What are the clotting factors involved in the intrinsic pathway, extrinsic pathway, and common pathway?

Clotting Factors in the Coagulation Pathways

Overview of the Three Pathways

The coagulation cascade consists of three interconnected pathways—intrinsic, extrinsic, and common—that work together to form a stable blood clot through sequential activation of clotting factors. 1

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Intrinsic Pathway (Contact Activation Pathway)

The intrinsic pathway is triggered when blood contacts negatively charged surfaces, such as exposed collagen in damaged blood vessels or artificial surfaces like glass. 1, 2

Key Factors Involved:

• Factor XII (Hageman factor): Activated to Factor XIIa when blood contacts negatively charged surfaces, initiating the intrinsic pathway 1, 2

• Factor XI: Activated by Factor XIIa (and also by thrombin during amplification), converting to Factor XIa 3

• Factor IX (Christmas factor): Activated by Factor XIa to become Factor IXa 1

• Factor VIII: A critical cofactor that is activated by thrombin to Factor VIIIa, which then forms a complex with Factor IXa on platelet surfaces (called the "tenase complex") 4

The Factor IXa-VIIIa tenase complex activates Factor X approximately 50-fold faster than the tissue factor pathway alone, representing a major amplification step. 4

Important Notes:

• The intrinsic pathway requires calcium ions (Ca²⁺) for proper function of the tenase complex 1
• Factor VIII circulates bound to von Willebrand factor (vWF) and is released upon activation by thrombin 4
• Modern understanding suggests Factor XII's role is more important in thrombus propagation and stabilization rather than initial coagulation initiation 5

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Extrinsic Pathway (Tissue Factor Pathway)

The extrinsic pathway is the primary physiological initiator of coagulation, triggered when blood contacts damaged tissue outside the blood vessel. 1

Key Factors Involved:

• Tissue Factor (Factor III/TF): A transmembrane protein exposed at sites of vascular injury that acts as a receptor for Factor VII 1, 6

• Factor VII: Circulates in blood and binds to exposed tissue factor, forming the TF-Factor VII complex (extrinsic tenase), which then becomes activated to Factor VIIa 1

The TF-Factor VIIa complex directly activates Factor X to Factor Xa, initiating the common pathway. 1

Important Notes:

• This pathway begins the initiation phase of coagulation in the modern cell-based model 4
• Factor VII requires calcium ions for binding to tissue factor 1
• The extrinsic pathway also activates Factor IX, creating cross-talk between the extrinsic and intrinsic pathways 4, 5

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Common Pathway (Final Common Pathway)

Both the intrinsic and extrinsic pathways converge at Factor X, leading to the common pathway that generates thrombin and fibrin. 1

Key Factors Involved:

• Factor X (Stuart-Prower factor): Activated to Factor Xa by either the TF-Factor VIIa complex (extrinsic) or the Factor IXa-VIIIa complex (intrinsic) 1, 7

• Factor V: Activated by thrombin to Factor Va, which combines with Factor Xa to form the prothrombinase complex 1

• Factor II (Prothrombin): Converted to thrombin (Factor IIa) by the prothrombinase complex (Factor Xa + Factor Va) 1, 6

• Factor I (Fibrinogen): Converted to fibrin by thrombin, forming the mesh structure of the clot 1, 6

• Factor XIII: Activated by thrombin to Factor XIIIa, which cross-links fibrin polymers to strengthen and stabilize the clot 1, 6

The prothrombinase complex (Factor Xa + Factor Va) catalyzes thrombin formation, which then converts fibrinogen to fibrin to form a stable clot. 1

Important Notes:

• The prothrombinase complex requires negatively charged phospholipid surfaces (provided by activated platelets and extracellular vesicles) and calcium ions 1
• Factors II, VII, IX, and X all require calcium for binding to procoagulant membranes 1
• Together, Factors Va and VIIIa can increase thrombin generation by one million-fold, providing critical amplification 4

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Clinical Pearls and Common Pitfalls

Key Points to Remember:

• Surface requirement: Both the tenase and prothrombinase complexes require negatively charged phospholipid surfaces (phosphatidylserine) exposed on activated platelets and extracellular vesicles 1

• Calcium dependency: Factors II, VII, IX, and X are vitamin K-dependent factors that require calcium ions for membrane binding 1

• Amplification is critical: The intrinsic pathway's Factor IXa-VIIIa complex provides massive amplification (50-fold) of Factor X activation, which is why Factor VIII deficiency (hemophilia A) causes severe bleeding despite an intact extrinsic pathway 4

Common Misconceptions:

• The older "cascade model" fails to account for the essential cell-surface interactions and cross-talk between pathways 4
• Factor XII deficiency does not typically cause bleeding problems, highlighting that the extrinsic pathway is the primary physiological initiator 5
• The intrinsic pathway is better understood as an amplification mechanism rather than a primary initiator in physiological coagulation 4, 5