Activated factor XI increases the procoagulant activity of the extrinsic pathway by inactivating tissue factor pathway inhibitor

Cristina Puy, Erik Tucker, Anton Matafonov, Qiufang Cheng, Keith D. Zientek, Dave Gailani, Andras Gruber, Owen McCarty

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Activation of coagulation factor XI (FXI) may play a role in hemostasis. The primary substrate of activated FXI (FXIa) is FIX, leading to FX activation (FXa) and thrombin generation. However, recent studies suggest the hemostatic role of FXI may not be restricted to the activation of FIX. We explored whether FXI could interact with and inhibit the activity of tissue factor pathway inhibitor (TFPI). TFPI is an essential reversible inhibitor of activated factor X (FXa) and also inhibits the FVIIa-TF complex. We found that FXIa neutralized both endothelium- and platelet-derived TFPI by cleaving the protein between the Kunitz (K) 1 and K2 domains (Lys86/Thr87) and at the active sites of the K2 (Arg107/Gly108) and K3 (Arg199/Ala200) domains. Addition of FXIa to plasma was able to reverse the ability of TFPI to prolong TF-initiated clotting times in FXI- or FIX-deficient plasma, as well as FXa-initiated clotting times in FX-deficient plasma. Treatment of cultured endothelial cells with FXIa increased the generation of FXa and promoted TF-dependent fibrin formation in recalcified plasma. Together, these results suggest that the hemostatic role of FXIa may be attributed not only to activation of FIX but also to promoting the extrinsic pathway of thrombin generation through inactivation of TFPI.

Original languageEnglish (US)
Pages (from-to)1488-1496
Number of pages9
JournalBlood
Volume125
Issue number9
DOIs
StatePublished - Feb 26 2015

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Factor XIa
Factor XI
Chemical activation
Hemostatics
Thrombin
Plasmas
Factor Xa
Hemostasis
Fibrin
Endothelium
Cultured Cells
Catalytic Domain
Endothelial cells
Blood Platelets
Endothelial Cells
Platelets
lipoprotein-associated coagulation inhibitor
Proteins

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Activated factor XI increases the procoagulant activity of the extrinsic pathway by inactivating tissue factor pathway inhibitor. / Puy, Cristina; Tucker, Erik; Matafonov, Anton; Cheng, Qiufang; Zientek, Keith D.; Gailani, Dave; Gruber, Andras; McCarty, Owen.

In: Blood, Vol. 125, No. 9, 26.02.2015, p. 1488-1496.

Research output: Contribution to journalArticle

Puy, Cristina ; Tucker, Erik ; Matafonov, Anton ; Cheng, Qiufang ; Zientek, Keith D. ; Gailani, Dave ; Gruber, Andras ; McCarty, Owen. / Activated factor XI increases the procoagulant activity of the extrinsic pathway by inactivating tissue factor pathway inhibitor. In: Blood. 2015 ; Vol. 125, No. 9. pp. 1488-1496.
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