Coagulation Cascade · What Is It, Steps, and More

The coagulation cascade, or secondary hemostasis, is a series of steps in response to bleeding caused by tissue injury, where each step activates the next and ultimately produces a blood clot. The term hemostasis is derived from “hem-”, which means “blood”, and “-stasis”, which means “to stop.” Therefore, hemostasis is the process by which bleeding stops. There are two phases of hemostasis. First, primary hemostasis forms an unstable platelet plug at the site of injury. Then, the coagulation cascade (i.e., secondary hemostasis) is activated to stabilize the plug, stop blood flow, and provide time for tissue repair. This process minimizes blood loss after injuries. 

The coagulation cascade involves the activation of a series of clotting factors, the proteins involved in blood clotting. Each clotting factor is a serine protease, an enzyme that speeds up the breakdown of another protein. Clotting factors circulate in their inactive form, known as zymogens. When placed with its co-factor, the clotting factor is activated and is then able to catalyze the next reaction. When a clotting factor becomes activated, it is denoted with an “a” following its respective Roman numeral (e.g., when activated, Factor V becomes Factor Va). 

Coagulation consists of three pathways: extrinsic, intrinsic, and common. Together, they interact to form a stable blood clot. The extrinsic and intrinsic coagulation pathways both lead into the final common pathway by independently activating factor X into factor Xa. The extrinsic pathway involves initiation by factor III (i.e., tissue factor) and its interaction with factor VII. On the other hand, factors XII, XI, IX, and VIII are utilized in the intrinsic pathway. Ultimately, the common pathway uses factors X, V, II, I, and XIII to form a stable blood clot. 

The extrinsic pathway is initiated by injury to the endothelial tissue (i.e., skin tissue), exposing and activating tissue factor (i.e., factor III) to the blood. Tissue factor then binds calcium and factor VIIa to activate factor X into factor Xa. Factor VII is present in the blood and requires vitamin K to be activated. 

Meanwhile, the intrinsic pathway begins when factor XII (i.e., Hageman factor) is exposed to endothelial collagen, kallikrein, and high molecular weight kininogen (HMWK) and is subsequently activated into factor XIIa. Factor XIIa activates factor XI into XIa, which in turn binds to a calcium ion and activates factor IX into factor IXa. Then, factor IXa, factor VIIIa, and calcium form a complex to activate factor X to Xa. Factor VIII is found circulating in the blood and is often activated by thrombin (i.e., factor IIa). 

The common pathway is initiated after the activation of factor X into factor Xa at the end of either pathway. The common pathway begins when factor Xa, Va, and calcium bind together, forming a prothrombinase complex. The prothrombinase complex then activates prothrombin (i.e., factor II) into thrombin (i.e., factor IIa), which in turn cleaves fibrinogen (i.e., factor I) into fibrin (i.e., factor Ia). Afterwards, thrombin cleaves the stabilizing factor (i.e., factor XIII) into XIIIa. Factor XIIIa binds calcium to create fibrin crosslinks that stabilize the clot. Thrombin has several functions, including activating platelets (i.e., cell fragments involved in clot formation) and activating factors V, VIII, and IX.  

Coagulation disorders are conditions which affect the coagulation cascade, leading to either excessive clotting (i.e., thrombotic disorders) or inadequate clotting (i.e., bleeding disorders). Coagulation disorders usually involve a deficiency in at least one clotting factor, and the most common disorders include von Willebrand disease, hemophilia, and vitamin K deficiency.  

Von Willebrand disease is among the most common inherited bleeding disorders and is characterized by a deficiency in von Willebrand factor due to an autosomal dominant genetic mutation. The von Willebrand factor is mostly involved in primary hemostasis, where it helps platelets stick together. The factor also plays a role in secondary hemostasis by helping stabilize factor VIII.   

Hemophilias are bleeding disorders caused by genetic mutations in clotting factor genes. Three types of hemophilia exist: hemophilia A (i.e., factor VIII deficiency)hemophilia B (i.e., factor IX deficiency), and hemophilia C (i.e., factor XI deficiency). All types of hemophilia affect the intrinsic pathway.  

A vitamin K deficiency may occur when an insufficient amount of vitamin K is absorbed from foods, or when not enough foods rich in vitamin K are consumed (e.g., leafy dark green vegetables like spinach). Vitamin K is a cofactor required to activate factors II, VII, IX, and X. Therefore, vitamin K deficiency affects all three pathways.