This site requires Javascript to work, please enable Javascript in your browser or use a browser with Javascript support
Intrinsic Prothrombin Activation Pathway | GeneGlobe

Intrinsic Prothrombin Activation Pathway


Pathway Description

Clotting or coagulation is the mechanism used by the body to stop bleeding. When a blood vessel is injured, bleeding is stopped by coagulation factors that form a thrombus/clot of fibrin threads which trap platelet aggregates and other blood cells. Next, small molecules called clotting factors, cause fibrin strands to adhere and seal the inside of the wound. Thrombin/TFIIa is a multifunctional serine protease that has an indispensable role in the coagulation cascade and is essential for fibrin formation and platelet activation. It resides in the cell in an inactive form, called prothrombin.Based on the activation of prothrombin, the coagulation cascade operates in 3 essential phases: 1) formation of a prothrombin activator complex, 2) activation of prothrombin, and 3) clot formation as a result of fibrinogen cleavage by activated thrombin.

The intrinsic mechanism for prothrombin activation begins with trauma to the blood vessel or exposure of blood to collagen in a traumatized vessel wall. Initiation of the intrinsic pathway occurs when prekallikrein, HK, FXI and FXII are exposed to a negatively charged surface. This is termed the contact phase. The assembly of contact phase components results in conversion of prekallikrein to kallikrein, which in turn activates FXII. FXIIa then hydrolyzes more prekallikrein to kallikrein, establishing a reciprocal activation cascade. FIX is a proenzyme that contains vitamin K-dependent γ-carboxyglutamate residues, whose serine protease activity is activated following calcium binding to these residues. FIXa cleaves FX to FXa. Activation of FXa is facilitated and stabilized by the assembly of the tenase Complex (Ca2+ and factors: FVIIIa, FIXa and FX) on the surface of activated platelets. Activated tenase complex ultimately leads to the activation of FX and FV. FVIIIa, FXa and FVa along with PF-3 then go on to form the prothrombin activating complex which converts prothrombin to thrombin. Thrombin converts fibrinogen (FI) to fibrin (FIa). Fibrin undergoes polymerization and the polymer is further stabilized by FXIIIa which sews up the clot. The fibrin mesh, in concert with platelets and some blood cells (RBCs and WBCs), plugs the break in the vessel wall. The damaged blood vessel heals and the blood clot dissolves after a few days.

Blood clot formation is essential for the maintenance of hemostasis. The absence of any of the clotting factors predisposes animals to severe, often life-threatening, bleeding disorders. In a similar way, over activity of this system can produce unwanted blood clots resulting in blockages to critical blood vessels, as occurs in such diseases as heart attack and stroke. In addition to the clotting factors and proteins, several other proteins operate to slow down the clotting process. Anti-thrombin serves to block the actions of multiple clotting factors involved in the formation of the prothrombin activator complex. The newly formed thrombin activates the formation of a complex of protein-C, protein-S and thrombomodulin that can inactivate FVIII and FV. As enhanced coagulation and thrombosis are linked to a variety of cardiovascular and metabolic diseases, as well as to cancer, inhibition is essential in order to prevent excessive clotting.