3 key components of the coagulation cascade:
Calcium ions, which are required for several key reaction steps.
Coagulation factors, which are the driving forces of the cascade; they comprise proenzyme factors are transformed to active enzymes, and are signified by the lower case "a." Many coagulation factors are synthesized by the liver; thus, coagulation disorders are associated with liver disease.
Co-factors are reaction accelerators; they form complexes with activated coagulation factors and calcium ions.
2 Pathways:
Traditionally, these pathways have been categorized as "intrinsic" and "extrinsic," but modern models emphasize their cooperation in thrombin formation.
Endothelial rupture exposes tissue factor to the blood; because tissue factor is exogenous to the blood, it is the start of the so-called "extrinsic" pathway(tissue factor is also known as thromboplastin or CD142).
Tissue factor activates coagulation factor VII, and, with calcium, forms a complex that activates factor IX (this complex is sometimes called extrinsic tenase).
Activated factor IX, with calcium and co-factor VIIIa, activates factor X.
Activated factor X combines with calcium and co-factor Va to form prothrombinase, which is the complex that transforms prothrombin (aka, factor II) to thrombin (factor IIa).
Thrombin converts fibrinogen to fibrin, which forms a meshwork that surrounds the aggregated platelets and traps other materials, including red and white blood cells and serum.
Return to the aggregated platelets to show how they influence thrombin production; because all the elements in this pathway are inherent to the blood, this is traditionally called the "intrinsic" pathway.
The negative surface of activated platelets activates Factor XII (aka, Hageman factor).
Factor XI Ia activates factor XI.
Factor XIa activates factor IX, which, as we've seen, forms a complex that ultimately leads to the production of thrombin and conversion of fibrinogen to fibrin.
Thrombin has other, indirect ways of promoting clotting:
It activates co-factors VIII and V, and factor XI; thus, it promotes its own production.
Thrombin also ensures the stability of the clot: show that it activates factor XIII, aka, fibrin stabilizing factor, which, as its name implies, strengthens the bonds of the fibrin mesh of the clot.
Retraction
Soon after the clot is formed, retraction occurs: the platelets contract and expel serum.
Serum lacks fibrinogen and clotting factors, so it cannot coagulate.
Thrombin also acts outside of the coagulation cascade via protease activation receptors (PARs):
Thrombin promotes platelet activation and release of thromboxane A2 for platelet plug formation.
It triggers endothelial activation and release of anticoagulants.
Thrombin also up-regulates pro-inflammatory mediators, such as cytokines and chemokines, implicating it in inflammatory conditions.
Endogenous anti-coagulation mechanisms:
Fibrin fibers absorb thrombin, which prevents excessive clotting.
Unabsorbed thrombin combines with anti-thrombin III, which neutralizes it.
Heparin, which is normally circulating in small concentrations but can be administered in higher doses, increases the effectiveness of anti-thrombin III and removes factors IX, X, XI, XII. Thus, it is prescribed to prevent thrombosis.
Healthy, intact endothelial cells produce nitric oxide, prostacyclin, and tissue plasminogen activator (t-PA) to prevent platelet adhesion and clot formation.
Fibrinolysis
Once the vessel wall heals, the clot must be removed via fibrinolysis, the breakdown of the fibrin mesh.
To illustrate, redraw the vessel, and show a platelet trapped by fibrin fibers.
Plasminogen binds to the fibrin; plasminogen is a proenzyme produced by the liver.
Endothelial cells release tissue plasminogen activator (t-PA) and urokinase-type plasminogen activator (u-PA), which bind to fibrin and cleave plasminogen to form active plasmin. Recall that thrombin itself is a stimulus for t-PA release.
Plasmin breaks down fibrin, fibrinogen, and some coagulation factors to dissolve the clot.
Fibrinolysis produces fibrin degradation products (FDPs), most notably D-dimer, which is measured to assess thrombotic states (an elevated result may indicate excessive thrombotic states).
When not bound to fibrin, plasminogen and plasmin activity is inhibited:
In a positive feedback cycle, plasmin also converts t-PA and u-PA into their more active forms, which promotes further fibrinolysis.
Unbound t-PA and u-PA are inhibited by plasminogen activator inhibitor 1 (PAI-1).
Alpha-2 antiplasmin inhibits unbound plasmin.
Vitamin K
Vitamin K is critical to hepatic synthesis of prothrombin and factors VII, IX, and X.
Thus, vitamin K antagonists, such as warfarin, are prescribed to inhibit clot formation in patients at risk of thrombosis.
