Nucleic acids as cofactors for factor XI and prekallikrein activation: Different roles for high-molecular-weight kininogen

The plasma zymogens factor XI (fXl) and prekallikrein (PK) are activated by factor Xlla (fXlla) during contact activation. Polyanions such as DNA and RNA may contribute to thrombosis and inflammation partly by enhancing PK and fXl activation. We examined PK and fXl activation in the presence of nucleic acids, and determine the effects of the cofactor high molecular weight kininogen (HK) on the reactions. In the absence of HK, DNA and RNA induced fXl autoactivation. Proteases known to activate fXl (fXlla and thrombin) did not enhance this process appreciably. Nucleic acids had little effect on PK activation by fXlla in the absence of HK. HK had significant but opposite effects on PK and fXl activation. HK enhanced fXlla activation of PK in the presence of nucleic acids, but blocked fXl autoactivation. Thrombin and fXlla could overcome the HK inhibitory effect on autoactivation, indicating these proteases are necessary for nucleic acid-induced fXl activation in an HK-rich environment such as plasma. In contrast to PK, which requires HK for optimal activation, fXl activation in the presence of nucleic acids depends on anion binding sites on the fXl molecule. The corresponding sites on PK are not necessary for PK activation. Our results indicate that HK functions as a cofactor for PK activation in the presence of nucleic acids in a manner consistent with classic models of contact activation. However, HK has, on balance, an inhibitory effect on nucleic acid-supported Da activation and may function as a negative regulator of fXl activation.