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Publications

by Keyword: Hemostasis

Witzdam, Lena, White, Tom, Rodriguez-Emmenegger, Cesar, (2024). Steps Toward Recapitulating Endothelium: A Perspective on the Next Generation of Hemocompatible Coatings Macromolecular Bioscience 24, 2400152

Endothelium, the lining in this blood vessel, orchestrates three main critical functions such as protecting blood components, modulating of hemostasis by secreting various inhibitors, and directing clot digestion (fibrinolysis) by activating tissue plasminogen activator. No other surface can perform these tasks; thus, the contact of blood and blood-contacting medical devices inevitably leads to the activation of coagulation, often causing device failure, and thromboembolic complications. This perspective, first, discusses the biological mechanisms of activation of coagulation and highlights the efforts of advanced coatings to recapitulate one characteristic of endothelium, hereafter single functions of endothelium and noting necessity of the synergistic integration of its three main functions. Subsequently, it is emphasized that to overcome the challenges of blood compatibility an endothelium-mimicking system is needed, proposing a synergy of bottom-up synthetic biology, particularly synthetic cells, with passive- and bioactive surface coatings. Such integration holds promise for developing advanced biomaterials capable of recapitulating endothelial functions, thereby enhancing the hemocompatibility and performance of blood-contacting medical devices. The activation of coagulation on the surface of blood-contacting medical devices often leads to thromboembolic complications. A concept for the next generation of hemocompatbile surfaces inspired by endothelium is proposed. This concept not only contribute to the fundamental understanding of hemocompatibility but also offer practical implications for the design and development of biomedical devices with enhanced biocompatibility and functionality. image

JTD Keywords: Animals, Antifouling coatings, Antifouling polymer brushes, Biocompatible materials, Blood coagulation, Coagulation-factor-xii, Coated materials, biocompatible, Endothelium, Endothelium, vascular, Endothelium-inspired, Endothelium‐inspired, Hemocompatibility, Hemocompatible surface coatings, Hemostasis, Heparin-induced thrombocytopenia, Humans, Nitric-oxide release, Of-the-art, Peptide macrocycle inhibitor, Plasma contact system, Protein-adsorption, Self-assembled monolayers, Surface modificatio, Synthetic endotheliu, Synthetic endothelium


Witzdam, L, Vosberg, B, Grosse-Berkenbusch, K, Stoppelkamp, S, Wendel, HP, Rodriguez-Emmenegger, C, (2024). Tackling the Root Cause of Surface-Induced Coagulation: Inhibition of FXII Activation to Mitigate Coagulation Propagation and Prevent Clotting Macromolecular Bioscience 24, e2300321

Factor XII (FXII) is a zymogen present in blood that tends to adsorb onto the surfaces of blood-contacting medical devices. Once adsorbed, it becomes activated, initiating a cascade of enzymatic reactions that lead to surface-induced coagulation. This process is characterized by multiple redundancies, making it extremely challenging to prevent clot formation and preserve the properties of the surface. In this study, a novel modulatory coating system based on C1-esterase inhibitor (C1INH) functionalized polymer brushes, which effectively regulates the activation of FXII is proposed. Using surface plasmon resonance it is demonstrated that this coating system effectively repels blood plasma proteins, including FXII, while exhibiting high activity against activated FXII and plasma kallikrein under physiological conditions. This unique property enables the modulation of FXII activation without interfering with the overall hemostasis process. Furthermore, through dynamic Chandler loop studies, it is shown that this coating significantly improves the hemocompatibility of polymeric surfaces commonly used in medical devices. By addressing the root cause of contact activation, the synergistic interplay between the antifouling polymer brushes and the modulatory C1INH is expected to lay the foundation to enhance the hemocompatibility of medical device surfaces.© 2023 The Authors. Macromolecular Bioscience published by Wiley-VCH GmbH.

