10 Aspects of the Clotting / Coagulation Cascade

clotting coagulation cascade
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Blood clotting is a part of hemostasis which is a critical protective mechanism of the body. The activity seals the wounds, stops bleeding, and in the process, initiates the healing course.

The mechanism occurs in two phases: Primary and secondary hemostasis.

The primary hemostasis serves as a quick plug against the bleeding, minimizing blood loss. The injured cells emit signals that enable the platelets to gather in the injured area of the blood vessel, allowing them to form a plug that seals the wound.

Secondary hemostasis is the coagulation cascade which is initiated after primary hemostasis. The process is controlled by a combination of signalling cascade that consists of more than ten coagulation factors that interact and activate each other, leading to the conversion of fibrinogen to fibrin.

This network of fibrin fibers further reinforces the closure of the wound. Platelets, as well as other blood components, form a blood clot called thrombus.

In the completion of the process, blood platelets and the endothelium produce growth factors that regulate the healing process of the damaged tissue. The process is completed with the dissolving of the fibrin by enzymes produced in the blood plasma.


The Clotting / Coagulation Cascade

Coagulation cascade follows alternative routes that are dependent on the initiating factors involved.

The extrinsic pathway is usually initiated by tissue thromboplastin, commonly known as factor III, related to calcium ions as well as factor VII.

On the other hand, the intrinsic pathway requires the activation of factors XII, XI, IX, and VIII by exposing them to subendothelial collagen and other foreign surfaces.

At the end, both the two pathways lead to the activation of factor X and later proceed to the common pathway that involves coagulation factors V, II, I, and XIII. This then leads to the formation of a fibrin clot.

1. Platelet activation

Platelets need to adhere to the exposed collagen for blood clotting to occur; where they release the contents of their granules and later aggregate.

The clinging of the platelets to the collagen on endothelial cell surfaces is made possible by von Willebrand factor (vWF) whose function is to connect specific glycoprotein complex and collagen fibrils.

The interaction between vWF and the GPIb-GPIX-GPV complex is paramount as demonstrated in bleeding disorders due to a lack of some of the proteins in the complex.

The first activation of platelets is caused by the action of thrombin binding to specific receptors that initiate a signal transduction cascade. Read more about platelet activation.

2. The Intrinsic Cascade / Contact Activation Pathway

The intrinsic cascade is less significant and initiated by the contact of blood and negatively charged surfaces that are exposed. It is also called contact activation pathway.

It begins with the formation of the complex on collagen by HMWK, prekallikrein, and Hageman factor. The process follows the conversion of Prekallikrein to kallikrein, and that of FXII becoming FXIIa. FIX is activated by Factor XIa, which activates FX to FXa.

3. The Extrinsic Cascade / Tissue Factor Pathway

The extrinsic pathway is initiated by injury of the blood vessels that results in the exposure of tissue factor (TF), known as factor III.

The main function of the tissue factor pathway is to form a thrombin burst, a process by which thrombin is released rapidly.

Thrombin is the most crucial constituent of the coagulation cascade as it gives feedback on the activation roles having the following activities:


– FVII leaving the circulation and coming in contact with tissue factor, forming an activated complex in response to blood vessel injury

– TF-FVIIa activating FIX and FX

– Activation of FVII by thrombin

– Activation of FX to FXa

– Formation of the prothrombinase complex that activates prothrombin to thrombin.

Thrombin later activates other aspects of the coagulation cascade, releasing FVIII. The final procedure here involves the formation of the tenase complex that activates FX.

4. The final common pathway

The two channels meet and converge during the activation of factor X to Xa. This factor (Xa) has a function on the activation of VII to VIIa.

Active factor Xa then hydrolyses prothrombin to thrombin. The active thrombin then activates factors XI, VIII, and V that leads to the other steps of the cascade.

Conversion of Fibrinogen to Fibrin is the core role of Thrombin and activating factor XIII to XIIIa. Factor XIIIa links fibrin polymers that solidify the clot formed.

5. The Kallikrein-Kinin process in Coagulation

The kallikrein-kinin process describes a complex form of proteins which when activated results in the release of vasoactive kinins from high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK).

The kinins form part of the physiological and pathological processes such as regulation of blood pressure and blood flow.

6. Regulation of Thrombin Levels

When it becomes impossible for the body to control the circulating level of active thrombin in the blood, harmful consequences can be expected.

There are two primary mechanisms of regulating thrombin activity. Activation is governed by some specific thrombin inhibitors such as Antithrombin III, which is the most important; as it can inhibit the function of factors Xa, XIa, XIIa, plasmin, and kallikrein in the body.

The other method is affected at each step in the cascade, where feedback mechanisms control the balance of active and inactive enzymes, including thrombin levels.

7. Control of Coagulation

Protein C (PC) serves as the chief regulator of the coagulation process while Protein S (PS) serves as a co-factor for the functions of PC.

Protein C undergoes some post-translational modifications that include several N-linked glycosylation sites. The residue in the amino terminus of PC is made up of the Gla domain of the protein.

8. Activation of Fibrinogen to Fibrin

Fibrinogen consists of three pairs of polypeptides. The fibrin peptide areas of fibrinogen have several glutamate and aspartate residue that cause an adverse charge to the regions.

The result is an increased solubility of fibrinogen in the plasma. Active thrombin then converts the inactive fibrinogen to active fibrin.

9. Formation of the clot

Since the sole purpose of the entire process is the formation of a clot to stop the bleeding and enhance the healing of the wound, all the occurrences are driven towards just that.

The fibrin forms a wire-like mesh at the location of the damage to help stop the bleeding and initiate the process of healing.

10. Dissolution of Fibrin Clots

After the blood clot formation is followed by the repair of the damaged tissue through the healing process, the next step involves the dissolution of the fibrin that had developed the clot.

The process is made possible by the availability of the required enzymes in the blood plasma, responsible for the dissolution of the formed clot.

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