journal article·2025-04Open access

Antithrombotic coating with sheltered positive charges prevents contact activation by controlling factor XII–biointerface binding

Haifeng Ji, Kai Yu, Srinivas Abbina, Lin Xu, Tao Xu, Shengjun Cheng, Sreeparna Vappala, S. M. Amin Arefi, Md Mohosin Rana, Irina Chafeeva, Matthew Drayton, Kevin Gonzalez, Yun Liu, Dana Grecov, Edward M. Conway, Weifeng Zhao, Changsheng Zhao, Jayachandran N. Kizhakkedathu

Nature Materials· Volume 24· Issue 4

Abstract

Abstract Antithrombotic surfaces that prevent coagulation activation without interfering with haemostasis are required for blood-contacting devices. Such materials would restrain device-induced thrombogenesis and decrease the need for anticoagulant use, thereby reducing unwanted bleeding. Here, by optimizing the interactions with coagulation factor XII rather than preventing its surface adsorption, we develop a substrate-independent antithrombotic polymeric coating with sheltered positive charges. The antithrombic properties of the coating were demonstrated in vitro with human blood and in vivo using a carotid artery–jugular vein shunt model in rabbits. The coating exhibits a strong interaction with factor XII, but results in a low reciprocal activation of the contact pathway that triggers clot formation. These findings contradict the prevailing strategy of designing antithrombotic materials through protein-repelling surfaces. Overall, the polymeric coating we describe can benefit most blood-contacting devices and is a useful engineering guideline for designing surfaces with improved antithrombotic properties.
Source: crossref · Quality: baseline

Research context

OpenAlex topics: Coagulation, Bradykinin, Polyphosphates, and Angioedema · Polymer Surface Interaction Studies · biodegradable polymer synthesis and properties

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

References (44)

