Factor XI Activation by Thrombin and Factor XIa

The classic intrinsic pathway of blood coagulation, first described in 1964 by Macfarlane 1 and by Davie and Ratnoff, 2 is initiated when zymogen Factor XII is con verted to the active serine protease, Factor XIIa, in the presence of a negatively charged surface. Subsequent work identified high molecular weight kininogen (HMWK) and prekallikrein as critical cofactors for this reaction in vitro (Fig. 1A).. 3-5 Factor XIIa propagates coagulation by activating the next protease in the cas cade, Factor XI. This model of hemostasis is at odds with clinical observations of individuals congenitally deficient in components of the intrinsic pathway. Despite having marked abnormalities in in vitro assays, which measure intrinsic pathway coagulation, 6 persons congenitally de ficient in one of the contact activation factors (Factor XII, HMWK, and prekallikrein) do not have abnormal bleed ing, 7 indicating that these proteins are not required for coagulation in vivo. In contrast, deficiency of Factor XI results in a mild to moderate bleeding diathesis that is usually most pronounced after surgery or trauma. 8 ' 9 These observations indicate that Factor XI is necessary for normal hemostasis and that it can be activated in vivo by a proteases other than Factor XIIa.