Gene Number: 2147

Location: 11p11.2

Key Functions: Blood coagulation, thrombin production, coagulation cascade regulation, hemostasis balance

F2 encodes coagulation factor II (prothrombin), a glycoprotein precursor that plays a central role in the coagulation cascade, the tightly regulated process responsible for preventing blood loss following vascular injury. Synthesized primarily in the liver, prothrombin requires vitamin K–dependent γ-carboxylation for its biological activity—a modification that enables calcium binding and proper interaction with phospholipid membranes during coagulation.

Upon activation by the prothrombinase complex—which includes activated factor X (FXa), activated factor V (FVa), calcium ions, and a phospholipid surface—prothrombin is converted into thrombin, the key serine protease responsible for catalyzing multiple downstream reactions:

1. Conversion of fibrinogen to fibrin, forming the structural basis of a stable clot.

   
   

2. Activation of platelets, promoting aggregation and reinforcing the clot structure.

   
   

3. Feedback activation of coagulation factors V, VIII, and XI, amplifying thrombin generation.

   
   

4. Regulation of anticoagulant and inflammatory pathways through interactions with protein C and protease-activated receptors (PARs), maintaining vascular integrity and immune balance.

   
   

At the genetic level, mutations in F2 profoundly affect clotting efficiency and disease susceptibility. The most well-characterized variant, F2 G20210A (rs1799963), located in the 3′ untranslated region, leads to elevated plasma prothrombin levels due to increased mRNA stability. This gain-of-function effect enhances thrombin formation and significantly elevates the risk of venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism.

The allele frequency of G20210A varies across populations—most common in individuals of European descent—and interacts synergistically with other thrombophilic mutations such as Factor V Leiden (F5 G1691A), compounding thrombotic risk.

Conversely, rare loss-of-function mutations in F2 can cause hypoprothrombinemia, resulting in excessive bleeding, delayed clot formation, and prolonged prothrombin time (PT). Such deficiencies may be congenital or acquired through vitamin K deficiency, liver disease, or anticoagulant

therapy (e.g., warfarin).

Thus, F2 exemplifies the fine-tuned equilibrium of hemostasis: its expression and activation must be precisely controlled to balance clot formation and dissolution. Disruption of this balance—whether through genetic, nutritional, or pharmacological factors—can tip the system toward bleeding or thrombosis, illustrating the critical role of prothrombin in vascular and systemic health.