Factor V's Role in the Clotting Cascade
Factor V functions as the essential non-enzymatic cofactor in the prothrombinase complex, binding with Factor Xa on platelet surfaces to convert prothrombin to thrombin, accelerating this reaction by over 10,000-fold and serving as a critical amplification point in hemostasis. 1
Primary Procoagulant Function
Factor V operates within the procoagulant cascade through a specific sequence of molecular interactions:
Factor Xa binds Factor Va to form the prothrombinase complex, which represents the enzymatic machinery responsible for activating prothrombin to thrombin 1
This prothrombinase complex accelerates prothrombin conversion by more than 10,000-fold compared to Factor Xa acting alone, making Factor Va indispensable for generating sufficient thrombin to form stable hemostatic plugs 2
Factor Va performs its cofactor role by binding to platelet membranes and functioning as the membrane receptor for Factor Xa in a high-affinity 1:1 stoichiometric complex (Kd = 10^-10 M) 3
Factor Va also participates in binding prothrombin to the enzymatic complex, facilitating the substrate positioning necessary for efficient proteolytic conversion 3
Amplification and Feedback Mechanisms
Factor V participates in critical amplification loops that exponentially increase thrombin generation:
Thrombin activates Factor V to Factor Va in a positive feedback loop, releasing it from von Willebrand factor and converting it to its active cofactor form 1
Together, Factors Va and VIIIa can potentially increase the rate of thrombin generation by one million-fold, providing major control points for regulating the entire coagulation cascade 1
Thrombin produces the hemostatic plug by cleaving fibrinogen to form fibrin monomers, activating platelets, and activating Factor XIII to crosslink fibrin strands into a stable clot 1
Dual Compartment System
Factor V exists in two distinct blood compartments with different functional significance:
Approximately 80% of total blood Factor V circulates in plasma, while 20% is stored within platelet α-granules 3
Platelet-derived Factor V appears to play a more important role in thrombin generation at sites of vascular injury compared to plasma-derived Factor V, as it is physically and functionally distinct 4
Megakaryocytes acquire Factor V through endocytosis of plasma-derived molecules via a two-receptor system involving LDL receptor-related protein-1 (LRP-1), followed by intracellular remodeling before α-granule storage 4
Regulatory Control Through the Protein C Pathway
Factor Va serves as a critical regulatory target for natural anticoagulation:
Activated Protein C (APC) inactivates Factor Va through proteolysis in the presence of Protein S, preventing excessive thrombin generation and pathologic thrombosis 1
Factor Va also acts as a cofactor in APC-mediated inactivation of Factor VIIIa, creating an intricate dual regulatory mechanism that modulates both the prothrombinase and tenase complexes 2
Down-regulation of Factor Va cofactor activity by the Protein C pathway is highly effective for maintaining hemostatic balance, as evidenced by the thrombotic complications seen with Factor V Leiden mutations that resist APC inactivation 2
Clinical Significance
The essential nature of Factor V is demonstrated by bleeding manifestations when deficient:
Factor V deficiency causes bleeding primarily from mucosal surfaces and postoperative hemorrhage, though hemarthroses and intracranial hemorrhages can occur 5
Factor V levels show limited correlation with bleeding risk, and patients with Factor V deficiency generally have a less severe phenotype than those with hemophilia A or B 5
Deletion of Factor Va from the prothrombinase complex decreases thrombin generation by four orders of magnitude (10,000-fold), explaining why even partial deficiencies can cause bleeding 3
Common Pitfall
Do not confuse Factor V with Factor VIII—while both serve as cofactors and are regulated by the Protein C pathway, Factor V functions in the prothrombinase complex (with Factor Xa to activate prothrombin), whereas Factor VIII functions in the tenase complex (with Factor IXa to activate Factor X). 1