Coagulation Cascade

What Is It, Steps, and More

Author: Corinne Tarantino, MPH

Editors: Ahaana Singh, Józia McGowan, DO

Illustrator: Jillian Dunbar

Copyeditor: David G. Walker

What is the coagulation cascade?

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 means to stop bleeding. There are two phases of hemostasis. First, primary hemostasis forms an unstable platelet plug at the site of injury. Then, the coagulation cascade is activated to stabilize the plug, stopping blood flow and allowing increased time to make necessary repairs. This process minimizes blood loss after injuries.

The coagulation cascade involves the activation of a series of clotting factors, which are proteins that are involved in blood clotting. Each clotting factor is a serine protease, an enzyme that speeds up the breakdown of another protein. The clotting factors are initially in an inactive form called zymogens. When placed with its glycoprotein 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).

What are the three pathways of coagulation?

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

The extrinsic pathway begins when there is injury to the endothelial tissue (i.e., skin tissue), exposing tissue factor (factor III) to the blood. Tissue factor then becomes bound with calcium and factor VIIa to activate factor X. Factor VII is present in the blood and requires vitamin K to be activated.

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

The common pathway may result after the activation of factor X 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 (factor II) into thrombin (factor IIa). Next, thrombin cleaves fibrinogen (factor I) into fibrin (factor Ia). Afterwards, thrombin cleaves the stabilizing factor (factor XIII) into XIIIa. Factor XIIIa binds with calcium to then create fibrin crosslinks to stabilize the clot. Thrombin has several functions, including activating platelets (cell fragments involved in clot formation) and activating factors V, VIII, and IX.

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When is fibrin produced during the coagulation cascade?

Fibrin (factor Ia) is a long, thin protein with branches produced at the end of the coagulation cascade when fibrinogen (factor I) is converted to fibrin, which stabilizes the blood clot.

What is the main goal of coagulation?

The main goal of coagulation is to form a stable blood clot to stop bleeding and allow time for the tissue to be repaired.

What are coagulation disorders?

Coagulation disorders are disorders which affect the coagulation cascade and can either cause excessive or inadequate clotting. 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 the most common bleeding disorder 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.  

There are three types of hemophilia that are caused by genetic mutations in clotting factor genes and can be passed on from parent to child. Hemophilia A is a deficiency in factor VIII, hemophilia B is a deficiency in factor IX, and hemophilia C is a deficiency in factor XI. All types of hemophilia affect the intrinsic pathway. 

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

What are the most important facts to know about the coagulation cascade?

The coagulation cascade refers to the series of steps that occur during the formation of a blood clot after injury by activating a cascade of proteins called clotting factors. There are three pathways: intrinsic, extrinsic, and common. The intrinsic pathway is activated by factors in the blood, while extrinsic is activated by tissue factor. Both pathways result in activation of factor X leading into the common pathway, which ends with converting fibrinogen into fibrin to form a stabilized blood clot. Coagulation disorders occur when there is a deficiency in a clotting factor involved, and the most common disorders are hemophilia and vitamin K deficiency.

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Related links

Coagulation (secondary hemostasis)
Coagulation disorders: Pathology review
Mixed platelet and coagulation disorders: Pathology review
Role of Vitamin K in coagulation
Bleeding disorders: Clinical practice

Resources for research and reference

Arruda V.R., & High K.A. (2018). Coagulation disorders. In Jameson J, & Fauci A.S., & Kasper D.L., & Hauser S.L., & Longo D.L., & Loscalzo J(Eds.), Harrison's Principles of Internal Medicine (20th ed.). McGraw-Hill. 

Levi M (2021). Control of coagulation reactions. In Kaushansky K, & Prchal J.T., & Burns L.J., & Lichtman M.A., & Levi M, & Linch D.C.(Eds.), Williams Hematology (10th ed.). McGraw-Hill. 

Palta, S., Saroa, R., & Palta, A. (2014). Overview of the coagulation system. Indian journal of anaesthesia, 58(5), 515–523. DOI: 10.4103/0019-5049.144643 

Kumar, V., Abbas, A., & Aster, J. (2014) Red Blood Cell and Bleeding Disorders. In Robbins & Cotran Pathologic Basis of Disease (9th ed.). Elsevier.