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Tissue factor pathway inhibitor primes monocytes for antiphospholipid antibody-induced thrombosis

Nadine Müller-Calleja, Anne Hollerbach, Svenja Ritter, Denise G. Pedrosa, Dennis Strand, Claudine Graf, Christoph Reinhardt, Susanne Strand, Philippe Poncelet, John H. Griffin, Karl J. Lackner and Wolfram Ruf

Key Points

  • Antiphospholipid antibodies (aPL) trigger coagulation and inflammatory signaling by dissociating an inhibited TF cell surface complex

  • Myeloid cell-expressed TFPI specifically supports aPL-induced thrombosis

Abstract

Antiphospholipid antibodies (aPL) with complex lipid and/or protein reactivities cause complement-dependent thrombosis and pregnancy complications. While cross-reactivities with coagulation regulatory proteins contribute to the risk for developing thrombosis in patients with antiphospholipid syndrome, the majority of pathogenic aPL retain reactivity with membrane lipid components and rapidly induce reactive oxygen species-dependent proinflammatory signaling and tissue factor (TF) procoagulant activation. Here, we show that lipid-reactive aPL activate a common species-conserved TF signaling pathway. aPL dissociate an inhibited TF coagulation initiation complex on the cell surface of monocytes, thereby liberating factor Xa for thrombin generation and protease activated receptor 1/2 heterodimer signaling. In addition to proteolytic signaling, aPL promote complement- and protein disulfide isomerase-dependent TF-integrin β1 trafficking that translocates aPL and NADPH oxidase to the endosome. Cell surface TF pathway inhibitor (TFPI) synthesized by monocytes is required for TF inhibition; and disabling TFPI prevents aPL signaling, indicating a paradoxical prothrombotic role for TFPI. Myeloid-cell specific TFPI inactivation has no effect on models of arterial or venous thrombus development, but remarkably prevents experimental aPL-induced thrombosis in mice. Thus, the physiological control of TF primes monocytes for rapid aPL pathogenic signaling and thrombosis amplification in an unexpected crosstalk between complement activation and coagulation signaling.

  • Submitted May 9, 2019.
  • Revision received August 21, 2019.
  • Accepted August 6, 2019.