Gene Number: 2153

Location: 1q24.2

Key Functions: Blood coagulation, thrombin generation, clot formation, hemostasis regulation, thrombosis susceptibility

F5 encodes coagulation factor V (FV), a large glycoprotein that plays an indispensable role in the coagulation cascade, serving as a critical procoagulant cofactor that amplifies thrombin generation. It functions as a molecular accelerator in the conversion of prothrombin (factor II) to thrombin (factor IIa)—the central enzyme responsible for fibrin formation and stable blood clot development.

Factor V circulates in plasma as an inactive precursor (procofactor). Upon vascular injury, it is activated by limited proteolysis through thrombin or factor Xa, forming factor Va (FVa). Activated FV then associates with factor Xa on phospholipid surfaces—typically provided by activated platelets—to form the prothrombinase complex, one of the most potent enzymatic assemblies in the coagulation system. This complex increases the rate of prothrombin cleavage to thrombin by several orders of magnitude, ensuring a rapid and localized clotting response that prevents excessive blood loss.

Beyond its procoagulant function, FV also exhibits anticoagulant regulatory properties, reflecting its dual role in maintaining hemostatic balance. In the protein C pathway, activated protein C (APC), together with its cofactor protein S, inactivates FVa by proteolytic cleavage at specific arginine residues. This degradation process is essential to limit thrombin generation once the clotting objective is achieved, thereby preventing pathological clot propagation.

A pivotal genetic variant within F5—the Factor V Leiden mutation (c.1691G>A; p.Arg506Gln, rs6025)—has been extensively studied for its clinical significance. This single nucleotide substitution results in a glutamine replacing an arginine at position 506, which is one of the primary cleavage sites for APC. Consequently, FVa Leiden becomes resistant to APC-mediated degradation, prolonging its procoagulant activity and leading to enhanced thrombin generation. This state, termed activated protein C resistance (APCR), markedly increases the risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE).

Epidemiological data show that heterozygous carriers of Factor V Leiden have a 3–8-fold increased risk of thrombosis, while homozygous individuals may have a 50–100-fold higher risk. Despite this, many carriers remain asymptomatic, suggesting that environmental and additional genetic factors—such as oral contraceptive use, immobility, pregnancy, or coinheritance of other prothrombotic mutations (e.g., prothrombin G20210A)—modulate the clinical manifestation.

Other F5 variants contribute to a wide phenotypic spectrum ranging from factor V deficiency (Owren’s disease)—a rare autosomal recessive bleeding disorder caused by loss-of-function mutations—to hypercoagulable states driven by altered cofactor function. Complete FV deficiency leads to reduced prothrombinase activity, resulting in delayed fibrin clot formation and a bleeding tendency. In contrast, hyperfunctional variants or resistance to natural anticoagulant pathways promote excessive clotting.

Beyond thrombosis and bleeding, Factor V has emerging roles in inflammation and immune regulation. FV and its activated form (FVa) interact with leukocytes and endothelial cells, influencing cytokine production, vascular permeability, and the recruitment of immune cells to sites of injury. These noncanonical functions illustrate how coagulation factors integrate hemostasis and innate immunity, forming part of the broader concept of immunothrombosis.

In clinical medicine, the F5 gene serves as a cornerstone in thrombophilia screening. Molecular testing for Factor V Leiden is standard in patients with unexplained thrombosis, family history of VTE, or recurrent pregnancy loss. Understanding a patient’s F5 genotype is also critical in evaluating anticoagulant therapy choices, since individuals with APC resistance may require adjusted prophylactic regimens in high-risk situations such as surgery or prolonged immobilization.

In summary, F5 encodes a pivotal regulator at the intersection of procoagulant and anticoagulant pathways, ensuring that clot formation is both efficient and tightly controlled. Its genetic variability—particularly the Factor V Leiden mutation—profoundly influences individual thrombotic risk, representing a prime example of how a single molecular alteration can tip the delicate balance between hemostasis and thrombosis.