What are clotting factors and what is their function?

What Are Clotting Factors and Their Functions?

Clotting factors are a series of plasma proteins that function as inactive enzymes (zymogens) and cofactors in an amplifying enzymatic cascade, ultimately generating thrombin to convert fibrinogen into a stable fibrin clot at sites of vascular injury. 1

The Coagulation Cascade: A Cell-Based Model

The modern understanding of coagulation has evolved from the older "cascade model" to a cell-based model that more accurately reflects in vivo processes and emphasizes the critical role of cellular surfaces in clot formation. 1, 2

Three Phases of Coagulation

Initiation Phase:

• Occurs on tissue factor (TF)-bearing cells (monocytes, macrophages, activated endothelial cells, smooth muscle cells) exposed at sites of vascular injury 1
• Tissue factor binds circulating Factor VII/VIIa, forming the TF-FVIIa complex (extrinsic tenase) 1
• This complex activates Factor IX to IXa and Factor X to Xa through limited proteolysis 1
• Small amounts of thrombin (Factor IIa) are generated 1, 2

Amplification Phase:

• The small amount of thrombin generated during initiation activates Factors V, VIII, and XI in a feedback amplification loop 1
• Factor VIII is released from von Willebrand factor and converted to its active form (FVIIIa) 2, 3
• Platelets are activated and provide phospholipid membrane surfaces essential for subsequent reactions 1

Propagation Phase:

• Factor IXa binds to Factor VIIIa on activated platelet surfaces, forming the "tenase complex" 2
• This complex activates Factor X to Xa approximately 50-fold faster than the TF-FVIIa complex, representing a major amplification step 2
• Factor Xa binds Factor Va to form the prothrombinase complex on platelet membranes 1
• The prothrombinase complex converts prothrombin (Factor II) to thrombin 1
• Together, Factors Va and VIIIa can increase the rate of thrombin generation by one million-fold, providing major control points for regulating coagulation 1, 2

Individual Clotting Factors and Their Functions

Factor I (Fibrinogen):

• Soluble plasma protein (physiological concentration 2-4 g/L) that is cleaved by thrombin to form insoluble fibrin monomers 1, 4
• Forms the structural mesh of the hemostatic plug 1

Factor II (Prothrombin):

• Vitamin K-dependent zymogen converted to thrombin (Factor IIa) by the prothrombinase complex 1
• Thrombin is the central enzyme that cleaves fibrinogen, activates platelets, activates Factor XIII, and amplifies its own production 1

Factor III (Tissue Factor):

• Transmembrane glycoprotein that initiates the extrinsic pathway when exposed to blood after vascular injury 1, 4
• Serves as the cofactor for Factor VIIa 1

Factor V:

• Non-enzymatic cofactor that is activated by thrombin to Factor Va 1
• Essential component of the prothrombinase complex, acting as both an enzyme receptor and catalytic effector 5
• Inactivated by activated protein C (APC) as a regulatory mechanism 1

Factor VII:

• Vitamin K-dependent serine protease that circulates with approximately 1% in active form (VIIa) 1, 5
• Forms the extrinsic tenase complex with tissue factor 1

Factor VIII:

• Non-enzymatic cofactor (Mr 200,000-300,000) that circulates bound to von Willebrand factor at concentrations of 100-200 ng/ml 3
• Activated by thrombin to FVIIIa, which forms the tenase complex with Factor IXa 2, 3
• Deficiency causes hemophilia A 3
• Inactivated by activated protein C and spontaneously by dissociation 2, 5

Factor IX:

• Vitamin K-dependent serine protease activated by the TF-FVIIa complex 1
• Forms the tenase complex with Factor VIIIa to activate Factor X 1, 2
• Deficiency causes hemophilia B 6

Factor X:

• Vitamin K-dependent serine protease activated by both tenase complexes 1
• Forms the prothrombinase complex with Factor Va 1

Factor XI:

• Activated by thrombin as part of the amplification feedback loop 1

Factor XIII:

• Activated by thrombin to Factor XIIIa 1
• Cross-links fibrin strands to form a stable, mechanically strong hemostatic plug 1, 4

Essential Cofactors for Coagulation

Calcium Ions (Ca²⁺):

• Required for binding of vitamin K-dependent factors (II, VII, IX, X) to phospholipid membranes 1, 7
• Essential for formation of tenase and prothrombinase complexes 1, 7
• Anticoagulants like citrate and EDTA work by chelating calcium ions 1

Phospholipid Membrane Surfaces:

• Provided by activated platelets, endothelial cells, and extracellular vesicles 1
• Expose negatively charged phospholipids (particularly phosphatidylserine) necessary for assembly of coagulation factor complexes 1
• Without adequate membrane surface, procoagulant complexes have limited catalytic efficiency 5

Natural Anticoagulant System

The anticoagulant system functions to confine the hemostatic plug to the site of injury and prevent pathologic thrombosis. 1

Antithrombin III:

• Serine protease inhibitor (SERPIN) that irreversibly inhibits thrombin, Factors IXa, Xa, XIa, and the FVIIa-TF complex 1
• Activity markedly increased by heparin 1, 4

Protein C:

• Vitamin K-dependent zymogen activated by the thrombin-thrombomodulin complex 1
• Activated protein C (APC) inactivates Factors Va and VIIIa through proteolysis in the presence of protein S 1

Protein S:

• Vitamin K-dependent cofactor for activated protein C 1

Tissue Factor Pathway Inhibitor (TFPI):

• Inhibits tissue factor, Factor VIIa, and Factor IXa 1

Critical Clinical Considerations

Common Pitfalls:

• The older cascade model fails to account for critical cell-surface interactions essential for factor function 2
• Factor VII and Factor VIII are often confused but have distinct roles: Factor VII initiates coagulation (extrinsic pathway), while Factor VIII amplifies it (intrinsic pathway) 2
• Laboratory testing can be affected by anticoagulant choice and sample collection methods 2

Inherited Deficiencies:

• Familial reductions in antithrombin III, protein C, or protein S are strongly associated with venous thromboembolism 1
• Factor V Leiden mutation (present in 5% of Caucasian Americans) causes resistance to activated protein C and is the most common genetic risk factor for venous thrombosis 1
• Deficiencies in procoagulant factors (VIII, IX, von Willebrand factor) cause bleeding disorders 6, 3

Therapeutic Implications:

• Prothrombin complex concentrates (PCCs) contain Factors II, VII, IX, and X but do not replace fibrinogen or Factor V 1
• Fibrinogen concentrates should only be used when plasma fibrinogen is below 1.5 g/L or functional deficiency is demonstrated on viscoelastic testing 1
• Recombinant Factor VIII is used for hemophilia A treatment 2
• Unfractionated heparin (300-500 U/kg) potentiates antithrombin III activity and is the primary anticoagulant for cardiopulmonary bypass 4