In Vivo Roles for Factor XII

Abstract SCI-19

The coagulation system is critical for limiting blood loss at a site of injury (hemostasis), but may also contribute to thrombotic disease. The model of a coagulation balance represents these two sides of the same coin. Thrombosis may occur in the venous or arterial circulation, causing pulmonary embolism or myocardial infarction and stroke, collectively the most common causes of death in the developed world.

Recent data from genetically altered mouse models have challenged the dogma of a coagulation balance. Deficiency of coagulation factor XII (Hageman factor), a serine protease, which initiates the intrinsic pathway of coagulation, severely impairs thrombus formation but is not associated with any excessive bleedings in humans or in mice. Targeting factor XII protects from occlusive disease in experimental animal models. Individuals with hereditary deficiency in the factor XII substrate factor XI are largely protected form ischemic stroke and deep-vein thrombosis. These findings indicate that fibrin-forming mechanisms, which operate during pathologic thrombus formation, involve pathways distinct from those proceeding during normal hemostasis. As the factor XII-driven contact system selectively contributes to thrombosis, but not to hemostasis, inhibition of the system offers novel anticoagulation strategies associated with minimal or no bleeding risk. In contrast to factor XII deficiency states, a single missense mutation (Thr328Lys) in the coagulation protein is associated with a life-threatening swelling disease, hereditary angioedema type III. Pharmacological factor XII inhibitors interfered both with pathological thrombosis and edema formation suggesting broad medical implications.

Factor XII is activated in vivo by platelet-released inorganic polyphosphate, a linear polymer of 60–100 phosphate residues that directly bound to the coagulation factor. Polyphosphates-driven factor XII activation triggered release of the inflammatory mediator bradykinin. Polyphosphates increased vascular permeability and induced skin edema formation in mice and animals deficient in factor XII or bradykinin receptors were resistant to polyphosphates-induced leakage. Polyphosphates were procoagulant via the intrinsic pathway of coagulation. Ablation of intrinsic coagulation pathway proteases factors XII and XI protected mice from polyphosphate-triggered lethal pulmonary embolism. Targeting polyphosphates with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Addition of polyphosphates restored defective plasma clotting of Hermansky-Pudlak Syndrome patients, who platelet lack storage organelles for polyphosphates. The data identify polyphosphates as the endogenous activator of factor XII having fundamental roles in platelet-driven proinflammatory and procoagulant disorders.