Immobilized transition metal ions stimulate contact activation and drive factor XII-mediated coagulation

J Thromb Haemost. 2012 Oct;10(10):2108-15. doi: 10.1111/j.1538-7836.2012.04890.x.


Background: Upon contact with an appropriate surface, factor XII (FXII) undergoes autoactivation or cleavage by kallikrein. Zn(2+) is known to facilitate binding of FXII and the cofactor, high molecular weight kininogen (HK), to anionic surfaces.

Objectives: To investigate whether transition metal ions immobilized on liposome surfaces can initiate coagulation via the contact pathway.

Methods and results: Liposomes containing a metal ion-chelating lipid, 1,2-dioleoyl-sn-glycero-3-{(N[5-amino-1-carboxypentyl]iminodiacetic acid)succinyl} ammonium salt (DOGS-NTA), were prepared by membrane extrusion (20% DOGS-NTA, 40% phosphatidylcholine, 10% phosphatidylserine, and 30% phosphatidylethanolamine). Ni(2+) immobilized on such liposomes accelerated clotting in normal plasma, but not factor XI (FXI)-deficient or FXII-deficient plasma. The results were similar to those obtained with a commercial activated partial thromboplastin time reagent. Charging such liposomes with other transition metal ions revealed differences in their procoagulant capacity, with Ni(2+) > Cu(2+) > Co(2+) and Zn(2+). Plasma could be depleted of FXI, FXII and HK by adsorption with Ni(2+) -containing beads, resulting in longer clot times. Consistent with this, FXI, FXII and HK bound to immobilized Ni(2+) or Cu(2+) with high affinity as determined by surface plasmon resonance. In the presence of Ni(2+) -bearing liposomes, K(m) and k(cat) values derived for autoactivation of FXII and prekallikrein, as well as for activation of FXII by kallikrein or prekallikrein by FXIIa, were similar to literature values obtained in the presence of dextran sulfate.

Conclusions: Immobilized Ni(2+) and Cu(2+) bind FXII, FXI and HK with high affinity and stimulate activation of the contact pathway, driving FXII-mediated coagulation. Activation of the contact system by immobilized transition metal ions may have implications during pathogenic infection or in individuals exposed to high levels of pollution.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adsorption
  • Binding Sites
  • Blood Coagulation* / drug effects
  • Chelating Agents / pharmacology
  • Cobalt / blood
  • Copper / blood*
  • Enzyme Activation
  • Factor XI / metabolism
  • Factor XII / metabolism*
  • Factor XIIa / metabolism
  • Humans
  • Kininogen, High-Molecular-Weight / blood
  • Liposomes
  • Lysine / analogs & derivatives
  • Lysine / pharmacology
  • Nickel / blood*
  • Oleic Acids / pharmacology
  • Partial Thromboplastin Time
  • Prothrombin Time
  • Succinates / pharmacology
  • Surface Plasmon Resonance
  • Time Factors
  • Zinc / blood


  • Chelating Agents
  • Kininogen, High-Molecular-Weight
  • Liposomes
  • N(alpha),N(alpha)-bis(carboxymethyl)-N(epsilon)-(1,2-dioleyl-sn-glycero-3-succinyl)-L-lysine
  • Oleic Acids
  • Succinates
  • Cobalt
  • Copper
  • Nickel
  • Factor XII
  • Factor XI
  • Factor XIIa
  • Zinc
  • Lysine