The clotting cascade refers to a series of biochemical reactions that occur in the blood to form a blood

clot (thrombus) in response to vascular injury. The process involves the activation of a series of proteins
known as clotting factors, which work in a complex sequence to convert the soluble protein fibrinogen
into an insoluble fibrin mesh, forming a stable clot that stops bleeding.

The clotting cascade is typically divided into three stages:

1. Vascular Phase (Vasoconstriction and Platelet Activation)

The vascular phase is the immediate response to injury. When a blood vessel is damaged, the following
happens:

 Vasoconstriction: The blood vessel constricts to reduce blood flow and minimize blood loss.

 Platelet adhesion: Platelets (thrombocytes) adhere to the exposed subendothelial matrix (e.g.,
collagen and von Willebrand factor) at the site of injury.

 Platelet activation: Activated platelets release chemical signals (e.g., ADP, thromboxane A2,
serotonin) that attract more platelets to the site and promote further aggregation.

This leads to the formation of a platelet plug at the site of injury, which is temporary and unstable until
the clotting cascade can form a more durable clot.

2. Coagulation (Clotting Cascade)

The coagulation phase involves a series of reactions that activate clotting factors (proteins) in a specific
order. The clotting cascade is divided into three main pathways: the extrinsic pathway, the intrinsic
pathway, and the common pathway. Each pathway leads to the conversion of fibrinogen into fibrin,
which stabilizes the clot.

Extrinsic Pathway (Tissue Factor Pathway)

The extrinsic pathway is triggered by tissue injury and is the initial response to bleeding. It is the fastest
pathway and involves the following steps:

1. Tissue Factor (TF): When the vessel wall is damaged, tissue factor (TF) (also known as Factor III)
is exposed to the bloodstream. TF is found on the surface of subendothelial cells and is required
for the activation of Factor VII.

2. Factor VII Activation: Tissue factor binds to Factor VII, forming the TF-Factor VIIa complex. This
complex activates Factor X (the start of the common pathway).

o Factor VII → Factor VIIa (activated by TF)

o TF-Factor VIIa → activates Factor X

Intrinsic Pathway (Contact Activation Pathway)

The intrinsic pathway amplifies the coagulation process and involves the following clotting factors:

1. Factor XII (Hageman factor): When blood contacts negatively charged surfaces (like exposed
collagen), Factor XII is activated to Factor XIIa.
 2. Factor XI Activation: Factor XIIa activates Factor XI to Factor XIa.

3. Factor IX Activation: Factor XIa activates Factor IX to Factor IXa.

4. Factor VIIIa Activation: In the presence of calcium ions (Ca²⁺), Factor VIII is activated to Factor
VIIIa. Factor VIIIa forms a complex with Factor IXa to activate Factor X.

o Factor XII → Factor XIIa

o Factor XI → Factor XIa

o Factor IX → Factor IXa

o Factor VIII → Factor VIIIa

o Factor IXa + Factor VIIIa → activates Factor X

Common Pathway

The common pathway is where the extrinsic and intrinsic pathways converge. Here, Factor X is activated,
and this leads to the formation of thrombin, which converts fibrinogen into fibrin.

1. Factor X Activation: Factor Xa is activated from Factor X by the Factor IXa + Factor VIIIa complex
(from the intrinsic pathway) or by the TF-Factor VIIa complex (from the extrinsic pathway).

2. Prothrombin Activation: Factor Xa (in complex with Factor Va) activates prothrombin (Factor II)
to thrombin (Factor IIa).

o Factor X → Factor Xa

o Factor Xa + Factor Va → activates prothrombin → thrombin (Factor IIa)

3. Fibrinogen to Fibrin: Thrombin (Factor IIa) converts fibrinogen (a soluble plasma protein) into
fibrin (an insoluble protein). Fibrin strands form a mesh that stabilizes the clot.

o Fibrinogen → fibrin (Factor IIa)

4. Factor XIII Activation: Thrombin also activates Factor XIII to Factor XIIIa, which cross-links the
fibrin strands, making the clot stronger and more stable.

o Factor XIII → Factor XIIIa (cross-links fibrin)

3. Fibrinolysis (Clot Removal)

After the clot has fulfilled its role in stopping bleeding, it is gradually broken down in a process called
fibrinolysis. This process involves the conversion of plasminogen (an inactive precursor) to plasmin,
which digests fibrin and dissolves the clot.

 Plasminogen Activation: Plasminogen is incorporated into the clot. It is activated to plasmin by

tissue plasminogen activator (tPA) and urokinase.

 Plasmin Digestion: Plasmin digests the fibrin mesh, leading to the dissolution of the clot.

Summary of Key Steps in the Clotting Cascade:

 1. Extrinsic Pathway: Injury → TF + Factor VII → Factor Xa (common pathway).

2. Intrinsic Pathway: Injury → Factor XII → Factor XIa → Factor IXa + Factor VIIIa → Factor Xa
(common pathway).

3. Common Pathway: Factor Xa + Factor Va → Prothrombin → Thrombin → Fibrinogen → Fibrin.

4. Fibrinolysis: Plasminogen → Plasmin → Fibrin degradation.

Summary of Clotting Factors:

1. Factor I: Fibrinogen

2. Factor II: Prothrombin

3. Factor III: Tissue Factor (TF)

4. Factor IV: Calcium (Ca²⁺)

5. Factor V: Proaccelerin

6. Factor VII: Proconvertin

7. Factor VIII: Anti-hemophilic factor

8. Factor IX: Christmas factor

9. Factor X: Stuart-Prower factor

10. Factor XI: Plasma thromboplastin antecedent

11. Factor XII: Hageman factor

12. Factor XIII: Fibrin-stabilizing factor

In summary, the clotting cascade is a complex and highly regulated process that involves multiple
proteins (clotting factors) and steps to stop bleeding by forming a stable fibrin clot. This cascade can be
divided into three main phases: the vascular phase, the coagulation phase (extrinsic, intrinsic, and
common pathways), and the fibrinolytic phase (clot breakdown).