Official Full Name
Factor XII
Background
Factor XII (XII) (Hageman Factor) is a single chain (Mr=78,000) glycoprotein zymogen that circulates in plasma at a concentration of 40 µg/ml. Reciprical activation of XII to the active serine protease factor XIIa (XIIa) by kallikrein is central to initiation of the intrinsic coagulation pathway. Surface bound α-XIIa in turn activates factor XI to XIa. Secondary cleavage of α-XIIa by kallikrein yields β-XIIa, which catalyzes solution phase activation of kallikrein, factor VII and the classical complement cascade.
The ability of a variety of negatively charged substances, both physiological and nonphysiological to promote XII activation and, thus, initiation of the intrinsic pathway has led to the psuedonym "contact activation". Binding to anionic surfaces induces a conformational change, making the XII zymogen more susceptible to cleavage by a variety of proteases. It is unlikely that binding to negatively charged surfaces alone is sufficient to activate XII, since highly purified preparations of XII and plasma deficient in prekallikrein and high molecular weight kininogen do not undergo this "autocatalysis".
A single cleavage by kallikrein at R353-Val354 of XII yields α-XIIa, a 2 chain protease (Mr=80,000) held together by disulfide bonds. The COOH-terminal light chain (Mr=28,000) contains the catalytic triad (His-40, Asp-89, Ser-191), while the NH2-terminal heavy chain (Mr=52,000) conatins the anionic surface binding portion of the molecule. A secondary cleavage of α-XIIa by kallikrein outside the disulfide bond yields β-XIIa (XIIf, BHFa, HFf, hageman factor fragments) (Mr=28,000), which no longer binds anionic surfaces. β-XIIa can activate prekallikrein, but has little procoagulant activity. Several other minor intermediate forms of XIIa are indicated in the figure above.
Inhibitors of XIIa include C1-INH, α2-antiplasmin, α2-macroglobulin and antithrombin III. At physiological concentrations, the relative effectiveness of these inhibitors is 91 : 4.5 : 3 : 1.5, respectively. The ratio of C1-INH to XII has been implicated in the "cold activation" of factor VII and the conversion of prorenin to renin on storage of plasma.
Human factor XII is prepared from fresh frozen plasma by immunoaffinity chromatography and supplied in 50% glycerol for storage at -20°C.
Synonyms
Human Factor XII; Factor XII
Factor XII, a pivotal player in the intricate network of blood coagulation cascades, has long stood as a mysterious enzyme with profound implications for hemostasis, thrombosis, and beyond. Delving into the depths of Factor XII unveils a complex interplay of structure, functions, mechanisms, regulations, diverse applications, and the transformative potential it holds for medical advancements.
Structure
Factor XII, also known as Hageman factor, arises as a zymogen—a precursor awaiting activation within the blood coagulation pathway. Structurally, Factor XII comprises multiple domains, including:
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Fibronectin Type II Domain: Facilitating interactions with other coagulation factors and cellular components.
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Catalytic Domain: Enabling enzymatic functions crucial for initiating the intrinsic coagulation cascade.
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Apple-3 Domain: Implicated in protein-protein interactions and modulating Factor XII activity.
Function
Factor XII orchestrates a myriad of functions central to hemostasis and thrombosis regulation, including:
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Initiation of Coagulation Cascade: Activation of Factor XII sets in motion the intrinsic pathway, culminating in the formation of fibrin clots.
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Inflammatory Responses: Factor XII triggers kinin generation, promoting inflammation and vasodilation processes.
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Fibrinolysis Regulation: Modulating fibrinolytic activities through interactions with plasminogen and other clot-dissolving factors.
Mechanism
The activation of Factor XII is a complex process that involves multiple steps. Upon binding to a negatively charged surface, Factor XII undergoes a conformational change that exposes its active site. This allows for the cleavage of the arginine-353-lysine-354 peptide bond within the catalytic domain, leading to the generation of activated Factor XII (Factor XIIa). Factor XIIa then initiates a series of proteolytic reactions that culminate in the formation of a fibrin clot.
Regulation
Factor XII activation is tightly regulated to prevent excessive clot formation and maintain hemostatic balance. Several endogenous inhibitors, such as C1-esterase inhibitor and alpha-2-macroglobulin, can inactivate Factor XIIa and prevent uncontrolled coagulation. Additionally, Factor XII activity is modulated by various physiological factors, including pH, temperature, and divalent cations. Dysregulation of Factor XII activity has been implicated in the pathogenesis of thrombotic disorders, such as deep vein thrombosis and pulmonary embolism.
Applications
In addition to its role in hemostasis, Factor XII has been implicated in various pathological conditions, including inflammation and ischemia-reperfusion injury. Recent studies have demonstrated that Factor XII can modulate the immune response and contribute to the development of inflammatory diseases, such as rheumatoid arthritis and atherosclerosis. Targeting Factor XII activity with specific inhibitors may offer new therapeutic opportunities for the treatment of these conditions.
Clinical Significance of Factor XII
Factor XII's clinical significance extends beyond its canonical role in hemostasis, encompassing implications in thrombotic disorders, inflammation, and vascular pathologies. Dysregulation of Factor XII activity has been linked to thromboembolic events, hereditary angioedema, and inflammatory conditions, underscoring the importance of understanding its molecular intricacies in the context of disease pathogenesis and therapeutic interventions.
Conclusion
Factor XII is a multifunctional enzyme with key roles in the intrinsic pathway of blood coagulation and the regulation of inflammatory responses. Its complex structure and activation mechanism make it an intriguing target for therapeutic intervention in various disease processes. Further research is needed to elucidate the precise mechanisms by which Factor XII influences pathological pathways and to develop novel strategies for modulating its activity. By understanding the biology of Factor XII, we can uncover new insights into hemostasis and inflammation and pave the way for innovative treatments for a wide range of human diseases.