Show source-provided references
1. Ivanov, I. et al. Proteolytic properties of single-chain factor XII: a mechanism for triggering contact activation. Blood 129, 1527–1537 (2017).10.1182/blood-2016-10-744110 ↗
2. Kizhakkedathu, J. N. & Conway, E. M. Biomaterial and cellular implants: foreign surfaces where immunity and coagulation meet. Blood 139, 1987–1998 (2022).10.1182/blood.2020007209 ↗
3. Maas, C. & Renne, T. Coagulation factor XII in thrombosis and inflammation. Blood 131, 1903–1909 (2018).10.1182/blood-2017-04-569111 ↗
4. Ashcraft, M., Douglass, M., Chen, Y. J. & Handa, H. Combination strategies for antithrombotic biomaterials: an emerging trend towards hemocompatibility. Biomater. Sci. 9, 2413–2423 (2021).10.1039/D0BM02154G ↗
5. Mackman, N. Triggers, targets and treatments for thrombosis. Nature 451, 914–918 (2008).10.1038/nature06797 ↗
6. Davenport, A. What are the anticoagulation options for intermittent hemodialysis? Nat. Rev. Nephrol. 7, 499–508 (2011).10.1038/nrneph.2011.88 ↗
7. Mackman, N., Bergmeier, W., Stouffer, G. A. & Weitz, J. I. Therapeutic strategies for thrombosis: new targets and approaches. Nat. Rev. Drug Discov. 19, 333–352 (2020).10.1038/s41573-020-0061-0 ↗
8. Jokinen, V., Kankuri, E., Hoshian, S., Franssila, S. & Ras, R. H. A. Superhydrophobic blood-repellent surfaces. Adv. Mater. 30, 1705104 (2018).10.1002/adma.201705104 ↗
9. Maitz, M. F. et al. The blood compatibility challenge. Part 4: surface modification for hemocompatible materials: passive and active approaches to guide blood-material interactions. Acta Biomater. 94, 33–43 (2019).10.1016/j.actbio.2019.06.019 ↗
10. Song, X. et al. Transient blood thinning during extracorporeal blood purification via the inactivation of coagulation factors by hydrogel microspheres. Nat. Biomed. Eng. 5, 1143–1156 (2021).10.1038/s41551-020-00673-x ↗
11. Xu, T. et al. Self-anticoagulant sponge for whole blood auto-transfusion and its mechanism of coagulation factor inactivation. Nat. Commun. 14, 4875 (2023).10.1038/s41467-023-40646-7 ↗
12. Fredenburgh, J. C., Gross, P. L. & Weitz, J. I. Emerging anticoagulant strategies. Blood 129, 147–154 (2017).10.1182/blood-2016-09-692996 ↗
13. Hedayati, M., Neufeld, M. J., Reynolds, M. M. & Kipper, M. J. The quest for blood-compatible materials: recent advances and future technologies. Mater. Sci. Eng. R Rep. 138, 118–152 (2019).10.1016/j.mser.2019.06.002 ↗
14. Douglass, M., Garren, M., Devine, R., Mondal, A. & Handa, H. Bio-inspired hemocompatible surface modifications for biomedical applications. Prog. Mater. Sci. 130, 100997–101029 (2022).10.1016/j.pmatsci.2022.100997 ↗
15. Smith, R. S. et al. Vascular catheters with a nonleaching poly-sulfobetaine surface modification reduce thrombus formation and microbial attachment. Sci. Transl. Med. 4, 153ra132 (2012).10.1126/scitranslmed.3004120 ↗
16. Leslie, D. C. et al. A bioinspired omniphobic surface coating on medical devices prevents thrombosis and biofouling. Nat. Biotechnol. 32, 1134–1140 (2014).10.1038/nbt.3020 ↗
17. Jaffer, I. H., Fredenburgh, J. C., Hirsh, J. & Weitz, J. I. Medical device-induced thrombosis: what causes it and how can we prevent it? J. Thromb. Haemost. 13, S72–S81 (2015).10.1111/jth.12961 ↗
18. Abbina, S. et al. Blood circulation of soft nanomaterials is governed by dynamic remodeling of protein opsonins at nano-biointerface. Nat. Commun. 11, 3048–3059 (2020).10.1038/s41467-020-16772-x ↗
19. Weber, C., Morsbach, S. & Landfester, K. Possibilities and limitations of different separation techniques for the analysis of the protein corona. Angew. Chem. Int. Ed. 58, 12787–12794 (2019).10.1002/anie.201902323 ↗
20. Vogler, E. A. Protein adsorption in three dimensions. Biomaterials 33, 1201–1237 (2012).10.1016/j.biomaterials.2011.10.059 ↗
21. Kalathottukaren, M. T. et al. Alteration of blood clotting and lung damage by protamine are avoided using the heparin and polyphosphate inhibitor UHRA. Blood 129, 1368–1379 (2017).10.1182/blood-2016-10-747915 ↗
22. Ronco, C. Endotoxin removal: history of a mission. Blood Purif. 37, 5–8 (2014).10.1159/000356831 ↗
23. La, C. C. et al. Smart thrombosis inhibitors without bleeding side effects via charge tunable ligand design. Nat. Commun. 14, 2177–2194 (2023).10.1038/s41467-023-37709-0 ↗
