Blood Coagulation Signaling Pathways

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Overview of the Extrinsic and Intrinsic Pathways of Blood Coagulation

Injuries that damage blood vessels promote blood coagulation to initiate hemostasis and prevent excessive blood loss. Blood coagulation results from a series of proteolytic reactions involving the step-wise activation of coagulation factors. Subsets of these factors can be activated by two distinct pathways, the extrinsic or tissue damage pathway, and the intrinsic or contact pathway. The extrinsic pathway of coagulation is initiated as a result of contact between the bloodstream and Coagulation Factor III/Tissue Factor, a glycoprotein constitutively expressed on the surface of subendothelial tissues that is exposed upon vascular injury. Coagulation Factor III/TF forms a complex with Coagulation Factor VIIa and phospholipid that activates Coagulation Factor Xa in the presence of Ca²⁺. Coagulation Factor Xa acts with Coagulation Factor Va to cleave Prothrombin/Coagulation Factor II, which subsequently cleaves Fibrinogen to produce Fibrin. The slower, intrinsic pathway of coagulation provides an alternate mechanism for activation of Coagulation Factor Xa. It is initiated when Coagulation Factor XII, Prekallikrein, and high molecular weight Kininogen are exposed to a negatively charged surface. This results in cleavage and activation of Coagulation Factor XIIa, which activates Coagulation Factor XIa. Coagulation Factor XIa subsequently cleaves and activates Coagulation Factor IXa. Coagulation Factor IXa forms a complex with Coagulation Factor VIIIa and phospholipid that then activates Coagulation Factor Xa. Events downstream of the activation of Coagulation Factor Xa are common to both the intrinsic and extrinsic pathways of blood coagulation. Activated Coagulation Factor Xa cleaves Prothrombin/Coagulation Factor II to generate active Thrombin/Coagulation Factor IIa, which then cleaves Fibrinogen to produce Fibrin monomers. These monomers are cross-linked by Coagulation Factor XIIIa to from a Fibrin clot. The Fibrin clot is dissolved by Plasmin once the tissue is repaired.

In addition to directly generating active Fibrin and Coagulation Factor XIIIa, Thrombin/Coagulation Factor IIa activates Coagulation Factors V, VIII, and Protein C. These factors enhance or inhibit Thrombin production through positive or negative feedback regulation. Coagulation factors Va and VIIIa promote Thrombin production by positively regulating either the cleavage of Prothrombin itself or the cleavage and activation of Coagulation Factor Xa, respectively. In contrast, activation of Protein C by Thrombin binding to Thrombomodulin leads to the degradation of Coagulation Factors Va and VIIIa and inhibits the cleavage of Prothrombin. These forms of feedback regulation, along with sequential activation of clotting factors, allow precise control of the blood coagulation cascade. This tight regulation is critical to prevent excessive blood loss associated with too little clotting, or too much clotting, which could result in blockage of a blood vessel and lead to a heart attack or stroke.

To learn more, please visit our Coagulation Research Area.