JTD Keywords: adsorption, binding, c1-esterase-inhibitor, coatings, contact activation, factor-xii, fxii activation, hemocompatibility, hemocompatible surface modification, heparin, polymer brushes, system, thrombosis, Adsorption, Anticoagulation, Antifouling agent, Article, Beta-fxiia, Biocompatibility, Blood, Blood clotting, Blood clotting factor 12, Blood clotting factor 12a, Blood clotting factor 12a inhibitor, Blood coagulation, C1-esterase-inhibitor, Cell activation, Chemical activation, Coagulation, Coating (procedure), Complement component c1s inhibitor, Complement system, Controlled study, Dendrimers, Enzyme immobilization, Enzymes, Erythrocyte, Esters, Factor xii, Factor xii activation, Factor xiia, Fibrin deposition, Functional polymers, Fxii activation, Haemocompatibility, Hemocompatibility, Hemocompatible surface modification, Hemostasis, Heparin, Human, Hydrogel, Medical devices, Metabolism, Plasma kallikrein, Plasma protein, Plastic coatings, Platelet count, Polymer, Polymer brushes, Polymerization, Polymers, Property, Root cause, Surface plasmon resonance, Surface property, Surface reactions, Surface-modification, Thrombocyte adhesion, Β-fxiia


Rosa Hernández, M., Urbán, P., Casals, E., Estelrich, J., Escolar, G., Galán, A. M., (2012). Liposomes bearing fibrinogen could potentially interfere with platelet interaction and procoagulant activity International Journal of Nanomedicine 7, 2339-2347

Background: The contribution of fibrinogen (FBN) to hemostasis acting on platelet aggregation and clot formation is well established. It has been suggested that FBN-coated liposomes could be useful in restoring hemostasis. In the present study, we evaluated the modifications induced by multilamellar raw liposomes (MLV) or fibrinogen-coated liposomes (MLV-FBN) on hemostatic parameters. Materials and methods: Different experimental settings using whole blood or thrombocytopenic blood were used. Thromboelastometry, aggregation studies, platelet function analyzer (PFA-100®) tests and studies under flow conditions were applied to detect the effect of MLVFBN on hemostatic parameters. Results: The presence of MLV-FBN in whole blood modified its viscoelastic properties, prolonging clot formation time (CFT) (226.5 ± 26.1 mm versus 124.1 ± 9.4 mm; P, 0.01) but reducing clot firmness (45.4 ± 1.8 mm versus 35.5 ± 2.3 mm; P, 0.05). Under thrombocytopenic conditions, FIBTEM analysis revealed that MLV-FBN shortened clotting time (CT) compared to MLV (153.3 ± 2.8 s versus 128.0 ± 4.6 s; P, 0.05). Addition of either liposome decreased fibrin formation on the subendothelium (MLV 8.1% ± 4.7% and MLV-FBN 0.8% ± 0.5% versus control 36.4% ± 6.7%; P, 0.01), whereas only MLV-FBN significantly reduced fibrin deposition in thrombocytopenic blood (14.4% ± 6.3% versus control 34.5% ± 5.2%; P, 0.05). MLV-FBN inhibited aggregation induced by arachidonic acid (52.1% ± 8.1% versus 88.0% ± 2.1% in control; P, 0.01) and ristocetin (40.3% ± 8.8% versus 94.3% ± 1.1%; P, 0.005), but it did not modify closure times in PFA-100® studies. In perfusion experiments using whole blood, MLV and MLV-FBN decreased the covered surface (13.25% ± 2.4% and 9.85% ± 2.41%, respectively, versus control 22.0% ± 2.0%; P, 0.01) and the percentage of large aggregates (8.4% ± 2.3% and 3.3% ± 1.01%, respectively, versus control 14.6% ± 1.8%; P, 0.01). Conclusion: Our results reveal that, in addition to the main contribution of fibrinogen to hemostasis, MLV-FBN inhibits platelet-mediated hemostasis and coagulation mechanisms.

JTD Keywords: Fibrin, Fibrinogen, Hemostasis, Liposomes, Procoagulant activity, Thrombocytopenia