Differential roles of factors IX and XI in murine placenta and hemostasis under conditions of low tissue factor

Steven P. Grover, Clare M. Schmedes, Alyson C. Auriemma, Emily Butler, Molly L. Parrish, Adam Miszta, Audrey C. Cleuren, Mayken Visser, Stefan Heitmeier, Jens J. Posma, Henri M. Spronk, Silvio Antoniak, Alisa S. Wolberg, Rafal Pawlinski, David Gailani, Nigel Mackman*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

4 Citations (Web of Science)

Abstract

The intrinsic tenase complex (FIXa-FVIIIa) of the intrinsic coagulation pathway and, to a lesser extent, thrombin-mediated activation of FXI, are necessary to amplify tissue factor (TF)-FVIIa-initiated thrombin generation. In this study, we determined the contribution of murine FIX and FXI to TF-dependent thrombin generation in vitro. We further investigated TF-dependent FIX activation in mice and the contribution of this pathway to hemostasis. Thrombin generation was decreased in FIX- but not in FXI-deficient mouse plasma. Furthermore, injection of TF increased levels of FIXa-antithrombin complexes in both wild-type and FXI-/- mice. Genetic studies were used to determine the effect of complete deficiencies of either FIX or FXI on the survival of mice expressing low levels of TF. Low-TF;FIX-/y male mice were born at the expected frequency, but none survived to wean. In contrast, low-TF;FXI-/- mice were generated at the expected frequency at wean and had a 6-month survival equivalent to that of low-TF mice. Surprisingly, a deficiency of FXI, but not FIX, exacerbated the size of blood pools in low-TF placentas and led to acute hemorrhage and death of some pregnant dams. Our data indicate that FIX, but not FXI, is essential for survival of low-TF mice after birth. This finding suggests that TF-FVIIa-mediated activation of FIX plays a critical role in murine hemostasis. In contrast, FXI deficiency, but not FIX deficiency, exacerbated blood pooling in low-TF placentas, indicating a tissue-specific requirement for FXI in the murine placenta under conditions of low TF.

Original languageEnglish
Pages (from-to)207-216
Number of pages10
JournalBlood advances
Volume4
Issue number1
DOIs
Publication statusPublished - 14 Jan 2020

Keywords

  • FACTOR PATHWAY INHIBITOR
  • THROMBIN GENERATION
  • EMBRYONIC LETHALITY
  • EXTRINSIC PATHWAY
  • PROTHROMBIN DEFICIENCY
  • BLOOD-COAGULATION
  • CARDIAC FIBROSIS
  • GROWTH-FACTOR
  • HEMOPHILIA-A
  • ACTIVATION

Cite this