Fibrinolysis and the Contact System: A Role for Factor XI in the Down-Regulation of Fibrinolysis

Introduction

Exposure of blood to negatively-charged surfaces, such as collagen, kaolin, or glass, results in the activation of the contact system of the intrinsic pathway of coagulation. Prekallikrein, factor XII, high molecular weight kininogen, and factor XI are the proteins involved in this contact reaction. The assembly of these components on a negatively-charged surface leads to the activation of factor XI, thereby propagating the intrinsic coagulation pathway. Simultaneously, several other reactions occur, such as the activation of factor VII and the initiation of the fibrinolytic system, kinin-forming pathway, and renin-angiotensin pathway.

The first step in the contact phase is to bind factor XII to the negatively-charged surface, making it highly susceptible for proteolysis by kallikrein.^1-3 Activated factor XII (α-factor XIIa) is formed in a process that may involve autoactivation.^4-7 Prekallikrein is bound to high molecular weight kininogen in plasma. High molecular weight kininogen associates with a negatively-charged surface, thereby localizing prekallikrein to the surface. Limited proteolysis by α-factor XIIa converts prekallikrein to kallikrein. Kallikrein can dissociate from the surface and act on surface-bound factor XII at distant sites, thereby propagating the reciprocal cycle.⁷ Factor XI circulates plasma in a complex with high molcular weight kininogen. High molecular weight kininogen links factor XI to a negatively charged surface where it is activated by surface bound:α-factor XIIa. Although the in vivo, activating, negatively-charged surface is unknown, assembly and activation of the contact system on biological membranes of endothelial cells, platelets, neutrophils, and monocytes can take place, suggesting that these surfaces are the actual activating surfaces in vivo.⁸

The physiological significance of the contact system in blood coagulation remains unclear, however, because a deficiency of factor XII, prekallikrein, and high molecular weight kininogen does not result in a bleeding disorder. In contrast, patients deficient in factor XI, most common among Ashkenazi Jews, do suffer from variable bleeding abnormalities, especially from tissues with high local fibrinolytic activity (e.g., urinary tract, nose, oral cavity, tonsils).^9,10 This suggested that there was an alternative route for the activation of factor XI, and recently, such a route was described.^11,12 Thrombin was found to activate factor XI even in the absence of a negatively-charged surface,^11-15 and factor XI was shown to play a role in the downregulation of fibrinolysis.¹⁶ In this article, the role of the contact system, with an emphasis on factor XI in the regulation of the fibrinolytic system, will be described.

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