What is the coagulation cascade?

From the Guidelines

The coagulation cascade is a complex process that involves the intrinsic and extrinsic pathways, which converge into a final common pathway, ultimately leading to the formation of a blood clot through the conversion of fibrinogen to fibrin, as described in the study by NIEUWLAND and SILJANDER 1.

Coagulation Cascade Overview

The coagulation cascade is initiated through two different routes: the intrinsic and extrinsic pathways.

• The intrinsic pathway is triggered by an activating surface, such as contact activation by glass, which activates factor XII to factor XIIa.
• The extrinsic pathway is triggered by tissue factor released from injured cells, which acts as a receptor for coagulation factor VII, resulting in the formation of activated factor VIIa. Both pathways converge into a final common pathway, where factor X is activated into factor Xa, and factors Xa and factor Va together form the prothrombinase complex, which catalyses thrombin formation from prothrombin, as illustrated in Figure 3 of the study by NIEUWLAND and SILJANDER 1.

Key Components of the Coagulation Cascade

The coagulation cascade involves numerous clotting factors, including:

• Factor XII, which is activated by contact with damaged vessel surfaces
• Factor VII, which is activated by tissue factor released from injured cells
• Factor X, which is activated by the intrinsic and extrinsic pathways
• Factor Va, which forms the prothrombinase complex with factor Xa
• Prothrombin, which is converted to thrombin by the prothrombinase complex
• Fibrinogen, which is converted to fibrin by thrombin

Regulation of the Coagulation Cascade

The coagulation cascade is regulated by natural anticoagulants, such as:

• Antithrombin, which inhibits the activity of thrombin and other clotting factors
• Protein C, which inhibits the activity of factors Va and VIIIa
• Protein S, which serves as a cofactor for protein C The coagulation cascade is also influenced by calcium ions and vitamin K, which are essential cofactors in many steps of the cascade, as mentioned in the study by NIEUWLAND and SILJANDER 1.

Clinical Significance of the Coagulation Cascade

Understanding the coagulation cascade is crucial for managing bleeding disorders, thrombotic conditions, and for the rational use of anticoagulant medications, such as warfarin, heparin, and direct oral anticoagulants, which target specific steps in the pathway, as described in the study by NIEUWLAND and SILJANDER 1.

From the Research

Definition of Coagulation Cascade

• The coagulation cascade is a complex process involving both cellular and biochemical components, with the key cellular players being thrombocytes or platelets 2.
• The biochemical component of blood clotting is represented by the plasma coagulation cascade, which includes plasma proteins also known as coagulation factors 2.
• The coagulation cascade is a series of enzymatic reactions leading to thrombin generation and fibrin formation, commonly illustrated in a waterfall-like manner 3.

Initiation of Coagulation Cascade

• The coagulation cascade can be initiated through the tissue factor (TF) pathway, once subendothelial TF is exposed and bound to coagulation factor VII (FVII) in blood 3, 4.
• The contact activation system is initiated by FXII, which is activated upon exposure to negatively charged surfaces, and is considered to contribute to thrombosis but is not required for hemostasis in vivo 4.
• There are two main mechanisms for triggering the blood clotting, termed the tissue factor pathway and the contact pathway, with only the tissue factor pathway functioning in normal hemostasis 5.

Process of Coagulation Cascade

• The cascade can be categorized into initiation by tissue factor (TF), amplification by the intrinsic tenase complex, and propagation on activated platelets 4.
• TF-FVIIa forms an extrinsic tenase complex and activates FX to FXa and FIX to FIXa, with FXa-FVa forming a prothrombinase complex that converts prothrombin into thrombin 4.
• The generated thrombin primes the subsequent coagulation reactions, activating platelets and in turn FV, FVIII, and FXI, leading to the formation of an insoluble fibrin network structure 4.