Abstract SCI-20

Factor XI (fXI) is the zymogen of an enzyme (fXIa) that contributes to blood coagulation through activation of factor IX (fIX). FXI has structural and mechanistic features that distinguish it from the vitamin K-dependent proteases of coagulation. The protein is a dimer of identical 80 kDa subunits, each containing four apple domains (A1-A4) that form a platform at the base of the trypsin-like protease domain. The apple domains contain binding sites for fIX, platelet receptors, and high molecular weight kininogen. FXI is converted to fXIa by cleavage of a single bond on each subunit, unmasking exosites required for fIX binding. Conversion of fXI to fXIa proceeds through an intermediate with only one activated subunit (1/2-fXIa). 1/2-fXIa, and monomeric forms of fXIa, activate fIX in a manner similar to fully activated fXIa, indicating each subunit functions as a complete enzyme. The importance of the dimeric structure of fXI is not clear at this point. It may facilitate activation, or allow fXIa to bind simultaneously to fIX and a surface (a platelet for example) at a wound site.

Congenital fXI deficiency is associated with a variable propensity to bleed excessively after trauma to certain tissues. Symptoms are usually milder than in fIX deficiency (hemophilia B), and many affected individuals are asymptomatic. In the cascade-waterfall model of coagulation, fXI is activated by factor XIIa (fXIIa) during a process called contact activation. However, current models often omit contact activation, because fXII deficiency is not associated with abnormal hemostasis. Thrombin activates fXI, providing an explanation for normal hemostasis in fXII deficiency. In contrast to its modest role in hemostasis, fXI may serve an important role in thromboembolic diseases. High fXI levels are a risk factor for arterial and venous thrombosis in humans; and deficiency or inhibition of fXI confers resistance to thrombosis in animal models. FXI deficient mice are as resistant to arterial thrombosis as fIX deficient mice, or wild type mice treated with a supra-therapeutic dose of heparin. In arterial thrombosis models in mice, rabbits and baboons, lack of fXI activity results in instability of platelet rich thrombi, preventing vessel occlusion. FXI deficiency also prolongs survival and lessens the severity of disseminated intravascular coagulation in a mouse polymicrobial sepsis model. Interestingly, mice with combined deficiencies of fXI and fIX are more resistant to arterial thrombus formation than mice deficient in only one of these proteins, indicating fXIa has proteolytic targets other than fIX.

The observation that fXII deficient mice are resistant to arterial thrombosis suggests that activation of fXI by contact activation, while unnecessary for hemostasis, contributes to thrombin generation in some pathologic processes. If the observations in mice apply to thromboembolism in humans, then fXIa and/or fXIIa may be excellent targets for novel antithrombotic strategies. In contrast to drugs such as heparin and warfarin, agents targeting fXIa or fXIIa would likely be associated with relatively few bleeding complications, and could be employed in clinical situations where anticoagulation therapy is currently contraindicated.


No relevant conflicts of interest to declare.