Titanium is a potent inducer of contact activation: implications for intravascular devices

• Published in: Journal of thrombosis and haemostasis 2023-05, Vol.21 (5), p.1200-1213
• Main Authors: Litvak, Maxim, Shamanaev, Aleksandr, Zalawadiya, Sandip, Matafonov, Anton, Kobrin, Anton, Feener, Edward P., Wallisch, Michael, Tucker, Erik I., McCarty, Owen J.T., Gailani, David
• Format: Article
• Language: English
• Subjects: contact activation; factor XI; Factor XI - metabolism; factor XII; Factor XII - metabolism; Humans; Kaolin; prekallikrein; Prekallikrein - metabolism; Titanium
• ISSN: 1538-7836; 1538-7933; 1538-7836
• DOI: 10.1016/j.jtha.2022.12.014

Titanium (Ti) and its alloys are widely used in manufacturing medical devices because of their strength and resistance to corrosion. Although Ti compounds are considered compatible with blood, they appear to support plasma contact activation and may be thrombogenic. The objective of this study was to compare Ti and titanium nitride (TiN) with known activators of contact activation (kaolin and silica) in plasma-clotting assays and to assess binding and activation of factor XII, (FXII), factor XI (FXI), prekallikrein, and high-molecular-weight kininogen (HK) with Ti/TiN. Ti-based nanospheres and foils were compared with kaolin, silica, and aluminum in plasma-clotting assays. Binding and activation of FXII, prekallikrein, HK, and FXI to surfaces was assessed with western blots and chromogenic assays. Using equivalent surface amounts, Ti and TiN were comparable with kaolin and superior to silica, for inducing coagulation and FXII autoactivation. Similar to many inducers of contact activation, Ti and TiN are negatively charged; however, their effects on FXII are not neutralized by the polycation polybrene. Antibodies to FXII, prekallikrein, or FXI or coating Ti with poly-L-arginine blocked Ti-induced coagulation. An antibody to FXII reduced FXII and PK binding to Ti, kallikrein generation, and HK cleavage. Titanium compounds induce contact activation with a potency comparable with that of kaolin. Binding of FXII with Ti shares some features with FXII binding to soluble polyanions but may have unique features. Inhibitors targeting FXII or FXI may be useful in mitigating Ti-induced contact activation in patients with titanium-based implants that are exposed to blood. •Intravascular devices made of titanium and its alloys require anticoagulation to prevent thromboembolic complications.•We investigated binding and activation of plasma contact proteins on titanium surfaces and compared them with the well-known contact activators silica and kaolin.•Contact activation on titanium surfaces may contribute significantly to the thrombogenicity of intravascular devices.•Therapies targeting contact proteases and surface coating with positively charged peptides may prove useful in blocking contact activation in patients with titanium-based intravascular devices.