Role of platelets in regulating activated coagulation factor XI activity

Stephanie E. Reitsma, Jiaqing Pang, Vikram Raghunathan, Joseph J. Shatzel, Christina U. Lorentz, Erik I. Tucker, András Gruber, David Gailani, Owen J.T. McCarty, Cristina Puy

Research output: Contribution to journalArticlepeer-review

Abstract

Factor XI (FXI) has been shown to bind platelets, but the functional significance of this observation remains unknown. Platelets are essential for hemostasis and play a critical role in thrombosis, whereas FXI is not essential for hemostasis but promotes thrombosis. An apparent functional contradiction, platelets are known to support thrombin generation, yet platelet granules release protease inhibitors, including those of activated FXI (FXIa). We aim to investigate the secretory and binding mechanisms by which platelets could support or inhibit FXIa activity. The presence of platelets enhanced FXIa activity in a purified system and increased coagulation Factor IX (FIX) activation by FXIa and fibrin generation in human plasma. In contrast, platelets reduced the activation of FXI by activated coagulation factor XII (FXIIa) and the activation of FXII by kallikrein (PKa). Incubation of FXIa with the platelet secretome, which contains FXIa inhibitors, such as protease nexin-II, abolished FXIa activity, yet in the presence of activated platelets, the secretome was not able to block the activity of FXIa. FXIa variants lacking the anion-binding sites did not alter the effect of platelets on FXIa activity or interaction. Western blot analysis of bound FXIa [by FXIa-platelet membrane immunoprecipitation] showed that the interaction with platelets is zinc dependent and, unlike FXI binding to platelets, not dependent on glycoprotein Ib. FXIa binding to the platelet membrane increases its capacity to activate FIX in plasma likely by protecting it from inhibition by inhibitors secreted by activated platelets. Our findings suggest that an interaction of FXIa with the platelet surface may induce an allosteric modulation of FXIa.

Original languageEnglish (US)
Pages (from-to)C365-C374
JournalAmerican Journal of Physiology - Cell Physiology
Volume320
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

  • Coagulation
  • Contact system
  • Factor XIa
  • Platelets

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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