrin meshwork.
A. Inactivating proteins
Proteins synthesized by the liver and by the blood vessels themselves balance the need to form clots at sites of vessel injury with the need to limit their formation beyond the injured area.