VPB0583 - Procoagulant Properties of Titanium and Titanium Nitride

Background: Titanium (Ti), its alloys, and ceramics (titanium nitride or TiN) are widely used in medical devices/implants because of their strength, resistance to corrosion and presumed inertness. Titanium compounds are considered hemocompatible because they do not induce hemolysis, have low albumin and fibrinogen adsorption, and have low platelet retention. However, cardiovascular implants made of titanium, such as ventricular assist devices, require anticoagulation to prevent thrombosis.

Aims: To compare the interaction of the plasma contact system with titanium surfaces to the well-known contact activator kaolin, and to study effects of contact activation inhibitors on titanium-initiated contact activation.

Methods: Clotting assays in normal plasma and plasmas deficient in factor XII, (fXII), prekallikrein, or high-molecular-weight kininogen (HK), chromogenic substrate assays and pull-down experiments were performed, using kaolin and nanoparticles made of silica (100nm, 26.8 m2/g); Ti (70nm, 20m2/g), TiN (80nm, 30-50m2/g) and aluminum (70nm, 15-30m2/g).

Results: Using equivalent surface amounts, Ti and TiN nanopowders were comparable to kaolin for inducing plasma coagulation, factor XII (fXII) autoactivation, prekallikrein activation and HK cleavage. While Ti and TiN particles carry a negative charge like many contact inducers, their effects were not neutralized by the polycation Polybrene or changes in salt concentration. Aluminum nanospheres, which carry a positive charge, did not induce contact activation. Ti and TiN, but not aluminum, rapidly bind FXII, prekallikrein and HK in plasma. Antibodies against fXIIa, kallikrein or factor XI abrogated Ti- and TiN-induced clotting. Anti-fXII antibodies inhibited fXII binding to Ti, and reduced kallikrein generation and HK cleavage.

Conclusion(s): Titanium compounds are potent contact pathway activators, although the mechanism underlying their effect differs in some respects from contact activation on other negatively charged surfaces. Inhibitors of the contact system may be useful for mitigating prothrombotic and proinflammatory consequences of contact activation in patients with vascular devices made of titanium.