24. Shenoi, R. A. et al. Affinity-based design of a synthetic universal reversal agent for heparin anticoagulants. Sci. Transl. Med. 6, 260ra150 (2014).10.1126/scitranslmed.3009427 ↗
25. Kalathottukaren, M. T. et al. A polymer therapeutic having universal heparin reversal activity: molecular design and functional mechanism. Biomacromolecules 18, 3343–3358 (2017).10.1021/acs.biomac.7b00994 ↗
26. Lee, H. A., Ma, Y. F., Zhou, F., Hong, S. & Lee, H. Material-independent surface chemistry beyond polydopamine coating. Acc. Chem. Res. 52, 704–713 (2019).10.1021/acs.accounts.8b00583 ↗
27. Lundbech, M., Krag, A. E., Christensen, T. D. & Hvas, A. M. Thrombin generation, thrombin-antithrombin complex, and prothrombin fragment F1+2 as biomarkers for hypercoagulability in cancer patients. Thromb. Res. 186, 80–85 (2020).10.1016/j.thromres.2019.12.018 ↗
28. Sperling, C., Maitz, M. F., Grasso, S., Werner, C. & Kanse, S. M. A positively charged surface triggers coagulation activation through factor VII activating protease (FSAP). ACS Appl. Mater. Interfaces 9, 40107–40116 (2017).10.1021/acsami.7b14281 ↗
29. Frank, R. D. et al. Role of contact system activation in hemodialyzer-induced thrombogenicity. Kidney Int. 60, 1972–1981 (2001).10.1046/j.1523-1755.2001.00009.x ↗
30. Yang, Z. L. et al. Mussel-inspired catalytic selenocystamine-dopamine coatings for long-term generation of therapeutic gas on cardiovascular stents. Biomaterials 178, 1–10 (2018).10.1016/j.biomaterials.2018.06.008 ↗
31. Branchford, B. R., Ng, C. J., Neeves, K. B. & Di Paola, J. Microfluidic technology as an emerging clinical tool to evaluate thrombosis and hemostasis. Thromb. Res. 136, 13–19 (2015).10.1016/j.thromres.2015.05.012 ↗
32. Hathcock, J. J. Flow effects on coagulation and thrombosis. Arterioscler. Thromb. Vasc. Biol. 26, 1729–1737 (2006).10.1161/01.ATV.0000229658.76797.30 ↗
33. Mohammad-Beigi, H. et al. Mapping and identification of soft corona proteins at nanoparticles and their impact on cellular association. Nat. Commun. 11, 4535–4550 (2020).10.1038/s41467-020-18237-7 ↗
34. Cox, A. et al. Evolution of nanoparticle protein corona across the blood-brain barrier. ACS Nano 12, 7292–7300 (2018).10.1021/acsnano.8b03500 ↗
35. Han, S. et al. Endosomal sorting results in a selective separation of the protein corona from nanoparticles. Nat. Commun. 14, 295–306 (2023).10.1038/s41467-023-35902-9 ↗
36. Heestermans, M. et al. Identification of the factor XII contact activation site enables sensitive coagulation diagnostics. Nat. Commun. 12, 5596–5612 (2021).10.1038/s41467-021-25888-7 ↗
37. Ivanov, I. et al. A mechanism for hereditary angioedema with normal C1 inhibitor: an inhibitory regulatory role for the factor XII heavy chain. Blood 133, 1152–1163 (2019).10.1182/blood-2018-06-860270 ↗
38. Shang, X. Q. et al. Unusual zymogen activation patterns in the protein corona of Ca-zeolites. Nat. Catal. 4, 607–614 (2021).10.1038/s41929-021-00654-6 ↗
39. Chen, J. et al. Quantitative lysine reactivity profiling reveals conformational inhibition dynamics and potency of aurora A kinase inhibitors. Anal. Chem. 91, 13222–13229 (2019).10.1021/acs.analchem.9b03647 ↗
40. Shamanaev, A. et al. Model for surface-dependent factor XII activation: the roles of factor XII heavy chain domains. Blood Adv. 6, 3142–3154 (2022).10.1182/bloodadvances.2021005976 ↗
41. Ryu, J. H., Messersmith, P. B. & Lee, H. Polydopamine surface chemistry: a decade of discovery. ACS Appl. Mater. Interfaces 10, 7523–7540 (2018).10.1021/acsami.7b19865 ↗
42. Smeets, R. et al. A novel hemostatic delivery device for thrombin: biodegradable poly(d,l-lactide-co-glycolide) 50:50 microspheres. J. Biomed. Mater. Res. 96A, 177–185 (2011).10.1002/jbm.a.32970 ↗
43. Qiu, H. et al. Phenolic-amine chemistry mediated synergistic modification with polyphenols and thrombin inhibitor for combating the thrombosis and inflammation of cardiovascular stents. Biomaterials 269, 120626 (2021).10.1016/j.biomaterials.2020.120626 ↗
44. Ivanov, I. et al. Protease activity in single-chain prekallikrein. Blood 135, 558–567 (2020).10.1182/blood.2019002224 ↗