FXII −/− mice and wild-type mice treated with FXIIa inhibitors were also protected from thromboembolic diseases, including stroke, atherothrombosis, and pulmonary embolism. 15 Reconstitutions of the animals with human FXII restored the defective thrombus formation, indicating a critical function of human FXII in pathological clotting. However, similar to FXII-deficient individuals, the hemostatic potential of FXII −/− mice remained unaffected. Our laboratory has generated the first FXII-deficient (FXII −/−) mouse model and reported in 2005 that occlusive thrombus formation in both arterial and venous beds was severely defective in these animals. Deficiency or a dysfunctional C1INH is associated with a BK-mediated life-threatening inherited swelling disorder, hereditary angioedema (HAE) type I or II, respectively. 11 Serpin C1 esterase inhibitor (C1INH) is the major plasma inhibitor of FXIIa and PK. 10 Locally produced FXIIa initiates the intrinsic pathway of coagulation via its substrate factor XI (FXI) and leads to liberation of the proinflammatory mediator bradykinin (BK) by PK-mediated cleavage of HK. 6-9 In addition, PK also binds to proteoglycans in a HK-independent manner. 4, 5 The plasma contact system components FXII and HK assemble on cell surface proteoglycans of various cardiovascular cells, with the latter 1 bound to FXI or PK. This suggests that surface binding is sufficient for inducing a conformation with some enzymatic activity that is amplified by proteolytic cleavage of the FXII zymogen form. 1-3 FXII also has limited proteolytic activity, when bound to contact-activating surfaces without undergoing proteolysis. FXII was first recognized as essential for surface-activated diagnostic blood coagulation assays (eg, the activated partial thromboplastin time) that are commonly used as a clinical measure of global plasma coagulation. During both contact-triggered autoactivation and PK-mediated heteroactivation, FXII zymogen undergoes limited proteolysis. Alternatively, active PK has the capacity to convert FXII zymogen to the active protease. FXII is activated to FXIIa following binding (“contact”) to negatively charged artificial or biologic surfaces (contact activation). FXII is the plasma zymogen form of the serine protease factor XIIa (FXIIa).
The plasma contact system is a procoagulant and proinflammatory protease cascade that is initiated by FXII, in a reaction involving high-molecular-weight kininogen (HK) and plasma kallikrein (PK) ( Figure 1). Elucidating the contact system offers the exciting opportunity to develop strategies for safe interference with both thrombotic and inflammatory disorders. The current review summarizes recent findings of the polyphosphate/factor XII–driven contact system at the intersection of procoagulant and proinflammatory disease states. In contrast to deficiency in factor XII providing safe thromboprotection, excessive FXII activity is associated with the life-threatening inflammatory disorder hereditary angioedema. This suggests that the polyphosphate/factor XII axis contributes to thrombus formation while being dispensable for hemostatic processes.
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Challenging the concept of the coagulation balance, targeting factor XII or its activator polyphosphate, provides protection from thromboembolic diseases without interfering with hemostasis. The biochemistry of the contact system in vitro is well understood however, its in vivo functions are just beginning to emerge. The factor XII–driven contact system starts coagulation and inflammatory mechanisms via the intrinsic pathway of coagulation and the bradykinin-producing kallikrein-kinin system, respectively. Combinations of proinflammatory and procoagulant reactions are the unifying principle for a variety of disorders affecting the cardiovascular system.
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