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

Ivan Ivanov, Ruhama Shakhawat, Mao fu Sun, S. Kent Dickeson, Cristina Puy, Owen J.T. McCarty, Andras Gruber, Anton Matafonov, David Gailani

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

The plasma zymogens factor XI (fXI) and prekallikrein (PK) are activated by factor XIIa (fXIIa) during contact activation. Polyanions such as DNA and RNA may contribute to thrombosis and inflammation partly by enhancing PK and fXI activation. We examined PK and fXI 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 fXI autoactivation. Proteases known to activate fXI (fXIIa and thrombin) did not enhance this process appreciably. Nucleic acids had little effect on PK activation by fXIIa in the absence of HK. HK had significant but opposite effects on PK and fXI activation. HK enhanced fXIIa activation of PK in the presence of nucleic acids, but blocked fXI autoactivation. Thrombin and fXIIa could overcome the HK inhibitory effect on autoactivation, indicating these proteases are necessary for nucleic acid-induced fXI activation in an HK-rich environment such as plasma. In contrast to PK, which requires HK for optimal activation, fXI activation in the presence of nucleic acids depends on anion binding sites on the fXI 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 fXI activation and may function as a negative regulator of fXI activation.

Original languageEnglish (US)
Pages (from-to)671-681
Number of pages11
JournalThrombosis and Haemostasis
Volume117
Issue number4
DOIs
StatePublished - 2017

Keywords

  • Coagulation factors
  • Contact phase
  • Proteases

ASJC Scopus subject areas

  • Hematology

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